Botulinum Toxin in Painful Diseases

Botulinum Toxin in Painful Diseases
Pain and Headache

Vol. 14
Series Editor
H. Reichmann
Dresden
Botulinum Toxin in Painful Diseases
Volume Editor
W.H. Jost
Wiesbaden
57 figures and 31 tables, 2003
Basel Freiburg Paris London New York Bangalore Bangkok Singapore Tokyo Sydney
Prof. Dr. med. Wolfgang H. Jost

Department of Neurology and Clinical Neurophysiology German Clinic of Diagnostics Wiesbaden (Germany)
Library of Congress Cataloging-in-Publication Data Botulinum toxin in painful diseases / volume editor, W. H. Jost. p. ; cm. (Pain and headache ; v. 14) Includes bibliographical references and index. ISBN 3805575009 (hard cover : alk. paper) 1. Botulinum toxinTherapeutic use. 2. PainChemotherapy. 3. Analgesia. I. Jost, Wolfgang H. II. Series. [DNLM: 1. Paindrug therapy. 2. Botulinum Toxin Type Atherapeutic use. 3. Neuromuscular Agentstherapeutic use. WL 704 B751 2003] RB127.B688 2003 615 .329364dc21 2002043380
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that durg selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2003 by S. Karger AG, P.O. Box, CH4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 02553910 ISBN 3805575009
Art. No. 16594
Contents
VII Preface 1 Pharmacology of Botulinum Neurotoxins Bigalke, H. (Hannover); Naumann, M. (Wrzburg) 14 Botulinum Toxin A in Pain Management: Mechanisms of Action and Rationale for Optimum Use Gbel, H. (Kiel) 23 Myofascial Pain Syndrome Reilich, P.; Pongratz, D. (Mnchen) 42 Type A Botulinum Toxin in Myofascial Facial Pain and Dysfunction von Lindern, J.-J. (Bonn) 54 Pain in Cervical Dystonia Erbguth, F.J. (Nrnberg) 71 Treatment of Painful Dystonia with Botulinum Toxin Naumann, M. (Wrzburg); Herting, B. (Dresden) 82 Botulinum Toxin in Tension-Type Headache Jost, W.H. (Wiesbaden); Gbel, H. (Kiel) 102 Botulinum Toxin in the Treatment of Migraine Gbel, H. (Kiel); Jost, W.H. (Wiesbaden)
126 Treatment of Spasticity-Related Pain Syndromes Wissel, J. (Beelitz-Heilsttten) 140 Treatment of Piriformis Syndrome with Botulinum Toxin Reichel, G. (Zwickau) 159 Botulinum Toxin in Low Back Pain Jost, W.H. (Wiesbaden); Reilich, P.; Pongratz, D. (Mnchen) 170 Subject Index
Contents
VI
Preface
Hardly any other drug has a similar history of success and a likely future as botulinum toxin. It was initially used for therapeutic application in strabismus, blepharospasm and hemifacial spasm, and continued in focal dystonia and spasticity, followed by the treatment of wrinkles, hyperhidrosis and a great number of ensuing indications. An analgesic effect was first noticed when treating symptoms or disorders associated with pain. Meanwhile, pain has become the target symptom in many diseases. Many studies conducted in recent years have come up with quite different results. First of all, there are the various headache syndromes. After having established the efficacy of the agent, researchers undertook the task of studying why botulinum toxin gives pain relief. There are a number of models that now explain its mode of action; however, a conclusive evaluation is still lacking. It is beyond doubt that botulinum toxin helps in certain pain syndromes. We have still got to find out which the major ones are, what would be the optimum dose of toxin, and where the preferred site of injection should be. On the one hand, we hope to relieve pain in patients whose symptoms could not be treated adequately before, and on the other, we expect new impulses as to the pathogenesis and therapy of pain disorders to enhance greater advances for the benefit of our patients. This book presents an overview on the current state of pain management with botulinum toxin. We do not claim to make a final and comprehensive judgement, but merely want to indicate positions and to awake an interest in this extraordinary therapeutical approach to pain. W.H. Jost
VII
Jost WH (ed): Botulinum Toxin in Painful Diseases. Pain Headache. Basel, Karger, 2003, vol 14, pp 113
Pharmacology of Botulinum Neurotoxins

Hans Bigalkea, Markus Naumannb
a b
Medical School of Hannover, Institute of Toxicology, Hannover Maximilian University, Clinic of Neurology, Wrzburg, Germany
Seven serotypes of botulinum toxin (BTX1) are known, but only types A and B are used therapeutically. They consist of two separate parts with different functions. One part is the pharmacokinetic unit which navigates the other part, the pharmacodynamic unit, through the plasma membrane into the compartment where the latter performs its crucial action. The pharmacodynamic unit is an enzyme interacting with high specificity with only one or a few chemically related substrates. The pharmacokinetic unit, termed the heavy chain (H-chain), is the larger part of the molecule (Mr 100,000), while the enzymatic portion (Mr 50,000) is referred to as the light chain (L-chain). The organisms produce the proteins as inactive single chains which, to become active, must be cleaved by limited proteolysis at a distinct nicking site. Physiologically, nicking is performed by co-released clostridial proteases which can, however, be replaced by trypsin or various other proteases [Weller et al., 1988; Habermann et al., 1991]. The resulting two proteins are connected by an interchain disulfide bond and ionic interactions and represent the actual neurotoxins (Mr 150,000). Once the chains are dissociated, toxicity vanishes because the H-chain has no enzymatic activity and the L-chain is not capable of penetrating membranes. Figure 1 provides an overview of the structure of the clostridial neurotoxins. The botulinum neurotoxins are embedded in a complex formed from hemagglutinins and a non-toxic, non-hemagglutinating protein. The complexes of serotypes A and B vary in molecular sizes (Mr 900,000 and 600,000, respectively). They enhance oral toxicity by stabilizing the neurotoxins and, most likely, facilitate their absorption from the intestine, as recently shown for type A and C1
In contrast to the common nomenclature of neurotoxins, in this book the abbreviation BTX stands for botulinum toxin and not for bungarotoxin.
1
Pharmacokinetic unit HOOC 1286 871 870 460 S Reduction (Thioredoxin reductase) S 440 499
H N Limited proteolysis (clostridial proteases) Nicking
H2N
Enzyme
448
C O
223 HELIH 227 2 Zn
1286
870
449
HC
HN
NH2
Zn
HOOC
x x
Fig. 1. a Schematic structure of single chain BTX-A. The numbers identify representative amino acid positions, e.g. nicking site. The resulting di-chain molecule consists of the L-chain (enzyme) in which the Zn2 -binding moiety is located and the H-chain (pharmacokinetic unit). The C-terminal (HC) of the H-chain is responsible for binding. The N-terminal portion (HN) of the H-chain is the translocation unit (see fig. 2). b Three-dimensional structure of BTX-A. The designations refer to the major components of the toxin as described in figure 1a. The Zn2 -containing active site is buried within the catalytic domain. The nicking site between the L- and H-chains is indicated by X. The translocation domain belt wraps around the catalytic domain and is indicated by arrows. For a stereo view, see Lacy et al. [1998]. (Courtesy of R. Stevens, University of California, Berkeley, Calif., USA.)
Bigalke/Naumann
neurotoxins [Sharma and Singh, 1998; Fujinaga et al., 1997]. The composition of the complexes may contribute to the differences in oral toxicity observed in various animals [Gill, 1982]. All therapeutically used toxins, type A and B, contain the respective complex. Whereas the pure neurotoxins of type A and B differ with respect to antigenicity, the accompanying proteins, i.e. the hemagglutinins, reveal cross-immunogenicity [DasGupta and Sugiyama, 1977]. All symptoms caused by BTXs are due to the inhibition of acetylcholine release from peripheral cholinergic, motor and autonomic nerve endings. It was found, however, that the toxins were capable of inhibiting the release not only of this transmitter, but also of glutamate, GABA, glycine, noradrenaline, acetylcholine, various peptides (e.g. substance P) and dopamine [for reviews, see Ahnert-Hilger and Bigalke, 1995, and Bigalke and Shoer, 2000].
Toxicokinetics of Clostridial Neurotoxins
Binding and Endocytosis It has been possible to divide the process of intoxication into several steps [Simpson, 1989; Dreyer, 1989]. The neurotoxins enter the neuron at the presynaptic region of the neuromuscular junction [Wernig et al., 1977; Dolly et al., 1984; Black and Dolly, 1986a,b] and at autonomic nerve endings [Ambache and Lippold, 1949; Hensel et al., 1973]. BTX types A and B bind preferentially to gangliosides containing more than one neuraminic acid residue [van Heyningen and Miller, 1961; Simpson and Rapport, 1971; van Heyningen and Mellanby, 1973; Ochanda et al., 1986; Kozaki et al., 1998]. The ganglioside recognition site is located in the C-terminal sequence of the H-chain [Shapiro et al., 1997]. From the three-dimensional structures of BTX-A a second recognition site was proposed [Lacy et al., 1998]. This part is thought to bind to a protein expressed selectively in neuronal tissue. BTX-B, for example, binds not only to gangliosides, but also to the N-terminal portion of the well-known vesicular protein, synaptotagmin [Nishiki et al., 1994, 1996]. The N-terminal part of synaptotagmin projects into the lumen of transmitter-containing vesicles [Nishiki et al., 1994]. It is exposed to the synaptic cleft only during exocytosis when vesicles fuse with the presynaptic plasma membrane. The affinity of toxins for gangliosides is low. Since ganglioside molecules are present in such large numbers in nerve cell membranes, it is possible that they serve as acceptor sites for the clostridial neurotoxins [Montecucco and Schiavo, 1995]. In the first step, the gangliosides filter the toxin from body fluid where it is present only in minute amounts. Following exocytosis, the putative protein receptor which is responsible for internalization appears on the cell surface. In the second step, presynaptically enriched toxin binds with high affinity to this protein receptor.
2 ADP
HC
ATP
R HN
H L SS 3 R 1 HN L SS S S HC
4 HN SH L L SH
N
HC
Binding and endocytosis
Translocation
Fig. 2. Binding, endocytosis and translocation of BTX. (1) Di-chain neurotoxin binds to a neuron-specific receptor (R). (2) The whole toxin molecule is taken up by receptormediated endocytosis and trapped inside a vesicle. (3) Following acidification of vesicles by an ATPase, the disulfide bond gains access to the cytosol where reductive enzymes are present. These enzymes severe the molecule in its two chains. (4) L-chain of BTX is released into the cytosol of motor nerve endings.
Thus, internalization into nerve endings takes place only when nerves are stimulated [Simpson, 1980; Schmitt et al., 1981] and endocytosis occurs [Matteoli et al., 1996] (fig. 2). Since BTX-A and -B bind to individual presynaptic receptors, the number of the total binding sites for each toxin may differ. This may explain the different effective doses for the two toxins in humans. Translocation and Priming Toxins which are trapped within the recycled vesicles do not interfere with exocytosis because their substrates are located in the cytosol. Translocation into the cytosol probably takes place when the vesicular content is acidified [Matteoli et al., 1996; Simpson et al., 1994; Williams and Neale, 1994]. Within an acidic environment the toxins probably undergo conformational changes allowing the insertion into the vesicular membrane. Only the L-chain is involved in the enzymatic reaction [Stecher et al., 1989a,b; Ahnert-Hilger et al., 1989a,b; Bittner et al., 1989; Dayanithi et al., 1990; de Paiva and Dolly, 1990; Schiavo et al., 1992ac, 1993; Link et al., 1992; Blasi et al., 1993a,b]. It is not clear, however, whether the entire toxin molecule leaves the vesicular compartment and enters the cytosol, or whether only the L-chain is involved. In any case, the disulfide bond connecting the H- and L-chains must be reduced to render the enzyme
Bigalke/Naumann
active. A likely candidate for performing this enzymatic reaction is the thioredoxin-reductase system [Kistner and Habermann, 1992; Erdal et al., 1995]. Thus, it is probably an endogenous neuronal enzyme which physiologically protects neurons from the destructive action of free radicals that acts to convert the pro-drug, the di-chain toxin, into the active drug, the L-chain (fig. 2). Degradation Clostridial neurotoxins remain intact within cells over a long period of time [Erdal et al., 1995; Keller et al., 1999]. Degradation is a slow process and occurs in autophagosomes. However, if only a few amino acids are removed, the toxins loses its activity [Kurazono et al., 1992; Fairweather et al., 1993]. Exocytosis will recover when the toxins are degraded to inactive fragments. BTXs may contain a sequence that protects them from being sorted into the lysosomal compartment where proteolytic enzymes are located. This would explain the long duration of action.
Enzymatic Action of Clostridial Neurotoxins
All clostridial neurotoxins are metalloproteases that selectively cleave proteins involved in vesicle fusion [Montecucco and Schiavo, 1995]. The substrates occur at two locations at membranes of small and large vesicles and in the presynaptic plasma membrane. They are termed soluble NSF-attachment protein receptors (SNAREs), where NSF stands for N-ethylmaleimide-sensitive fusion protein. NSF is a co-factor, an ATPase, which is necessary for fusion to occur. It is currently believed that one v(vesicle)SNARE, synaptobrevin, is located mainly in the membrane of synaptic vesicles, and two t(target)SNAREs, syntaxin and SNAP-25 (synaptosomal-associated protein of Mr 25,000), associated with the plasma membrane, are involved in transmitter release. A small number of C-terminal residues of synaptobrevin and syntaxin are inserted into the membranes, while palmitoyl groups attach SNAP-25 loosely to cysteine residues in the plasma membrane. SNAP-25 does not possess a transmembrane region. The v- and tSNAREs form a complex which represents the core of the fusion machinery [Sdhof et al., 1993; Hanson et al., 1997; Sutton et al., 1998]. The proteins of the core complex are attacked exclusively by the L-chains of clostridial neurotoxins. The L-chain-BTX-B cleaves synaptobrevin while the L-chain-BTX-A cleaves SNAP-25 [for a review, see Montecucco and Schiavo, 1995] (fig. 3). They are capable of severing the substrates prior to complex formation. Once united, the SNAREs are not susceptible to the toxins [Pellegrini et al., 1994]. If SNAP-25 is cleaved, a complex can still be formed, but one which is not fully functional. It is the cleaved peptide itself, SNAP-25,
Calcium binding site Synaptotagmin v-SNAREs Synaptobrevin SNAP-25 Ternary complex
N-typeCa2 -channel
Neurexin Syntaxin t-SNAREs
Synaptic vesicle Plasma membrane
Fig. 3. Fusion model of a vesicle with the plasma membrane. A synaptic vesicle is docked inside the plasma membrane close to the active zone (fig. 4) via a complex consisting of synaptobrevin, syntaxin and SNAP-25. The vesicle is prevented from fusion by the adjacent synaptotagmin. Following depolarization, the voltage-dependent Ca2 channels are activated. Incoming Ca ions bind to synaptotagmin which unfolds. The complex pulls the vesicle to the plasma membrane while contracting. If synaptobrevin and SNAP-25 are cleaved by BTX-B and BTX-A, respectively, complex formation is inhibited. Consequently, acetylcholine release is interrupted.
which inhibits fusion [Keller et al., 1999]. If synaptobrevin or syntaxin are cleaved, even complex formation cannot occur. Since the formation of the complex is a prerequisite for fusion, the lack of complex formation leads to an inhibition of transmitter release.
Function of SNAREs
The SNAREs are involved in cell vesicle trafficking [Sllner et al., 1993; Scheller, 1995; Sdhof, 1995; Calakos and Scheller, 1996]. These pathways link the cell interior to the environment. They maintain the communication between cells, they eliminate metabolic waste, and transport cellular products from the location of manufacture to the point of consumption. Cell trafficking
Bigalke/Naumann
F Folding zone aZ P
a
See Fig. 3 Vesicels
0.5 m
Active zone Nerve ending Synaptic cleft
Folding zone
ACh-receptors
Folding zone
Muscle fibre
c Fig. 4. Presentation of synaptic structures. a Scanning electron micrograph of the surface of a muscle fiber. The folding zone is marked by arrows. The area is densely covered by acetylcholine receptors that do not occur outside the folding zone. b The neural active zone (aZ) is located opposite to the muscular folding zone. The structures marked with P represent Ca2 channels. In close proximity to the active zone, fusion events occur (F). c Sketch of a neuromuscular junction. Vesicles are docked close to the active zone. Following Ca2 entry, acetylcholine is liberated by fusing vesicles. In a short distance from the fusion events, acetylcholine receptors are located that are activated by the transmitter leading to muscle contraction. The box is enlarged in figure 3. (Courtesy by F. Dreyer, Rudolf-BuchheimInstitute, Giessen, Germany.)
resembles the highly sophisticated logistics underlying the turnover of goods in a modern society. Both the single cell and modern society accomplish this task by using codes to define the target of the carrier and the fate of the goods. Thus, the intracellular transport systems, the vesicles, are decorated with signals that navigate them to a distinct destination [Sdhof, 1995]. Transmitter-containing vesicles find their way to a distinct location at the presynaptic plasma membrane, the active zone which is juxtaposed against the folding zone at the postsynaptic site (fig. 4). This is where the acetylcholine receptors are located.
At this site only, vesicles accumulate and fusion occurs, liberating the transmitter into the synaptic cleft. The fusion of transmitter-containing vesicles is regulated and requires Ca2 which is provided by voltage-activated Ca2 channels [Chapman et al., 1995; Banerjee et al., 1996; Martin, 1997]. In nerve endings, they are in close proximity to the active zone. Following arrival at the active zone, vesicles must be primed for fusion. The proteins forming the core complex play an essential role in this event. Since the vSNARE is mainly located in vesicular membranes and the tSNAREs at the active zones, a model of fusion was proposed. In this model, the vSNARE of the vesicles arriving at the plasma membrane form a tight ternary complex having a 1:1:1 stochiometry with the tSNAREs, resulting in vesicle docking [Hayashi et al., 1994]. The three proteins bind to one another with high affinity and will not dissociate spontaneously [Hanson et al., 1997]. Synaptotagmin, another vesicular protein which is closely connected to the complex, functions as a Ca2 sensor [Chapman et al., 1995]. Upon depolarization and intracellular increase in the Ca2 concentration, synaptotagmin was found to bind several calcium ions. Synaptotagmin then undergoes a conformational change and binds to phospholipids of the plasma membrane. Moreover, it interacts with one of the complexs proteins, syntaxin [Bennet et al., 1992]. The primed vesicles fuse with the plasma membrane thereby releasing their contents into the synaptic cleft. Thus, synaptotagmin works like a brake, preventing the primed vesicles from approaching the plasma membrane. The synaptotagmin brake on the vesicles can be released by Ca2 . Following exocytosis, the membrane patches deriving from the vesicles are recycled within seconds by endocytosis [Rothman and Wieland, 1996; Wendland et al., 1998; Warren and Malhotra, 1998; Kaiser and Ferro-Novick, 1998].
Clinical Use of Clostridial Neurotoxins
Clostridial neurotoxins are extremely toxic to mammals by virtue of the fact that they cleave proteins which are crucial to neurotransmission. Because both proteins have similar molecular mass and charge, the volume of distribution of the BTXs is probably identical to that of immunoglobulins, i.e., 0.6 l/kg. It can be estimated from therapeutic doses of BTX-A that as low a blood concentration as 0.15 pg/ml causes recordable muscle weakness [Girlanda et al., 1992; Olney et al., 1988]. Since concentration response curves derived from human striated muscles in vivo are steep [Wohlfarth et al., 1997], one can expect that a 50- to 100-fold increase in concentration may be fatal. Thus, if applied parenterally, the lethal adult dose would be between 100 and
Bigalke/Naumann
1,000 ng of pure neurotoxin. This is approximately 10- to 100-fold of the therapeutically applied dose. BTXs are, however, not cytotoxic. Nonetheless, transmitter release does not seem to be important to single cells. It is only crucial to the whole organism. If the organism survives, the toxin will be metabolized [Erdal et al., 1995] and exocytosis will recover. Lack of cytotoxicity and long-lasting action are prerequisites for the use of BTXs as therapeutic agents [Montecucco et al., 1996]. When locally injected into a dystonic or spastic muscle, BTXs cause paralysis of the affected muscle. Thus, the BTXA-hemagglutinin complex has been used for the treatment of neurological disorders which are characterized by an unremitting overactivity of motoneurons and spasms of striated muscles such as in focal dystonia (e.g., blepharospasm, torticollis spasmodicus, laryngeal dystonia and many other forms of dystonia) and focal spasticity. The toxin has also been used to curb hyperactivity of salivary and sweat glands [Naumann et al., 1997], as many functions of autonomic nerves are mediated by acetylcholine. Moreover, the tone of smooth muscles could be decreased in patients suffering from achalasia and anal fissures, thereby reducing pain. The toxin has even been employed recently to smooth facial wrinkles caused by contractions of the platysma and small facial muscles. In all these cases, only a few nanograms were injected into the muscle near the endplate region or close to the hyperactive glands. In general, the toxins effect is restricted to nerve endings in close proximity to the injection site. Systemic side effects, though possible, are rare, and occur mainly if a very high dose is applied or if the injection is off target. Within 35 days, cholinergic transmission gradually diminishes and the muscle weakens or the gland dries up. This results in the disappearance of pain and improvement of motor function or adiaphoresis. In rare cases, undesirable effects last as long as the beneficial effects, i.e., weeks to months. Eventually, nerve function recovers. It is not fully understood so far why the duration of the action is much longer, i.e. 612 months, in autonomic nerve fibers, compared to 34 months in case of motor nerves. Normally, BTXs do not stimulate the immune system because the doses necessary to paralyze a muscle are much lower than those required for antibody production. Antibodies are produced in a small number of patients in sufficient titer to render the patient refractory to further treatment with the respective BTX [Gschel et al., 1997]. Patients with an antiBTX-A or -B antibody titer, however, do respond to the other serotype, because different serotypes lack cross-immunogenicity. Recently, hemagglutinin complexes of BTX-C1 and -F were found to be active in man [Sheean and Lees, 1995; Green and Fahn, 1996; Sloop et al., 1997; Eleopra et al., 1997]. It would be desirable to make also these serotypes available for therapeutic usage.
References
Ahnert-Hilger G, Bader MF, Bhakdi S, Gratzl M: Introduction of macromolecules into bovine adrenal medullary chromaffin cells and rat pheochromocytoma cells (PC12) by permeabilization with streptolysin O: Inhibitory effect of tetanus toxin on catecholamine secretion. J Neurochem 1989a;52:17511758. Ahnert-Hilger G, Weller U, Dauzenroth ME, Habermann E, Gratzl M: The tetanus toxin light chain inhibits exocytosis. FEBS Lett 1989b;242:245248. Ahnert-Hilger G, Bigalke H: Molecular aspects of tetanus and botulinum neurotoxin poisoning. Prog Neurobiol 1995;46:8396. Ambache N, Lippold OCH: Bradycardia of central origin produced by injections of tetanus toxin into the vagus nerve. J Physiol (Lond) 1949;108:186196. Banerjee A, Kowalchyk JA, DasGupta BR, Martin TFJ: SNAP-25 is required for a late postdocking step in Ca2 -dependent exocytosis. J Biol Chem 1996;271:2022720230. Bennett MK, Calakos N, Scheller RH: Syntaxin: A synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 1992;257:255259. Bennett MK, Scheller RH: The molecular machinery for secretion is conserved from yeast to neurons. Proc Natl Acad Sci USA 1993;90:25592563. Bigalke H, Shoer LF: Clostridial neurotoxins. Handb Exp Pharmacol 2000;145:407443. Bittner MA, DasGupta BR, Holz RW: Isolated light chains of botulinum neurotoxins inhibit exocytosis. Studies in digitonin-permeabilized chromaffin cells. J Biol Chem 1989;264: 1035410360. Black JD, Dolly JO: Interaction of 125I-labelled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol 1986a;103:521534. Black JD, Dolly JO: Interaction of 125I-labelled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 1986b;103:535544. Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, Sdhof TC, Niemann H, Jahn R: Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 1993a; 365:160163. Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, Jahn R: Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. EMBO J 1993b;12: 48214828. Calakos N, Scheller RH: Synaptic vesicle biogenesis, docking and fusion: A molecular description. Physiol Rev 1996;76:129. Chapman ER, Hanson PI, An S, Jahn R: Ca2 regulates the interaction between synaptotagmin and syntaxin 1. J Biol Chem 1995;270:2366723671. DasGupta B, Sugiyama H: Inhibition of Clostridium botulinum type A and B hemagglutinins by sugars. Can J Microbiol 1977;23:12571260. Dayanithi G, Ahnert-Hilger G, Weller U, Nordmann JJ, Gratzl M: Release of vasopressin from isolated permeabilized neurosecretory nerve terminals is blocked by the light chain of botulinum A toxin. Neuroscience 1990;39:711715. de Paiva A, Dolly JO: Light chain of botulinum neurotoxin is active in mammalian motor nerve terminals when delivered via liposomes. FEBS Lett 1990;277:171174. Dolly JO, Black JD, Williams RS, Melling J: Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature 1984;307:457460. Dreyer F: Peripheral actions of tetanus toxin; in Simpson LL (ed): Botulinum Neurotoxin and Tetanus Toxin. New York, Academic Press, 1989, pp 179197. Eleopra R, Tugnoli V, Degrandis D: The variability in the clinical effect induced by botulinum toxin type A The role of muscle activity in humans. Mov Disord 1997;12:8994. Erdal E, Bartels F, Binscheck T, Erdmann G, Frevert J, Kistner A, Weller U, Wever J, Bigalke H: Processing of tetanus and botulinum A neurotoxins in isolated chromaffin cells. Naunyn Schmiedebergs Arch Pharmacol 1995;351:6778.
Bigalke/Naumann
10
Fairweather NF, Sanders D, Slater D, Hudel M, Habermann E, Weller U: Production of biologically active light chain of tetanus toxin in Escherichia coli. Evidence for the importance of the C-terminal 16 amino acids for full biological activity. FEBS Lett 1993;323:218222. Fujinaga Y, Inoue K, Watanabe S, Yokota K, Hirai Y, Nagamachi E, Oguma K: The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig small intestine, leading to the efficient absorption of the toxin. Microbiology 1997;143:38413847. Gill DM: Bacterial toxins: A table of lethal amounts. Microbiol Rev 1982;46:8694. Girlanda P, Vita G, Nicolosi C, Milone S, Messina C: Botulinum toxin therapy: Distant effects on neuromuscular transmission and autonomic nervous system. J Neurol Neurosurg Psychiatry 1992;55:844845. Gschel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H: Botulinum A toxin: Neutralizing and nonneutralizing antibodies Therapeutic consequences. Exp Neurol 1997;147:96102. Greene PE, Fahn S: Response to botulinum toxin F in seronegative botulinum toxin A-resistant patients. Mov Disord 1996;11:181184. Habermann E, Weller U, Hudel M: Limited proteolysis of single-chain tetanus toxin by tissue enzymes, in cultured brain tissue and during retrograde axonal to the spinal cord. Naunyn Schmiedebergs Arch Pharmacol 1991;343:323329. Hanson PI, Heuser JE, Jahn R: Neurotransmitter release Four years of SNARE complexes. Curr Opin Neurobiol 1997;7:310315. Hayashi T, McMahon H, Yamasaki S, Binz T, Hata Y, Sudhof TC, Niemann H: Synaptic vesicle membrane fusion complex: Action of clostridial neurotoxins on assembly. EMBO J 1994;3:50515061. Hensel B, Seib UC, Wellhoner HH: Vagal ascent and distribution of 125I-tetanus toxin after injection into the anterior wall of the stomach. Naunyn Schmiedebergs Arch Pharmacol 1973;276:395402. Kaiser C, Ferro Novick S: Transport from the endoplasmic reticulum to the Golgi. Curr Opin Cell Biol 1998;10:477482. Keller J, Neale E, Oyler G, Adler M: Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett 1999;456:137142. Kistner A, Habermann E: Reductive cleavage of tetanus toxin and botulinum neurotoxin A by the thioredoxin system from brain. Evidence for two redox isomers of tetanus toxin. Naunyn Schmiedebergs Arch Pharmacol 1992;345:227234. Kozaki S, Kamata Y, Watarai S, Nishiki T, Mochida S: Ganglioside GT1b as a complementary receptor component for Clostridium botulinum neurotoxins. Microb Pathog 1998;25:9199. Kurazono H, Mochida S, Binz T, Eisel U, Quanz M, Grebenstein O, Wernars K, Poulain B, Tauc L, Niemann H: Minimal essential domains specifying toxicity of the light chains of tetanus toxin and botulinum neurotoxin type A. J Biol Chem 1992;267:1472114729. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC: Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 1998;5:898902. Link E, Edelmann L, Chou JH, Binz T, Yamasaki S, Eisel U, Baumert M, Sdhof TC, Niemann H, Jahn R: Tetanus toxin action: Inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem Biophys Res Commun 1992;189:10171023. Martin TFJ: Stages of regulated exocytosis. Trends Cell Biol 1997;7:271276. Matteoli M, Verderio C, Rossetto O, Iezzi N, Coco S, Schiavo G, Montecucco C: Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons. Proc Natl Acad Sci USA 1996;93:1331013315. Montecucco C, Papini E, Schiavo G: Bacterial protein toxins and cell vesicle trafficking. Experientia 1996;52:10261032. Montecucco C, Schiavo G: Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 1995;28:423472. Naumann M, Flachenecker P, Broecker EB, Toyka KV, Reiners K: Botulinum toxin for palmar hyperhidrosis. Lancet 1997;349:252253. Nishiki T, Kamata Y, Nemoto Y, Omori A, Ito T, Takahashi M, Kozaki S: Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J Biol Chem 1994;269:1049810503.
11
Nishiki T, Tokuyama Y, Kamata Y, Nemoto Y, Yoshida A, Sekiguchi M, Takahashi M, Kozaki S: Binding of botulinum type B neurotoxin to Chinese hamster ovary cells transfected with rat synaptotagmin II cDNA. Neurosci Lett 1996;208:105108. Ochanda JO, Syuto B, Ohishi I, Naiki M, Kubo S: Binding of Clostridium botulinum neurotoxin to gangliosides. J Biochem (Tokyo) 1986;100:2733. Olney RK, Aminoff MJ, Gelb DJ, Lowenstein DH: Neuromuscular effects distant from the site of botulinum neurotoxin injection. Neurology 1988;38:17801783. Pellegrini LL, OConnor V Betz H: Fusion complex formation protects synaptobrevin against proteoly, sis by tetanus toxin light chain. FEBS Lett 1994;353:319323. Rothman JE, Wieland FT: Protein sorting by transport vesicles. Science 1996;272:227234. Scheller RH: Membrane trafficking in the presynaptic nerve terminal. Neuron 1995;14:893897. Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C: Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 1992a;359:832835. Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C: Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc. EMBO J 1992b;11:35773583. Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C: Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D and E. J Biol Chem 1993a;268:2378423787. Schiavo G, Rossetto O, Santucci A, DasGupta BR, Montecucco C: Botulinum neurotoxins are zinc proteins. J Biol Chem 1992c;267:2347923483. Schiavo G, Santucci A, DasGupta BR, Mehta PP, Jontes J, Benfenati F, Wilson MC, Montecucco C: Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett 1993b;335:99103. Schiavo G, Shone CC, Rossetto O, Alexander FC, Montecucco C: Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J Biol Chem 1993c;268:1151611519. Schmitt A, Dreyer F, John C: At least three sequential steps are involved in the tetanus toxin-induced block of neuromuscular transmission. Naunyn Schmiedebergs Arch Pharmacol 1981;317: 326330. Shapiro RE, Specht CD, Collins BE, Woods AS, Cotter RJ, Schnaar RL: Identification of a ganglioside recognition domain of tetanus toxin using a novel gangliosides photoaffinity ligand. J Biol Chem 1997;272:3038030386. Sharma SK, Singh BR: Hemagglutinin binding mediated protection of botulinum neurotoxin from proteolysis. J Nat Toxins 1998;7:239253. Sheean GL, Lees AJ: Botulinum toxin F in the treatment of torticollis clinically resistant to botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;59:601607. Simpson LL: Kinetic studies on the interaction between botulinum toxin A and the cholinergic neuromuscular junction. J Pharmacol Exp Ther 1980;212:1621. Simpson LL: Peripheral actions of botulinum toxins; in Simpson LL (ed): Botulinum Neurotoxin and Tetanus Toxin. New York, Academic Press, 1989, pp 153173. Simpson LL, Coffield JA, Bakry N: Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J Pharmacol Exp Ther 1994;269:256262. Simpson LL, Rapport MM: Ganglioside inactivation of botulinum toxin. J Neurochem 1971;18: 13411343. Sloop RR, Cole BA, Escutin RO: Human response to botulinum toxin injection Type B compared with type A. Neurology 1997;49:189194. Sllner T, Whiteheart SW, Brunner M, Erdjument Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptors implicated in vesicle targeting and fusion. Nature 1993;362:318324. Stecher B, Gratzl M, Ahnert-Hilger G: Reductive chain separation of botulinum A toxin A prerequisite to its inhibitory action on exocytosis in chromaffin cells. FEBS Lett 1989a;248:2327. Stecher B, Weller U, Habermann E, Gratzl M, Ahnert-Hilger G: The light chain but not the heavy chain of botulinum A toxin inhibits exocytosis from permeabilized adrenal chromaffin cells. FEBS Lett 1989b;255:391394.
Bigalke/Naumann
12
Sdhof TC: The synaptic vesicle cycle: A cascade of protein-protein interactions. Nature 1995;375: 645653. Sdhof TC, DeCamilli P, Niemann H, Jahn R: Membrane fusion machinery: Insights from synaptic proteins. Cell 1993;75:14. Sutton RB, Fasshauer D, Jahn R, Brunger AT: Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 resolution. Nature 1998;395:347353. Van Heyningen WE, Mellanby J: A note on the specific fixation, specific deactivation and nonspecific inactivation of bacterial toxins by gangliosides. Naunyn Schmiedebergs Arch Pharmacol 1973;276:297302. Van Heyningen WE, Miller PA: The fixation of tetanus toxin by gangliosides. J Gen Microbiol 1961; 24:107119. Warren G, Malhotra V: The organisation of the Golgi apparatus. Curr Opin Cell Biol 1998;10: 493498. Weller U, Mauler F, Habermann E: Tetanus toxin: Biochemical and pharmacological comparison between its protoxin and some isotoxins obtained by limited proteolysis. Naunyn Schmiedebergs Arch Pharmacol 1988;338:99106. Wendland B, Emr SD, Riezman H: Protein traffic in the yeast endocytic and vacuolar protein sorting pathways. Curr Opin Cell Biol 1998;10:513522. Wernig A, Stover H, Tonge D: The labelling of motor endplates in skeletal muscle of mice with 125 I-tetanus toxin. Naunyn Schmiedebergs Arch Pharmacol 1977;298:3742. Williamson LC, Neale EA: Bafilomycin A1 inhibits the action of tetanus toxin in spinal cord neurons in cell culture. J Neurochem 1994;63:23422345. Wohlfarth K, Goschel H, Frevert J, Dengler R, Bigalke H: Botulinum A toxins: Units versus units. Naunyn Schmiedebergs Arch Pharmacol 1997;355:335340.
Prof. Hans Bigalke Medical School of Hannover, Institute of Toxicology, Carl-Neuberg-Strasse 1, D30625 Hannover (Germany) Tel. 49 511 5322815, Fax 49 511 5322879, E-Mail bigalke.hans@mh-hannover.de
13
Botulinum Toxin A in Pain Management: Mechanisms of Action and Rationale for Optimum Use
Hartmut Gbel
Kiel Pain Clinic, Kiel, Germany
Botulinum Toxin A Usage in Pain Therapy
Botulinum toxin A (BTX-A) has been used successfully in different indications for approximately 20 years. These disorders were characterized by an extreme muscle contraction. Present research projects are concentrating on new areas of use, especially in pain therapy. Patients with therapy-resistant chronic pain disorders are encouraged to hope for new therapeutic solutions. From a scientific standpoint, additional perspectives for fundamental research, clinical analysis of these disorders and mechanisms of actions must be re-evaluated. The scientific evidence due to study design in the areas of pain treatment is not complete in many areas of treatment. For example, injection techniques, injection areas, blinding study groups, dosage, just to name a few, need to be evaluated. In this chapter, the rationale and working principle of BTX-A in specific pain treatment will be described.
Mechanism of Action
Normalization of Muscular Hyperactivity The analgesic effects of BTX-A have been known for quite some time through publications on cranial cervical dystonia and spastic disorder treatments [13]. These pain symptoms are due to either constant muscle contraction or muscular hyperactivity resulting from a secondary irritation of
neural structures [4, 5]. Due to the duration of the illness, degenerative changes of the skeletal system could occur and these changes can additionally cause local pain symptoms. The constant muscular contraction can cause hypertrophy in the involved muscles. Dystonia is by itself not a disease but similar to spasticity or headache, a diagnosis according to symptoms. A common major symptom of focal dystonia is the abnormal movement or position of the affected body region. While the therapy with oral medication was the most common procedure, the local injection of BTX-A has in the last few years definitely improved the treatment of cranial cervical dystonia. The therapeutic influence of the pain is especially successful and is effective in most of the treated patients [69]. The actual movement disorder is by comparison less effectively influenced. The therapy success rates in blepharospasmus and spasmodic dysphonia are about 90% and in cervical dystonia about 80%. The pain reduction is commonly perceived before the muscular relaxation is observed [10]. Also, the pain reduction can be more explicit than the improvement of the muscular disorder. At first, one assumes that the common feature of these painful disorders where use of BTX-A has been effective would be the disturbance of normal muscle activity. Thus, the BTX-A injection would explain the pain reduction. Clinical observations force us to consider a more complex mode of action [11]. Pain reduction is also observed in muscle regions where a decreased muscle tonus could not be accomplished. For example, the pain reduction achieved by treatment of torticollis spasmodicus is observed several days after injection long before the excessive muscle contraction abates. Other observations are that pain reduction lasts longer than the period of muscle relaxation. In multifocal and segmental dystonia, BTX-A usage often has a positive effect on untreated muscle groups. Therefore, the neuromuscular denervation through the blockade of acetylcholine transmission is unsuitable as an explanation for the analgesic therapy effects. Normalization of Excessive Neuromuscular Spindle Activity The muscle-relaxing characteristic of BTX-A is put to use in treating several other striated muscle disorders, for example, spasticity and myofascial pain syndrome. The increasing and constant muscle relaxation caused by BTX-A can be utilized in myofascial pain syndrome where a decompression of afferent nociceptors, neurons of the muscle and the muscular blood vessels is achieved. An influence on the increased neuromuscular spindle activity can also be a result [12, 13]. Studies from Filippi et al. [12] show that BTX-A directly affects sensory muscle characteristics. Within 80 min after BTX-A application a blockade of -fibers can be detected. A reduction of the neuromuscular spindle activity
Botulinum Toxin A in Pain Management
15
causes a reflectory decrease of the -motoneuron activity without making a chemical denervation necessary. Also studies from Rosales et al. [13] show that BTX-A works on extrafusal as well as on intrafusal muscle fibers and that the change in the neuromuscular spindle activity represents an important mode of action. The change in the motor reflex activity is not limited to the peripheral mechanism but also change in the spinal neurotransmitter expression can initiate processes of neural reorganization [14]. As a result, central afferent and efferent control mechanisms of muscle activity can be modulated and reorganized [15]. For this reason, effects are possible outside the injection area.
Retrograde Neural Uptake in the Central Nervous System
Further studies suggest a retrograde uptake of BTX-A in the peripheral and central nervous system (CNS). Radioactive marked BTX-A was found 48 h after injection in the spinal roots and in the spinal cord [16]. This also defines the timepoint when the pain reduction becomes effective, clinically speaking. Other investigations show that BTX-A in a spinal application inhibits immediately the motor neuron [17]. New data from Aoki [4] using radioactive marked BTX-A prove that BTX-A is absorbed retrogradely in the CNS neuron. Simultaneously it will diffuse in a wide area surrounding the muscular injection site. These investigations suggest that not the entire protein is retrogradely transported in the CNS but rather metabolites. It is possible that this has an effect on sensory nociceptor systems that are much more extensive than the chemodenervation of BTX-A as has been observed to date [18]. Possibly, these effects concern generally the exocytosis of neurotransmitters and neuropeptides which are involved in the process of dissolving/disintegration and maintenance of pain.
Inhibition of Substance P Release and Effects on Other Neurotransmitters
BTX-A not only inhibits acetycholine release but also the release of substance P from distal trigeminal nerve fibers [19]. Substance P is a potent neurotransmitter during activation of neurogenic inflammation [20]. The Ca-dependent inhibition of substance P in rodent spinal cord neurons can also be used for testing of different toxin subtypes [20]. Humm et al. [14] studied the effect of chemodenervation with BTX-A on the expression of enkephalin, neurotension, glanin, substance P, vascular-active polypeptide (VIP) and neuropeptide Y in the spinal cord of rats after chemodenervation with BTX-A in gastrocnemius muscle. The expression of enkephalin was bilaterally
Gbel
16
increased in the spinal cord whereas the extracted area of the spinal nerve root was also included. The maximal activation was found 714 days after injection and remained for 3 months. Also the expression of substance P in nucleus raphe can be activated through BTX-A [21]. In studies on animals and in cell cultures it was detected that the light chain of BTX-A not only inactivated the transport protein SNAP-25 and VAMP, but also reduced the release of acetylcholine, numerous neurotransmitters and neuropeptides (substance P, CGRP, VIP, neuropeptide Y) [20, 2224]. This leads to a sensitization of the pain-processing system (wind-up, pain memory). Their inhibition can result in a normalization of pain sensitization (wind-down, pain distraction) and utilized therapeutically. Also in the pathogenesis of migraines, the described neuropeptides are important [25, 26]. The exact role that they play in clinical phenomena requires further research. Based on these in vitro studies and experimental data [27], the immediate neural modulations and analgesic effects of BTX-A in the CNS can be assumed. BTX-A can be incorporated through retrograde absorption in the axonal neural transport into the CNS [16]. In another study, the results were an unchanged activity of spinal Renshaw cells after intramuscular injection [28], although cholinergic activity of spinal Renshaw cells could be modulated through intraspinal application.
Anti-Inflammatory Effects
In a new study from Cui and Aokis group [29], the immediate antinociceptor effects of BTX-A could be proved on pain resulting from inflammation. Furthermore, a dose-dependent reduction of nociceptive response was shown on formaldehyde-induced arthritis in rat paws 12 days after injection. With a dosage of 3.57 units/kg/paw, a reduction of 2946% in comparison to placebo. Interesting was also that the chosen dose showed no muscular effect. The basis of migraine pain is a neurogenic inflammation of dural and meningeal arteries. Based on the investigation of Cui and Aokis group [29], it is possible that the retrograde uptake of BTX-A in the CNS blocks the inflammatory changes of the trigeminal-vascular system. BTX-A achieves as a result a direct influence on the pathophysiology of migraines. In several case studies, a possible positive effect of BTX-A in the treatment of cluster headache is also being considered [30]. In cluster headache, the cause of pain is assumed to be a phlebitis in the area of sinus cavernosus. It could be shown in an investigation from Gbel et al. [31], where an impressive plasma extravasation of 99mTc-marked human serum albumin was found in the area of sinus cavernosus and sinus petrosus superior in patients during an
17
Taut bands
Relaxed muscle fibers
Local twitch of band
b Fig. 1. a, b Characteristics of muscular trigger points.
active cluster attack. Recent pilot studies with BTX-A in the treatment of therapy-refracting cluster headaches show clinical effectivity. Also here, the prevention of inflammatory changes through retrograde neural uptake and inhibition of excitatory neural transmitters is a possible explanation for the therapeutic usage.
Effect on Muscular Trigger Points
A myofascial trigger point is hypersensitive muscle area [32]. Typically, they are found in a contracted sector of striated muscle or in a muscle fascia which is painful when compressed (fig 1). Trigger points are origins of radiating pain, sensitivity and autonomic reaction [32, 33]. Their clinical mastery can be reliably attained [34], however it requires training. Relevant characteristics are
Gbel
18
Table 1. Clinical characteristics and classification of trigger points (modified from Gerwin et al. [34]) Clinical characteristics of trigger points Local point with extreme pain after compression in a tense muscle band Local spasmodic movement Jump sign involuntary reaction Projected pain Stimulating the primary pain situation/status Hinderance of movement Muscle weakness without atrophy Autonomic symptoms (local flushing) Reliability for decision/evaluation
b Fig. 2. ac Palpation of muscular trigger points.
listed in table 1. The palpation technique is shown schematically in figure 2. The pathophysiology of muscular trigger points has only been partly investigated. According to the end-plate hypothesis [35], a local muscular trauma leads to a partial overload through ischemia causing a local release of acetylcholine. The result is a localized damage of the neuromuscular end plate. A recurring, frequent depolarization of muscle cells leads to nodes of contraction below the affected synapse. Neighboring inactive muscle fibers will be stretched passively forming taut bands. A pathophysiologic correlation in the area of trigger points can be found in the form of highly frequent spontaneous depolarizations also known as end-plate noise [36]. The pathomechanism
19
Table 2. Mechanisms of action of BTX-A in pain therapy Mechanism Blockade of cholinergic innervation Effect Reduction of muscular hyperactivity for 36 months Prevention of degenerative changes in head/neck muscles Decompression of nociceptive afferent fibers of pericranical muscles Dispersion/scattering of trigger and tender points in pericranical muscles Normalization of muscle tone Modulation in central control mechanisms of muscle activity Elimination of oromandibular dysfunction Elimination of muscular stress factors Stimulation of substance P expression in the spinal cord Stimulation of enkephalin expression in the spinal cord Stimulation of substance P in nucleus raphe (migraine generator) Blockade of neurogenic inflammation as pathophysiological substrate of primary headache Prevention of sensitization of nociceptive system with an increase of migraine attack frequency Prevention medication/drug-induced/related headache Elimination of compression-related ischemia Elimination of end-plate dysfunction Prevention of muscle degeneration Reduction of inflammation mediators
Normalization of muscle spindle activity
Retrograde uptake in CNS
Inhibition of sterile inflammation
Elimination of muscular trigger points
leads to further muscle trauma and through a vicious circle the pain status is maintained. Additionally, spinal and supraspinal sensitizing mechanisms [35, 32] will be activated (wind-up, see above). BTX-A can be utilized as a causal treatment method to block the excessive acetylcholine release and terminate the local muscle trauma [35, 32]. An overview of the BTX-A mode of action in pain treatment is shown in table 2.
Gbel
20
Usage
The effectiveness of BTX-A in the treatment of pain due to muscular hyperactivity especially when resulting in dystonia and spasticity has been proved empirically. Myofascial pain and muscular trigger points could be successfully treated when one considers the individual clinical presence. Also anal fissures and achalasia are well-documented areas of treatment with BTX-A. In other areas, especially in primary headache, the opinions differ according to dosage, injection areas and procedure (placebo control, efficacy parameters, etc.). Also, comparative studies on standard medication are lacking. Therefore, at the present time, the use of BTX-A in these disorders can only be realized after the entire spectrum of accepted methods has been exploited. This evaluation should occur in specialized therapy centers. Contradictory findings require further study to a greater extent. The consideration for usage of BTX-A in specific pain therapy represents a new option for patients and physicians. However, the usage requires exact functional anatomic knowledge and also extensive experience.
References
1 2 3 4 5 6 7 8 Chalkiadaki A, Rohr UP, Hefter H: Early pain reduction in the treatment of spasticity after a single injection of botulinum A toxin. Dtsch Med Wochenschr 2001;126:13611364. Kelm S, Gerats G, Chalkiadaki A, Hefter H: Reduction of pain and muscle spasms by botulinum toxin A. Nervenarzt 2001;72:302306. Tarsy D, First ER: Painful cervical dystonia: Clinical features and response to treatment with botulinum toxin. Mov Disord 1999;14:10431045. Aoki KR: Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001;248 (suppl 1):310. Porta M, Perretti A, Gamba M, Luccarelli G, Fornari M: The rationale and results of treating muscle spasm and myofascial syndromes with botulinum toxin type A. Pain Digest 1998;8:346352. Gbel H; Deuschl G: Dauerkontraktionen kranialer oder zervikaler Muskel Wenn Dystonien Kopfschmerzen bereiten. Mnch Med Wochenschr 1999;139:3031. Gbel H, Lindner V, Krack P, Heinze A, Gaartz N, Deuschl G: Treatment of chronic tension-type headache with botulinum toxin. Cephalalgia 1999;19:455. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E: Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 1990;40: 12131218. Jankovic J, Schwartz K: Botulinum toxin injections for cervical dystonia. Neurology 1990;40:277280. Brin MF, Fahn S, Moskowitz C, Friedman A, Shale HM, Greene PE, Blitzer A, List T, Lange D, Lovelace RE et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Adv Neurol 1988;50:599608. Brin MF, Fahn S, Moskowitz C, Friedman A, Shale HM, Greene PE, Blitzer A, List T, Lange D, Lovelace RE et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237254. Filippi GM, Errico P, Santarelli R, Bagolini B, Manni E: Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol 1993;113:400404. Rosales RL, Arimura K, Takenaga S, Osame M: Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve 1996;19:488496.
9 10
11
12 13
21
14
15
16 17 18 19
20 21 22 23 24
25 26 27 28
29 30 31
32 33 34 35 36
Humm AM, Pabst C, Lauterburg T, Burgunder JM: Enkephalin and aFGF are differentially regulated in rat spinal motoneurons after chemodenervation with botulinum toxin. Exp Neurol 2000;161:361372. Giladi N: The mechanism of action of botulinum toxin type A in focal dystonia is most probably through its dual effect on efferent (motor) and afferent pathways at the injected site. J Neurol Sci 1997;152:132135. Wiegand H, Erdmann G, Wellhoner HH: 125I-labelled botulinum A neurotoxin: Pharmacokinetics in cats after intramuscular injection. Naunyn Schmiedebergs Arch Pharmacol 1976;292:161165. Benecke R: Botulinum toxin treatment in spasticity of lower extremities; in Hallet M (ed): Therapy with Botulinum Toxin. New York, Dekker, 1994, pp 463473. Guyer BM: Mechanism of botulinum toxin in the relief of chronic pain. Curr Rev Pain 1999;3:427431. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, Shimizu K: Presynaptic effects of botulinum toxin type A on the neuronally evoked response to albino and pigmented rabbits iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106109. Welch MJ, Purkiss JR, Foster KA: Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000;38:245258. Van den Bergh P, DeBeukelaer M, Deconinck N: Effect of muscle denervation on the expression of substance P in the ventral raphe-spinal pathway of the rat. Brain Res 1996;707:206212. Puffer EB, Lomneth RB, Sarkar HK, Singh BR: Differential roles of developmentally distinct SNAP-25 isoforms in the neurotransmitter release process. Biochemistry 2001;40:93749378. Sala C, Andreose JS, Fumagalli G, Lomo T: Calcitonin gene-related peptide: Possible role in formation and maintenance of neuromuscular junctions. J Neurosci 1995;15:520528. Suzuki N, Hardebo JE, Kahrstrom J, Owman C: Neuropeptide Y co-exists with vasoactive intestinal polypeptide and acetylcholine in parasympathetic cerebrovascular nerves originating in the sphenopalatine, otic and internal carotid ganglia of the rat. Neuroscience 1990;36:507519. Ferrari MD: Migraine. Lancet 1998;351:10431051. Poungvarin N: The first world report of botulinum A toxin injection for status migrainosus. J Med Assoc Thai 2001;84:11991203. Aoki KR, Weber J, Patten P et al: United States Patent 6113915; Sept 5, 2000. Hagenah R, Benecke R, Wiegand H: Effects of type A botulinum toxin on the cholinergic transmission at spinal Renshaw cells and on the inhibitory action at Ia inhibitory interneurones. Naunyn Schmiedebergs Arch Pharmacol 1977;299:267272. Cui ML, Khanijou S, Rubino J, Aoki KR: Botulinum toxin inhibits the inflammatory pain in the rat formalin model. Society for Neuroscience Annual Meeting, 2000, Poster 246.2. Freund B, Schwartz M: The use of botulinum toxin A in the treatment of refractory cluster headache: Case reports. Cephalalgia 2000;20:329330. Gbel H, Czech N, Heinze-Kuhn K, Heinze A, Brenner W, Muhle C, Kampen WU, Henze E: Nachweis einer regionalen plasmaeiweiss-extravasation bei Clusterkopfschmerzen mittels TC99m Albumin SPECT in vensen Blutleitern der Hirnbasis. Schmerz 2000;14:S36. Simons DG, Mense S: Understanding and measurement of muscle tone as related to clinical muscle pain. Pain 1998;75:117. Hong CZ, Simons DG: Pathophysiologic and electrophysiologic mechanisms of myofascial trigger points. Arch Phys Med Rehabil 1998;79:863872. Gerwin RD, Shannon S, Hong CZ, Hubbard D, Gevirtz R: Interrater reliability in myofascial trigger point examination. Pain 1997;69:6573. Mense S: Neurobiologische Grundlagen von Muskelschmerz. Schmerz 1999;13:317. Hubbard DR, Berkoff GM: Myofascial trigger points show spontaneous needle EMG activity. Spine 1993;18:18031807. Prof. Dr. med. Dipl.-Psych. Hartmut Gbel Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Heikendorfer Weg 927, D24149 Kiel (Germany) Tel. 49 431 2009965, Fax 49 431 2009935, E-Mail h.gobel@neurologie.uni-kiel.de
Gbel
22
Myofascial Pain Syndrome

Peter Reilich, Dieter Pongratz
Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany
Myofascial pain syndrome (MPS) is apparently one of the most common causes of both chronic and acute musculoskeletal pain in general practice. Among 283 consecutive admissions to a comprehensive pain clinic, in 85% a MPS was found to be the cause of patients pain patterns [1]. Among 296 patients referred to a dental clinic for chronic head and neck pain, the primary diagnosis of myofascial pain was established in 55% of cases [2].
Definition and Clinical Signs
MPS as a local or regional pain syndrome is characterized by presence of a hyperirritable tender spot in skeletal muscle. It is associated with a hypersensitive palpable nodule and the fact that patients recognize their pain when pressure is applied to this so called trigger point [3]. The syndrome is combined with stiffness, tenderness and fatigue [4]. General cause of myofascial pain is a mechanical abuse due to various conditions like muscular overload, overwork fatigue, trauma, radiculopathy and degenerative skeletal disorders with consecutive posture problems, frequently in addition with perpetuating factors. Up to now, diagnostic criteria had not been established but typical clinical characteristics lead to the diagnosis of a MPS. Besides the trigger point, the clinical hallmark of MPS, the following main clinical findings are essential: Taut band: A group of tense muscle fibers with rope-like induration extending from a trigger point to the muscle attachments. The tension of fibers is caused by contraction knots that are located in the region of the trigger point.
Referred pain: Stimulation (digital pressure, needling) of an active trigger point elicit a referred pain pattern specific of the trigger point in the involved muscle and remote of its source (so-called zone of reference). The pattern of referred pain is reproducibly related to its site of origin and may or may not mimic more traditionally recognized dermatomal or myotomal pain patterns (see fig. 6). Local twitch response: Stimulation of a trigger point frequently causes a transient contraction (twitch) of a group of tense muscle fibers ( taut band) that traverse a trigger point. Limited range of motion: Muscles with active trigger points have a limited stretch range of motion caused by the pain pattern. An attempt of passive stretch to the muscle can produce increasing pain. Comprisingly, MPS is a regional pain syndrome defined by presence of a hyperirritable active trigger point in a taut band of muscle fibers associated with tenderness, local twitch response and referred pain into well-defined areas remote from the trigger point area [5]. Latent trigger points are clinically silent and may result primarily in muscle tightness and dysfunction without the presence of spontaneous pain but could cause pain on palpation. MPS and fibromyalgia are different conditions. According to the American College of Rheumatology 1990 criteria [6], fibromyalgia is a more widespread pain condition that lasts for 3 or more months and is associated with pain in at least 11 of 18 tender points sites on digital palpation. Myofascial trigger points should be distinguished from fibromyalgia tender points. Tender points are not associated with a twitch on palpation and are usually clinically silent unless stimulated by palpation. Tender points usually do not cause a referred pain on palpation. Patients with fibromyalgia tend to have more constitutional symptoms than patients with MPS. Table 1 lists characteristics of MPS and fibromyalgia.
The Pathophysiologic Concept: Integrated Trigger Point Hypothesis
The todays most accepted theory on the pathophysiology of myofascial pain is summarized as the integrated trigger point hypothesis according to Simons et al. [8] (fig. 1). The hypothesized primary dysfunction is an abnormal increase in release of acetylcholine from the motor endplate due to a muscular overload. This leads to a sustained depolarization of the post-junctional membrane of the muscle fiber and could cause a continuous release and inadequate uptake of calcium ions from local sarcoplasmatic reticulum with a sustained contraction of sarcomeres. While all these changes would increase energy demand, the
Reilich/Pongratz
24
Table 1. Distinguishing MPS from fibromyalgia [modified after 7] Characteristics Prevalence Sex Onset Fibromyalgia syndrome 23% of general population 10:1 female Exaggeration of central summation of nociceptive input from muscles Established (American College of Rheumatology, 1990) Tenderness of tendon insertions (tender points) by palpation or algometry in at least 11 of 18 points Good for palpation or algometry Myofascial pain syndrome 5093% of pain clinic patients 1.53:1 female Muscular overload
Diagnostic criteria Clinical findings
Not established, only typical clinical characteristics Local or regional tender spots within a palpable taut band of muscle fibers with twitch response to stimulation and referred pain pattern Good for all features with experienced and trained examiners Localized, in relation to trigger points Localized Often Rarely Uncommon Local myofascial release by manual therapies and needling techniques Good results in case series Frequently chronification in presence of perpetuating factors 20% also have fibromyalgia
Inter-rater reliability
Pain Pain referral Sleep disorder Fatigue Irritable bowel symptoms Treatment
Diffuse, no relation to tender points Rarely About 40% of patients Common Common Medications, manual therapies
Local injections Outcome
Uncertain Usually chronic
Comment
72% also have active trigger points
continuous muscle fiber contraction compresses local blood vessels reducing further nutrient and oxygen supply. The increased energy demand in face of impaired energy supply would produce a local energy crisis. The result is an elevation of sensitizing substances like bradykinin and 5-HT that could interact with traversing sensory and autonomic nerves. Subsequent release of neuroactive
25
Muscular overload Dysfunctional endplate
Vasoneur. substances (Bk, 5-HT)
Nociceptive nerve fibers (SP)
Autonomic nerve fibers Motor nerve terminal Excessive acetylcholine release
Energy crisis Depolarization Decreased energy supply Increased energy demand
SR Muscle fiber Calcium release
Sarcomere contracture (sustained) Decreased energy supply Failed Ca Compression of vessels (Hypoxemia) -reuptake
Fig. 1. Integrated trigger point hypothesis [modified after 8].
substances like substance P and glutamate could contribute to further excessive acetylcholine release from the nerve terminal. A vicious cycle closes.
Morphological Findings
The main histopathologic finding in trigger points is an accumulation of contraction knots. A contraction knot is a segment of muscle fiber with extremely contracted sarcomeres probably connected to an endplate structure as
Reilich/Pongratz
26
Fig. 2. Histopathology of human trigger point: contraction disks. Light microscopy. 400.
Fig. 3. Histopathology of human trigger point: shortening of Z-bands. Electron microscopy. (Courtesy of Prof. Dr. Mller-Hcker, Munich, Germany).
it has been shown in canine muscle [9]. In humans, such contraction knots have been repeatedly noted as a characteristic finding in trigger points many years ago but their significance has not been appreciated [10, 11]. In our laboratory we could find in only a few patients so-called contraction discs (fig. 2). By electron microscopy one can show shortened Z-bands in the middle of the trigger points (fig. 3) and additionally some disturbance of the Z-bands structure (fig. 4).
27
Fig. 4. Histopathology of human trigger point: disturbance of Z-bands structure. Electron microscopy. (Courtesy of Prof. Dr. Mller-Hcker, Munich, Germany).
Electrodiagnostic Criteria
Needle Electromyography There is no doubt that in every active trigger point region spontaneous electrical activity can be recorded. Subsequent electromyographic studies in rabbits and humans have confirmed the presence of spontaneous low-voltage motor endplate activity (endplate noise or endplate spikes, respectively) that is a highly characteristic finding in myofascial trigger points but not pathognomonic (fig. 5). Some authors believe that the endplate activity in trigger points differ in amplitude from normal endplate activity and therefore support the theoretical approach of a dysfunctional motor endplate with excessive acetylcholine release as a cause of MPS [12, 13]. Electromyography is not helpful in making the diagnosis of a MPS, but in exact localization of a trigger point within a muscle. Ultrasound Imaging Visualization of local twitch response by high-resolution ultrasound (especially M-mode technique) has, in addition, a strong potential to objectively circumstantiate the clinical diagnosis of an active trigger point especially in deeper muscles or obese subjects. Local twitch response has to be elicited during the test by digital palpation or preferably by needle stimulation of the trigger point [14].
Reilich/Pongratz
28
50 mV 10 ms
Fig. 5. Electromyography: spontaneous electrical activity in a trigger point (endplate noise besides endplate spikes; sweep speed 10 ms/div, amplification 50 V/div).
Established Therapeutic Possibilities
Acute myofascial pain is usually remarkably responsible when treated with prompt efficacious therapy such as simple stretch therapy, the avoidance of muscle immobilization and elimination of perpetuating factors. Specific outcome measures for these treatment modalities, however, are limited and based on practical observations without the necessary prospective control of rigorous trials [15]. If the pain has become chronic, a multidisciplinary approach to treatment containing manual therapies like stretching, dry needling and injection techniques, furthermore drug therapy and general principles of restoration of the muscle to its normal length, posture and full range of motion appears to be most beneficial [16]. Active and passive stretching of the muscle is a quite effective method to increase its pain-free range of motion. Besides other augmentation techniques like post-isometric relaxation (stretching after active contraction) or reciprocal inhibition for example, the stretching effect can be augmented preferably with intermittent cold. This approach contains the surface administration of a vapocoolant spray (spray and stretch) to the overlying skin while stretching the affected muscle and exerts additionally remarkable local anti-inflammatory, analgesic and muscle relaxant effects. In addition to muscle stretch, other local tissue stretch techniques like trigger point pressure release and deep-stroking massage produce a localized elongation of contracted sarcomeres and are as well effective physical therapeutic procedures. Post-treatment surface heat or
29
electrical stimulation are supplementary modalities in the treatment of myofascial pain. Needling methods can be divided into dry needling and injection techniques. Dry needling most likely is effective because it mechanically disrupts the integrity of dysfunctional endplates. Injection of any solution may be additionally helpful. Comparative studies [17] indicate a comparable effect of dry needling versus lidocaine injections and lend emphasis to the importance of eliciting a local twitch response while performing needling techniques. The effectiveness seems to be much greater if a twitch response was obtained. Additionally, local twitch response elicitation seems to be a primary inhibitory factor on the endplate activity in trigger points during needling [18]. In terms of reducing post-needling soreness, injection techniques are recommended. Corticosteroid trigger point injections are more effective than saline injections [19] but have a stronger potential to myotoxicity especially in form of depot preparations. Saline injections are found to be as effective as the long-acting anesthetic mepivacaine [20]. Comprisingly, among needling methods injections with local anesthetics or saline are recommended. The critical therapeutic factor for the therapeutic effectiveness seems to be the mechanical disruption by the needle. Adjuvant drug therapy contains mainly analgesic substances preferable with additional muscle relaxant properties like flupirtine and muscle relaxants like tolperisone with poor side effects, occasionally like tetrazepam for shortterm use. Anti-inflammatory drugs like diclofenac may be valuable effective. If necessary, restoration of a normal sleep architecture is essential and the use of short-term pharmacotherapy may be appropriate.
Indications for Botulinum Toxin Therapy
According to the integrated trigger point hypothesis, botulinum toxin (BTX) may operate as a nearly causal acting substance by inhibition of the excessive presynaptic acetylcholine release and thereby preventing the sustained muscle fiber contraction as well as the energy crisis. Additionally, inhibition of the release of substance P and glutamate from nociceptive fibers is decreased. On basis of the published data (following passage) BTX therapy in myofascial pain conditions is reserved primarily to those chronic and disabling syndromes refractory to established therapies or with multiple clinical relapses in presence of resistant perpetuating factors. For now, BTX is used as an off-label therapy in myofascial pain but with increasing acceptation. The predominant benefit of BTX injections is the long-lasting duration of
Reilich/Pongratz
30
action. The combination with manual and adjuvant therapeutic procedures is mandatory to augment the long-term outcome. As a matter of course, contraindications for the use of BTX like hypersensitivity, generalized disorders of the neuromuscular endplate (myasthenia gravis, LEMS) and gravidity, have to be ruled out.
Published Clinical Data
The analgesic properties of BTX are well known and were first described in 1985 in the treatment of torticollis spasmodicus by Tsui et al. [21]. While significant relief of motor symptoms was seen in about 69% of patients with focal dystonia, 74% of them experienced pain relief [22]. Since now (July 2002) the research on the potentials on BTX in pain conditions has been extended and nearly 300 publications are listed in a PubMed search containing the words botulinum and pain. The first publications concerning the effects of BTX in myofascial pain were released by Acquadro and Borodic [23] as a case report in 1994 and by Cheshire et al. [24] as a small controlled pilot study in the same year. Table 2 summarizes these and other substantial papers on this topic. Acquadro and Borodic [23] reported on 2 patients with disabling chronic myofascial pain originating from trapezius and splenius capitis muscles and resistant to conventional therapies. Each patient received two treatments 4 weeks apart. Four weeks after the first injection of 50 MU Botox/1 ml saline in total at several sites provided the patients with slight improvement but pain still remained disabling. At this time the patients received 150 MU BTX/3 ml saline at the same sites. Four weeks later the patients reported a greater pain relief and a marked improvement in lifestyle [25]. Cheshire et al. [24] described 6 patients with chronic MPS involving cervical paraspinal and shoulder girdle muscles. In a randomized double-blind, placebo-controlled cross-over pilot study they were injected with either saline or 50 MU Botox/4 ml saline divided equally among 23 sites. The time between the treatment sessions (verum/placebo) and the time of assessment after the second injection was both 8 weeks. Four of the 6 subjects experienced a significant improvement in visual analog scale and verbal descriptors for pain intensity, palpable muscle spasm and pressure algometry following BTX but not saline treatment. Onset of responses occurred within the first 7 days with a mean duration of the effect of 56 weeks. In 1997, Alo et al. [25] tested the long-term effect of BTX in the treatment of refractory chronic myofascial pain related to muscles of the neck and shoulder girdle or to the paraspinal thoracolumbar and pelvic muscles. 52 patients
31
Table 2. Main published trials on BTX treatment in myofascial pain (main publications)
Authors Pain syndrome/ injected muscles n (verum/placebo), total dose/dilution Study design Results EBM level
Wheeler, 2001 [30] negative Foster, 2001 [29] positive
Chronic neck pain/ 21/24, mean 231 50 MU multiple sites: cervical, Botox vs. saline (no more thoracic, trapezius data are available) Low back pain/ paravertebral muscles L1 to S1 at 5 sites unilaterally Scalenus syndrome (n 10), piriformis syndrome (23), psoas syndrome (7) 14/14, 200 MU Botox/2 ml vs. saline divided into 5 injection points 20 (4 scal. 13 pirif. 3 iliops.)/20 (6 scal. 10 pirif. 4 iliops.) 80 MU/2 ml (scal.), 100 MU/2 ml (pirif.) or 150 MU/3 ml (iliops.) Botox 2 ml bupivacaine vs. methylprednisolone (2 or 3 ml) bupivacaine (2 ml)
Randomized plc-controlled double-blind Randomized plc-controlled double-blind
No signif. effect on VAS, NPAD and GAS after 4, 8, 12, and 16 weeks VAS and OLBPQ after 3 and 8 weeks post BTX-treatment signif. improved
Ib
Ib
Porta, 2000 [28] positive
Randomized No signif. difference subst.-controlled (VAS) after 30 days double-blind post-injection, but significant reduction of pain (VAS) after 60 days compared to steroids
Ib
Freund, 2000 [27] positive
Whiplash assoc. chronic neck pain (WAD-II-chronic)/ spl. cap., rect. cap., semispin. cap. trapez. Chronic unilateral neck pain/cervicothoracic paravertebral muscles
14/12, 100 MU Botox/ 1 ml vs. 1 ml saline each divided into 5 injection points 11 11/11, 50 or 100 MU Botox/2 ml vs. saline at one site
Randomized plc-controlled double-blind
No signif. difference after 2 weeks, 4 weeks after BTX signif. improvement in VAS, ROM
Ib
Wheeler, 1998 [26] negative
Randomized plc-controlled double-blind
No signif. effect on NPAD, Ib GAS and pressure algometry compared to placebo after 1, 3, 6, 9, 12 and 16 weeks Positive 22 of 33 patients (head, neck, shoulder) satisfied 6 months after treatment 10 of 19 patients (low back) satisfied 6 months after treatment Positive reduction of pain severity (VAS) 30% in 4 of 6 pts Positive subjective reduction of pain severity IV
Alo, 1997 [25] positive
Myofascial pain related to head, neck or shoulder girdle Myofascial pain related to low back pain
33/, 10300 MU Botox (MPS neck) (10 MU/ml)
Open study
19/, 90300 MU Botox (10 MU/ml) (MPS low back) n 6 (cross-over) 50 MU/4 ml Botox divided equally among 23 sites 2/, 50 MU/1 ml followed by 150 MU/3 ml Botox after 4 weeks divided each among several sites Randomized plc-controlled double-blind cross-over Case report
Cheshire, 1994 [24] positive
Chronic myofascial pain syndrome of the cervical paraspinal or shoulder girdle muscles
IIb
Acquadro, 1994 [23] Chronic myofascial positive pain of trapezius and splenius capitis muscle
IV
VAS Visual Analogue Scale; OLBPQ Oswestry Low Back Pain Questionnaire; NPAD Neck Pain and Disability Visual Analogue Scale; GAS Global Assessment of Symptoms; ROM Objective Range of Motion (measurements of rotation, flexion, extension, lateral bending).
Reilich/Pongratz
32
received 10300 MU (cervicothoracic myofascial pain, n 33) or 90300 MU Botox (low back pain, n 19) at several sites in an individualized scheme according to the physical examination. The dilution of the toxin was 10 MU/1 ml saline. The correct localization of the muscle was obtained by fluoroscopy showing intramyofascial spread of contrast solution (Isovue 180-M, 2 ml). Up to 3 treatments were given at least 4 weeks apart to prior injection if persistent muscle spasm were present and patients pain continued. Measurements were obtained at 4-week intervals for up to 6 months. More than 50% reduction in the level of palpable muscle spasm and patients own assessment of effectiveness were achieved in 63% of the cervicothoracic and 43% of the low back pain group 6 months after treatment. Side effects such as flu-like symptoms and nausea were seen in 62% of patients after the first injection with a mean duration of 4 days. One patient suffered from transient dysphagia for 7 days. Regarding todays experience on the safety profile of BTX, it has to be annotated that the high incidence of flu-like symptoms in this study could be due rather to the preinjected contrast solution under fluoroscopy than the toxin itself. Wheeler et al. [26] reported the lack of efficacy of BTA (Botox) over placebo when injected into trigger points in 33 patients with chronic unilateral neck pain caused by trigger points in the cervicothoracic paravertebral muscles in a randomized, double-blind study. Subjects were divided randomly to receive either 50 MU Botox/2 ml saline, 100 MU/2 ml saline or 2 ml saline alone at one injection site corresponding to the most tender trigger point. Patients were re-evaluated every 3 weeks over a 4-month period by assessment of algometry, visual analog scales (Neck Pain and Disability Visual Analog Scale, NPAD) and patients subjective global assessment of symptoms, and then offered each group a second injection of 100 MU Botox/2 ml which 11 patients received in the same site and 2 patients in an adjacent symptomatic site. All three groups showed similar clinical improvement after treatment without any significant benefit of BTX over placebo. There was a notable but not significant trend among the groups in response to the second injection towards a higher incidence of clinical improvement in the verum groups. In 2000, Freund and Schwartz [27] looked at outcome measures in 26 patients with chronic whiplash-associated neck pain following BTX treatment of the cervical musculature in a randomized, double-blind, placebo-controlled trial. Fourteen subjects received 100 MU Botox/1 ml, the rest received 1 ml saline alone both divided equally among 5 injection sites. Those who received BTX experienced a non-significant trend towards improvement in pain and in neck flexibility at 2 weeks after treatment. At 4 weeks post-injection the treatment group showed significant improvement of visual analog scales for neck pain, headache and shoulder pain as well as the range of motion of the neck
33
compared to preinjection levels. None of the patients experienced any side effects. Porta [28] compared the effects of steroid versus BTX injections in 40 patients suffering from chronic myofascial pain of the scalenus anterior (n 10), piriformis (n 23) and psoas muscles (n 7) in a single-blind, randomized matter. After a local anesthetic preinjection of 2 ml bupivacaine, 0.5% subjects received either 80 MU/2 ml saline (scalenus m.), 100 MU/2 ml saline (piriformis m.), 150 MU/3 ml saline Botox or 80 mg depot methylprednisolone diluted in a corresponding volume of saline. All injections were performed as compartment injections into the affected muscle under CT scan guidance. Thirty days after treatment followed by post-injection physiotherapy (daily passive and active stretch techniques), pain severity had decreased significantly from baseline in both treatment groups, with no significant difference between the two treatment groups. At 60 days post-injection, the reduction in pain score in the BTX-treated group was greater than at 30 days providing at this time a statistically significant improvement compared to the steroid whose effect had begun to wane. No major side effects were observed. Foster et al. [29] reported on the efficacy of BTX in 28 patients with chronic unilateral myofascial low back pain using a randomized, doubleblind, placebo-controlled study design. Participants received a total amount of 200 MU Botox/2 ml saline or 2 ml saline alone, respectively, divided equally among five lumbar paravertebral levels at the sites of maximum discomfort. Outcome parameters were assessed 3 weeks post-injection (visual analogue scale) and 8 weeks after treatment (visual analog scale and functional ability score concerning daily living: Oswestry Low Back Pain Questionnaire). Three weeks post-injection, 73% of the verum-treated patients showed significant ( 50%) pain relief whereas only 25% of the control group did so. At 8 weeks, there was also a significant improvement on pain in 60% (BTX-A) and 12.5%, respectively (saline). The Oswestry Low Back Pain Questionnaire at 8 weeks was significantly improved in 67% of the verum group versus 21% in the control group. No patient experienced side effects. In 2001, Wheeler et al. [30] published their new data of a randomized, double-blind trial comparing 45 patients with chronic myofascial neck pain on the effects of BTX and normal saline for 4 months using measurements of pressure algometry and a comprehensive set of neck pain aimed visual analog scales (Neck Pain and Disability Scale). Injections were placed in multiple sites in symptomatic muscles at the discretion of the physician. The mean dosage of BTX was 231 50 MU Botox in the verum group. Both BTX (n 21) and control groups (n 23) showed a significant decline in pain and
Reilich/Pongratz
34
disability during the monthly visits and an improvement of tenderness in pressure algometry. Adverse effects were recorded significantly more in the BTX group at 4 and 8 weeks post-injection and presented as flu-like symptoms, pain or sore at the injection site and excessive weakness of treated muscles, however. Comprisingly, on the basis of the published data BTX seems to be effective in MPS. However, these studies are partly uncontrolled or performed only with a small number of patients. Even no insights exist whether BTX injections are superior to dry needling technique. Therefore, this conclusion can be made provided until further data are available.
Injection Technique
In general, there are some major kinds of injection techniques which differ from each other. The compartment technique contains the approach to the involved muscle as a dysfunctional unit independent from a precise localization of the underlying trigger points. Therefore, this technique is especially useful in muscles which are difficult to localize and to palpate or even to differentiate from adjacent muscles (psoas, multifidus, piriformis muscle, for example). In most cases the localization of the target muscle takes place under ultrasound, CT, fluoroscopy or EMG guidance. Normally, with this technique higher dosages of BTX are recommended compared to the trigger point-aimed approach (see below). The muscle relaxant effect on the trigger point via the -motoneurons and its efferents, the -fibers, is mainly obtained by diffusion of the toxin. In principle, in most other muscles a direct positioning of the injection needle near or directly into the trigger point (TrP-aimed approach) is preferable. The TrP-aimed approach contains several kinds of techniques, (a) the commonly used direct injection near the trigger point after its palpation, (b) an optimized form of the latter technique injecting directly into the trigger point after its exact localization by EMG and ultrasound guidance and (c) the injection in a grid pattern around the trigger point gaining more diffuse spread. The advantages and disadvantages of the specific forms and their potential benefit regarding therapeutic success and minimization of side effects especially in areas with adjacent sensitive structures (e.g. anterior neck region, forearm region) and economization of the dose have been not reviewed so far. Practical experience and comparison of unpublished data suggest that a grid pattern technique has no additional benefit. The injection after digital palpation of the trigger point may raise difficulties regarding the appropriate depth and direction of the injection needle within the muscle.
35
Fig. 6. Referred pain pattern from trigger point (indicated with subscapularis muscle [modified after 8].
) of the left
It is recommendable to place the needle preferably directly into the trigger point to elicit a twitch response during injection. This is well known from studies which showed that eliciting a local twitch response during injection is a major parameter for a better clinical outcome. To achieve this the injection needle can be repeatedly pushed forward and back during injection in a fanshaped way similar to dry needling technique to get a more diffuse spread of the substance and a better chance to elicit a twitch response. Otherwise the injection can follow directly into the trigger point by technical support according to the electrodiagnostic criteria (see above) of ultrasound and electromyography (fig. 7). A combined EMG injection needle is slowly pushed forward in direction of the palpated trigger point (fig. 8) until spontaneous electrical activity can be recorded (fig. 5). Mostly at this point a twitch response can be elicited and simultaneously be documented by high-resolution ultrasound, preferably in M-mode technique. Aside from the different injection methods it is surely important to treat the affected muscles sufficiently. It is recommended to deactivate all of the active trigger points that cause the main clinical syndrome in order to give the patient better relief of symptoms and to avoid secondary sustaining pain
Reilich/Pongratz
36
Fig. 7. BTX in myofascial pain. Settings at injections: ultrasound and electromyography.
Fig. 8. Injection of a trigger point in scalenus anterior muscle by guidance of ultrasound and electromyography.
sources. Therefore, in most cases multiple injection sites also partly in one muscle are required to gain a sufficient clinical outcome. Reducing the treatment to one injection site is sufficient only in the great minority of patients. The above-mentioned studies support this position [26, 30]. For the same reason, individualized injection schemes performed by experienced and trained
37
Table 3. Recommended unit dose ranges (MU) for BTX type A (Botox) in frequently affected muscles [according to 32] Sternocleidomastoid Scalenus Splenius capitis Semispinalis capitis Trapezius Levator scapulae Teres major Brachioradialis 50100 2550 1030 1030 25100 2550 2575 2575 Biceps brachii Flexor carpi ulnaris Flexor carpi radialis Iliopsoas Quadratus lumborum Piriformis Gastrocnemius Tibialis anterior 75125 1050 1050 50100 50100 50100 50100 50100
physicians will be superior to standardized schemes. At this time, in Germany, comparison trials are underway to prove this assumption. There are no generally recommended dosages in treatment of myofascial trigger points which makes physicians own estimation and experience necessary. Generally, BTX administered in a smaller amount than the motor effective dose is already analgesically effective [21]. According to our experience, using the EMG-guided approach to the trigger point 1530 MU Botox and 50100 MU Dysport per trigger point, respectively, are sufficient. A total maximum dosage should not exceed about 300 MU Botox (1,000 MU Dysport) in respect to systemic side effects. In non-EMG-guided methods the dosage of BTX is somewhat dependent on the size of the muscle. CT-guided compartment injections in piriformis and psoas muscle are effective from 100 MU up to 150 MU Botox (300 and 500 MU Dysport, respectively). Most of the other frequently affected muscles are equally treated with dosages around 1550 MU Botox (50 MU up to 150 MU Dysport) [31]. An overview of recommended dose ranges of other muscles using injections guided by palpation is shown in table 3. Up to now there are no published trials concerning the use of Dysport. Therefore, the corresponding dosage is about 3-fold of the recommended amount of Botox. BTX type B (Myobloc) seems to be about 4050 times less potent than type A. At this time, studies concerning the efficacy of Dysport and Myobloc in myofascial pain are presently being conducted. The injection of BTX type A reconstituted in local anesthetics provides an immediate feedback on the extent of effect to be expected and may additionally enhance the safety and predictability of the injections [33]. The use of a local anesthetics as diluent seems not to affect the efficacy of the toxin on myofascial pain. Nevertheless, current recommendations of the manufacturers contain the use of saline as diluent only. Open questions concerning the kind and the volume of the diluent as well as the optimal dose of the toxin and the
Reilich/Pongratz
38
most effective injection technique have to be clarified in further studies which are partly underway. Besides the use of injections, the importance of physiotherapeutic therapies as a necessary programmatic element should not be neglected. They represent the basis of the multimodal approach on myofascial pain and suggest an augmentation of the effect and long-term outcome of BTX treatment.
Conclusion
BTX type A is a useful therapeutic element in chronic myofascial pain caused by trigger points and refractory to established therapeutic modalities. According to currently accepted pathophysiological concepts it may operate as a nearly causal acting substance breaking the vicious cycle of excessive acetylcholine release sustained sarcomere contraction energy crisis release of nociceptive substances sustained acetylcholine release. Injections of BTX are an additional element in the multimodal therapeutic approach based on physiotherapeutic management. Until upcoming investigations may further circumstantiate the superiority of BTX it remains a helpful and longlasting off-label method in myofascial pain to achieve the rehabilitation of the patient.
References
1 2 Skootsky SA, Jaeger B, Oye RK: Prevalence of myofascial pain in general internal medicine practice. West J Med 1989;151:157160. Fricton JR, Kroening R, Haley D, Siegert R: Myofascial pain syndrome of the head and neck: A review of clinical characteristics of 164 patients. Oral Surg Oral Med Oral Pathol 1985;60: 615623. Simons DG: Examining for myofascial trigger points. Arch Phys Med Rehabil 1993;74: 676677. Wolfe F, Simons DG, Fricton J, Bennett RM, Goldenberg DL, Gerwin R, Hathaway D, McCain GA, Russell IJ, Sanders HO, et al: The fibromyalgia and myofascial pain syndromes: A preliminary study of tender points and trigger points in persons with fibromyalgia, myofascial pain syndrome and no disease. J Rheumatol 1992;19:944951. Simons DG, Travell JG, Simons LS: Travell & Simons Myofascial Pain and Dysfunction: The Trigger Point Manual, vol I: Upper Half of Body, ed 2. Baltimore, Williams & Wilkins, 1999. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160172. Goldenberg DL: Controversies in fibromyalgia and myofascial pain syndromes; in Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. Baltimore, Williams & Wilkins, 1999.
3 4
39
9 10 11 12 13 14 15 16 17 18
19 20 21 22
23 24 25 26
27 28
29 30 31
Simons DG, Travell JG, Simons LS: Travell & Simons Myofascial Pain and Dysfunction: The Trigger Point Manual, vol I: Upper Half of Body, ed 2. Baltimore, Williams & Wilkins, 1999. Simons DG, Stolov WC: Microscopic features and transient contraction of palpable bands in canine muscle. Am J Phys Med 1976;55:6588. Glogowski G, Wallraff J: Ein Beitrag zur Klinik und Histologie der Muskelhrten (Myogelosen). Z Orthop 1951;80:237238. Miehlke K, Schulze G, Eger W: Klinische und experimentelle Untersuchungen zum Fibrositissyndrom. Z Rheumaforsch 1960;19:310330. Kimura J: Electrodiagnosis in Diseases of Nerve and Muscle. Philadelphia, Davis, 1989, vol 2. Simons DG, Hong CZ, Simons LS: Endplate potentials are common to midfiber myofascial trigger points. Am J Phys Med Rehabil 2002;81:212222. Gerwin RD, Duranleau D: Ultrasound identification of the myofascial trigger point. Muscle Nerve 1997;20:767768. McCain GA: Fibromyalgia and myofascial pain syndromes; in Wall PD, Melzack R (eds): Textbook of Pain, ed 3. New York, Churchill Livingstone, 1994, pp 475493. Han SC, Harrison P: Myofascial pain syndrome and trigger-point management. Reg Anesth 1997; 22:89101. Hong CZ: Lidocaine injections versus dry needling to myofascial trigger point: The importance of the local twitch response. Am J Phys Rehabil 1994;73:256263. Chen JT, Chung KC, Hou CR, Kuan TS, Chen SM, Hong CZ: Inhibitory effect of dry needling on the spontaneous electrical activity recorded from myofascial trigger spots of rabbit skeletal muscle. Am J Phys Med Rehabil 2001;10:729735. Day BH, Govindasamy N, Patnaik R: Corticosteroid injections in the treatment of tennis elbow. Practitioner 1978;220:459462. Frost FA, Jessen B, Siggaard-Anderson J: A control, double-blind comparison of mepivacaine injection versus saline injection for myofascial pain. Lancet 1980;i:499501. Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB: Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;ii:245247. Brin MF, Fahn S, Moskowitz C, Friedman A, Shale HM, Greene PE, Blitzer A, List T, Lange D, Lovelace RE, et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237254. Acquadro MA, Borodic GE: Treatment of myofascial pain with botulinum A toxin. Anesthesiology 1994;80:705706. Cheshire WP, Abashian SW, Mann JD: Botulinum toxin in the treatment of myofascial pain syndrome. Pain 1994;59:6569. Alo KM, Yland MJ, Kramer DL, Charnov JH, Redko V: Botulinum toxin in the treatment of myofascial pain. Pain Clin 1997;10:107116. Wheeler AH, Goolkasian P, Gretz SS: A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine 1998;23:16621666. Freund BJ, Schwartz M: Treatment of whiplash associated neck pain with botulinum toxin-A: A pilot study. J Rheumatol 2000;27:481484. Porta M: A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain 2000;85: 101105. Foster L, Clapp L, Erickson M, Jabbari B: Botulinum toxin A and chronic low back pain: A randomized, double-blind study. Neurology 2001;56:12901293. Wheeler AH, Goolkasian P, Gretz SS: Botulinum toxin A for the treatment of chronic neck pain. Pain 2001;94:255260. Childers MK: Use of Botulinum Toxin Type A in Pain Management. Columbia, Academic Information Systems, 1999.
Reilich/Pongratz
40
32
33
Royal M: The use of botulinum toxins in the management of myofascial pain and other conditions associated with painful muscle spasm; in Brin MF, Hallett M, Jankovic J (eds): Scientific and Therapeutic Aspects of Botulinum Toxin. Philadelphia, Lippincott Williams & Wilkins, 2002. Gassner HG, Sherris DA: Addition of an anesthetic agent to enhance the predictability of the effects of botulinum toxin type A injections: A randomized controlled study. Mayo Clin Proc 2000;75:701704.
Dr. Peter Reilich, MD, Prof. Dr. Dieter Pongratz, MD Friedrich-Baur-Institut an der Neurologischen Klinik, Klinikum der Universitt Mnchen Innenstadt, Ziemssenstrasse 1a, D80336 Mnchen (Germany) Tel. 49 89 51607400, Fax 49 89 51607402, E-Mail fbi@fbs.med.uni-muenchen.de
41
Type A Botulinum Toxin in Myofascial Facial Pain and Dysfunction

Jens-Jrg von Lindern
Department of Oral and Maxillofacial Surgery, University of Bonn, Germany
Dysfunctions of the masticatory organ are often characterized by dysfunctions of the masticatory muscles, temporomandibular joint function and occlusion [14]. While occlusal disturbances used to be regarded as the key aetiological factor in the genesis of dysfunctions of this kind, muscular and psychological factors are coming increasingly to the fore today. Also discussed are inadequate stress management, as well as changes in the proprioceptors and disorders in the area of the motor pathways [5, 6]. The predominant causes of muscular pain in the maxillofacial area are the jaw-closing and protracting muscle groups. The jaw-opening muscles, as well as the muscles of the tongue and larynx may also be affected in the context of oromandibular dystonia. Table 1 shows an overview of the causal muscle groups. The fact that tension of the masticatory muscles can also result from disorders of the extrapyramidal motor pathways is illustrated by the example of cervical and facial dystonia induced by neuroleptic drugs. This is thought to be caused by an imbalance between the neurotransmitters dopamine and acetylcholine, where the excessive release of acetylcholine leads to the undesirable, involuntary muscle contraction [5]. The genesis of pain in the context of myalgia of the masticatory muscles can be explained by chronic nociceptive irritation of the tendons and fascias of the muscles, on the one hand, and by secondary irritation of adjacent tissue, on the other (e.g. irritation of the periosteum, overloading of the temporomandibular joint) [7, 8]. At the same time, pain can also result from contractions, ischaemic and hyperaemic conditions, and microtraumas in the muscles. This pain is generally described as a sensation of non-throbbing, variable and partly diffuse pain. There is a more or less constant background of pain, which
Table 1. Overview of the causal muscle groups in myofascial facial pain and dysfunction Dysfunction Painful myalgia of the masticatory muscles Hypermobility disorders Hypertrophy of the masseter and temporalis muscle Trismus Oromandibular dystonia Type jaw-opening Type jaw-closing Lingual dystonia Causal muscle/group of muscles Masseter, temporalis, medial pterygoid muscle Lateral pterygoid, temporalis muscle (anterior part) Masseter, temporalis muscle Masseter, temporalis, medial pterygoid muscle Lateral pterygoid, digastric, suprahyoidal, platisma muscle Masseter, temporalis, medial pterygoid muscle Hypoglossus, pharyngeal muscles
can be interspersed with attacks of violent pain. The pain is frequently perceived not only in topographic connection with the muscle of origin, but also characteristically with the radiation typical of every masticatory muscle. For example, some patients report the pain radiating into the mandible, the mandibular teeth and the ear region. Others report radiation into the maxilla, the lateral and front maxillary teeth, above the eye and into the temporal region (fig. 1, 2). Functional impairment, such as restricted mandibular movement, is rare. Precise differentiation of the individual causal aetiological factors is generally not possible. Consequently, diagnosis and therapy mainly aim to reduce and eliminate pathological findings obtained in a functional analysis of the masticatory system. Symptomatic therapy involves both dental and medical measures. The dental measures applied are occlusal appliances and the grinding or reconstruction of teeth, tooth groups or the entire masticatory system. Due to their wide range of indications, occlusal appliances are the primary form of dental therapy after informing and instructing the patient. The action principle is based on various neuromuscular mechanisms aimed at harmonizing the functions of the teeth, jaw, muscles and joint. The main objective in this context is to eliminate parafunctions, such as grinding and clenching of the teeth.
BTX-A Toxin in Myofascial Facial Pain and Dysfunction
43
Fig. 1. a Typical radiation of the upper part of the masseter muscle. b Typical radiation of the middle part of the masseter muscle. c Typical radiation of the lower part of the masseter muscle.
Fig. 2. a Typical radiation of the anterior part of the temporalis muscle. b Typical radiation of the middle part of the temporalis muscle. c Typical radiation of the posterior part of the temporalis muscle.
The adjuvant medical measures include not only exercises and behavioural regimens, but particularly also targeted physiotherapy. Alternatives include all relaxation techniques, acupuncture and acupressure, as well as biofeedback methods. In the past, up to 80% of patients with painful myalgia of the maxillofacial muscles could be treated successfully using these conventional, conservative methods. Despite appropriate measures of the kind described above, 20% of patients failed to benefit from conventional treatment methods, meaning that different therapeutic options had to be discussed. A temporary, positive therapeutic effect on dysfunctions and pain symptoms has been known for a long time from the treatment of cervical dystonia
von Lindern
44
Table 2. Overview of literature in the treatment of myofascial facial pain and dysfunction Author/year Freund et al., 2000 [20] Indication TMD Patients 46 Substance/dose Botox/50 U masseter muscle, 25 U temporalis muscle Botox/50 U masseter muscle, 25 U temporalis muscle Dysport/200 U masseter, muscle, temporalis muscle Dysport/200 U masseter muscle, temporalis, muscle Perioral muscles Design Open label Results Significant decrease of pain Significant decrease of pain Decrease of pain
Freund et al., 1999 [13]
TMD
15
Open label
von Lindern, 2001 [16]
Facial pain and TMD Pain trismus Facial pain
41
Open label
von Lindern et al., 2000 [15] Kunig et al., 1998 [12]
55
Open label
Decrease of pain
1 case
Decrease of pain
with botulinum toxin (BTX) [9, 10]. It thus seems logical that the targeted chemical partial denervation of the affected masticatory muscles using BTX can improve the pain symptoms in patients with painful myalgia, should conventional, conservative measures prove ineffective.
Overview of the Literature
Type A botulinum toxin (BTX-A) has long been familiar as a local muscle relaxant in the treatment of focal dystonia [10] and also pain [11]. Numerous new potential applications have emerged recently. These also include the use of BTX in dysfunctions of the masticatory organ (temporomandibular disorders) and chronic facial pain [1216]. An overview can be found in table 2: Although all the scientific studies show that the local injection of BTX-A has a positive effect on pain and dysfunctions in the maxillofacial area, this cannot be taken as a general indication for the treatment of chronic, muscle-induced pain. Rather, the injection of BTX-A must constitute an alternative for refractory patients at the end of the therapeutic chain when all conventional therapeutic options have been exhausted. At the same time, all other causes must be ruled out in advance, especially arthrogenic factors in the region of the temporomandibular joints. The following indication system for BTX-A has proven successful in clinical routine: (1) chronic, function-independent pain in relation to the
45
Table 3. Overview of treated muscles, doses and approaches Muscle Botox MU per muscle 3550 3550 50 5 20 Dysport MU per muscle 150200 150200 200 20 80 Approach
Masseter muscle Temporalis muscle Lateral pterygoid muscle Medial pterygoid muscle Frontalis muscle
Extraoral/intraoral Extraoral Extraoral simultaneous with EMG Extraoral Extraoral
affected masticatory muscles; (2) typical radiation analogous to the insertions of the masticatory muscles; (3) general signs of general hyperactivity of the masticatory muscles (attrition of the teeth, muscular hypertrophy, etc.); (4) interdigitation disorders and arthrogenic causes ruled out; (5) resistance to therapy, despite appropriate conventional, conservative therapy for at least 3 months, and (6) no findings contraindicating BTX therapy. Under the above conditions, it is our experience that the targeted injection of BTX-A in refractory patients is capable of improving pain symptoms by up to 80%. Both the injection technique and the dosage vary in the studies to date. For this reason, the topography, the injection technique and the dosage for each muscle will be specifically presented in detail below (table 3).
Masseter Muscle
With its deep part and its superficial part, the masseter muscle extends from the zygomatic bone attachment to the angle of the mandible. Its primary function is jaw closure, as well as dynamic and static occlusion. This muscle is fundamentally involved in case of dysfunction (e.g. grinding and clenching of the teeth). Pain on pressure mainly exists in the deep part in the insertion area of the muscle on the zygomatic bone and typically tends to radiate into the maxilla and mandible, as well as the lateral teeth. The lower area of the muscle on the angle of the mandible is less often affected, and then frequently in connection with significant masseter hypertrophy. As a result, both extraoral and intraoral injection is possible. Freund et al. [13, 14] prefer the extraoral injection of doses of 5 U Botox distributed over the entire muscle area (total dose: 25 to 50 MU Botox). The injection can be EMG-controlled or performed simultaneously
von Lindern
46
Fig. 3. Injection of the upper part of the masseter muscle with an intraoral approach.
Fig. 4. Injection of the lower part of the masseter muscle with an extraoral approach.
with the help of targeted triggering of the muscle. As the majority of patients have pain on pressure in the region of insertion on the zygomatic bone, we consider the intraoral injection of approximately 35 U Botox/150 U Dysport to be clinically more practicable (fig. 3). In case of extraoral injection, the front parts of the muscle must be avoided owing to the vicinity to the levator anguli oris, as must the lower parts close to the parotid gland (fig. 4).
47
Fig. 5. Injection of the anterior part of the temporalis muscle.
Temporalis Muscle
The temporalis muscle is divided into the anterior part and the posterior part. While the anterior part with its vertical fibre orientation is primarily responsible for protrusive movement of the mandible (protrusion), the posterior part is used for closing the jaw and occlusion. In case of dysfunction, it is generally the anterior part that is affected, often accompanied by hypertrophy. Typical pain on pressure is found in the temporal region, radiating into the front and lateral teeth of the maxilla, as well as above the eye. The temporalis muscle is no doubt also of great significance as regards the genesis and treatment of tense headaches. The injection is generally given extraorally and predominantly in the anterior part. 3550 U Botox/150200 U Dysport can be distributed in a fan shape by administering one or two intramuscular injections at different points in accordance with the maximum pain on pressure. The front insertion of the muscle should be avoided because of its vicinity to the orbicularis oculi and the position of the temporalis blood vessels taken into account (fig. 5).
Medial Pterygoid Muscle
The medial pterygoid muscle runs along the inside of the mandible, similarly to the masseter muscle, from the pterygoid fossa to the angle of the
von Lindern
48
mandible. Although this muscle often causes pain in cases of dysfunction, it should only be included in BTX therapy with very great caution. On account of its exposed location in close proximity to the muscles of the floor of the mouth, the pharynx and the larynx, side effects, such as speech and swallowing disorders, must be expected, even at low doses. If appropriate, a maximum of 5 U Botox/20 U Dysport can be injected immediately at the insertion on the angle of the mandible.
Lateral Pterygoid Muscle
The lateral pterygoid muscle is likewise divided into two parts and originates on the pterygoid lamina. The upper part runs towards the head of the mandible and inserts in the capsule, with some fibres radiating directly into the anterior suspensory ligament of the articular disk. It is thus assigned the function of tensioning and guiding the disk during jaw movement. The lower, much stronger part inserts directly on the condyle and is mainly responsible for protrusive movement of the mandible. Dysfunctions of the lateral pterygoid muscle are to be found in all forms of hypermobility disorders. These are generally accompanied by extensive protrusion and a tendency of the condyle to sublux. This can cause not only pain, but also, in the medium term, disk displacement with cracking joints and, in extreme cases, recurrent, fixed dislocation of the temporomandibular joint. Functional disorders are often to the fore when treating the lateral pterygoid muscle with BTX-A. Above all, neurogenically induced dislocation of the temporomandibular joint in cases of disease of the motor pathways can be treated very successfully. In cases of painful myopathy of the masticatory muscles, injecting the lateral pterygoid muscle should always be considered if the case history and the clinical findings primarily reveal extreme bruxism and/or extensive protrusion of the mandible. The injection should always be given extraorally and monitored by EMG. To this end, the lateral pterygoid muscle is located on an imaginary line from the middle of the tragus to the infraorbital margin, approximately 33.5 cm in the anterior direction at a depth of approximately 2.53 cm. The patient is then requested to perform protrusive movements with the mandible. After recording the muscle potentials, between 35 and 50 U Botox/150 and 200 U Dysport are injected simultaneously with the help of a Teflon-coated injection needle (fig. 6, 7). The resultant partial denervation becomes apparent after approximately 68 days in the form of a reduced protrusion tendency of the temporomandibular joint and, thereafter, by an approximately 1 cm reduction in mouth opening. As in the case of the other masticatory muscles, the patient already perceives a noticeable reduction in pain after 35 days.
49
Fig. 6. Injection of the lateral pterygoid muscle simultaneous with EMG.
Fig. 7. EMG for simultaneous injection of the lateral pterygoid muscle.
Other Muscle Groups
In many cases, the BTX injection has to be extended to other facial and, in particular, pericranial and cervical muscles, in order to exploit corresponding synergistic effects. The appropriate injection points and dosages for the nuchal and cervical muscles can be found in the relevant chapters. It must generally be emphasized that the BTX injection must be adapted to the needs of the individual patient in terms of the type of injection and the dosage administered. The case history and the clinical findings of the patient
von Lindern
50
are important parameters in this context. Standardized injection schemes must be rejected, since they do not do justice to the individual patient and the treatment is thus doomed to failure before it starts. As the effect of the toxin differs between individuals, a low dose should always be administered in the first injection. All intramuscular injections should be performed after sufficient skin disinfection and with repeated aspiration. For intraoral injection, brief insertion of a CHX swab in the envisaged injection area will suffice. Although many scientific studies in the field of pain research have already confirmed a clearly positive effect of local BTX injection, it has not yet been registered in Europe and America for headache and facial pain or pericranial pain syndromes. In view of the enormous scientific efforts in evidence-based neurological research, BTX-A could perhaps be approved for headache in the medium term. For this reason, the treatment of myogenic facial pain with BTX can and must continue to constitute an alternative treatment in refractory patients. An alternative treatment is defined as the use of a method that is not yet established, but gives the affected patient the prospect of a cure, an improvement or some other benefit. It is a treatment and thus to be rated as such in terms of liability law. A new method is only justified if conventional methods are not suitable for reliably bringing about therapeutic success. The newer and less tested the method is, the greater the amount of information that has to be given to the patient. In this context, every patient must be informed, both verbally and in writing, about the treatment, the risks and alternatives, as well as the possible costs before being given the injection. Pre-printed information and consent form has proven effective for this purpose in clinical practice.
Analgesic Effect of Botulinum Toxin Type A
Targeted injection of BTX-A not only leads to direct attenuation of these muscular contractions. An improvement in aerobic muscle metabolism has also been discussed. In the medium term, the chemical partial denervation results in disuse atrophy of the affected muscles, which in turn counteracts the aetiological causes [1719]. In macroscopic terms, the masseter muscle can be reduced by half, both clinically and in animal experiments. In microscopic terms, there is a change in the myofibrils, muscle cells and neuromuscular end-plates, similar to the changes following axotomy. These changes are entirely reversible after approx. 3 months [18]. In addition, an effect of BTX on muscle fibre afferences is seen, which is in turn said to lead to a central reduction of muscle contraction.
51
More recent studies show that the above mechanisms alone cannot explain the analgesic effect of BTX and that a far more complex mechanism of action can be assumed. The muscle-relaxing property of BTX can enable decompression of afferent nociceptive neurons and muscular blood vessels in cases of myogenic pain syndromes. A mechanism of action involving the sensory muscle functions is also apparent [19, 20]. This means that central afferent and efferent control mechanism of muscular activity can also be modulated and reorganized, which could also explain effects in areas outside the injected muscle [21]. Clinical experience also confirms these complex mechanisms of action, since the improvement in the pain symptoms often begins before complete chemical denervation of the muscles and the patients also report improvements in other, adjacent muscle groups. In addition, BTX is assumed to have a direct inhibitory effect on neurotransmitters. It has been demonstrated that BTX directly inhibits Substance P from trigeminal nerve endings, which is a potent neurotransmitter in the activation of neurogenic inflammations. Aoikis group [22] was additionally able to demonstrate a direct anti-inflammatory effect of BTX in formalin-induced arthritis in the rat model. Although not all the analgesic mechanisms of action of BTX have yet been explained conclusively, it can still be said in summary that the local injection of BTX in refractory patients with painful myalgia of the masticatory and facial muscles constitutes an innovative and efficient method for reducing pain. An improvement in the pain symptoms can be observed in approximately 80% of cases.
References
1 2 3 4 5 6 7 8 9 10 Schwartz LL: Temporomandibular joint syndrome. J Prosth Dent 1957;7:489499. Franks AST: The social character of TMJ dysfunction. Dent Pract 1964;15:94100. Gross D: Multifaktorielle Therapie des chronischen Kopfschmerzes; in Gross D, Frey R (eds): Schmerzstudium 5: Kopfschmerz. Stuttgart, Fischer, 1981, pp 250257. Laskin DM: Etiology of pain-dysfunction syndrome. J Am Dent Assoc 1996;12:147153. Nishioka GJ, Montgomery MT: Masticatory muscle hyperactivity in temporomandibular disorders: Is it an extrapyramidally expressed disorder? J Am Dent Assoc 1988;116:514520. Reich RH, Rossbach A: Erscheinungsformen muskulrer Hyperaktivitt im Kiefer und Gesichtsbereich. Dtsch Zahnrztl Z 1988;43:1116. Schulte W: Zur funktionellen Behandlung der Myoarthropathien des Kauorgans. Ein diagnostisches und physiotherapeutisches Programm. Dtsch Zahnrztl Z 1970;25:422436. Graber G: Was leistet die funktionelle Therapie und wo findet sie ihre Grenzen? Dtsch Zahnrztl Z 1985;40:165169. Brin MF, Blitzer A, Green PE, Fahn S: Botulinum toxin for the treatment of oromandibulolingual dystonia. Ann Otol Rhinol Laryngol 1989;89:9397. Brin MF: Interventional neurology: Treatment of neurological conditions with local injection of botulinum toxin. Arch Neurobiol 1991;54:173189.
von Lindern
52
11 12 13 14 15 16 17
18 19 20
21 22
Childers MK, Wilson DJ, Galate JF, Smith BK: Treatment of painful muscle syndromes with botulinum toxin: A review. J Back Musculoskelet Rehabil 1998;10:8992. Kunig G, Pogarell O, Oertel WH. Facial pain in a case of cranial dystonia: A case report. Cephalagia 1998;18:709711. Freund B, Schwartz M, Symington JM: The use of botulinum toxin for the treatment of temporomandibular disorders: Preliminary findings. J Oral Maxillofac Surg 1999;57:916920. Freund B, Schwartz M, Symington JM: Botulinum toxin: New treatment for temporomandibular disorders. Brit J Oral Maxillofac Surg 2000;38:466471. von Lindern JJ, Niederhagen B, Appel T, Berg S, Reich RH: Die Behandlung muskulrer Hyperaktivitt der Kaumuskulatur mit Botulinumtoxin Typ A. Dtsch Zahnrztl Z 2000;55:2629. von Lindern JJ: Typ A botulinum toxin in the treatment of chronic facial pain associated with temporomandibular dysfunction. Acta Neurol Belg 2001;101:3941. Capra NF, Bernanke JM, Porter JD: Ultrastructural changes in the masseter muscle of Macaca fascicularis resulting from intramuscular injection of botulinum toxin type A. Arch Oral Biol 1991;36:827836. Filippi GM, Errico P, Santarelli R, Bagolini B, Manni E: Botulinum A toxin effect on jaw muscle spindles. Acta Otolaryngol (Stockh) 1993;113:400404. Guyer BM: Mechanism of botulinum toxin in the relief of pain. Curr Rev Pain 1999;3:427431. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, Shimizu K: Presynaptic effects of botulinum toxin type A on the neuronally rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106109. Rosales RL, Arimura K, Takenaga S, Osame M: Extrafusal and intrafusal muscle effects in experimental botulinum toxin A injection. Muscle Nerv 1996;19:488496. Cui M, Aoki R. Botulinum toxin A reduces inflammatory pain in the rat formalin model. Cephalalgia 2000;20:41.
Jens-Jrg von Lindern, MD, DMD Department of Oral and Maxillofacial Surgery, University of Bonn, Sigmund-Freud-Strasse 25, D53105 Bonn (Germany) Tel. 49 228 2872452, Fax 49 228 2872406, E-Mail vonlindern@mkgchirurg.de
53
Pain in Cervical Dystonia

Frank J. Erbguth
Department of Neurology, City Hospital Nuremberg, Germany
Outline of Cervical Dystonia
Definition Cervical dystonia (CD) is defined as an involuntary turning and/or twisting of the head and neck caused by abnormal muscle contractions. The disease is sometimes also referred to as spasmodic torticollis, but this term does not adequately reflect the dystonic nature of the disease [13]. Epidemiology CD is the most common form of adult-onset focal dystonia with an estimated prevalence of 6090 cases per million [4, 5]. Some authors presume even higher prevalence rates. Women are affected in all series 1.52 times more than men. The average age of onset is in the early 40s [13, 6]. Aetiology In the 1960s, CD was claimed as a psychiatric or psychosomatic disorder (conversion neurosis) resulting from castration anxiety or from symbolizing a turning away from problems [7]. The disease meanwhile is viewed as an extrapyramidal brain disorder. True psychogenic torticollis is an exceedingly rare condition. Most cases are idiopathic. There is some anecdotal data with few case reports of patients with CD secondary to an underlying systemic (e.g. Wilsons disease) or focal (e.g. tumour, encephalitis, stroke) extrapyramidal disease. There is no clear evidence that a proportion of adult-onset CD is genetically determined. However, focal dystonias are now being analysed in the light of the knowledge of genetic abnormalities in generalized dystonia [8]. Familial CD as other focal dystonias may be caused by an autosomal dominant gene with reduced
penetrance. There is a controversial discussion on the role of trauma for the development of CD [911]. Studies which underline the important role of the afferent sensory system in dystonia suggest that painful sensory inputs resulting from trauma may lead to central nervous motor dysfunction. Dopamine receptorblocking pharmacotherapy with neuroleptics, metoclopramide or the calcium channel blocker flunarizine may cause a tardive form CD. The most frequent presentation of tardive CD is retrocollis. Symptoms Symptoms usually begin within days or weeks, with patients complaining of a pulling or drawing in the neck or an involuntary twisting or jerking of the head. Accompanying pain leads in some patients to the incorrect diagnoses of degenerative cervical radiculopathy. CD is classified according to different deviation patterns: (1) rotational or rotatory torticollis with rotation of the chin around the longitudinal axis is the most frequent type, present in over 50% of patients; (2) laterocollis or lateral head tilt with a movement of the ear to the shoulder, and (3) anterocollis and retrocollis with deviations of the head in the sagittal plane towards the chest (forward flexion) or the back (neck extension). Some unusual variants include lateropulsion with sideway shift of the head or propulsion with forward shift of the head. In complex forms of CD these deviation patterns may be combined and show variable head positions. In about 15% of patients tremulous presentations occur with jerky tremor of the head, usually in a no-no fashion. Extracervical dystonic or otherwise extrapyramidal movement disorder manifestations are found in up to 33% of patients with CD [12]. Sensory tricks (geste antagonistique) in CD by touching the head, face or chin are helpful in a majority of patients but tend to lose effectiveness as the disease progresses [13]. Other symptom-alleviating manoeuvres include leaning the head against something in the back. Depression is also a common feature of CD causing sometimes the misdiagnosis of psychogenic dystonia. Jahanshahi [14] documented depression in 24% of patients with CD. Pain (see below: The Role of Pain in Cervical Dystonia) which is most frequently located in the neck is a major source of discomfort in CD and contributes significantly to disability [15]. It is present in about 7080% of patients at some time of the illness [13, 6, 12, 13]. In most cases, pain is associated with muscular spasms and localized at the hypercontracting muscles of the neck. However, to some degree, pain may increase independently of the involved dystonic muscle regions due to the development of spondylosis with resulting radiculopathy and/or myelopathy. Though some patients with blepharospasm or writers cramp complain of local pain, the high incidence of pain distinguishes CD from nearly all other types of focal dystonia.
55
Natural Course and Prognosis About 15% of patients may experience some degree of remission, typically in the first few months or years. Younger age is the only consistent predictor of a possible remission. However, the majority of those with remissions relapse within the next 37 years and then develop permanent CD. While the majority of patients with CD has a stabile clinical course after 25 years of development, some patients present with a symptom progression with increasing severity and/or increasing complexity of the abnormal movement pattern and/or with a spread of dystonia to other body regions [16]. Diagnosis A first step must exclude non-dystonic causes of an abnormal head and neck posture such as lesions of cranial nerves, the cervical spine or the cerebellum or brain stem and posterior fossa. If a dystonic nature of the abnormal movement pattern is revealed, in a second step, secondary dystonia should be excluded. Early-onset Parkinsons disease or other causes of parkinsonism (e.g. corticobasal degeneration) should be ruled out. The history should focus on additional neurological complaints or drug-induced torticollis (e.g. neuroleptics) and the neurological examination should search for associated abnormal corticospinal, cerebellar, sensory, oculomotor or cortical signs which may result from a neurological illness causing secondary CD. However, a secondary cause of CD is only rarely found: in the study of Duane [3] of more than 1,000 patients, not a single case of Wilsons disease was found and a central nervous system tumour was uncovered in only 2 patients. If the clinical presentation of adultonset CD is definitely clear there is no need for further extensive investigation. Nevertheless, in patients under the age of 50 it is advisable to exclude Wilsons disease by measurement of serum copper and caeruloplasmin, by search for Kayser-Fleischer corneal rings and by a slit-lamp examination [17]. An imaging study of the brain with CT or MRI should be performed at least once during the course in each patient. Additionally, in cases with a fixed painful neck posture, an MRI of the cervical spine should be performed. Treatment Options Apart from Botulinum Toxin (BTX) The era prior to BTX was characterized by the relative ineffectiveness of therapeutic measures. BTX has become the first-line treatment of CD. Pharmacological Therapy Apart from BTX, medical treatment options are poor. With different oral pharmacotherapies, up to 40% of patients are reported to have some degree of benefit [17, 18]. Different approaches to influence the neurotransmitter system were tried, such as anticholinergic, dopaminergic, antidopaminergic,
Erbguth
56
anticonvulsive medications. Other substances focus on the muscle relaxation such as benzodiazepines or baclofen. Appropriate prospective controlled studies are very rare, and some positive data exist for anticholinergics and tetrabenazine. However, reports specifically evaluating anticholinergics in CD have found them unhelpful [19] and producing more adverse effects and resulted in less efficacy than BTX [20]. Surgical Therapy A variety of surgical techniques involving lesioning of muscles, nerve roots, nerves or central nervous system structures (thalamotomy, pallidotomy) have been suggested [21, 22]. Peripheral denervation procedures designed to denervate dystonic muscles selectively are the most widely practised surgical procedures. In cases with a secondary BTX treatment failure due to antibody formation, a selective peripheral denervation should be considered. It is difficult to predict which patients are the best candidates for this operation, although there is an impression that those with rotatory CD and/or a marked past response to BTX are most likely to benefit [23]. Operations on muscles are obsolete; thalamotomy or pallidotomy were historical approaches which should be reserved only for cases with severe generalized dystonia. Most recently, deep brain stimulation in cases with generalized or CD has shown promising results [24].
The Role of Pain in Cervical Dystonia
The high incidence of pain distinguishes CD from nearly all other types of dystonia and is a major source of discomfort and disability in CD [15]. In nearly all studies, pain is present in about 60% of patients at presentation and in about 80% at some time during the illness. Our own series revealed pain in 124 out of 180 patients [6]. Pain usually affects the neck and/or shoulder region (fig. 1). In most CD patients, pain is localized at the hypercontracting muscles of the neck. Pain may also result from the development of spondylosis with radiculopathy and/or myelopathy due to the permanent dysbalance in head position or from mechanical traction on musculoskeletal structures [25]. Aching pain and paraesthesia may radiate into the arm and hand. These brachial symptoms have been termed radicular but they frequently do not conform to segmental dermatomes, and reflex and motor signs are absent. Although the neck and shoulder pain is usually of muscular origin, some patients have midline posterior neck pain with tenderness on spinal concussion. This seems to be more skeletal of origin and may be secondary to the muscle spasms and abnormal head posture.
57
Fig. 1. MRI of painful and hypertrophic neck muscles ipsilateral to the head rotation (arrow) in a patient with CD.
Chawda et al. [26] evaluated the pattern of premature degenerative changes of the cervical spine in patients with CD. In 14 of 34 patients, moderate or severe degenerative changes were detected. They were predominantly found at the C2/C3 and C4/C5 levels and were significantly more likely to occur on the side of the head deviation. However, there was no significant difference in pain severity between the groups with either no or minimal changes and the group with moderate or severe changes. Inadequate treatment was found to be the most important predictor for the development of degenerative changes. Patients with degenerative changes responded poorly to selective peripheral denervation. Only few studies have focused especially on pain in CD. The study by Kutvonen et al. [27] assessed 39 patients with CD for the presence, location and quality of pain, as well as for the correlation between pain and postural abnormality. Muscle tenderness was evaluated by manual palpation and pressure algometry. Measurements were made on muscles either actively maintaining or opposing abnormal head posture, as well as on muscles not contributing to it. Control measurements were made in 18 healthy subjects. Two-thirds of patients reported continuous or intermittent recurrent pain. Pain was reported as widespread and diffuse over the neck and shoulders, with some radiation, predominantly on the side toward which the head was twisted. There were no differences between study groups when compared for pressure algometry and only moderate differences when compared for manual palpation. No correlation was found between the severity of posture abnormality and pain. Degenerative changes seen on X-rays were similar in painful and pain-free patients. The authors conclude that
Erbguth
58
pain associated with spasmodic torticollis does not arise in muscles alone, and hypothesize that central mechanisms may also be involved. The study conducted by Tarsy and First [28] assessed pain and its response to BTX retrospectively. 75% of the 72 patients who were mailed a questionnaire had painful CD. Of the 35 questionnaires suitable for analysis 91%, had painful CD. Only 57% of the non-analysable group had pain. The location of pain was most frequently in the neck (100%), followed by the shoulder (73.5%), lower back (29.4%), upper back (17.6%) and arm (14.7%). Neck pain was localized as follows: right posterior 56.3%; left posterior 34.5%; bilateral posterior 6.2%; right anterior 3.1%, and left anterior 0.0%. Maximal neck pain was significantly more frequently ipsilateral (71.8%) than contralateral (28.2%) to the side of head deviation (tilt, turn, or both). The most common quality of pain was aching (43.8%) followed by pulling (34.3%), burning and tightness (9.4% each), and other (3.1%). A sensory trick improved torticollis in 59.4% of patients but reduced pain in only 26.6% of patients. Common sensory tricks that reduced torticollis included touching the face or chin with the fingers or repositioning the neck. By contrast, sensory tricks or manoeuvres that reduced pain consisted of physically supporting the neck or lying down. The 14.7% incidence of arm pain indicated that radiculopathy was a less frequent cause of pain, whereas the 73100% neck and shoulder involvement suggested the greater importance of local musculoskeletal causes. In contrast, Jankovic et al. [9] found that 31.5% of patients with CD experienced radicular pain, whereas 68.5% experienced local pain. In most patients with CD the sternomastoid muscle contributes greatly to abnormal head deviation and becomes hypertrophied secondary to excessive contraction. The sternomastoid is involved contralaterally in all cases of rotational torticollis and ipsilaterally in most cases of laterocollis. If the pain is primarily muscular in origin, the anterior sternomastoid muscle, which strongly contributes to the abnormal head deviation, would be expected to be a frequent location of pain. However, only 3.1% of the patients in the study by Tarsy and First [28] reported anterior cervical pain compared with 96.9% who reported posterior cervical pain. The authors claimed that the sternomastoid muscle was not a significant source of pain because in the majority of patients maximal neck pain was located ipsilaterally to the side of head deviation. The location of pain posteriorly and ipsilaterally to the side of head deviation reported by most patients indicates that pain probably originates from posterior cervical muscles or their skeletal attachments, while sternomastoid contraction does not seem to be painful. These findings are similar to those cited by Kutvonen et al. [27], who also found that neck pain in patients with CD was asymmetric, involving primarily the splenius capitis and trapezius muscles with relatively little cervical radicular
59
pain. However, the studies do not clarify whether posterior cervical pain originates from muscle, tendon, or periosteal attachments. Chan et al. [1] raised the possibility that a higher density of deep pain receptors in neck muscles may account for the unique association of pain with CD.
Treatment of Cervical Dystonia with Botulinum Toxin
Effects on Pain Pain improved in all open and controlled BTX trials in CD, in which pain was assessed, with the exception of the study by Koller et al. [29] in which pain was not mentioned. In the controlled studies with Botox and Dysport, between 63% [30] and 88% [31] of patients reported pain improvement that was statistically significant compared with placebo; in the open studies the range of pain response was between 65% [32] and 90100% [33]. In the two controlled studies with Neurobloc there was also a significant pain relief [34, 35]. The comparability of different studies is limited because some authors expressed pain reduction as the mean percentage of pain reduction in the BTX group while others assessed the percentage of patients who improved substantially with regard to pain severity. In addition, some authors reported the same patients several times by publishing results with escalating patient numbers. A summary of the studies with respect to pain relief is given in table 1. Some of the studies are commented as follows: The first pilot study of the effective use of local injections of BTX (Oculinum Botox) in 12 patients with CD was published in 1985 by Tsui et al. [36]. In 1986 the authors presented the first prospective placebo-controlled trial with BTX and developed a rating scale to measure changes in posture and a scale for pain assessment [31]. 19 patients were treated with BTX and placebo and showed objective and subjective improvement. Pain relief occurred in 14 of the 16 patients with pain and was more significant than the objective improvement of head posture and the subjective global severity score. Interestingly, the global subjective rating scale correlated significantly with improved posture, but not with reduced pain. In the double-blind, placebo-controlled study by Greene et al. [37], group means of pain relief were analysed and Botox reduced the mean magnitude of pain by 63%, which was statistically significant in comparison with the placebo group. In the study of Lorentz et al. [30], pain was effectively reduced in the Botox group. On the other hand, transient local pain was one of the major side effects of the injections (see below: Pain as a Side Effect of BTX Injections in CD). Similarly, the study by Gelb et al. [39] reported 16 patients with pain improvement but the total number of patients with pain and the number with pain improvement in the placebo group were not given.
Erbguth
60
Table 1. Summary of the studies with respect to pain relief Group (first author) Design Number of patients (BTX group) Mean dose Pain response (%) (in DB studies vs. placebo)
Botox Tsui, 1986 [31] Gelb, 1989 [39] Perlmutter, 1989 [42] Greene, 1990 [37] Lorentz, 1991 [30] Jankovic, 1987 [43] Jankovic, 1990 [44] Jankovic, 1990 [33] Brin, 1987 [45] Comella, 1992 [46] Koller, [29] Boghen, 1993 [32] Dysport Stell, 1988 [40] Blackie, 1990 [38]
DB DB DB O DB DB O O O O DB O O DB
19 20 21 34 21 5 205 195 28 52 29 32 10 19
100 280 100 118 150 170 209 209 276 374 150 75280 1,200 960
88 vs. 24 80 vs. n.g./ m.r. 50% Significant m.r. 63% 63 vs. 5 n.g. 76 93 74 86 n.g. 65 100 75 vs. 13 (pain score pre post 6.1 3.3) 77 78 n.g. 68 91 84 85 80 84.7; m.r. 83.9% 80 82.6 87.0 significant significant not
Blackie, 1990 [38] Ceballos-Baumann, 1990 [47] Moore, 1991 [48] Lees, 1992 [49] DCosta, 1991 [50] Poewe, 1992 [51] Wissel, 1992 [52] Brans, 1995 [20] Erbguth, 1996 [6]
O O DB O O O O O O
50 45 20 89 12 37 108 60 Total 180 Dosis 1: 15 Dosis 2: 83 Dosis 3: 82 109 77
875 692 1,000 666 520 632 594 240 1,000 750 500 5,000/10,000 10,000
Neurobloc, Myobloc Brashear, 1999 [34] Brin, 1999 [35] DB given.
DB DB
Double-blind study; O
open-label study; m.r.
mean pain reduction; n.g.
61
In the first double-blind, placebo-controlled trial with the UK-manufactured toxin Dysport, Stell et al. [40] reported a significant improvement of head position and a 100% reduction of pain. After the controlled phase the trial was continued in an open fashion. In 39 patients with pain there was a benefit by 77% of treatment periods. In the study of Blackie and Lees [38], 12 of 16 patients (75%) had pain improvement after Dysport and pain severity scores improved from a mean of 6.1 to 3.3 (010 scale) in the Dysport group, but this was not statistically analysed. In our own trial [6], 105 of the 124 patients (84.7%) with pain prior to the Dysport injection reported pain relief of more than 70% of the pre-treatment level. The mean degree of pain reduction was 83.9% (SD 22.9). Two large multicentre double-blind studies were published for BTX type B [34, 35]. In the first study, BTX-B was studied in patients who had previously responded well to BTX-A. In the second study, antibody carriers against the type A toxin were injected with BTX-B. Improvement occurred in pain reduction as well as for global disease burden measured by the TWSTRS Scale. Based on the TWSTRS pain scores, BTX-B produced a dose-dependent reduction in pain. In the first study, mean improvements from baseline to week 4 were 0.5, 3.6 and 4.2 for the placebo, 5,000 MU and 10,000 MU groups, respectively. In the second study they were 0.1 and 3.6 for the placebo and 10,000 MU groups respectively. All differences were significant compared with placebo. BTX-B also improved mean values for the pain VAS assessment. Patients had less pain compared with their pre-treatment status [41]. It is apparent from these studies that improvement of pain associated with CD is a major advantage of BTX injections. More recent studies have addressed pain relief in particular. All 32 patients in the above-mentioned study by Tarsy and First [28] who experienced pain prior to BTX treatment reported relief of pain following treatment. Mean pain severity was significantly lower during the month following BTX treatments than prior to initial treatment and did not return to baseline by the time of follow-up treatments. Pain never returned to pre-treatment levels in 59.4% of patients. With respect to duration of pain, the majority of patients had pain more than 75% of the time before initial treatment and less than 50% of the time during the first month after injection. The finding that pain was relieved more satisfactorily than torticollis in 23.5% of patients is consistent with previous observations that pain is frequently more BTXresponsive than abnormal head posture. In summary, the authors concluded that pain associated with CD was responsive to BTX, did not return to baseline levels prior to follow-up treatment, did not originate from sternomastoid muscle, and probably, originated from posterior cervical muscles or their skeletal attachments.
Erbguth
62
In the retrospective study by Kelm et al. [53], 85.7% of the 35 patients with CD reported pain; of those, 96.7% reported pain reduction after the BTX injection. Pain scores of the TWSTRS Scale (05) were 3.6 before injection, 1.5 four weeks after injection and 2.7 twelve weeks after injection. Mechanisms of Pain Reduction with BTX During the first years of BTX therapy in CD the pain relief was simply attributed to the muscle-relaxing effect of BTX. However, some of the abovementioned observations of the characteristics of pain reduction in CD prompted speculation on a direct influence of BTX on pain mediation in addition to the inhibition of acetylcholine release [53]. Pain responds (1) in most cases before the movement abnormality is reduced, (2) sometimes better than muscle tension and (3) sometimes even in low doses which do not improve head deviation. In the cited study by Tarsy and First [28], for example, significant reductions in pain sometimes occurred significantly earlier than improvements in head posture. The alleviation of muscle pain by BTX is thought to occur due to an effect on the release of nociceptive neuropeptides, among which substance P seems to have a key function. A recently reported small open study by Relja and Klepac [54] used three different doses of Botox in 31 patients. Pain relief outweighed the degree of motor benefit and BTX injection resulted in significant improvement in pain associated with CD. The major benefit of BTX treatment for pain reduction compared with dystonia improvements was the duration of action and the lower beneficial dose. Even a small dose of BTX (50 MU of Botox) significantly reduced pain without any change in muscle activity and TWSTRS Scale score. The authors concluded that BTX may have a direct antinociceptive effect distinct from its influence on the muscle-relaxing properties. However, there are few pilot studies which failed to detect a direct antinociceptive effect of BTX in humans. Its efficacy in various pain syndromes must therefore be explained by other pathways [55, 56]. An antinociceptive effect of BTX is supported by some experimental data [5759]. Attractive, and to some degree justified, as such considerations may be, they have to be proved by experimental and further clinical studies focusing on this item. Pain as a Side Effect of BTX Injections in CD Local pain as a possible side effect after BTX injections is reported in up to 38% of patients [6, 30, 60]. Although the injections themselves may be perceived to be uncomfortable (particularly in deeper muscles) and injectionrelated pain sometimes persists for some days, none of the patients of our series has stopped treatment for this reason.
63
Practise of Injection with BTX
Pre- and Post-Injection Assessment of CD For the evaluation of BTX therapy in CD, many different subjective and objective rating scales have been used. Some studies used very simple subjective rating scales based on global impression or global severity rating. For research purposes as well as for the clinical use, objective scales provide some advantage. The objective Tsui Scale [31] was used most often in the beginning of BTX treatment and grades severity and amplitude of postural deviance, duration of spasms, and presence or absence of tremor. Other scales include the Comella et al. modification of the Burke-Fahn-Marsden Dystonia Scale, the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Columbia Torticollis Rating Scale [6163]. These rating scales are commonly used to compare CD before and after therapy and in some studies the patients were videotaped for later scoring by a blinded observer. Functional Anatomical Considerations The following muscles are most frequently involved in the dystonic pattern in CD: Sternocleidomastoid muscle: Rotation of chin to the opposite side in rotational torticollis. Pulling of the head towards the ipsilateral shoulder in laterocollis. Propulsion of the head forward in propulsion patterns and pulling of the chin downwards in antecollis. Splenius capitis muscle: Rotation of the head in the ipsilateral direction. Tilt of the head in ipsilateral position in laterocollis and backward extension of the head in retrocollis. Levator scapulae muscle: Elevation of ipsilateral shoulder and tilt or rotation of the neck in laterocollis and rotational torticollis. Trapezius muscle: Elevation of shoulder and pulling of the neck ipsilaterally in laterocollis and backward extension in retrocollis. In rotatory torticollis it may in concern with the contralateral splenius rotate the head to the contralateral side. Semispinalis capitis muscle: Neck extension in retrocollis contributes also to ipsilateral tilt in laterocollis or to contralateral rotation in rotational torticollis. Anterior neck muscles such as longus colli, longus capitis, rectus capitis are deep-seated and pull the chin downward or forwards in antecollis or propulsion. Those muscles are not easy to inject with BTX. Infrahyoid and suprahyoid muscles are mainly involved in speech, swallowing and respiration, but spasms of these muscles may contribute to antecollis.
Erbguth
64
Platysma spasms may contribute to abnormal head posture by pulling the chin downward in antecollis or pull the head laterally and downward in combinations of ante- and laterocollis. Injection Technique Identification of Muscles Muscles requiring BTX injections are identified clinically according to the following criteria: deviation pattern of head and neck, painful areas, individual provocation situations and detection of muscle hyperactivity or tenderness by inspection and palpation. Many experienced users find EMG-guided injections not necessary for the selection of muscles for routine cases. However, few studies suggested that EMG-guided injections result in a greater magnitude of improvement or lower doses needed than injections based solely on clinical examination [46]. Especially deeper neck muscles may be difficult to be injected clinically with sufficient accuracy. Dose Equivalence between the Three Commercially Available BTX Preparations Although theoretically Mouse Units of the three available toxins or at least of the two type A toxins should be more or less identical, dose ratios derived from clinical experience between Botox, Dysport and Neurobloc in the treatment of CD are about 100200 MU Botox 500 MU Dysport 5,00010,000 MU Neurobloc, which means a mean conversion ratio of 1:3.5:75. Two studies with direct comparisons between the two type A products in CD suggested a dose equivalence Botox:Dysport of about 1:3.5, but were spoiled by some methodological problems [64, 65]. Some authors claimed that with Dysport a higher injection volume or the addition of albumin allows a 1:1 ratio in comparison with Botox [66, 67]. Doses and Injection Sites The selected total dose is diluted with normal saline to 25 ml. Many experts use as initial total dose 100250 MU of Botox or 500 MU of Dysport or 5,00010,000 MU of Neurobloc [68]. Recommended starting doses for a single muscle are given in table 2. However, the injection must consider anatomical and functional aspects of the patient e.g. normal or thin neck and must be tailored individually. Subsequent doses are modified according to the response. Single or multiple injections seem to result in similar rates of improvement. One trial found more favourable improvement from the multiple site approach [69].
65
Table 2. Dose recommendations (MU) for various muscles in CD Muscle Botox Dysport Neurobloc Number of injection sites (1) 24 24 24 24 24 26 24
Sternomastoid Scalenus complex Splenius capitis Semispinalis capitis Longissimus capitis Trapezius Levator scapulae
3050 3050 5070 3070 3070 3070 3070
150200 50150 300 100300 100200 200300 150300
1,0003,000 1,0003,000 1,0005,000 1,0005,000 1,0005,000 1,0005,000 1,0004,000
Response Benefit. As indicated above, it can be concluded from the trials and from clinical experience, that there is a 90% chance of some improvement and a 75% chance of substantial improvement. However, patients should be told beforehand that the posture rarely becomes completely normal and some spasms often persist. The mean time to onset of response is 47 days after injection and to peak benefit 2 weeks. Median duration of significant benefit is 1016 weeks, with most patients reporting fairly rapid decline of effect over the subsequent 13 weeks. Therefore, re-injection is usually required every 3 months, although some patients benefit for longer periods. Complex patterns and antecollis are the torticollis variants which sometimes show lower response rates. Adverse Effects. Apart from local pain, the following side effects may occur: Dysphagia is the most common and potentially troublesome side effect and its incidence was reported between 6 and 90%. To some degree it occurs in about 15% of patients [6, 60]. Dysphagia is probably caused by direct diffusion of toxin through fascial boundaries to the pharyngeal muscles and is more likely after injections of one or both of the sternomastoid muscles. Dysphagia develops about 410 days after the injection and typically persists for 2 weeks. Other side effects are less worrying and include dry mouth (highest rates with the type B BTX of about 50%), dysphonia (6%), some degree of neck weakness (especially after bilateral injections of neck muscles) (1560%). Influenza-like symptoms and a brachial neuritis occur extremely rare. All side effects wear off within a few days or weeks. Up to 8% of patients become resistant due to the formation of antibodies [6, 70]. Secondary Non-Response due to Antibody Formation. About 510% of patients with BTX injections in CD may develop antibodies. Clues to possible antibody formation are a marked fall-off in response and an absence of side
Erbguth
66
effects without any other adequate explanation such as inadequate injection technique, increased complexity of dystonic pattern or inadequate patients expectations. Short inter-treatment intervals (booster injections) have been identified as a risk factor for antibody development [71]. In case of antibody formation against the type A preparations, toxin type B offers an effective new treatment option for continuing the treatment with BTX. However, there are some anecdotal reports that type A secondary non-responders may subsequently develop antibodies against the type B toxin as well.
References
1 2 Chan J, Brin MF, Fahn S: Idiopathic cervical dystonia: Clinical characteristics. Mov Disord 1991; 6:119126. Duane DD: Spasmodic torticollis: Clinical and biological features and their implications for focal dystonia; in Fahn S, Marsden CD, Calne DB (eds): Advances in Neurology. New York, Raven Press, 1988, vol 50, pp 473492. Duane DD: Spasmodic torticollis; in Jankovic J, Tolosa E (eds): Advances in Neurology. New York, 1988, vol 49, pp 135150. Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ: Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988;3:188194. Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group: A prevalence study of primary dystonia in eight European countries. J Neurol 2000;247:787792. Erbguth F: Das Krankheitsbild der zervikalen Dystonie (Torticollis spasmodicus). Regensburg, Roderer Verlag, 1996. Mitscherlich M: Spasmodic torticollis. Psychother Psychosom 1971;19:6275. Namath AH: The genetics of primary dystonias and related disorders. Brain 2002;125: 695721. Jankovic J, Leder S, Warner D, Schwartz K: Cervical dystonia: Clinical findings and associated movement disorders. Neurology 1991;41:10881091. Jankovic J: Can peripheral trauma induce dystonia and other movement disorders? Yes! Mov Disord 2001;16:712. Weiner WJ: Can peripheral trauma induce dystonia? No! Mov Disord 2001;16:1322. Rondot P, Marchand MP, Dellatolas G: Spasmodic torticollis Review of 220 patients. Can J Neurol Sci 1991;18:143151. Tsui JKS: Cervical dystonia; in Tsui JKS, Calne DB (eds): Handbook of Dystonia. New York, Dekker, 1995, pp 115127. Jahanshahi M: Psychosocial factors and depression in torticollis. J Psychosom Res 1991;35: 493507. Hilker R, Schischniaschvili M, Ghaemi M, Jacobs A, Rudolf J: Health-related quality of life is improved by botulinum neurotoxin type A in long-term treated patients with focal dystonia. J Neurol Neurosurg Psychiatry 2001;71:193199. Lowenstein DH, Aminoff MJ: The clinical course of spasmodic torticollis. Neurology 1988; 38:530532. Dauer WT, Burke RE, Greene P, Fahn S: Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 1998;121:547560. Greene P, Shale S, Fahn S: Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord 1988;3:4660. Lang AE, Sheehy MP, Marsden CD: Anticholinergics in adult-onset focal dystonia. Can J Neurol Sci 1982;9:313319. Brans JW, Lindeboom R, Snoek JW, Zwarts MJ, van Weerden TW, Brunt ER: Botulinum toxin versus trihexyphenidyl in cervical dystonia: A prospective, randomised, double-blind controlled trial. Neurology 1996;46:10661072.
3 4 5 6 7 8 9 10 11 12 13 14 15
16 17 18 19 20
67
21 22 23 24 25 26
27 28 29 30
31 32 33
34
35
36 37
38 39 40 41 42 43 44
Maccabe JJ: Surgical treatment of spasmodic torticollis; in Marsden CD, Fahn S (eds): Movement Disorders. 2. London, Butterworths, 1987, pp 308314. Putnam TJ, Herz E, Glaser GH: Spasmodic torticollis. III. Surgical treatment. Arch Neurol Psychiatry 1949;3:240247. Braun V, Richter HP, Schrder JM: Selective peripheral denervation for spasmodic torticollis: Is the outcome predictable? J Neurol 1995;242:504507. Volkmann J, Benecke R: Deep brain stimulation for dystonia: Patient selection and evaluation. Mov Disord 2002;17(suppl 3):S112S115. Waterston JA, Swash M, Watkins ES: Idiopathic dystonia and cervical spondylotic myelopathy. J Neurol Neurosurg Psychiatry 1989;52:14241426. Chawda SJ, Mnchau A, Johnson D, Bhatia K, Quinn NP, Stevens J, Lees AJ, Palmer JD: Pattern of premature degenerative changes of the cervical spine in patients with spasmodic torticollis and the impact on the outcome of selective peripheral denervation. J Neurol Neurosurg Psychiatry 2000;68:465471. Kutvonen O, Dastidar P, Nurmikko T: Pain in spasmodic torticollis. Pain 1997;69:279286. Tarsy D, First ER: Painful cervical dystonia: Clinical features and response to treatment with botulinum toxin. Mov Disord 1999;14:10431045. Koller W, Vetere-Overfield B, Gray C, Dubinsky R: Failure of fixed-dose, fixed muscle injection of botulinum toxin in torticollis. Clin Neuropharmacol 1990;13:355358. Lorentz IT, Subramaniam SS, Yiannikas C: Treatment of idiopathic spasmodic torticollis with botulinum toxin A: A double-blind study on twenty-three patients. Mov Disord 1991;6: 145150. Tsui JKC, Eisen A, Stoessl AJ, Calne S, Calne DB: Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;ii:245247. Boghen D, Flanders M: Effectiveness of botulinum toxin in the treatment of spasmodic torticollis. Eur Neurol 1993;33:199203. Jankovic J, Schwartz K, Donovan DT: Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633639. Brashear A, Lew MF, Dykstra DD, Comella CL, Factor SA, Rodnitzky RL, Trosch R, Singer C, Brin MF, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M: Brashear safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology 1999;53:14391446. Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, OBrien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999;53:14311438. Tsui JKC, Eisen A, Mak E, Carruthers J, Scott AB, Calne DB: A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 1985;12:314316. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E: Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 1990; 40:12131218. Blackie JD, Lees AJ: Botulinum toxin treatment in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1990;53:640643. Gelb DJ, Lowenstein DH, Aminoff MJ: Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis. Neurology 1989;39:8084. Stell R, Thompson PD, Marsden CD: Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1988;51:920923. Trosch R: Botulinum toxin type B decreases pain in patients with cervical dystonia. Pain Med 2001;2:253. Perlmutter JS, Tempel LW, Burde R: Double-blind, placebo-controlled, crossover trial of muscle activity following botulinum A toxin for torticollis. Neurology 1989;39:352. Jankovic J, Orman J: Botulinum toxin for cranial-cervical dystonia. A double-blind, placebocontrolled study. Neurology 1987;37:616623. Jankovic J, Schwartz K: Botulinum toxin injections for cervical dystonia. Neurology 1990; 40:277280.
Erbguth
68
45
46
47
48 49 50 51 52 53 54 55
56
57
58
59
60 61 62 63 64
65
66
Brin MF, Fahn S, Moskowitz C, Friedman A, Shale HM, Greene PE, Blitzer A, List T, Lange D, Lovelace RE, McMahon D: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237254. Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz CG: Botulinum toxin injections for spasmodic torticollis: Increased magnitude of benefit with electromyographic assistance. Neurology 1992;42:878882. Ceballos-Baumann AO, Konstanzer A, Dengler R, Conrad B: Lokale Injektionen von Botulinumtoxin A bei zervikaler Dystonie: Verlaufsbeobachtungen an 45 Patienten. Aktuel Neurol 1990;17:139145. Moore AP, Blumhardt LD: A double-blind trial of botulinum toxin a in torticollis, with one year follow-up. J Neurol Neurosurg Psychiatry 1991;54:813816. Lees AJ, Turjanski N, Revest J, Whurr R, Lorch M, Brookes G: Treatment of cervical dystonia, hand spasms, and laryngeal dystonia with botulinum toxin. J Neurol 1992;239:14. DCosta DF, Abbott RJ: Low-dose botulinum toxin in spasmodic torticollis. J R Soc Med 1991; 84:650651. Poewe W, Schelosky L, Kleedorfer B, Heinen F, Wagner M, Deuschl G: Treatment of spasmodic torticollis with local injections of botulinum toxin. J Neurol 1992;239:2125. Wissel J, Poewe W: Dystonia A clinical, neuropathological and therapeutic review. J Neural Transm 1992;38:91104. Kelm S, Gerats G, Chalkiadaki A, Hefter H: Reduktion von Schmerzen und Muskelanspannung durch Botulinum-Toxin A. Nervenarzt 2001;72:302306. Relja MA, Klepac N: Different doses of botulinum toxin A and pain responsiveness in cervical dystonia. AAN Abstracts, 2002, Poster P06.124. Krmer H, Angerer C, Erbguth F, Schmelz M, Birklein F: Botulinum toxin A reduces neurogenic flare but has almost no effect on cutaneous pain and hyperalgesia in humans. J Neurol 2002 (in press). Schulte-Mattler WJ, Blersch W, Przywara S, May A, Bigalke H, Wohlfarth K: Botulinum toxin A and the cutaneous nociception in humans (abstract). Naunyn Schmiedebergs Arch Pharmacol 2002;365(suppl 2):R39. Cui M, Chaddock JA, Rubino J, Khanijou S, et al: Retargeted clostridial endopeptidase: Antinociceptive activity in preclinical models of pain. Naunyn Schmiedebergs Arch Pharmacol 2002; 365(suppl 2):R16. Cui M, Li Z, You S, Khanijou S, Aoki KR: Mechanisms of the antinociceptive effect of subcutaneous Botox: Inhibition of peripheral and central nociceptive processing. Naunyn Schmiedebergs Arch Pharmacol 2002;365(suppl 2):R17. Moulsdale HJ, Hall Y, Kirby ER, et al: Retargeted endopeptidase-dependent inhibition of neurotransmitters from neurons involved in nociception. Naunyn Schmiedebergs Arch Pharmacol 2002;365(suppl 2):R85. Ceballos-Baumann AO: Evidence-based medicine in botulinum toxin therapy for cervical dystonia. J Neurol 2001;248(suppl 1):I/14I/20. Consky ES, Lang AE: Clinical assessments of patients with cervical dystonia; in Jankovic J, Hallett M (eds): Therapy with Botulinum Toxin. New York, Dekker, 1994, pp 211237. Lindeboom R, Brans JW, Aramideh M, Speelman HD, De Haan RJ: Treatment of cervical dystonia: A comparison of measures for outcome assessment. Mov Disord 1998;13:706712. Tarsy D: Comparison of clinical rating scales in treatment of cervical dystonia with botulinum toxin. Mov Disord 1997;12:100102. Oldergren T, Hjaltason H, Kaakkola S, et al: A double-blind, randomised, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment in cervical dystonia. J Neurol Neurosurg Psychiatry 1998;64:612. Ranoux D, Gury C, Fondarai J, Mas JL, Zuber M: Respective potencies of Botox and Dysport: A double-blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002;72:459462. Laubis-Herrmann U, Fries K, Topka H: Low-dose botulinum toxin a treatment of cervical dystonia: A double-blind, randomized pilot study. Eur Neurol 2002;47:214221.
69
67
68
69 70 71
Rollnik JD, Matzke M, Wohlfarth K, Dengler R, Bigalke H: Low-dose treatment of cervical dystonia, blepharospasm and facial hemispasm with albumin-diluted botulinum toxin type A under EMG guidance. An open label study. Eur Neurol 2000;43:912. Poewe W, Deuschl G, Nebe A, et al for the German Dystonia Study Group: What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia. Results of a double-blind, placebo-controlled dose-ranging study using Dysport. J Neurol Neurosurg Psychiatry 1998;64:1317. Borodic GE, Pearce LB, Smith K, Joseph M: Botulinum toxin for spasmodic torticollis: Multiple vs. single injection points per muscle. Head Neck 1992;1:3337. Singer C, Shulman LM, Parra A, Weiner WJ: Analysis of variables affecting botulinum toxin response in spasmodic torticollis (abstract). Ann Neurol 1994;36:317. Dressler D, Munchau A, Bhatia KP, Quinn NP, Bigalke H: Antibody-induced botulinum toxin therapy failure: Can it be overcome by increased botulinum toxin doses? Eur Neurol 2002;47: 118121.
Prof. Dr. med. Dipl. Psych. Frank Erbguth Department of Neurology, City Hospital Nrnberg, Breslauer Strasse 201, D90471 Nrnberg (Germany) Tel. 49 911 3982491, Fax 49 911 3983164, E-Mail erbguth@klinikum-nuernberg.de
Erbguth
70
Treatment of Painful Dystonia with Botulinum Toxin

Markus Naumanna, Birgit Herting b
Departments of Neurology, University of aWrzburg and bDresden, Germany
Dystonia is a neurological syndrome characterized by involuntary muscle contractions that may be sustained (tonic), spasmodic (rapid or clonic), irregular or repetitive. The increased muscle activity causes abnormal postures including twisting (e.g. torticollis), flexion or extension (e.g. anterocollis, retrocollis, writers cramp), adduction or abduction. Muscle spasms may involve any voluntary muscle and are frequently associated with pain in affected muscle groups. Painful muscle spasms occur in all forms of primary focal dystonia including cervical dystonia, limb, axial and oromandibular dystonia. Painful dystonic contractions can also be one of the leading symptoms in Parkinsons disease, other atypical parkinsonian syndromes such as corticobasal degeneration, progressive supranuclear palsy and multiple system atrophy, and in complex regional pain syndrome. This chapter summarizes the role of botulinum toxin (BTX) in the management of dystonia-associated pain and provides treatment strategies.
Pain in Primary Dystonia
Pain is a well-known phenomenon in focal upper and lower limb, axial, and oromandibular dystonia and may even be the leading symptom of the disease in some cases. Typical postures of upper limb dystonia are elevation, extension, abduction or internal rotation of the shoulder, elbow extension, and wrist and finger flexion or extension. At the lower limb, knees are extended, the foot plantar flexed and inverted, and toes flexed or extended. Axial dystonia typically presents with extension of the trunk. While the effect of BTX on pain has been evaluated in several studies in cervical dystonia, only limited information is available on its effect in other parts of the body.
Limb Dystonia Marsden and Sheehy [1] described the characteristics of writers cramp in 91 patients. Only 13% (12/91) of them reported pain but many more complained about tension or discomfort in the fingers, forearm, and even in the upper arm and shoulder. They observed that pain in writers cramp did not only arise from increased muscle tone but may also be due to carpal tunnel syndrome in 7% (6/91) of their patients which occurred after an interval of 120 years. Turjanski et al. [2] reported 45 patients with occupational cramps of whom 17 had mild, 7 moderate, and 7 severe pain. All were treated with BTX injections for a mean period of 12 (range 348) months. Improvement of writing and reduction of pain were rated using self-assessment scales. Patients reported a significant improvement of pain after 62% of treatment sessions. In 16 patients who remained on BTX treatment with a mean follow-up of 21 (range 348) months, improvement of pain was present after 79% of the treatment sessions. In a prospective open label study, Pullman et al. [3] injected 187 patients with limb disorders (136 with dystonia, 37 with parkinsonian, essential, and cerebellar tremors, and 14 with spasticity) with BTX-A. BTX-A injections relieved pain, independent of motor function, in 82.7% of patients with painful muscle spasms. The management of focal dystonia of the extensor hallucis longus muscle with BTX injections was described by Sherman et al. [4] in a patient with severe painful foot dystonia with sustained extension of the great toe. Two weeks after the injection into the extensor hallucis longus muscle, the patient was symptom-free and could place her left foot into a shoe. There is only little information on pain in musicians cramp. Newmark and Hochberg [5] identified 57 instrumental musicians with a focal dystonia of the hand (or arm) among a population of 450 musicians with occupational upper limb complaints. All had painless interference in manual coordination (fig. 1a,b, 2, 3). Axial Dystonia Truncal extension dystonia manifests by involuntary back arching and is often associated with pain and severe motor disability. Comella et al. [6] evaluated the effect of BTX-A in 4 women and 1 man with severe idiopathic (2 patients) or tardive (3 patients) truncal and cervical dystonia in a singleblind study. BTX-A was injected into the paravertebral muscles of the lumbar region. Particularly pain secondary to dystonia improved substantially in all patients.
Naumann/Herting
72
a Fig. 1. Idiopathic focal hand dystonia with predominant finger flexion (a) or finger extension (b).
Fig. 2. Idiopathic foot dystonia with painful flexion of D 15.
Oromandibular Dystonia Oromandibular dystonia presenting as jaw-opening or jaw-closing dystonia may be associated with discomfort and pain in hyperactive jaw muscles. Although no studies on the effect of BTX-A on oromandibular dystonia-associated pain are available, it is the common clinical experience that pain can be reduced by local injection of the toxin into affected jaw muscles.
Treatment of Painful Dystonia with BTX
73
Fig. 3. Idiopathic foot dystonia with equinovarus position of the right foot.
Painful Dystonia in Parkinsonian Syndromes
Parkinsons Disease Foot dystonia (fig. 4) including the so-called striatal toe with painful extension of the hallucis longus muscle is a well-known symptom of patients with Parkinsons disease (PD). Some patients may develop a striatal hand which is characterized by excessive flexion of the fingers at the metacarpophalangeal joint and proximal and distal interphalangeal joints. Foot dystonia may be observed in early stages of untreated PD, but occurs more frequently in advanced stages of PD in connection with chronic levodopa therapy. It predominates on the side most affected by parkinsonism and can be very painful. In advanced PD, foot dystonia is related to levodopa intake and may occur during the on phase (peak dose dystonia; onset and end-of-dose dystonia) or the off phase (late night or early morning dystonia). Pain arises from sustained muscle contractions mostly of lower leg muscles, predominantly muscles of the dorsal compartment such as the tibial posterior muscle. The upper extremity is only rarely involved. If painful dystonic muscle spasms cannot be controlled sufficiently by modification of drug dosing and timing, BTX-A may be a very useful treatment option for this severely disabling condition.
Naumann/Herting
74
Fig. 4. Painful focal foot dystonia in a patient with PD (equinovarus position and striatal toe on the right side).
Pacchetti et al. [7] reported 30 patients with PD (22 men, 8 women) with off painful dystonia (OPD) of the foot who were treated with BTX-A. BTX-A was injected into the tibialis posterior, tibialis anterior, gastrocnemius, flexor digitorum longus, and extensor hallucis longus muscles. In all patients, pain improved within 10 days, whereas in 21 patients, pain completely disappeared for 4 (range 37) months; a concomitant improvement of dystonic spasms was also observed.
Atypical Parkinsonian Syndromes
Focal or segmental painful dystonia may be part of the clinical spectrum of various atypical parkinsonian syndromes. In contrast to PD, it is frequently not related to levodopa intake. Up to 50% of patients with progressive supranuclear palsy (PSP) exhibit clinical signs of focal dystonia presenting as blepharospasm, axial dystonia, limb dystonia or hemidystonia. Particulary, limb dystonia can be painful in PSP. In corticobasal degeneration (CBD), a frequently fixed and painful dystonic posture of one or both upper limbs belongs to the hallmarks of the disease. Focal dystonia may also be present in patients suffering from MSA. Recently, Mller et al. [8] evaluated the efficacy of BTX-A treatment in patients with atypical parkinsonian disorders associated with disabling focal dystonia. They observed that BTX-A treatment of limb dystonia in CBD
75
Fig. 5. Hand dystonia in a patient with corticobasal degeneration.
temporarily improved hand and arm function in early disease stages while treatment in advanced stages reduced pain, facilitated hygiene and prevented secondary contractures. This confirms our personal experience in 5 patients with advanced CBD and painful dystonic contractions where only the injection of BTX-A into painful forearm muscles markedly improved pain without improvement of hand function. Vanek and Jankovic [9] reported their findings about contractures and pain in CBD patients. In dystonia patients, 29 (74%) had fixed postures, and 24 (62%) had evidence of fixed contractures. Contractures mainly affected the joints of the upper extremity, mostly the wrist and the fingers (fig. 5). Pain was seen in 16 (42%) which was present in the dystonic hand. In their series of 6 patients who were treated with local BTX-A injections into dystonic and painful muscles, 2 had marked improvement of dystonia and pain, and 4 had mild to moderate improvement. In another small series of 9 patients reported by Kompoliti et al. [10], 6 experienced improvement of dystonia and pain after BTX-A injections.
Painful Dystonia in Complex Regional Pain Syndrome
Complex regional pain syndrome (CRPS) is characterized by sensory, autonomic and motor features that occur spontaneously, after trauma, or in the setting of neurological or rheumatic disease. The accompanying motor abnormalities include dystonia, tremor and other involuntary movements. The dystonia is tonic, has a predominant involvement of flexors, and initiates on the distal extremities. It may progress to involve proximal extremity, axial, cervical and facial muscles. Dystonia of the upper extremity is typified by fingers fixed in flexion, or the clenched-fist syndrome. Dystonia in the lower extremity often
Naumann/Herting
76
Fig. 6. Hemidystonia in a patient with CRPS. Involvement of the right upper extremity (clenched fist), trunk, and lower leg (equinovarus position).
presents as an equinovarus position of the foot. Range of movement may be compromised on the affected side, and contractures may develop in severe cases. Spread of dystonia may finally result in a very painful and functionally disabling hemidystonia (fig. 6). Cordivari et al. [11] treated 4 patients with CRPS-associated dystonia with BTX-A and obtained inconsistent results. While 3 of them had relief of pain, functional and posture improvements were observed in a single patient only. We injected 2 patients with severe painful hemidystonia repeatedly over a period of 2 years at 3-month intervals. Finger flexors, wrist flexors and the tibialis posterior muscles were treated. Pain in the forearm and lower leg markedly and consistently improved after BTX-A injections. There was only minimal improvement of hand function and no improvement of gait due to fixed contractions at the ankle [Naumann, unpubl. data].
Rare Forms of Painful Dystonia
Various basal ganglia lesions may lead to painful dystonia. In these cases, dystonia may be associated with other movement disorders such as spasticity or athetosis (fig. 7). Motoi et al. [12] reported a 67-year-old woman who developed severe pain and dystonia in her left upper and lower extremity after
77
Fig. 7. Painful dystonic-athetoid hand posture after thalamic nucleus lesion.
a thalamic infarction (thalamic posture of the left hand, pronation of the left forearm with flexion at the elbow joint, extension in the knee joint and plantar flexion in the ankle joint of the left lower extremity). A few days after BTX-A injection into the biceps brachii, triceps brachii and wrist flexors, both dystonic posture and pain markedly improved. The author suggested that BTX-A could be useful for post-hemiplegic painful dystonia. An overview over the BTX treatment of non-occupational limb and trunk dystonia of different etiology was given by Quirk et al. [13]. A total of 18 clinical problems were identified (e.g., difficulty in walking due to painful dorsiflexion of the toe, foot inversion and clawing toes; painful involuntary movements of the upper limb or back muscles; abnormal postures). Outcomes were assessed in terms of pain relief and improvement in posture and function as rated by both the patient and the physician. Reduction in pain was achieved in 9 of 10 painful problems, with a relief in 4 cases (idiopathic focal foot dystonia, post-stroke lower limb dystonia, congenital hemiplegic dystonia, hemorrhagic infantile hemiplegia with hemidystonia).
Treatment
BTX injections are the treatment of choice in any forms of focal dystonia with and without pain. Standard medications for dystonia such as anticholinergics (i.e. trihexyphenidyl), baclofen or benzodiazepines are usually not very
Naumann/Herting
78
Table 1. Dose ranges for BTX-A in oromandibular dystonia [modified from 14] Muscle M. masseter M. temporalis M. pterygoideus internus M. pterygoideus externus M. digastricus Dose (units) Botox 1550 540 1035 2.520 Dose (units) Dysport 60200 20160 40160 1080
Table 2. Dose ranges for BTX-A in upper limb dystonia [modified from 14] Muscle Deltoid Pectoralis major Extensor carpi radialis Extensor carpi ulnaris Extensor digitorum communis Adductor pollicis longus Flexor carpi radialis Flexor carpi ulnaris Flexor digitorum superficialis/profundus Flexor pollicis longus Dose (units) Botox 5075 3075 1030 1030 515 (per fascicle) 1025 2050 1540 1020 (per fascicle) 1020 Dose (units) Dysport 200300 120300 40120 40120 2040 (per fascicle) 40100 80200 60160 4080 (per fascicle) 4080
effective but may be considered in selected cases as an adjunct therapy to BTX. A trial of levodopa should be considered when dopa-responsive dystonia is possible, especially for dystonia beginning in the leg. Before BTX is injected, the following steps have to be considered: (1) identification of overactive muscles; (2) selection of overactive muscles for injection; (3) choosing the dose; (4) injection, and (5) follow-up. After identification of the overactive painful muscles, choosing the muscles for injection requires a detailed clinical examination before treatment with BTX. The location of any muscular discomfort and palpation of painful muscles can be a clue to injecting the appropriate muscles. For the first injection, take a typical starting dose (tables 13) and modify it according to several factors. These include the degree of muscle overactivity, the size of the muscle, and the patients likely tolerance of excessive weakness of the muscle. Usually, patients with primary dystonia do not tolerate major muscle weakness which would interfere with function, while patients with fixed dystonic
79
Table 3. Dose ranges for BTX-A in lower limb dystonia [modified from 14] Muscle Tibialis anterior Extensor digitorum longus Extensor hallucis longus Peroneus longus Gastrocnemius Flexor hallucis longus Flexor digitorum longus Tibialis posterior Flexor digitorum brevis Dose (units) Botox 75100 5080 2050 4080 50100 2050 3050 50100 1030 Dose (units) Dysport 300500 200300 80200 160300 200400 80200 120200 200400 4080
contractions and restricted motor skills as frequently observed in CRPS or CBD primarily benefit from pain reduction despite even major muscle weakness. In general, it is recommended to begin with a relatively low dose because excessive weakness could discourage the patient from continuing with treatment. Diffusion increases with volume and hence with dilution. In primary dystonia, injection demands highly accurate placement. Therefore, injections are given with a needle that can also record EMG or deliver electrical stimuli. In other dystonic syndromes where no functional benefit can be expected, injections can be given without EMG guidance. Depending on the effect of the initial injection, the dose can be modified in consecutive injections until an optimal treatment effect is achieved. Re-injections should not be given within 810 weeks to minimize the risk of antibody formation. In summary, based on the clinical experience and a few small open studies, BTX is a very useful and highly effective treatment option for painful focal dystonia. Larger or even controlled studies are lacking so far. BTX is the treatment of choice in primary focal dystonia where frequently both pain and function can be improved by local injections of the toxin. In other forms of painful dystonia being part of PD, atypical parkinsonian syndromes or CRPS BTX injections should be considered after other drug treatments have failed as it may markedly improve pain despite no or only moderate functional benefit. Larger controlled studies are needed to evaluate the role of BTX in painful focal dystonia.
References
1 2 Marsden CD, Sheehy MP: Writers cramp. Trends Neurosci 1990;13:148153. Turjanski N, Pirtosek Z, Quirk J, Anderson TJ, Rivest J, Marsden CD, Lees AJ: Botulinum toxin in the treatment of writers cramp. Clin Neuropharmacol 1996;19:314320.
Naumann/Herting
80
3 4
5 6 7 8 9 10 11 12
13 14
Pullman SL, Green P, Fahn S, Pedersen SF: Approach to the treatment of limb disorders with botulinum toxin A. Arch Neurol 1996;53:617624. Sherman AL, Willick SP, Cardenas DD: Management of focal dystonia of the extensor hallucis longus muscle with botulinum toxin injection: A case report. Arch Phys Med Rehabil 1998;79: 13031305. Newmark J, Hochberg FA. Isolated painless manual incoordination in 57 musicians. J Neurol Neurosurg Psychiatry 1987;50:291295. Comella C, Shannon K, Jaglin J: Extensor truncal dystonia: successful treatment with botulinum toxin injections. Mov Disord 1998;13:552555. Pacchetti C, Albani G, Martignoni E, Godi L, Alfonsi E, Nappi G: Off painful dystonia in Parkinsons disease treated with botulinum toxin. Mov Disord 1995;10:333336. Mller J, Wenning GK, Wissel J, Seppi K, Poewe W: Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J Neurol 2002;249:300304. Vanek ZF, Jankovic J: Dystonia in corticobasal degeneration. Adv Neurol 2000;82:6167. Kompoliti K, Goetz CG, Boeve BF, Maraganore DM, Ahlskog JE, Marsden CD: Clinical presentation and pharmacological therapy in corticobasal degeneration. Arch Neurol 1998;55:957961. Cordivari C, Mistra P, Catania S, Lees A: Treatment of dystonic clenched fist with botulinum toxin. Mov Disord 2001;16:907913. Motoi Y, Hattori Y, Miwa H, Shina K, Mizuno Y: A case of post-hemiplegic painful dystonia following thalamic infarction with good response to botulinum toxin. Clin Neurol 1997;37: 881886. Quirk JA, Sheean GL, Marsden CD, Lees AJ: Treatment of nonoccupational limb and trunk dystonia with botulinum toxin. Mov Disord 1996;11:377383. Moore AP, Naumann M (eds): Handbook of Botulinum Toxin Treatment. Oxford, Blackwell Science, 2003.
Markus Naumann, MD, Assist. Prof. Neurology, Department of Neurology, University of Wrzburg, Josef-Schneider-Strasse 11, D97080 Wrzburg (Germany) Tel. 49 931 20124621, Fax 49 936 7980388, E-Mail naumann@mail.uni-wuerzburg.de
81
Botulinum Toxin in Tension-Type Headache

Wolfgang H. Jost a, Hartmut Gbel b
a
Department of Neurology and Clinical Neurophysiology, German Clinic of Diagnostics, Wiesbaden, bKiel Pain Clinic, Kiel, Germany
Tension-type headache (TTH) is the most common form of cephalalgia. Its pathogenesis is not clear, an interplay of vascular, myofascial and supraspinal compounds is most probable. It is felt that myofascial stimuli might trigger the headache. Therapeutic accomplishments are limited in the chronic type. Application of botulinum toxin (BTX) is helpful when the pericranial muscles are involved. It reduces stress, muscular ischemia and muscle tone. We do not know whether additional mechanisms are involved as well. Both frequency and intensity of the headaches are lessened by BTX. Major unwanted effects are unlikely. The ideal dose and best-suited injection sites have not yet been established, an individual set-up injection scheme is thus most promising (follow the pain). Injection into the trigger points obviously makes sense.
Classification
Etiopathogenetic classification criteria apart, the classification for headache disorders, cranial neuralgias and facial pain of the International Headache Society (IHS) [1] is formally oriented along the phenomenologic criteria gained from history. According to the IHS classification, headache disorders are divided into a total of 13 major categories and approximately 165 subcategories (table 1). Primary (idiopathic) headache disorders are etiologically distinguished from secondary (symptomatic) ones. Whereas in primary headaches we cannot identify any pathologic organic changes that account for the pain, secondary headaches are usually a symptom of provable organic pathology or substance abuse.
Table 1. Classification for headache and migraine, International Headache Society (IHS) and WHO (ICD10-NA) Headache classification Main categories Migraine Tension-type headache Cluster headache and chronic paroxysmal hemicrania Miscellaneous headaches unassociated with structural lesion Headache associated with trauma Headache associated with vascular disorder Headache associated with nonvascular intracranial disorder Headache associated with substances or their withdrawal Headache associated with non-cephalic infection Headache associated with metabolic disorder Headache or facial pain associated disorder of cranium, neck, eyes, nose, sinuses, teeth, mouth or other facial or cranial structures Cranial neuralgias, nerve trunk pain and deafferentation pain Headache not classifiable IHS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. ICD-10-NA G43.9 G44.29 G44.09 G44.80 G44.88 G44.81 G44.82 G44.4 resp. G44.83 G43.88 G44.88 G44.84G G44.88G R51
Definition
From the criteria of the IHS, TTH is characterized by mostly bilateral dull pressing to pulling pain, not pulsating, mildly to fairly severe intense, and not aggravated by physical activities. Vegetative symptoms are absent or insignificant as compared with migraine for instance. Further differentiation of episodic or chronic TTH according to the IHS criteria centers around the presence of absence of impairment of the pericranial muscles (see below). Increased tenderness of the pericranial muscles can be verified by manual palpation or via pressure algometer, increased EMG activity can be recorded as well (see below).
Epidemiology
Headaches are the most frequent pain symptom there is and may rightfully be termed a popular disease. It is responsible for more than 10 million annual calls on doctors. Every 10th patient complains of considerable or severe headaches, which have even been growing in recent years [2]. In Germany, too, headaches have surpassed fatigue, backaches and neck pain as the most common symptom.
83
TTH (episodic) 38%
Others
Cluster headache 0.1% Migraine with aura 4%
TTH (chronic) 23% Migraine without aura 24%
Fig. 1. Headaches, lifetime prevalence.
Following representative studies, which in contrast to earlier studies have applied the IHS criteria consequentially, [3, 4] we must assume a lifetime prevalence 70% for all headaches. The far greater percentage, 90%, is taken up by two primary headache disorders according to the IHS criteria, without clinically evident organic pathology. Tension headache with a lifetime prevalence of about 3540% unrelated to sex [4] is the most frequent form of episodical headache [46]. The other third is reserved to migraine with and without aura. Females are overrepresented in this headache group based on its gender-related prevalence. The remaining 163 forms of headaches according to IHS classification amount to 8% (fig. 1). Tension type headache is the most common form of headache, the episodical variant prevailing in more than one third of the population, while chronic tension type headache is found in about 3% [47]. Women are more frequently afflicted [4, 6]. The prevalence increases with advancing age.
Etiopathogenesis
Etiology and pathogenesis of TTH have to date not been elucidated in full. It strikes as highly complex occurrence. A genetic component is most likely. First-grade relatives of patients with chronic TTH present with a 3 times higher risk of developing TTH as well [8, 9].
Jost/Gbel
84
The neurotransmitter involved to whatever degree has not yet been identified. Definite disturbances in the serotonin metabolism could not be verified in chronic TTH [10] as had been possible for migraine. The therapeutic effects of serotonin uptake inhibitors (SSRI) have overall been disappointing. Involvement of the noradrenergic system is suggested in one study by the efficacy of the central 2-adrenergic agonist tizanidine, since elevated plasma levels of 3-methoxy-4-hydroxyphenyglycol (MHPG) consistent with increased central noradrenergic activity had been found in TTH patients [11]. Decreased plasma catecholamines have been described on the other hand [12]. Phenomena have also been noted with endogenous opioids, and increased inactivation of endorphins was discussed [13]. That TTH is related to emotional factors has widely been recognized, with considerably divergent views regarding the degree and interdependence. It is disputed in particular whether increased emotional stress is a causative element, and/or whether chronic TTH is due to depression or somatic disturbance [14]. It is postulated that these primarily emotional changes result in secondarily decreased pain thresholds, these patients will even encounter physiologic stimuli as painful. A basically depressive mood is increasingly found in such subjects, but it is not clear whether this is consecutive or causative feature. A vascular theory has been formulated for TTH in analogy to migraine. The present data do not yet permit a final judgement [15, 16]. Muscular Causes Muscular causes accounting for TTH are still most commonly discussed. A relation to myofascial pain is repeatedly demonstrated [17]. Increased muscular tension is a frequent finding, but we do not have the proof that this increased muscular tension is really the cause of headaches rather than a stress reaction owing to headaches. TTHs have therefore been subdifferentiated into forms associated with impairment of the pericranial muscles, and others unrelated to such impairment of the pericranial muscles. In the classification, a major criterion for differentiation is obtained by manual palpation or checking on the tenderness of the pericranial muscles via pressure algometer. This is a calibrated device for the mechanical induction of pain, e.g. by a stamp. Increased electromyographic activity in the pericranial muscular system at rest or during provocation tests is an additional parameter. Raised EMG activity of the pericranial muscles is, inversely, no predicator or etiological factor for the development of TTH [18]. EMG activity does not correlate with pain, stress or physical activity either, headache and stress, however, do correlate [19]. Intensive stimulation tests have been carried out following the above subdifferentiation, with the result of new pathophysiologic insights. Recent
85
studies have shown that pain sensitivity of the pericranial muscles is increased in 5065% of the patients suffering from episodic TTH. From the pathophysiologic viewpoint it is very important to distinguish between normal and impaired pericranial muscles, as it enables us to differentiate subgroups of patients, in whom headaches are generated by various pathogenetic factors. For the time being, these findings do not yet warrant to regard this subdifferentiation as binding. In more recent studies, hardness is being considered as the objective measure of muscle consistency, of the trapezius muscle in particular [20]. In chronic TTH, it is unrelated to the presence of headache and it correlates with tenderness. Tenderness is defined as the subjective pericranial muscular sensitivity on manual palpation, it is found in two thirds of the patients. With regard to pain sensitivity, 914 pericranial muscle pairs are tested by a scale from 0 to 3, from which the total tenderness score (TTS) is derived. Increased tenderness is present in 87% of the chronic patients, 67% of the episodic TTH patients, and aggravated during the period of headache [21]. There was no evidence of muscular ischemia to account for temporal tenderness in chronic TTH [22]. A comprehensive model that incorporates not only the purely peripheral muscular pathogenesis but centrally acting mechanisms as well, appears to be closer to what is really going on. The pain threshold and pain tolerance for mechanical stimuli is found to be significantly decreased in chronic TTH with pericranially increased tenderness compared with chronic TTH without aggravated tenderness. A continuous painful input of myofascial tissue is believed to sensitize the central pain-processing systems (central misinterpretation) thereby impeding the balance between peripheral input and central modulation. Muscular factors could thus play an important part in the transition from episodic to chronic TTH [23]. There is also discussion about a peripheral trigger evoking a cascade that leads to TTH [24]. It could be shown, for instance, that 69% of 58 patients with frequent TTH developed TTH within 24 h after they had been ordered to keep their mandibles pressed together for 30 min, while only 17% of the 30 controls presented with TTH after this test. The pain threshold that remained stable in the headache patients, was, however, significantly increased in the headache-free subjects. We might thus conclude that peripheral muscular components can be involved in initiating an episode of headache. The results are, on the other hand, indicative of impaired activation of the antinociceptive system in TTH patients, which is normally responsible for the counterregulation of the raised peripheral nociceptive input [25].
Jost/Gbel
86
Analyzing the pathophysiology of TTH, we cannot directly assume development of a clinical headache syndrome based on the morphologic changes in the muscle. Additional mechanisms are required, which have not been experimentally clarified in every detail. It is likely that the pathophysiologic chain is offset by initial microlesions in the muscle, in particular by choking of the muscular microcirculation. A microlesion does not necessarily result in a pathologic condition but can be compensated by repair mechanisms. Peripheral repair mechanisms in the initial period of clinical symptoms are likely to prevent later secondary changes in the central nervous system (CNS), this is therapeutically significant, and justifies the speedy intervention into the pathophysiologic mechanism. Excessive microlesions that have been present for some time and occupying space, will bring about changes in the modulation of pain in both the brain and spinal cord. Supraspinal sensitization to pain stimuli seems to be the major prerequisite for the development of chronic TTH. There may be various reasons for the increased number of microlesions in the muscle. Excessive muscular stress due to unfavorable muscular strain from external circumstances, i.e. a detrimental body position at work over a longer period of time may be involved. Stress, anxiety and other emotional factors can be contributory to or solely responsible for peripheral microlesions in the muscle via muscular tension. Muscle contraction is primarily centrally controlled, and inadequate innervation of the locomotor system related to defective central control is the main source of improper muscle function. Multiply reproducible empirical proof for this assumption is deranged behavior of antinociceptor brain stem reflexes in patients with chronic TTH [26]. We can thus conclude that an increased impulse on the brain stem structures involved in the reflex circuit is exerted by increased activation from the periphery, as it may occur owing to muscular stress or increased central efferent activity, e.g. in the form of emotional stress, depressiveness, etc. Restraint on the inhibitory brain stem neurons can be due to this increased afferent and efferent activation. These inhibiting brain stem neurons are allegedly located in the aqueductal gray and in the nucleus raphe magnus, which are felt to be in relation with the antinociceptive system. Such permanent activation with restraint of the inhibitory interneurons in the antinociceptive system may well be responsible for primary headache. Chronification Etiologic factors given, episodic TTH may also occur in subjects entirely healthy otherwise. The headache episode is consistent then with a temporary disturbance of the normal nociception and of the central mechanisms of control due to transitory unphysiologic strain. An increased peripheral nociceptive input from the overchallenged pericranial muscles (owing to excessive strain or
87
lack of rest) seems to be initially involved. Emotional factors may either contribute to increased muscular tension, or increase algesia by sensitization of peripheral and central nociceptive mechanisms. Progressive permanent sensitization in the myofascial tissue is induced by failing repair mechanisms or recurrent episodes of headache within a short period of time. Increased activation could lead to constant long-term activation of nociceptive neurons and to permanent blockade of inhibitory antinociceptive mechanisms. Permanent activation of central nociceptive neurons could thus become the basis of chronic TTH. Peripheral as well as central sensory and motor mechanisms may thus condition chronic headache in individual cases. Aggravating Factors of Chronification The IHS classification of TTHs enables us to indicate an aggravating factor. Nine different conditions of TTH are specified: (0) no aggravating factor detected; (1) more than 1 factor of the conditions listed from 29 (ranked according to significance); (2) oromandibular dysfunction; (3) psychosocial stress; (4) anxiety; (5) depression; (6) headache as a conception or idea; (7) muscular stress; (8) drug abuse (analgesics) in TTH, and (9) one of the disorders listed in groups 511 of the IHS classificaton. Chewing dysfunction (so-called oromandibular dysfunction or myarthropathy) deserves special attention in connection with BTX injection. Regulation of mandibular and masticatory movements requires most detailed and differentiating control mechanisms on the part of the CNS. Disorders of mandibular function call for permanent counterregulation from the CNS. Such disorders are noted by mandibular sounds on movement of the masticatory apparatus or by restricted motion of the mandibles. These disorders can be generated by pain on mandibular movements, or teeth grinding or consistent forceful biting. It remains completely open whether headaches are the sequela or cause of such malfunction. Interestingly enough, there is no difference between the incidence of oromandibular dysfunction in the group of people suffering from migraine, TTH, or who are not afflicted at all. Solitary symptoms of oromandibular dysfunction, however, have been observed significantly more often in patients with chronic TTH than in patients without TTH. Current pathophysiology can be summarized as follows: The picture of episodic TTH is characterized by peripheral mechanisms. The conversion to chronic TTH is enhanced by secondary central sensitization and/or impaired supraspinal modulation of nociceptive stimuli from myofascial tissue and resulting muscular tenderness. Chronic TTH is definitely marked by central alterations (reduction) of pain threshold and pain tolerance. It looks as if it just takes minor myofascial stimuli to trigger a headache.
Jost/Gbel
88
Table 2. Subgroups of TTH G44.29 Tension-type headache 2.1 Episodic TTH At least 10 recurrent episodes, duration 30 min or 7 days Less than 15 headache days/month and/or 180/year 2.1.1 With increased tenderness of the pericranial muscles 2.1.2 Without increased tenderness of the pericranial muscles 2.2 Chronic TTH Headache on at least 15 days/month for a period of at least 6 months 2.2.1 With increased tenderness of the pericranial muscles 2.2.2 Without increased tenderness of the pericranial muscles 2.3 TTH not in keeping the above criteria Any of the above criteria met with one exception Criteria with migraine without aura not met
G44.20 G44.21
G44.22 G44.23 G44.28
Symptomatology
We distinguish the episodic from chronic TTH. Episodic TTH is characterized by bilateral attacks of mild to moderate intensity, lasting from 30 min to 7 days, and occurring less than 180 times a year or 15 times a month. It is described to be pressing or dragging in character. Pain is, in essence, not enhanced by physical activity, and not associated with relevant vegetative symptoms. Photophobia or phonophobia may be present. A group with increased tenderness of the pericranial muscles is delimited in episodic TTH. Evidence of increased tenderness is furnished by palpation or via pressure algometer. Headache in chronic TTH occurs at least on 15 days/month within half a year, other than that it presents with the same diagnostic criteria like episodic TTH. Subgroups can be singled out here as well (table 2).
Diagnostic Workup
The characteristics of headache are rather unspecific and may, in principle, be present in symptomatic types of headache as well. Very diligent general and neurologic evaluation is thus mandatory in TTH. Clinical examination must include manual palpation of the pericranial muscles, and use of the pressure algometer if needed. The exclusion of organic disease is of utmost diagnostic importance.
89
Table 3. Differential diagnosis between TTH and migraine Tension-type headache Bilateral Fronto-occipital Dull-pressing (like a helmet, iron band and burden) Intensity of pain ( ) to Vegetative symptoms 0 to ( ) Physical activity no effect Migraine without aura Unilateral bilateral Fronto-temporal, temporal Knocking, hammering, pulsating Intensity of pain to Vegetative symptoms Physical activity enhances headache
The proper diagnosis of TTH requires diligent physical examination. Owing to its frequent incidence, the information provided by the patient put us on the right diagnostic track in most cases. A headache calendar kept by the patient on a regular basis is a helpful tool in the process. Additional diagnostic procedures, e.g. CT scan or MRI of the head, should only be ordered when medical findings are suggestive of other types of headache. Special attention is always called for when the patient tells us that his headaches have been changing over the past few weeks or months. This holds particularly true when both the incidence and intensity of headaches have been continuously growing. Concomitant symptoms such as muscle or joint pain, dizziness, instability of gait, fatigue, poor concentration or vomiting, must always prompt diligent physical and neurologic workup. Analgesic drug abuse in primary episodic headaches is the most common precondition in the genesis of a headache disorder compatible with chronic TTH. A headache disorder of that kind is easily identified by registering the days per month on which painkillers are used for headache. The likelihood of drug-induced and drug-supported headaches is very high if this registration reveals more than 10 days/month.
Differential Diagnosis
Migraine is the most important differential diagnosis versus TTH (see Introduction). Transitions between these two headache entities are fluent as to muscular tension, and do not constitute a per se specific criterion of distinction (table 3). Note that migraine and TTH are often jointly present in many patients. Transitions between TTH and migraine without aura are specifically discussed against the background of chronic daily headache (CDH) [27, 28]. Migraine without vegetative symptoms and not overly painful, as well as
Jost/Gbel
90
migraine with bilateral involvement can create a problem. Onset of both headache types may be similar, too. The afflicted patient is faced with the unpleasant expectation of a dreaded migraine attack developing from his dull-pressing matutinal headache. This frequently moves him or her to preventive application of an analgesic, bearing the risk of analgetically induced permanent headache. Pathophysiological and biochemical factors TTH and migraine have in common are being discussed as well [27]. Especially TTH with an occipital onset is not rarely felt to be related to the cervical spine, with the result of dilatory and fruitless diagnostic measures and therapeutic aberrations. Such symptoms should be addressed with all due caution, since degenerative processes of the cervical spine are widely spread and not correlated with TTH [29]. Neither X-ray films nor CT scan or MRI of the head or cervical spine are called for in the presence of a clear constellation and normal neurological status. Conspicuous findings, e.g. evidence of nonspecific degenerations of the cervical spine, are often misleading and tend to disconcert the patient and, occasionally, the physician as well. Problems in delimiting chronic TTH versus combined or drug-induced headache disorders must furthermore be taken into account in making a differential diagnosis. Additional differential diagnostic definitions are listed in table 4.
Therapy
Considering that a generally accepted pathophysiological concept is missing, it is understandable that empirical observation has been the basis for therapeutic approaches so far. Prior to any treatment and as a rule, the patient should be informed about his disease and the therapeutic measures suggested. A headache calendar is helpful for both patient and physician. An unfavorable lifestyle is quite common in patients with tension headache, it is marked by considerable stress factors, overstraining ones limits and defective coping with everyday chores. Short of these psychological features, we usually find faulty postural habits, lack of physical activity and unwholesome diets in those patients. This warrants a multimodality therapeutic concept, which would have to incorporate the modification of lifestyle (stop overcharging oneself, adequate physical activity, e.g. endurance training, regular daytime structures and getting enough sleep, medical behavioral measures apart. Stress coping training, biofeedback and relaxation techniques (e.g. Jacobsons progressive muscle relaxation) and cognitive approaches have proved to be beneficial.
91
Table 4. Relevant differential diagnoses in primary headache Headache Duration Migraine 472 h Tension headache Drug-induced 30 min to 7 days Lasting Cervicogenic Hours to 1 day, may become constant Cluster 15 min to 3 h
Frequency
Variable, solitary episodes to several times a week Severe to fairly severe
Episodic: 180 days/year Chronic: 180 days/year Mild to fairly severe
Daily, mostly in the morning (ergotamines) Fairly severe to mild Dull-pressing, stabbing
Related to evoking In clusters: mechanism, daily 18/24 h, mostly at night Fairly severe to severe Constant, with frequently superimposed attacks Strictly unilateral, occipital to parietal-facial Little prominent, sensation as of a lump in the throat, strain-avoiding posture of head and neck Extremely severe Terebrant, lancinating
Intensity Character
Pulsating, knocking, Dull-pressing, beating constricting
Localization Unilateral (2/3), varying sides temporal, frontal Associated symptoms Nausea, vomit, photophobia, phonophobia. Aura: (1015%): fortifications, migrating focalneurol. deficits. Need for rest, stimulus protection
Diffuse holocranial None or very little prominent
Diffuse holocranial Mild nausea, mild photo-, phonophobia. Ergotamines: vasospasms, ergotism. Analgesics: nephropathy, tumors in the urogenital tract, gastric ulcers, anemia
Strictly unilateral, (retro-) orbital Strictly unilateral: watering eyes, nasal congestion, red eyes, miosis, ptosis
Provoking factors
Stress, food, hormones
Hardly specific, Withdrawal initial, stress, after abuse of changing weather ergotamines, triptanes and other analgesics
Certain head postures with root irritation. C2/3, cough, straining
Histamines, nitrates, alcohol
Next to the prevention of muscular stress, there are active and passive physiotherapeutic measures for direct and positive intervention in the muscular system, such as (a) isometric exercises, (b) active mobility training, and (c) passive massage techniques. When muscular factors are present in TTH, isometric exercises are capable of making up for muscular stress. These exercises are easy to perform, also by
Jost/Gbel
92
the patient himself, and can be applied adjunctively in any situation. Moreover, they are not time-consuming, have an immediate good effect on the muscle, thereby making whatever job easier to handle. An obvious depression requires specific treatment. Acupuncture, acupressure and transcutaneous nerve stimulation (TENS) are frequently applied, but the effect of these methods on TTH has not yet been overly convincing. Mimical facial exercises and automassage can be helpful. Classical massages and chiropractic procedures are presently not indicated in TTH. This might change after validation of differentiating massage techniques in the future. The therapeutic specter is rounded off by application of heat and topical use of peppermint oil 10% in ethanolic solution. There is no objection to the intake of analgesics in TTH if this does not go beyond 10 days a month. Drug treatment in acute TTH is advised by acetyl salicylic acid (ASA) in a single dose of 5001,000 mg. A total of 1,500 mg ASA or paracetamol should not be exceeded. Nonsteroid antirheumatic agents such as ibuprofen (400600 mg), naproxene (5001,000 mg) are an alternative. In some cases, combination preparations may prove to be more effective than monopreparations in some cases, but in general, they are advised against. They do contain caffeine, codeine, central or peripheral muscle relaxants, antihistaminics, tranquilizers or ergotamine tartrate and/or dihydroergotamine tartrate, which may lead to dependency or abuse. Triptanes are absolutely useless in TTH. Chronic TTH should generally not be managed by analgesics because of the risk of overuse. TTHs lasting for more than 3 months or occurring every other day or daily even require prophylactic drug management on a long-term basis. Tricyclic antidepressants such as amitriptyline and amitriptyline oxide are the agents of choice followed by doxepin and clomipramine [30, 31]. Good results have also been reported with other antidepressants, with the exception of SSRIs. Good effects with antidepressants have altogether been achieved in merely 4050% of the patients (placebo rate 2025%). Adverse effects of tricyclic antidepressants, be it amitriptyline or the alternative agents doxepin and clomipramine, include dry mouth, weariness, weight gain, voiding problems in the presence of hypertrophic prostate, cardiac symptoms, allergies, glaucoma and rare epileptic fits. Good results have been reported with other substances, e.g. muscle relaxants, valproate, pizotifen, sulpiride, cyproheptadine (Peritol) and MAO inhibitors; the data available are, however, limited. Misdiagnosis, doses too low or initially too high, short duration of treatment (e.g. 13 weeks), or analgesic headache gone unrecognized are possible factors accounting for resistance to treatment. The aforementioned observation that some of the patients with chronic TTH present with clinically increased tension of the pericranial muscles has in recent years led to therapeutic trials with BTX, which was injected into these muscles.
93
Treatment with Botulinum Toxin
Indications for BTX This treatment should be considered now when the patient has verified chronic TTH, and after preventive drug treatment supported by nondrug measures have failed. Aggravating factors like oromandibular dysfunction and muscular stress foster the indication. BTX should not be used in fearful and depressive patients or in some with a history of medication overuse. In the long run it may even be indicated prior to oral drug treatment. From our experience to date, BTX injections seem to be particularly promising when there is associated pericranial muscle tenderness in chronic TTH. The indication is given in cases of: (1) refractory headache failed multiple prophylactic treatments; (2) poor compliance or inability to use oral prophylactic treatment; (3) tender spastic cervical muscle contributing to headaches; (4) detoxification from medication overuse headache, and (5) cTTH with associated pericranial muscle tenderness.
Review of Data Back in 1992 already, Binder et al. [32] found out that headaches subsided in patients who had undergone treatment of their frontal wrinkles. This was confirmed in a retrospective study on 134 patients who had received Botox injections 1240 units into the m. frontalis or m. orbicularis oculi for cosmetic reasons. The headaches of 9 patients also complaining of TTH were improved afterwards [33]. Over the following years, various work groups submitted papers on the application of BTX in TTH [24, 3450]. These studies, unfortunately, do not compare, as there are some with low doses [45] and others using a standardized vial [34, 35, 37, 47]. The selection of the muscles to be injected is highly diversified as well. While some examiners just stuck to the frontal and temporal muscles [45], others chose to distribute the toxin in many sites [43, 44, 47]. In one of the early studies by Zwart et al. [50], 6 patients had the temporal muscle treated on one side only, the result was negative, as we would expect from such a procedure. After extensive examinations with the American product Botox, we can avail ourselves of the results now, obtained with the British product Dysport [46]. The results have improved with growing experience. A number of current studies are indicative of satisfying effects [5154]. Blumenfeld [51] retrospectively rates a good outcome in 271 headache patients after 3.4 1.6 treatments. He chose a fixed site in migraine and a follow-the-pain approach in TTH. On the average, he injected 63.2 14.5 U (Botox). In his analysis, Miller [55] in turn described the efficiency of both methods.
Jost/Gbel
94
Table 5. BTX in TTH selection of some studies Group (first author) Relja [40] Gbel [36] Schulte-Mattler [46] Porta [39] Relja [43] Rollnik [44] Smuts [48] Smuts [49] Freund [35] n 10 10 8 20 27 11 22 55 21 Design 1535 U Botox, open 80 U Botox, double-blind 200 U Dysport, open, standardized 515 U/side Botox, vs. methylprednisolone 4090 U Botox 200 U Dysport, double-blind 100 U Botox, open 100 U Botox, open 100 U Botox Outcome Positive Negative Positive Positive Positive Negative Positive Positive Positive
It is noteworthy within this context that most studies included only patients refractory to the common medications. In other words, they represent a negative selection, which even uprates the outcome. Why do most of the open studies [4043, 4649] come up with positive results, whereas some double-blind studies [36, 44] have quoted negative results? This may be explained by the fact that individual injection schemes had been chosen for the double-blind studies, contrary to standardized doses and injection sites in controlled studies. The consideration of trigger points certainly plays a part as well. The most important studies are compiled in table 5. A few studies are exemplarily summed up below: (1) Freund and Schwartz [34, 35]: It is a special feature in the work of Freund and Schwartz that one of their examinations is based on chronic cervicogenic headache [34], in another publication, they interpret headache to be due to focal dystonia [35], a theory frequently stated lately. Twenty-six patients with cervicogenic headache (subsequent to cervical whiplash injury) were enrolled in a double-blind, placebo-controlled study. Fourteen patients received a fixed dose of 100 units of BTX type (Botox). Twelve patients received placebo. The duration of this trial was 4 weeks. Both head pain intensity and the range of neck motion was improved [34]. In an open retrospective study, Freund and Schwartz [35] were also able to achieve significant improvement in 18 of 21 patients with chronic TTH. They chose an individual injection scheme and 100 units each of Botox distributed to 5 injection sites representing the tender muscles. Within the framework of the study, they establish a relation between cTTH and focal dystonia. (2) Klapper et al. [37]: This study is worth mentioning owing to its very design and the fact that it deals with patients treated for chronic daily headache. Sorry to say that only the abstract has been published to date.
95
Patients received either (1) placebo only, or BTX (2) per frontal (27.5 U) and suboccipital injection (72.5 U); (3) got BTX (27.5 U) frontally and placebo suboccipitally, respectively; (4) placebo frontally and BTX suboccipitally (72.5 U). The best results were obtained in the group that received BTX per frontal and suboccipital injections. (3) Porta [39]: This study is remarkable because of two characteristics. The patients were tested against prednisolone for once. The trigger points were injected on the other hand. Porta treated 20 patients with episodic (n 7) or chronic TTH (n 13) in a randomized, single-blind comparative trial. BTX was injected plus lidocaine (n 5) versus 40 mg methylprednisolone plus lidocaine (n 5). Injections were applied to solitary tender points selected algometry among 13 possible tender points. A total of 515 U per site (mean dose 8.9 per site) was injected depending on the clinical picture. Porta [39] found an effect in both groups after 30 and 60 days, but BTX proved superior to methylprednisolone, especially after 3 months. (4) Relja [4043]: Relja has repeatedly published her results over the past 5 years. Her collectives are probably overlapping. In her first publication of 1997 [40], she describes 10 patients who had 1535 U of Botox injected into their pericranial muscles. Muscular spasm was improved in all of them 12 weeks after the injection, headaches improved as well, for up to 8 weeks. In a study published in 2001, she reports on an open-label study in which 28 patients with chronic TTH were enrolled. They received BTX type A (Botox) injections, 4090 U every 3 months for a total of 18 months. Injections were applied bilaterally to the most tender pericranial muscles. The frontal, temporal, trapezius and sternocleidomastoid muscles were individually injected after manual palpation. The outcome measure was defined as headache-free days per month. All patients were resistant to standard therapy, and 5 patients had a history of migraine. A significant decrease in headaches was overall noted in the long run. Relevant side effects did not occur. (5) Smuts [4749]: Authentic results have been submitted by Smuts and co-workers. Thirty-seven patients with cTTH were enrolled in a double-blind, placebo-controlled study. Twenty-two of them received BTX, and 15 placebo (saline). The examiners selected a defined dose (100 U Botox), spread to 12 sites including the temporal, cervical and trapezius muscles as well as the m. splenius capitis. Improvement in headache was observed in the patients treated with BTX, marked by the number of headache-free days and restored quality of life. (6) Troost [56]: In this study, 134 patients with refractory headache were treated with BTX type A (Botox) in an open-label manner. The vast majority of these patients had previously failed 3 or more pharmacologic therapies. Four categories of patients were treated: chronic daily HA (CDH) (n 98), migraine
Jost/Gbel
96
with aura (n 9), migraine without aura (n 24), and ETT (episodic TTH) (n 2). Patients were treated with injections of BTX-A in the forehead, temples, neck and shoulders. Doses were 30200 U Botox for CDH (mean 102 U) and 15240 U for migraine (mean 117 U). The medium dose per day was 100 U Botox. Across all treatments, improvement was reported by 84% of the patients, improvement rates rising with multiple treatments (appear to be progressive and may also be cumulative). This high response rate is probably due to the fact that each injection was individually tailored to the specific patient, dependent on factors such as pain, location and muscle spasm.
Injection Procedure
Dilution There is no need for great volumes as the standard dilutions are adequate. It is recommended to use 2 or 4 cm3 saline solution to a 100 U vial of Botox (0.1 ml consistent with 5 or 2.5 U). For Dysport, use 2.5 or 5 cm3 to a 500 U vial (0.1 ml consistent with 20 or 10 U). There are no adequate data for Neurobloc yet, comparable volumes are recommended for the dilution. Where and How to Inject Our present analysis of the data available does not yet permit a binding recommendation as to injection sites and dosage. From the empirical point of view, fixed injection sites are not promising in TTH. An individual injection scheme is based on the patients history, pain location (follow the pain) and transmission, lateral affliction and clinical findings. When present, do inject into the trigger points. The muscle is well palpable in most sites, an EMG is needed only in rare cases. Setting up on an injection plan has been helpful to guide oneself for future injections and to be able to pass on information to other physicians. Thin needles are well suited for injection, a 27- to 30-gauge needle can be used for frontal injections, 27-gauge needles in the neck. Keep a good distance to the m. levator palpebrae with injections in the frontal region to prevent ptosis this way. Periosteal injection, too, must be avoided because of the risk of bad pain. Dose per Muscle In order to prevent untoward effects, the dose injected per muscle should not be too high (table 6). Deviations from the recommendations listed in table 6 may be indicated in some cases. The average dose ranges from 60 to 130 U for Botox, and from 200 to 500 MU for Dysport.
97
Table 6. Dose recommendations for Botox and Dysport Muscle or site Glabella region Frontal region M. temporalis Masseter muscle Sternocleidomastoid muscle Trapezius muscle Splenius capitis muscle Rhomboid muscle Botox 12 sites 2.57.5 MU each 46 sites 1.252.5 MU each 23 sites 2.510 MU each 23 sites 520 MU each 12 sites 510 MU each 13 sites 510 MU each 13 sites 510 MU each 12 sites 510 MU each Dysport 12 sites 1030 MU each 46 sites 510 MU each 23 sites 140 MU each 23 sites 2070 MU each 12 sites 2040 MU each 13 sites 2040 MU each 13 sites 2040 MU each 12 sites 2040 MU each
Concomitant Treatment BTX injections should be part of a multimodal therapeutic concept if possible. This would include physiotherapeutic procedures as well as relaxation exercises. Psychologic pain treatment may also be called for. Costs and Reimbursement The toxin costs approximately EUR 100400 per treatment. BTX has not yet been admitted for that therapeutic purpose, and is not expected to in the nearer future.
Socioeconomical Aspects
Although TTH does not present with the dramatic impact of migraine or cluster headache, a great number of patients are temporarily unfit for work. Twenty-seven workdays are lost on the average in 12% of chronic TTH patients, 46% complain about reduced proficiency on about 20 days [5]. These data clearly demonstrate how important it is to optimize our diagnostic and therapeutic possibilities under socioeconomical aspects, more so when we know that just 16% of the patients with TTH consult their family doctor, and only 4% go to see a specialist [57]. Indirect costs would certainly be saved should the good effects in TTH be confirmed. Blumenfeld [58] was able to show in his study with 50 migraine patients that the total costs incurred could be curtailed from USD 1,020.24 to 747.19.
Jost/Gbel
98
References
1 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. Rozen TD, Swanson JW, Stang PE, McDonnell SK, Rocca WA: Increasing incidence of medically recognized migraine headache in a US population. Neurology 1999;53:14681473. Lipton RB, Goadsby P, Silberstein SD: Classification and epidemiology of headache. Clin Cornerstone 1999;1:110. Gbel H, Petersen-Braun M, Soyka D: The epidemiology of headache in Germany: A nationwide survey of a representative sample on the basis of the headache classification of the International Headache Society. Cephalalgia 1994;14:97106. Schwartz BS, Stewart WF, Simon D, Lipton RB: Epidemiology of tension-type headache. JAMA 1998;279:381383. Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiology of headache in a general population A prevalence study. J Clin Epidemiol 1991;44;11471157. Launer LJ, Terwindt GM, Ferrari MD: The prevalence and characteristics of migraine in a population-based cohort: The GEM study. Neurology 1999;53:537542. Oestergaard S, Russell MB, Bendtsen L, Olesen J: Increased familial risk of chronic tension-type headache. Br Med J 1997;314:10921093. Russel MB, Ostergaard S, Bendtsen L, Olesen J: Familial occurrence of chronic tension-type headache. Cephalalgia 1999;19:207210. Bendtsen L, Jensen R, Hindberg I, Gammeltoft S, Olesen J: Serotonin metabolism in chronic tension-type headache. Cephalalgia 1997;17:843848. Shimomura T, Awaki E, Kowa H, Takahashi K: Treatment of tension-type headache with tizanidine hydrochloride: Its efficacy and relationship to the plasma MHPG concentration. Headache 1991;31:601604. Castillo J, Martinez F, Leira R, Lema M, Noya M: Plasma monoamines in tension-type headache. Headache 1994;34:531535. Mazzotta G, Sarchielli P, Gaggioli A, Gallai V: Study of pressure pain and cellular concentrations of neurotransmitters related to nociception in episodic tension-type headache patients. Headache 1997;37:565571. Pfaffenrath V Brune K, Diener HC, Gerber WD, Gbel H: Die Behandlung des Kopfschmerzes vom , Spannungstyp. Therapieempfehlungen der Deutschen Migrne- und Kopfschmerzgesellschaft. Nervenheilkunde 1998;17:91100. Heckmann JG, Mck-Weymann M, Katalinic A, Hilz MJ, Claus D, Neundrfer B: TCD-ErgometerTest bei Patienten mit chronischem Kopfschmerz vom Spannungstyp. Nervenarzt 1998;69:131136. Hannerz J, Jogestrand T: Is chronic tension-type headache a vascular headache? The relation between chronic tension-type headache and cranial hemodynamics. Headache 1998;38:668675. Jensen R: Pathophysiological mechanisms of tension-type headache: A review of epidemiological and experimental studies. Cephalalgia 1999;19:602621. Gbel H: Die Kopfschmerzen. Heidelberg, Springer, 1997. Clark GT, Sakai S, Merrill R, Flack VF, McCreary C: Cross-correlation between stress, pain, physical activity, and temporalis muscle EMG in tension-type headache. Cephalalgia 1995;15: 511518. Ashina M, Bendtsen L, Jensen R, Sakai F, Olesen J: Muscle hardness in patients with chronic tension-type headache: Relation to actual headache state. Pain 1999;79:201205. Jensen R, Rasmussen BK: Muscular disorders in tension-type headache. Cephalalgia 1996;16: 97103. Langemark M, Jensen K, Olesen J: Temporomuscle blood flow in chronic tension-type headache. Arch Neurol 1990;47:654658. Jensen R, Bendtsen L, Olesen J: Muscular factors are of importance in tension-type headache. Headache 1998;38:1017. Wheeler AH: Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 1998;38:468471.
2 3 4
5 6 7 8 9 10 11
12 13
14
15 16 17 18 19 20 21 22 23 24
99
25 26 27 28 29 30
31
32
33 34 35 36 37 38 39 40 41 42 43 44
45
46 47
48 49
Jensen R, Olesen J: Initiating mechanisms of experimentally induced tension-type headache. Cephalalgia 1996;16:175182. Langemark M, Bach FW, Jensen TS, Olesen J: Decreased nociceptive flexion reflex threshold in chronic tension-type headache. Arch Neurol 1993;50:10611064. Goadsby PJ: Chronic tension-type headache: Where are we? Brain 1999;122:16111612. Sheftell FD: Chronic daily headache. Neurology 1992;42(suppl 2):3236. Wber-Bingl C, Wber C, Zeiler K, Heimberger K, Baumgartner C, Samec P, Wessely P: Tension headache and the cervical spine Plain X-ray findings. Cephalalgia 1992;12:152154. Gbel H, Hamouz V, Hansen C, Heininger K, Hirsch S, Lindner V Heuss D, Soyka D: Chronic , tension-type headache: Amitriptyline reduces clinical headache duration and experimental pain sensitivity but does not alter pericranial muscle activity readings. Pain 1994;59:241249. Pfaffenrath V, Diener HC, Isler H, Meyer C, Scholz E, Taneri Z, Wessely P, Zaiser-Kaschel H, Haase W, Fischer W: Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: A multi-centre controlled study. Cephalalgia 1994;14:149155. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM: Botulinum toxin type A (Botox) for the treatment of migraine headaches: An open-label study. Otolaryngol Head Neck Surg 2000;123:669676. Carruthers A, Langtry JA, Carruthers J, Robinson G: Improvement of tension-type headache when treating wrinkles with botulinum toxin A injections. Headache 1999;39:662665. Freund BJ, Schwartz M: Treatment of chronic cervical-associated headache with botulinum toxin type A: A pilot study. Headache 2000;40:231236. Freund BJ, Schwartz M: A focal dystonia model for subsets of chronic tension headache. Cephalalgia 2000;20:433. Gbel H, Lindner V, Krack P, Heinze A, Gaartz N, Deuschl G: Treatment of chronic tension-type headache with botulinum toxin. Cephalalgia 1999;19:455. Klapper JA, Mathew NT, Klapper A, Kailasam J: Botulinum toxin type A (BTX-A) for the prophylaxis of chronic daily headache. Cephalalgia 2000;20:292293. Krack P, Hornig C, Dorndorf W: Resolution of chronic tension headache after botulinum toxin treatment of idiopathic blepharospasm. Mov Disord 1995;10:388. Porta M: A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache. Curr Rev Pain 2000;4:3135. Relja MA: Treatment of tension-type headache by local injection of botulinum toxin. Eur J Neurol 1997;4(suppl 2):S71S73. Relja MA, Korsic M: Treatment of tension type headache by injections of botulinum toxin type A: Double-blind, placebo-controlled study. Neurology 1999;52:A203. Relja MA: Treatment of tension-type headache with botulinum toxin: One-year follow-up. Cephalalgia 2000;20:336. Relja MA, Klepac N: Botulinum toxin type A as a prophylactic treatment in chronic tension-type headache: Long-term follow-up study. Neurology 2001;56(suppl 3):A349A350. Rollnik JD, Tanneberger O, Schubert M, Schneider U, Dengler R: Treatment of tension-type headache with botulinum toxin type A: A double-blind, placebo-controlled study. Headache 2000;40:300305. Schmitt WJ, Slowey E, Fravi N, Weber S, Burgunder JM: Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: A double-blind, placebo-controlled trial. Headache 2001;41:658664. Schulte-Mattler WJ, Wieser T, Zierz S: Treatment of tension-type headache with botulinum toxin: A pilot study. Eur J Med Res 1999;4:183186. Smuts JA, Baker MK, Smuts HM, Rheta-Stassen JM, Rossouw E, Barnard PWA: Prophylactic treatment of chronic tension-type headache using botulinum toxin type A. Eur J Neurol 1999; 6(suppl 4):S99S102. Smuts JA, Baker MK, Smuts HM, Stassen JMM, Rossouw E, Barnard PWA: Botulinum toxin type A as prophylactic treatment in chronic tension-type headache. Cephalalgia 1999;454. Smuts JA, Barnard PWA: Botulinum toxin type A in the treatment of headache syndromes: A clinical report of 79 patients. Cephalalgia 2000;20:332.
Jost/Gbel
100
50 51 52 53
54 55
56 57 58
Zwart JA, Bovim G, Sand T, Sjaastad O: Tension headache: Botulinum toxin paralysis of temporal muscles. Headache 1994;34:458462. Blumenfeld A: Botulinum toxin type A (Botox) as an effective prophylactic treatment in headache. Cephalalgia 2002;22:20. Lin JJ, Chang DC: Efficient treatment of chronic tension-type headache with botulinum toxin A. Cephalalgia 2002;22:15. Lopez-Lozano JJ, Mata M, Dorado R, Tuduri L: Clinical study of the value of botulinum toxin A (Botox) in the treatment of chronic tension-type headache with associated pericranial muscle tenderness. Cephalalgia 2002;22:32. Padberg M, De Bruijn SFTM, Tavy DLJ: Treatment of chronic tension-type headache with botulinum toxin: A double-blind, placebo-controlled trial. Cephalalgia 2002;22:10. Miller T: Retrospective cohort analysis of 48 chronic headache patients treated with botulinum toxin type A (Botox) in a combination fixed injection site and follow-the-pain protocol. Headache 2002;42:430431. Troost B: Botulinum toxin type A (Botox) therapy for intractable headache. Headache 2002;42: 435436. Rasmussen BK, Jensen R, Olesen J: Impact of headache on sickness absence and utilisation of medical services: A Danish population study. J Epidemiol Community Health 1992;46:443446. Blumenfeld A: Decrease in headache medication use and cost after botulinum toxin type A (Botox) treatment in a high tryptan use population. Presented at the AHS, Istanbul, June 2123, 2002.
Prof. Dr. med. Wolfgang H. Jost Department of Neuroloy and Clinical Neurophysiology, Deutsche Klinik fr Diagnostik, Aukammallee 33, D65191 Wiesbaden (Germany) Tel. 49 611 577321, Fax 49 611 577311, E-Mail jost.neuro@dkd-wiesbaden.de
101
Botulinum Toxin in the Treatment of Migraine

Hartmut Gbel a, Wolfgang H. Jost b
a b
Kiel Pain Clinic, Kiel, Department of Neurology and Clinical Neurophysiology, German Clinic of Diagnostics, Wiesbaden, Germany
Definition
Migraine is a chronic headache disorder manifesting in attacks lasting 472 h. Characteristics of headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia and phonophobia. The migraine aura is a complex of neurological symptoms, which occurs just before or at the onset of migraine headache. About 90% of patients have exclusively attacks without aura. Headache with the features of migraine without aura usually follows the aura symptoms. Premonitory symptoms occur hours to a day or two before a migraine attack. They include various combinations of fatigue, difficulty concentrating, neck stiffness, sensitivity to light or sound, nausea, blurred vision, yawning and pallor (table 1).
Clinical Picture
The typical migraine headache is characterized by its pulsating, throbbing nature and is usually unilateral, occurring on alternate sides [15]. The pain can become very intense and can be exacerbated by routine physical activities such as bending down or climbing stairs. The characteristic concomitant symptoms are nausea and vomiting, photophobia and phonophobia. The diagnostic criteria [6, 7] are listed in table 2.
Table 1. Classification of migraine (IHS Classification, second edition) 1.1 1.2 1.3 Migraine without aura Probable migraine without aura Migraine with aura 1.3.1 Typical aura with migraine headache 1.3.2 Typical aura with non-migraine headache 1.3.3 Typical aura without headache 1.3.4 Familial hemiplegic migraine 1.3.5 Sporadic hemiplegic migraine 1.3.6 Basilar type migraine Probable migraine with aura Childhood periodic syndromes 1.5.1 Cyclical vomiting 1.5.2 Abdominal migraine 1.5.3 Benign paroxysmal vertigo of childhood Retinal migraine Complications of migraine 1.7.1 Chronic migraine 1.7.2 Status migrainosus 1.7.3 Persistent aura without infarction 1.7.4 Migrainous infarction 1.7.5 Migraine triggered seizures
1.4 1.5
1.6 1.7
Table 2. Diagnostic criteria of migraine (IHS Classification, second edition) A. At least 5 attacks fulfilling BD. Migraine days 15 days/month B. Headache attacks lasting 472 h (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance from routine physical activity (i.e., walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another disorder
In approximately 10% of migraine sufferers, the actual migraine attack begins with focal cerebral disturbances, an aura [1, 813]. Typically, aura symptoms tend to spread during a period of several minutes. The individual aura symptoms are fully reversible within a period of 1 h and the headache phase begins at the latest 1 h after the last aura symptoms have subsided.
BTX in the Treatment of Migraine
103
Approximately 90% of all migraine aura affect the visual system. The disturbances can take very different forms, ranging from bright flashing lights, fortification spectra and scintillating scotomas to homonymous hemianopia. A typical sensory aura is the spreading of tingling paraesthesias and/or hypaesthesia from the fingertips up to the lower arm, over the upper arm and the lower jaw to the tongue. Motor aura range from slight clumsiness to complete paralysis of the extremities. Speech disturbances can take the form of dysarthric or aphasic symptoms. In almost 50% of those affected, the aura and headache phase may be preceded by premonitory symptoms. Excitatory premonitory symptoms include general hyperactivity, a sudden craving for high-calorie foods and general hypersensitivity of all sensory organs, including increased tension and sensitivity of the pericranial muscles. Inhibitory precursors are fatigue, exhaustion, depression and obstipation [1423].
Epidemiology
With a lifetime prevalence of approximately 11%, migraine is the second most frequently occurring form of headache after tension-type headaches [2426]. The first migraine attack typically occurs during adolescence or early adulthood. During the last few decades, however, there has been a growing incidence of migraines in school-age children. In adults, women predominate at a ratio of 2.5:1. On average, migraine attacks occur on 3 days a month, causing the sufferer to be unfit for work on an average of 1 day a month and to have to forgo planned recreational activities on 1 further day a month. The most common days on which migraine attacks occur are Saturday and Sunday.
Pathophysiology
Vascular Theory of Migraine For many years, it was thought that the headache phase of a migraine attack was triggered by extracranial vasodilatation and that intracranial vasoconstriction was responsible for the neurological symptoms (vascular theory of migraine). Studies evaluating the regional blood flow have shown that patients with migraine with aura have moderate hypoperfusion, beginning in the visual cortex and spreading at a rate of 23 mm/min. Blood flow is reduced by an average of 2530%. This is not sufficient to allow the neurological symptoms to be explained in terms of ischaemia. The reduced blood flow continues in a frontally moving wave pattern, regardless of the topography of the cerebral
Gbel/Jost
104
arteries. In isolated cases, the hypoperfusion remains in this region even after the symptoms have subsided [2735]. It is a matter of continuing controversy as to whether the above vascular changes are capable of triggering the symptoms of migraine. In particular, the hypoperfusion which has been observed does not seem significant enough to cause focal neurological symptoms. Secondly, an increased blood flow is not painful in itself. Vasodilatation alone cannot be held responsible for local oedema and focal pain in migraine patients. Furthermore, in migraine without aura, there is usually no change in blood flow. It is thus unlikely that the pathomechanism of migraine can be attributed solely to vasoconstriction and vasodilatation [28, 3638]. Neuronal Theory of Migraine In 1941, K.S. Lashley described the progression of his own visual migraine aura, which was characterized by a slowly enlarging visual scotoma with shining edges [30, 39, 40]. He was able to calculate that his own scotoma was spreading at a rate of 3 mm/min. He assumed that a wave of intense excitation was moving over the visual cortex, followed by a wave of complete loss of activity. In 1944, the Brazilian physiologist, Leo, described a phenomenon occurring in the cerebral cortex of laboratory animals which is now known as spreading depression according to Leo [4147]. It involves a slowly spreading (23 mm/min) depression of cortical activity during which potassium is released. It is followed by a wave of increased activity. Various experimental stimuli such as hypoxia, mechanical trauma or the topical application of potassium can trigger this condition. These observations suggest that neuronal abnormalities, probably originating in the brain stem, are responsible for a migraine attack. Furthermore, in a recent migraine study using positronemission tomography (PET), changes were shown to occur in both the cortex and in the brain stem [48, 49]. The Trigeminovascular System in Migraine As early as 1937, Lewis described neurogenic inflammation as a nocifensive system which protects against damage in tissue injury. The main components of neurogenic inflammation are vasodilatation, plasma extravasation and degranulation of mast cells. In this model, the increased sensitivity to pain which occurs in migraine is explained by an increased sensitization of sensory perivascular fibres in the meninx. Activation of the cells in the caudate nucleus of the trigeminal nerve in the medulla results in a release of vasoactive neuropeptides at the vascular terminals of the trigeminal nerve, including Substance P and the calcitonin gene-related peptide (CGRP). These neurotransmitters, which consist of peptides, are thought to be responsible for a
105
sterile inflammation, which contributes to an additional pain increase by activating trigeminal nociceptive afferents, originating in the vascular wall [27, 28, 36, 5052]. This mechanism offers a possible explanation for the tissue swelling and vascular pain sensitivity which occur during a migraine attack [53]. Through this increased sensitization, vascular pulsations, which are not normally painful, become potent pain stimuli and cause the pulsating, throbbing pain associated with migraine. This also explains the observation of migraine patients, that physical exertion or bending down aggravates the pain, as the pulsations are thereby intensified. Neurogenic inflammation is triggered by a release of vasoactive neuropeptides, Substance P, neurokinin A and CGRP. The release is mediated by unmyelinated C-fibres which accompany the trigeminal nerve. 5-HT1D receptor agonists, such as the ergot alkaloids and the triptans, can inhibit neurogenic inflammation by blocking the release of vasoactive neuropeptides such as CGRP via C-fibre-dependent mechanisms. Simultaneously, the 5-HT1 agonists have a vasoactive effect. The origin of neurogenic inflammation, however, still remains unclear [28, 36, 54]. Based on PET examinations, it is thought that a so-called migraine generator is located in the brain stem and that this is activated by the various migraine trigger factors [49]. Serotonin About 40 years ago, it was established that the substance methysergide antagonizes certain peripheral effects of 5-HT. It was the first drug introduced for migraine prophylaxis. Later it was confirmed that, at the outset of a migraine attack, a decrease of the 5-HT concentration occurs in the platelets and that drugs which cause 5-HT release could trigger migraine attacks [55]. The introduction of the triptans as anti-migraine drugs reawakened interest in the role of 5-HT in migraine [5662]. Due to their special structure, triptans can selectively stimulate a specific subgroup of 5-HT receptors. Molecular studies have shown that at least 14 specific 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT1B, 5-HT1D and 5-HT1F receptors. They are less effective on 5-HT1A and 5-HT1E receptors. An increasing number of study results are indicating that the efficiency of the triptans in migraine therapy stems from their ability to stimulate 5-HT1B receptors, which are found in the blood vessels and nerve terminals [6367]. Electrical stimulation in the proximity of neurones of the dorsal raphe nuclei can lead to migraine-like headache [6870]. During a migraine attack the blood flow increases focally in the pons and the mesencephalon. This change appears to be due to an increased cell activity in the dorsal raphe and the locus coeruleus. There are nerve tracts in the dorsal raphe nuclei which end
Gbel/Jost
106
at cerebral arteries and thus influence cerebral blood flow. Further significant nerve tracts lead to important visual centres such as the lateral geniculate body, the cranial colliculus, the retina and the visual cortex. These various serotonergic tracts may present the neural substrate for the visual symptoms of migraine. The cells of the dorsal raphe nuclei transmit no excitation during deep sleep and sleep is known to help migraine. Furthermore, prophylactic anti-migraine drugs suppress the activity of cells in the dorsal raphe by means of direct or indirect agonistic effects. Dopamine in Migraine Almost all migraine symptoms can be induced by dopaminergic stimulation. Migraine patients also show hypersensitivity of the dopamine receptor. Yawning, nausea, vomiting, hypotension and other symptoms of migraine were triggered by dopamine agonists at a dose which produced no effects in volunteers without migraine [7173]. On the other hand, dopamine receptor antagonists are effective drugs in the treatment of migraine, particularly when they are administered parenterally or together with other migraine drugs [74]. Sympathetic Nervous System During all phases of migraine attacks, changes occur in the sympathetic nervous system (SNS). Factors which activate the SNS can also be trigger factors for a migraine [29, 36, 7577]. These include both environmental changes (stress, sleeping habits, hormonal changes, hypoglycaemia) and also substances which cause a release and consecutive reduction in peripheral catecholamines (tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine and reserpine). Dopamine antagonists and prostaglandin-synthesis inhibitors can be effective in the treatment of an acute migraine attack. Susceptibility to trigger factors may thus depend upon genetically determined deviations which influence the ability to maintain an adequate concentration of certain neurotransmitters in the post-ganglial sympathetic nerve terminals. This hypothesis is called the empty neurone theory of migraine. Genetic Predisposition There is a known genetic predisposition associated with migraine [7881]. The MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), for instance, is caused by a point mutation at nucleotide position 3243 on a mitochondrial gene which codes for tRNALeu(UUR) [8285]. Particularly at the outset, this syndrome often causes episodic migraine-like headaches [82, 86]. Familial hemiplegic migraine (FHM) is accompanied by episodes of recurrent hemiparesis or hemiplegia during the aura phase of a migraine attack. Approximately half of all FHM cases are
107
probably triggered by a mutation of the gene CACNL1A4 localized on chromosome 19 [80, 8794]. This gene codes for a calcium channel subunit of the P/Q type, which is found exclusively in the central nervous system (CNS). An analysis of the haplotypes of two families with the same mutation indicates that each mutation occurs independently of the other. Certain subtypes of FHM are thus caused by mutations of the gene CACNL1A4. The function of this gene is unclear. It is probable, however, that it plays a key role in calcium-induced neurotransmitter release and in the contraction of smooth muscle. Other mutations on this gene cause movement disorders such as type 2 episodic ataxia. In a further genetic study, polymorphism on the gene which codes for the dopamine D2 receptor (DRD2) was found more frequently in migraine patients with aura than in a control group of persons without migraine. Susceptibility to migraine with aura thus appears to be modified by certain DRD2 alleles [93, 95102]. The function of the dopamine receptor may thus influence susceptibility to migraine. Nevertheless, not all those who possess this specific DRD2 genotype suffer from migraine with aura. Additional genes or other factors must also be involved. Migraine thus seems to be a complex disorder which is influenced by heredity and environmental conditions [102].
Therapy
Non-Medicinal Prophylaxis First of all, individual trigger factors for migraine must be identified and actively avoided, as far as possible. It is essential to plan a regular daily routine, as an irregular sleeping-waking rhythm and the irregular intake of meals are regarded as the principal migraine triggers. Relaxation techniques such as progressive muscle relaxation according to Jacobson can help to manage stress situations and thus effectively to prevent migraine attacks. The technique is based upon active perception of tension and relaxation in the muscles and enables the subject actively to introduce a deep relaxation during situations of tension. Food and stimulants should only be avoided if it is certain that they have repeatedly triggered migraine attacks [103, 104]. Prophylactic Medication Prophylactic medication is indicated if at least 3 migraine attacks occur per month, if migraine attacks recur following successful acute therapy or if there have been recurrent migraines with extensive aura (basilar-type migraine, FHM, migraine with prolonged aura, migrainous infarction). It must be made clear to the patient that such prophylactic medication has to be taken regularly and long-term. The medicines cannot achieve a complete remission of the
Gbel/Jost
108
Table 3. Drugs of choice (a) and drugs to be avoided (b) in migraine prophylaxis depending upon the individual patient situation a. Drugs of choice Accompanying features Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine high blood pressure cardiac vessel disease stress depression insomnia below-normal weight adiposity epilepsy mania stroke systremma obstipation craniocervical dystonia hypersensitivity to side effects Preferred choice -Blockers Calcium channel blockers -Blockers, antidepressants Antidepressants Antidepressants Antidepressants, pizotifen, flunarizine Topiramate, lisinopril Valproic acid Valproic acid Aspirin Magnesium Magnesium Botulinum toxin A Root extract of Petasitis spissum (Petasites)
b. Drugs to be avoided Accompanying features Migraine Migraine Migraine Migraine Migraine Migraine Migraine Migraine epilepsy depression advanced age/cardiac disease adiposity asthma high level of sporting activity high concentration and cognitive activity liver disease Avoid Antidepressants -Blockers, flunarizine Antidepressants Antidepressants, pizotifen -Blockers, topiramate -Blockers Antidepressants, -blockers Valproic acid
migraine. The aim of prophylaxis is to reduce the frequency of attacks by at least 50% and to reduce the intensity of attacks. It usually requires a period of at least 6 weeks before any improvement can be ascertained. Treatment is initially limited to a period of 69 months, after which time further developments are monitored. The various drugs used in migraine prophylaxis are only successful in 3070% of patients treated. Many substances are available. The choice of drug used depends upon the characteristics of the individual attacks and of the patient (table 3a,b).
109
Attack Therapy Patients should retire to a quiet, darkened room and try to relax physically. In individual cases, use of a learned relaxation technique may be helpful. In order to combat a mild migraine attack, the combination of an anti-emetic agent with an analgesic has proved effective. Anti-emetics, such as metoclopramide or domperidone, specifically reduce nausea and vomiting and also normalize gastric motility which is disturbed due to the migraine. This improves and accelerates absorption of the analgesic. For the optimal use of this effect, aspirin, paracetamol or ibuprofen are given after a latency period of 15 min. In severe migraine attacks, a combination of an anti-inflammatory analgesic and an anti-emetic is often not sufficiently effective if the agents are not administered parenterally. In such cases, specific anti-migraine drugs, the triptans, are required [64, 105110]. Pharmacologically, the triptans are specific 5-HT1B- and 5-HT1D-receptor agonists. An agonistic effect on serotonin 5-HT1B receptors causes vasoconstriction of the intracranial extracerebral vessels, which are dilated during a migraine attack. Excitation of serotonin 5-HT1D receptors, on the other hand, blocks sterile neurogenic inflammation by inhibiting neuropeptide release (Substance P, CGRP) and simultaneously inhibits pain transmission via central trigeminal projections. As the projections to the nucleus of solitary tract, which are responsible for nausea and vomiting, are also inhibited, the additional administration of anti-emetic agents is not necessary. The high efficacy of the triptans in practice can be explained by their ability to influence specifically those mechanisms which are highly relevant to the pathophysiology of migraine. At the same time, however, it is also obvious why they are ineffective in other pain conditions.
Rationale for Using Botulinum Toxin (BTX) in Migraine Prophylaxis
Data on the pathophysiology of migraine show that sensory stimuli which are constantly too severe or which occur suddenly in combination with an increased sensory sensitivity can lead to a permanent sensory overflow of the CNS. This can result in hyperactivity of the sensory brain stem nuclei, leading to a release of vasoactive neuropeptides at the vascular terminals of the trigeminal nerve, including Substance P and CGRP, and finally to a sterile vascular inflammation [14, 111115]. BTX can interfere with this pathomechanism at various points. For approximately 20 years, BTX-A has been successfully used in numerous diseases which are characterized by pathologically increased muscle activity [116119]. Blockade of cholinergic innervation reduces muscular hyperactivity for 36 months, degenerative changes in the musculoskeletal system of the head and neck are prevented, nociceptive afferents and blood vessels of the pericranial
Gbel/Jost
110
muscles are decompressed and muscular trigger points and tender points are resolved [120131]. Normalization of muscle spindle activity simultaneously causes a normalization of muscular sensory function and the central control mechanisms of muscle activity and removes oromandibular dysfunction and muscular stress factors [125, 132137]. The effects of BTX-A are not, however, limited to muscular targets. Retrograde uptake of BTX-A into the CNS modulates the expression of Substance P and encephalin in the spinal medulla and in the raphe nucleus and could thus inhibit excessive trigeminovascular activity [138141]. Recent studies also confirm a prophylactic inhibition of sterile inflammation, which can contribute clinically to a blockade of the neurogenic inflammation thought to be the pathophysiological substrate of primary headache [140]. Patients who frequently experience severe migraine attacks often also suffer from frequent tension-type headaches; more than half of migraine patients experience episodic or chronic tension-type headaches [26, 120, 142145]. Prophylactic treatment of frequent migraine attacks is thus aimed initially at relieving or removing the tension-type headache using BTX-A. Several clinical modes of action are evident in tension-type headaches. The reduction in muscular stress through immediate muscle relaxation leads to a reduced sensory input into the nervous system [128, 142, 146155]. The removal of oromandibular dysfunction as an aggravating factor in chronic headache syndrome relieves the sensory and motor system [156162]. The direct treatment of tender points and trigger points leads to a decompression of afferent nociceptive muscle neurones [121131]. Compression of muscular blood vessels is resolved and the excessive concentration of excitatory metabolites is reduced [139, 163]. Normalization of excessive muscle spindle activity can reduce the permanent tone of the pericranial muscles in tension-type headache [125, 132, 137]. Thus, a significant stress factor acting as a trigger for additional migraine attacks is reduced or removed. Simultaneously, intake of acute medication for the treatment of tension-type headache is reduced. This reduction in acute medication allows a reduction in the high frequency of drug intake, thus avoiding drug-induced permanent headache. During the transition period there is usually a higher frequency of migraine attacks, which can be reduced by BTX-A treatment. Also of significance is the immediate removal of muscular triggers for migraine attacks. These can take the form of local, painful muscle areas and work as permanent and potent triggers for migraine attacks [130, 164168]. Just as excessive noise or light can trigger a migraine attack, permanent noxious stimulation from the pericranial muscles can also work as a migraine trigger. Elimination of these triggers avoids setting off further migraine attacks. As a consequence, the CNS is protected from excessive sensory overflow. Furthermore, a new study by Cui and Aoki [140, 141] demonstrated immediate antinociceptive effects of BTX-A on inflammatory pain in animal models.
111
A dose-dependent reduction of the nociceptive response was observed in formalin-induced arthritis on the rat paw, 12 days after injection. Doses of 3.5 and 7 units/kg/paw caused reductions of 29 and 46%, respectively, in comparison to placebo. Interestingly, there was no muscular effect at the doses chosen. The basis of migrainous pain is neurogenic inflammation of the dural and meningeal arteries. Following the investigations of Cui and Aoki [141], it is conceivable that by retrograde uptake of BTX-A into the CNS, these inflammatory changes are blocked by direct effects on the trigeminovascular system and thus that BTX-A interferes directly in the pathophysiology of migraine. BTX-A in Migraine Prophylaxis It is interesting that studies have generally reported a good and consistent efficacy for BTX-A in migraine prophylaxis [130, 169175]. Of particular note are the controlled studies performed by Brin et al. [170] and Silberstein et al. [172]. These studies observed a reduction in both the intensity and frequency of migraine attacks. The required BTX-A doses were relatively low, particularly in the study performed by Silberstein et al. [172] with 25 MU Botox. The studies also demonstrated the crucial importance of choosing the injection sites on an individual basis, depending upon the clinical findings. Injecting specifically into muscular trigger points and tender points has proved effective. The use of BTX in migraine therapy has not yet been sufficiently justified through studies. At the moment, because of the modes of action described, the differential therapeutic use of BTX appears to be worth attempting in migraine patients with the following characteristic features: (1) muscular stress as migraine trigger, for example in (a) craniocervical dystonia, (b) pericranial painful muscular trigger points or tender points, and (c) oromandibular dysfunction; (2) concurrent chronic tension-type headache with the aggravating factors of muscular stress or oromandibular dysfunction, and (3) chronic migraine with frequent migraine attacks on more than 15 days per month for longer than 3 months and if other therapeutic options have been either ineffective or have not been tolerated. As with other prophylactic agents, the prerequisite for effective use is that non-medicinal preventative measures are also considered and that any druginduced increase in attack frequency or drug-induced permanent headache is absent or effectively excluded before use.
Clinical Studies
The first evidence for the efficacy of BTX-A in migraine was reported as a surprising side effect in patients primarily treated for hyperfunctional facial
Gbel/Jost
112
lines [146, 171]. Since these early starts, several clinically studies have investigated the efficacy of BTX-A in migraine both in open and in controlled designs. Table 4a and b lists the studies currently available [130, 169175]. Since no guidelines, meta-analyses or systematic reviews have been published on this topic yet, the highest level of evidence is achieved by randomized and controlled studies. Using the 1999 SIGN Criteria [149, 176] for rating clinical studies, these studies reach a level of evidence of Ib. In the year 2000, two randomized and controlled studies were published which showed the efficacy of BTX-A in the treatment of migraine. Brin et al. [170] and Silberstein et al. [172] both conducted double-blind and placebocontrolled studies using a standardized injection design of BTX-A. These studies observed a significant reduction in the intensity of the migraine attacks and Silberstein et al. also found a reduction in the frequency of the attacks. The required doses of BTX-A were relatively low, particularly in the case of the study by Silberstein et al. with 25 MU Botox. The non-significant clinical efficacy of 75 MU in the study by Silberstein et al. is probably explained by a randomization error due to the standardized choice of injection sites. Furthermore, low doses are often more effective than high ones in headache prophylaxis. This is demonstrated by the use of tricyclic antidepressants in headache prophylaxis. The study also shows that if standardized injection schemes are used, there is a risk that treatment will be administered at clinically inappropriate sites and that relevant muscular trigger points will be missed. Open studies with a consequently lower level of evidence (SIGN III) underline the results of the controlled trials. Mauskop and Basedo [171] using 25100 MU Botox in an open study with individual injection choice documented a reduction in frequency of migraine attacks or a reduction in pain intensity in 23 out of 27 patients. Using a similar open study design, Smuts and Barnard [173] found positive results in 13 out of 19 patients. Binder et al [169] treated 77 migraine patients in an open study with individual injection choice. 51% of the patients reported complete response defined as complete symptom elimination for an average of 4.1 months. A further 38% reported a partial response defined as a reduction of migraine frequency or severity by at least 50%. An important finding of experience to date with BTX-A in therapy of tension-type headache is that the injection should be performed at the site of the pain or the trigger points, and not on a standardized basis. Just as the injection is made specifically into the affected muscle in the treatment of dystonia, this must also be done in the treatment of pain. It is essential that this crucial point be observed in future controlled studies and in open use. If one considers the range of doses of BTX-A used, which in the positive studies ranged from 15 to 100 MU Botox or 160 to 200 MU Dysport, the total dose injected would appear to be of secondary importance.
113
Table 4. Overview of clinical studies: BTX-A in the treatment of (a) migraine and (b) migraine plus tension-type headache
a. Treatment of migraine Study Binder et al., 2000 [169] Design Open (individual injection choice), n 77/0 (active drug/placebo) Double-blind, placebo-controlled (standardized injection) n 36/12 (active drug/placebo) Open (individual injection choice), n 27/0 (active drug/placebo) Double-blind, placebo-controlled (standardized injection) n 82/41 (active drug/placebo) Open (individual injection choice), n 19/0 (active drug/placebo) Open Injection in corrugator supercilii muscle n 29/0 25 MU Botox Outcome Positive 51% migraine free for an average of 4.1 months 38% reduction for migraine frequency of severity by at least 50% Positive Reduction in pain intensity Reduction in number of migraine attacks and duration of attacks, but not significant Positive (23 out of 27) Reduction in frequency of migraine attacks Or Reduction in pain intensity Positive for a subgroup with lower dose of 25 MU Botox (n 42, active drug) Reduction in frequency of migraine attacks Reduction in average pain intensity Reduction in number of days with vomiting Reduction in number of days with acute medication Positive 13 out of 19 (68%) showed positive result (not defined in detail) Positive 24 out of 29 showed positive result (16 complete remission, 8 reduction more than 50%); BTX response is reliable predictor of surgical outcome SIGN level III
Brin et al., 2000 [170]
Ib
Mauskop and Basedo, 2000 [171]
III
Silberstein et al., 2000 [172]
Ib
Smuts and Barnard, 2000 [173]
III
Guyuron, Tucker and Davis, 2002 [174]
III
b. Treatment of migraine plus tension-type headache Study Wheeler, 1998 [130] Design Open (individual injection choice), n 4/0 (active drug/placebo) Double-blind, placebo-controlled (standardized injection), n 38/18 (active drug/placebo) Outcome Positive Increase in number of pain-free days Reduction in pain intensity Positive for a subgroup with 2 injection regions (n 19, active drug) Reduction in headache duration Reduction in frequency of moderate and severe headaches SIGN level IV
Klapper et al., 2000 [175]
Ib
Gbel/Jost
114
It would also appear to be important that a particularly good efficacy seems to result in cases where both migraine and tension-type headache exist [175, 130]. Most studies dealt with either one syndrome or the other. Klapper et al. [175] treated patients with chronic daily headache in a double-blind, placebo-controlled trial using 25.572.5 MU Botox. In a subgroup with 2 injection regions (n 19, active drug) they found a reduction in headache duration and in frequency of moderate and severe headaches. Wheeler achieved the same results in a group of 4 patients treated open with 20120 MU Botox. In a prospective study of Guyuron et al. [174] the role of removal of corrugator supercilii muscles, transection of the zygomaticotemporal branch of the trigeminal nerve, and temple soft-tissue repositioning in the treatment of migraine headaches was investigated. Using the criteria set forth by the International Headache Society, the research teams neurologist evaluated patients with moderate to severe migraine headaches, to confirm the diagnosis. Subsequently, the patients completed a comprehensive migraine headaches questionnaire and the teams plastic surgeon injected 25 units of BTX-A (Botox) into each corrugator supercilii muscle. Patients in whom the injection of Botox resulted in complete elimination of the migraine headaches then underwent resection of the corrugator supercilii muscles. Those who experienced only significant improvement underwent transection of the zygomaticotemporal branch of the trigeminal nerve with repositioning of the temple soft tissues, in addition to removal of the corrugator supercilii muscles. Twenty-four of 29 patients reported a positive response to the injection of Botox, 16 observed complete elimination, 8 experienced significant improvement (at least 50% reduction in intensity or severity), and 5 did not notice a change in their migraine headaches. Twenty-two of the 24 patients who had a favourable response to the injection of Botox underwent surgery, and 21 observed a postoperative improvement. Ten patients reported elimination of migraine headaches and 11 patients noted a considerable improvement. This study shows that the treatment with BTX is an extremely reliable predictor of surgical outcome. The results support allowing individual choice of injection areas in migraine therapy. If there is a functional trigger effect, the treatment target is local muscular hyperactivity.
Treatment Procedures
The main focus of the use of BTX-A in specific pain therapy is the treatment of primary headache with involvement of the pericranial muscles. There follows a summary of the experience gained from the available clinical studies and clinical use. Subclinically, a decrease in motor action potentials is evident
115
after only a few hours. A clinical effect of the injection is not felt for at least 210 days (with a scatter of 120 days). Onset of action depends upon muscle size and the BTX-A dose. Complete restitution of function can be expected after 35 months (in isolated cases after 9 months). No permanent muscle atrophy occurs. A re-injection should not be given for at least 810 weeks. Otherwise, if re-injections are given while the effect of the first injection is still evident, the effect will be poorly controlled. Furthermore, if the intervals between re-injections are too short, there is a risk of antibody formation and subsequent secondary resistance. Absolute contraindications to BTX-A treatment must be observed [147, 177, 178]. Apart from the usual range of side effects caused by an intramuscular injection (risk of infection, haemorrhage etc.), undesired paresis of non-injected muscles may occur in isolated cases during BTX treatment, due to local diffusion. These are completely reversible as are the other desirable side effects but may occasionally cause obvious cosmetic (in the facial area) or functional impairment (dysphagia, masticatory muscle weakness). These side effects can be minimized by administering higher concentrations with smaller injection volumes, choosing the lowest effective doses on an individual basis and by precise location of the injection points. In the large and superficial muscles which are involved in headache therapy, unwanted paresis does not generally occur. There are currently two commercially available forms of BTX-A (Botox and Dysport) and one of BTX-B (Neurobloc). There has been no experience with the use of BTX-B in migraine therapy. 1 MU Botox is equivalent in efficacy to approximately 35 MU Dysport. The substance is reconstituted by the addition of a 0.9% sodium chloride solution. It has proved practical in pain treatment to fill one ampoule of Botox with 5 ml NaCl or one ampoule of Dysport with 5 ml NaCl. Reconstitution with local anaesthetics brings no benefit and should be avoided. For injection, the use of a 1-ml tuberculin syringe with a 30-G cannula has proved effective. At higher dilutions, the usual 2- or 5-ml syringes can also be used. The units used must then be converted accordingly. The injection strategy should be decided on an individual patient basis according to the degree of local muscle hyperactivity and muscle trigger points [128, 131]. A better effect can be achieved if trigger points are precisely located and the injection is directed at these. Figure 1 shows frequent areas for injection. Therapy results can be improved by concurrent EMG leads, particularly in craniocervical dystonia and oromandibular dysfunction. These also serve to record efficacy. Initially it is important to establish a sufficiently accurate diagnosis of the headache type. It makes no sense treating patients with drug-induced permanent headache or other secondary forms of headache without beginning concurrent causal therapy in such patients [179].
Gbel/Jost
116
Fig. 1. Frequent sites of muscular trigger points.
The injection technique is mainly determined by the surrounding anatomical structure. According to the muscle volume and the degree of muscle hyperactivity, an injection of 520 MU Botox or 25100 MU Dysport per trigger point should be given. In the case of oromandibular dysfunction, the injection is administered into the middle of the superficial part of the masseter muscle, approximately 23 cm above the lower edge of the mandible. This ensures that the vessels (facial artery/vein) lying medially are not punctured and that the parotid gland, which lies laterally, is neither injured nor influenced. The injection should not be directed too tangentially as otherwise superficial muscles related to facial expression, such as the risorius muscle, which originates in the masseteric fascia, may be weakened. The amount of injection should be kept low and the toxin concentration high, in order to avoid any diffusion into the mylohyoid muscles. Injection into the temporal muscle can either be close to the attachment, i.e., approximately 2 cm, or further from the attachment, i.e., approximately 5 cm above the upper edge of the zygomatic arch. Both injections must penetrate the temporal fascia, the strongest fascia of the head. For this reason, the injection must be as near to perpendicular as possible, particularly if performed close to the attachment, in order to pass through the fascias pronounced fat padding, which increases caudally. If the injection is administered further from the attachment, the close proximity of the temporal artery must be borne in mind, in order to avoid any injury. The injection into the frontal muscle (occipitofrontal muscle, frontalis muscle) is made approximately 34 cm above the orbital edge. The direction of the puncture should run parallel to the eyebrow. A flat injection is recommended in order to avoid any retromuscular sinking of the injection fluid with subsequent possible ptosis. Injection during muscle contraction is more accurate and is well tolerated by the patient.
117
Injection into the splenius muscle of the head is performed close to the attachment, between the lateral edge of the descending part of the trapezius muscle and the attachment of the sternocleidomastoideus muscle. The horizontal part of the trapezius muscle should be injected at least twice on each side, because, due to the amount of the muscle mass, sufficient diffusion of the toxin cannot be guaranteed if it is only administered in small amounts. Suitable injection sites are the points between the middle and outer third or between the middle and inner third of the area between the cervical attachment and the acromion.
Future Prospects
BTX-A represents a completely new option for patients with chronic pain conditions, particularly migraine and tension-type headache. The use of the agent does not cause CNS side effects. Headache patients, in particular, often suffer greatly, as a result of the adverse effects of the drugs used, from fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair loss and changes in libido. These side effects are not known in association with BTX-A. To date, neither organic damage nor allergic complications have been reported. Thus, both the tolerability and the safety of this therapeutic measure are extremely high. Because of its long-term effect over many months, patients do not have to remember to take medication several times daily. The efficacy of repeat injections builds upon the therapeutic success of the previous treatment in a staircase effect [180] and does not begin at the level of efficacy of the first injection. If muscle stress and trigger points and tender points are the cause or the aggravating factors in headache disorders, it is possible, with a single treatment, to break the pain cycle and thus to prevent it from becoming chronic. No further treatment is required. Numerous clinical studies are currently investigating in detail the new area of application of BTX-A in specific pain therapy. In the treatment of primary headache, opinion still differs as to dosage, the areas of injection and methodical procedures. Comparative studies with standard medicines are also still needed. Thus, the current use of BTX-A in these disorders is only justified after all standard therapeutic procedures have been exhausted and only following evaluation in specialist centres. Its use requires precise functionalanatomical knowledge and extensive experience and practice in its application.
References
1 Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB: Migraine without aura: A population-based twin study. Ann Neurol 1999;46:606611.
Gbel/Jost
118
2 3 4 5 6
9 10 11 12 13 14 15 16
17 18 19 20 21 22 23
24
25 26 27
Stang P, Sternfeld B, Sidney S: Migraine headache in a prepaid health plan: Ascertainment, demographics, physiological and behavioral factors. Headache 1996;36:6976. Cull RE: Investigation of late-onset migraine. Scott Med J 1995;40:5052. Ottman R, Lipton RB: Comorbidity of migraine and epilepsy. Neurology 1994;44:21052110. Breslau N, Davis GC: Migraine, physical health and psychiatric disorder: A prospective epidemiologic study in young adults. J Psychiatr Res 1993;27:211221. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. Gbel H, Olesen J, Prilipiko L: ICD-10 Guide for Headaches. Guide to the classification, diagnosis and assessment of headaches in accordance with the Tenth Revision of the International Classification of Diseases and Related Health Problems and Its Application to Neurology. Cephalalgia 1997;17:191. Carolei A, Marini C, De Matteis G: History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet 1996; 347:15031506. Henry P, Auray JP, Gaudin AF, et al: Prevalence and clinical characteristics of migraine in France. Neurology 2002;59:232237. Hoekstra-van Dalen RA, Cillessen JP, Kappelle LJ, van Gijn J: Cerebral infarcts associated with migraine: Clinical features, risk factors and follow-up. J Neurol 1996;243:511515. Park-Matsumoto YC, Tazawa T, Shimizu J: Migraine with aura-like headache associated with moyamoya disease. Acta Neurol Scand 1999;100:119121. Pfaffenrath V, Kommissari I, Pollmann W, Kaube H, Rath M: Cerebrovascular risk factors in migraine with prolonged aura and without aura. Cephalalgia 1991;11:257261. Russell MB, Hilden J, Sorensen SA, Olesen J: Familial occurrence of migraine without aura and migraine with aura. Neurology 1993;43:13691373. Welch KM, Goadsby PJ: Chronic daily headache: Nosology and pathophysiology. Curr Opin Neurol 2002;15:287295. Waldie KE, Poulton R: Physical and psychological correlates of primary headache in young adulthood: A 26-year longitudinal study. J Neurol Neurosurg Psychiatry 2002;72:8692. Hasvold T, Johnsen R, Forde OH: Non-migrainous headache, neck or shoulder pain, and migraine Differences in association with background factors in a city population. Scand J Prim Health Care 1996;14:9299. Breslau N, Davis GC, Andreski P: Migraine, psychiatric disorders and suicide attempts: An epidemiologic study of young adults. Psychiatry Res 1991;37:1123. Breslau N: Psychiatric comorbidity in migraine. Cephalalgia 1998;18(suppl 22):5658. Glover V, Jarman J, Sandler M: Migraine and depression: Biological aspects. J Psychiatr Res 1993;27:223231. Hudson JI, Goldenberg DL, Pope HG Jr, Keck PE Jr, Schlesinger L: Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 1992;92:363367. Merikangas KR, Risch NJ, Merikangas JR, Weissman MM, Kidd KK: Migraine and depression: Association and familial transmission. J Psychiatr Res 1988;22:119129. Ryan RE Jr: Headache diagnosis. Clin Cornerstone 1999;1:1120. Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW: Mental disorders and the incidence of migraine headaches in a community sample: Results from the Baltimore Epidemiologic Catchment Area Follow-Up Study. Arch Gen Psychiatry 2000;57:945950. Gbel H, Petersen-Braun M, Soyka D: The epidemiology of headache in Germany: A nationwide survey of a representative sample on the basis of the headache classification of the International Headache Society. Cephalalgia 1994;14:97106. Lipton RB, Goadsby PJ, Silberstein SD: Classification and epidemiology of headache. Clin Cornerstone 1999;1:110. Rasmussen BK, Olesen J: Epidemiology of migraine and tension-type headache. Curr Opin Neurol 1994;7:264271. Goadsby PJ, Edvinsson L: The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993;33:4856.
119
28 29
30 31 32 33 34
35 36 37 38
39 40 41 42 43 44 45
46 47 48 49 50 51
52 53
Humphrey PP, Goadsby PJ: The mode of action of sumatriptan is vascular? A debate. Cephalalgia 1994;14:401410. May A, Goadsby PJ: The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999;19:115127. Mraovitch S, Calando Y, Goadsby PJ, Seylaz J: Subcortical cerebral blood flow and metabolic changes elicited by cortical spreading depression in rat. Cephalalgia 1992;12:137141. Barinagarrementeria F, Gonzalez-Duarte A, Miranda L, Cantu C: Cerebral infarction in young women: Analysis of 130 cases. Eur Neurol 1998;40:228233. Bogousslavsky J, Regli F, Van Melle G, Payot M, Uske A: Migraine stroke. Neurology 1988;38: 223227. Gupta VK: Migrainous stroke: Are antiphospholipid antibodies pathogenetic, a biological epiphenomenon, or an incidental laboratory aberration? Eur Neurol 1996;36:110111. Larsen BH, Sorensen PS, Marquardsen J: Transient ischaemic attacks in young patients: A thromboembolic or migrainous manifestation? A 10-year follow-up study of 46 patients. J Neurol Neurosurg Psychiatry 1990;53:10291033. Rothrock JF, Walicke P, Swenson MR, Lyden PD, Logan WR: Migrainous stroke. Arch Neurol 1988;45:6367. Edvinsson L, Goadsby PJ: Neuropeptides in migraine and cluster headache. Cephalalgia 1994; 14:320327. Goadsby PJ: Advances in the pharmacotherapy of migraine. How knowledge of pathophysiology is guiding drug development. Drugs R D 1999;2:361374. Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alperovitch A: Association between migraine and endothelin type A receptor (ETA-231 A/G) gene polymorphism. Neurology 2001; 56:12731277. Kaube H, Goadsby PJ: Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. Eur Neurol 1994;34:3035. Goadsby PJ: Migraine, aura and cortical spreading depression: Why are we still talking about it? Ann Neurol 2001;49:46. Leao AA: Spreading depression. Funct Neurol 1986;1:363366. Olesen J, Jorgensen MB: Leaos spreading depression in the hippocampus explains transient global amnesia. A hypothesis. Acta Neurol Scand 1986;73:219220. Vanopdenbosch L, Herroelen L: Leaos cortical spreading depression and the somatosensory homunculus: A contradiction? Headache 1998;38:322323. Jarvis CR, Anderson TR, Andrew RD: Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices. Cereb Cortex 2001;11:249259. Dreier JP, Kleeberg J, Petzold G, et al: Endothelin-1 potently induces Leaos cortical spreading depression in vivo in the rat: A model for an endothelial trigger of migrainous aura? Brain 2002; 125:102112. Aurora SK, Welch KM: Migraine: Imaging the aura. Curr Opin Neurol 2000;13:273276. Lauritzen M: Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994; 117:199210. May A, Kaube H, Buchel C, et al: Experimental cranial pain elicited by capsaicin: A PET study. Pain 1998;74:6166. Weiller C, May A, Limmroth V, et al: Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1:658660. Goadsby PJ, Edvinsson L, Ekman R: Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183187. Knight YE, Edvinsson L, Goadsby PJ: Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: A comparison of avitriptan and CP122,288. Neuropeptides 1999;33:4146. May A, Goadsby PJ: Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs 2001;10:673678. Hoskin KL, Bulmer DC, Lasalandra M, Jonkman A, Goadsby PJ: Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. J Anat 2001;198:2935.
Gbel/Jost
120
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69
70
71 72 73 74 75 76 77 78
79
80
Goadsby PJ: Neuropeptides and migraine A useful biological marker? Cephalalgia 1995;15: 333334. Lance JW, Lambert GA, Goadsby PJ, Zagami AS: 5-Hydroxytryptamine and its putative aetiological involvement in migraine. Cephalalgia 1989;9(suppl 9):713. Cady RK: Diagnosis and treatment of migraine. Clin Cornerstone 1999;1:2132. Goadsby PJ: Is a central action of acute antimigraine drugs essential? Cephalalgia 1997; 17(suppl 17):1011. Goadsby PJ: Current concepts of the pathophysiology of migraine. Neurol Clin 1997;15:2742. Goadsby PJ: Serotonin receptors and the acute attack of migraine. Clin Neurosci 1998;5: 1823. Goldstein D: Vasoconstrictive properties of the 5-HT1B/1D agonists: Response to Dahlof and Mathew. Cephalalgia 1999;19:536537. Hanington E: Migraine: The platelet hypothesis after 10 years. Biomed Pharmacother 1989;43:719726. Hoskin KL, Kaube H, Goadsby PJ: Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain 1996;119:14191428. Tepper SJ: Safety and rational use of the triptans. Med Clin North Am 2001;85:959970. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ: Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001;358:16681675. Goadsby PJ, Zagami AS, Donnan GA, et al: Oral sumatriptan in acute migraine. Lancet 1991;338: 782783. Tfelt-Hansen P, Saxena PR, Dahlof C, et al: Ergotamine in the acute treatment of migraine: A review and European consensus. Brain 2000;123:918. Lipton RB, Pascual J, Goadsby PJ, et al: Effect of rizatriptan and other triptans on the nausea symptom of migraine: A post-hoc analysis. Headache 2001;41:754763. Goadsby PJ, Gundlach AL: Localization of 3H-dihydroergotamine-binding sites in the cat central nervous system: Relevance to migraine. Ann Neurol 1991;29:9194. Kaube H, Knight YE, Storer RJ, Hoskin KL, May A, Goadsby PJ: Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat. Cephalalgia 1999;19: 592597. Lamy C, Giannesini C, Zuber M, et al: Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: The PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002;33:706711. Ladabaum U, Hasler WL: Novel approaches to the treatment of nausea and vomiting. Dig Dis 1999;17:125132. Richman PB, Reischel U, Ostrow A, et al: Droperidol for acute migraine headache. Am J Emerg Med 1999;17:398400. Ducharme J: Canadian Association of Emergency Physicians Guidelines for the acute management of migraine headache. J Emerg Med 1999;17:137144. Vinson DR: Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 2002;39:215222. Rashed H, Abell TL, Familoni BO, Cardoso S: Autonomic function in cyclic vomiting syndrome and classic migraine. Dig Dis Sci 1999;44:74S78S. Goadsby PJ, Lipton RB: A review of paroxysmal hemicranias, SUNCT syndrome and other shortlasting headaches with autonomic feature, including new cases. Brain 1997;120:193209. Goadsby PJ, Edvinsson L: Neuropeptide changes in a case of chronic paroxysmal hemicrania Evidence for trigemino-parasympathetic activation. Cephalalgia 1996;16:448450. Iniesta JA, Corral J, Gonzalez-Conejero R, Rivera J, Vicente V: Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease. Headache 1999;39: 486489. Jones KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ: Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. Genomics 2001;78:150154. Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR: Familial typical migraine: Linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 1998;50:14281432.
121
81 Nyholt DR, Dawkins JL, Brimage PJ, Goadsby PJ, Nicholson GA, Griffiths LR: Evidence for an X-linked genetic component in familial typical migraine. Hum Mol Genet 1998;7:459463. 82 Riikonen R, Santavuori P: Hereditary and acquired risk factors for childhood stroke. Neuropediatrics 1994;25:227233. 83 Di Gennaro G, Buzzi MG, Ciccarelli O, et al: Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance. Headache 2000;40:568571. 84 Buzzi MG, Di Gennaro G, DOnofrio M, et al: mtDNA A3243G MELAS mutation is not associated with multigenerational female migraine. Neurology 2000;54:10051007. 85 Montagna P, Cortelli P, Barbiroli B: A case of cluster headache associated with mitochondrial DNA deletions. Muscle Nerve 1998;21:127129. 86 Majamaa K, Finnila S, Turkka J, Hassinen IE: Mitochondrial DNA haplogroup U as a risk factor for occipital stroke in migraine. Lancet 1998;352:455456. 87 Ophoff RA, Terwindt GM, Vergouwe MN, et al: Familial hemiplegic migraine and episodic ataxia type 2 are caused by mutations in the Ca2+ channel gene Cacnl1a4. Cell 1996;87:543552. 88 Doyle J, Ren X, Lennon G, Stubbs L: Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice. Mamm Genome 1997;8:113120. 89 Ducros A, Joutel A, Vahedi K, et al: Mapping of a second locus for familial hemiplegic migraine to 1q21q23 and evidence of further heterogeneity. Ann Neurol 1997;42:885890. 90 Gardner K, Barmada MM, Ptacek LJ, Hoffman EP: A new locus for hemiplegic migraine maps to chromosome 1q31. Neurology 1997;49:12311238. 91 Ophoff RA, Terwindt GM, Vergouwe MN, Frants RR, Ferrari MD: Familial hemiplegic migraine: Involvement of a calcium neuronal channel. Neurologia 1997;12(suppl 5):3137. 92 Spranger M, Spranger S, Schwab S, Benninger C, Dichgans M: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis. Eur Neurol 1999;41:150152. 93 Gardner K: The genetic basis of migraine: How much do we know? Can J Neurol Sci 1999; 26(suppl 3):S37S43. 94 Munchau A, Valente EM, Shahidi GA, et al: A new family with paroxysmal exercise induced dystonia and migraine: A clinical and genetic study. J Neurol Neurosurg Psychiatry 2000;68:609614. 95 Heinrichs L: Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum and migraine headache. Am J Obstet Gynecol 2002;185:S215S219. 96 Maude S, Curtin J, Breen G, et al: The -141C Ins/Del polymorphism of the dopamine D2 receptor gene is not associated with either migraine or Parkinsons disease. Psychiatr Genet 2001;11: 4952. 97 Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR: Evidence for allelic association of the dopamine -hydroxylase gene with susceptibility to typical migraine. Neurogenetics 2000; 3:3540. 98 Del Zompo M, Cherchi A, Palmas MA, et al: Association between dopamine receptor genes and migraine without aura in a Sardinian sample. Neurology 1998;51:781786. 99 Gardner K, Hoffman EP: Current status of genetic discoveries in migraine: Familial hemiplegic migraine and beyond. Curr Opin Neurol 1998;11:211216. 100 Mascia A, Afra J, Schoenen J: Dopamine and migraine: A review of pharmacological, biochemical, neurophysiological and therapeutic data. Cephalalgia 1998;18:174182. 101 Peroutka SJ, Price SC, Wilhoit TL, Jones KW: Comorbid migraine with aura, anxiety and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Mol Med 1998;4:1421. 102 Peroutka SJ, Wilhoit TL, Jones KW: Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology 1997;49:201206. 103 Gbel H, Diener HC, Ziegler A, Soyka D: Selbstmedikation primrer Kopfschmerzerkrankungen. Empfehlungen der Deutschen Migrne- und Kopfschmerzgesellschaft. Dtsch Apothekerzeitung 1995;135:763778. 104 Diener HC, Brune K, Gerber WD, Gbel H, Pfaffenrath V: Behandlung der Migrneattacke und Migrneprophylaxe. Dtsch rztebl 1997;94:C2277C2283. 105 Lipton RB, Hamelsky SW, Dayno JM: What do patients with migraine want from acute migraine treatment? Headache 2002;42(suppl 1):39. 106 Tfelt-Hansen P: Triptan medications to treat acute migraine. Lancet 2002;359:1152.
Gbel/Jost
122
107 Gupta A, Rothner AD: Treatment of childhood headaches. Curr Neurol Neurosci Rep 2001;1: 144154. 108 Freitag FG: Acute treatment of migraine and the role of triptans. Curr Neurol Neurosci Rep 2001; 1:125132. 109 Diener HC, Limmroth V: Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs 2001;10:18311845. 110 Pham B: A systematic review of the use of triptans in acute migraine. Can J Neurol Sci 2001;28:272. 111 Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J: Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci 2002;15:18031809. 112 Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J: CGRP may play a causative role in migraine. Cephalalgia 2002;22:5461. 113 Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L: Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 2002;22:112116. 114 Choudhuri R, Cui L, Yong C, et al: Cortical spreading depression and gene regulation: Relevance to migraine. Ann Neurol 2002;51:499506. 115 Edvinsson L: Calcitonin gene-related peptide and the pathophysiology of headache: Therapeutic implications. CNS Drugs 2001;15:745753. 116 Comella CL, Jankovic J, Brin MF: Use of botulinum toxin type A in the treatment of cervical dystonia. Neurology 2000;55:S15S21. 117 Gelb DJ, Lowenstein DH, Aminoff MJ: Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis. Neurology 1989;39:8084. 118 Johnson EA: Clostridial toxins as therapeutic agents: Benefits of natures most toxic proteins. Annu Rev Microbiol 1999;53:551575. 119 Sherman AL, Willick SP, Cardenas DD: Management of focal dystonia of the extensor hallucis longus muscle with botulinum toxin injection: A case report. Arch Phys Med Rehabil 1998;79: 13031305. 120 Gbel H, Heinze A, Heinze-Kuhn K, Austermann K: Botulinum toxin A in the treatment of headache syndromes and pericranial pain syndromes. Pain 2001;91:195199. 121 Cheshire WP, Abashian SW, Mann JD: Botulinum toxin in the treatment of myofascial pain syndrome. Pain 1994;59:6569. 122 Criscuolo CM: Interventional approaches to the management of myofascial pain syndrome. Curr Pain Headache Rep 2001;5:407411. 123 Freund BJ, Schwartz M: Treatment of chronic cervical-associated headache with botulinum toxin A: A pilot study. Headache 2000;40:231236. 124 Freund BJ, Schwartz M: Treatment of whiplash associated neck pain (corrected) with botulinum toxin A: A pilot study. J Rheumatol 2000;27:481484. 125 Hubbard DR, Berkoff GM: Myofascial trigger points show spontaneous needle EMG activity. Spine 1993;18:18031807. 126 Micheli F, Scorticati MC, Radi Orueta I, Diaz S: Hemifacial spasm triggered by vasodilators. Clin Neuropharmacol 1998;21:199200. 127 Samii A, Pal PK, Schulzer M, Mak E, Tsui JK: Post-traumatic cervical dystonia: A distinct entity? Can J Neurol Sci 2000;27:5559. 128 Simons DG, Mense S: Understanding and measurement of muscle tone as related to clinical muscle pain. Pain 1998;75:117. 129 Wheeler AH, Goolkasian P, Gretz SS: A randomized, double blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine 1998;23:16621666. 130 Wheeler AH: Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 1998;38:468471. 131 Wheeler AH, Goolkasian P, Gretz SS: Botulinum toxin A for the treatment of chronic neck pain. Pain 2001;94:255260. 132 Filippi GM, Errico P, Santarelli R, Bagolini B, Manni E: Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol 1993;113:400404.
123
133 Giladi N: The mechanism of action of botulinum toxin type A in focal dystonia is most probably through its dual effect on efferent (motor) and afferent pathways at the injected site. J Neurol Sci 1997;152:132135. 134 Guyer BM: Mechanism of botulinum toxin in the relief of chronic pain. Curr Rev Pain 1999;3: 427431. 135 Jankovic J, Tintner R: Botulinum toxin for the treatment of cervical dystonia. Expert Opin Pharmacother 2001;2:19851994. 136 Rosales RL, Arimura K, Takenaga S, Osame M: Extrafusal and intrafusal muscle effects in experimental botulinum toxin A injection. Muscle Nerve 1996;19:488496. 137 Silberstein SD: Review of botulinum toxin type A and its clinical applications in migraine headache. Expert Opin Pharmacother 2001;2:16491654. 138 Humm AM, Pabst C, Lauterburg T, Burgunder JM: Enkephalin and aFGF are differentially regulated in rat spinal motoneurons after chemodenervation with botulinum toxin. Exp Neurol 2000; 161:361372. 139 Suzuki N, Hardebo JE, Kahrstrom J, Owman C: Neuropeptide Y co-exists with vasoactive intestinal polypeptide and acetylcholine in parasympathetic cerebrovascular nerves originating in the sphenopalatine, otic, and internal carotid ganglia of the rat. Neuroscience 1990;36:507519. 140 Aoki KR: Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001;248 (suppl 1):310. 141 Cui ML, Khanijou S, Rubino J, Aoki KR: Botulinum toxin inhibits the inflammatory pain in the rat formalin model. Society for Neuroscience Annual Meeting, 2000, poster 246.2. 142 Gbel H, Lindner V, Krack P, Heinze A, Gaartz N, Deuschl G: Treatment of chronic tension-type headache with botulinum toxin. Cephalalgia 1999;19:455. 143 Olesen J, Rasmussen BK: Classification of primary headaches. Biomed Pharmacother 1995;49: 446451. 144 Rasmussen BK: Migraine and tension-type headache in a general population: Psychosocial factors. Int J Epidemiol 1992;21:11381143. 145 Rasmussen BK: Migraine and tension-type headache in a general population: Precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain 1993;53:6572. 146 Mauskop A: The use of botulinum toxin in the treatment of headaches. Curr Pain Headache Rep 2002;6:320323. 147 Mathew NT, Kaup AO: The use of botulinum toxin type A in headache treatment. Curr Treat Options Neurol 2002;4:365373. 148 Lainez MJ, Monzon MJ: Chronic daily headache. Curr Neurol Neurosci Rep 2001;1:118124. 149 Gbel H, Heinze A, Heinze-Kuhn K, Jost WH: Evidence-based medicine: Botulinum toxin A in migraine and tension-type headache. J Neurol 2001;248(suppl 1):3438. 150 Wollina U: Botulinum A toxin for wrinkles: Release from tension headache. J Eur Acad Dermatol Venereol 2000;14:142143. 151 Rollnik JD, Tanneberger O, Schubert M, Schneider U, Dengler R: Treatment of tension-type headache with botulinum toxin type A: A double-blind, placebo-controlled study. Headache 2000; 40:300305. 152 Porta M: A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache. Curr Rev Pain 2000;4:3135. 153 Relja MA, Korsic M: Treatment of tension-type headache by injections with botulinum toxin type A: A double-blind, placebo-controlled study. Neurology 1999;52(suppl 2):203. 154 Krack P, Horig C, Dorndorf W: Resolution of chronic tension-type headache after botulinum toxin treatment of idiopathic blepharospasm. Mov Disord 1995;10:388. 155 Zwart JA, Bovim G, Sand T, Sjaastad O: Tension headache: Botulinum toxin paralysis of temporal muscles. Headache 1994;34:458462. 156 Biondi DM: Headaches and their relationship to sleep. Dent Clin North Am 2001;45:685700. 157 Blitzer A, Sulica L: Botulinum toxin: Basic science and clinical uses in otolaryngology. Laryngoscope 2001;111:218226. 158 Brin MF, Fahn S, Moskowitz C, et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237254.
Gbel/Jost
124
159 Freund B, Schwartz M, Symington JM: The use of botulinum toxin for the treatment of temporomandibular disorders: Preliminary findings. J Oral Maxillofac Surg 1999;57:916920. 160 Freund B, Schwartz M, Symington JM: Botulinum toxin: New treatment for temporomandibular disorders. Br J Oral Maxillofac Surg 2000;38:466471. 161 Girdler NM: Use of botulinum toxin to alleviate facial pain. Br J Hosp Med 1994;52:363. 162 Von Lindern JJ: Type A botulinum toxin in the treatment of chronic facial pain associated with temporo-mandibular dysfunction. Acta Neurol Belg 2001;101:3941. 163 Sala C, Andreose JS, Fumagalli G, Lomo T: Calcitonin gene-related peptide: Possible role in formation and maintenance of neuromuscular junctions. J Neurosci 1995;15:520528. 164 Yanguela J, Pareja JA, Lopez N, Sanchez Del Rio M: Trochleitis and migraine headache. Neurology 2002;58:802805. 165 Moskowitz MA: Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43:S16S20. 166 Evans RW: Some observations on whiplash injuries. Neurol Clin 1992;10:975997. 167 Olesen J: Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs. Pain 1991;46:125132. 168 Ziegler DK: An overview of the classification, causes and treatment of headache. Hosp Community Psychiatry 1984;35:263267. 169 Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM: Botulinum toxin type A (Botox) for treatment of migraine headaches: An open-label study. Otolaryngol Head Neck Surg 2000;123: 669676. 170 Brin MF, Swope DM, OBrian C, Abbasi S, Pogoda JM: Botox for migraine: Double-bind, placebocontrolled region-specific evaluation. Cephalalgia 2000;20:421422. 171 Mauskop A, Basdeo R: Botulinum toxin A is an effect prophylactic therapy of migraines. Cephalalgia 2000;20:422. 172 Silberstein S, Mathew N, Saper J, Jenkins S: Botulinum toxin type A as a migraine preventive treatment. For the Botox Migraine Clinical Research Group. Headache 2000;40:445450. 173 Smuts JA, Barnard PWA: Botulinum toxin type A in the treatment of headache syndromes: A clinical report of 79 patients. Cephalalgia 2000;20:332. 174 Guyuron B, Tucker T, Davis J: Surgical treatment of migraine headaches. Plast Reconstr Surg 2002;109:21832189. 175 Klapper JA, Mathew NT, Klapper A, Kailasam J: Botulinum toxin type A for the prophylaxis of chronic daily headache. Cephalalgia 2000;20:291292. 176 Jost WH, Kohl A: Botulinum toxin: Evidence-based medicine criteria in rare indications. J Neurol 2001;248(suppl 1):3944. 177 Adler CH: Botulinum toxin A therapy in dystonia. Hosp Pract (Off Ed) 1991;26:35, 38, 4132. 178 Verheyden J, Blitzer A, Brin MF: Other noncosmetic uses of Botox. Semin Cutan Med Surg 2001; 20:121126. 179 Gbel H: Die Kopfschmerzen. Ursachen, Mechanismen, Diagnostik und Therapie in der Praxis. Berlin, Springer, 1997. 180 Relja MA: Treatment of tension-type headache with botulinum toxin: One-year follow-up. Cephalalgia 2000;20:336.
Prof. Dr. med. Dipl. Psych. Hartmut Gbel Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Heikendorfer Weg 927, D24149 Kiel (Germany) Tel. 49 431 20099 65, Fax 49 431 20099 35, E-Mail h.gobel@neurologie.uni-kiel.de
125
Treatment of Spasticity-Related Pain Syndromes

Jrg Wissel
Neurological Rehabilitation Hospital, Kliniken Beelitz GmbH, Beelitz-Heilsttten, Germany
It is not widely recognized that spasticity and other symptoms of the upper motor neurone syndrome (UMNS) can be extremely painful [1]. Spasticity by itself, abnormal posture and soft tissue changes in severe spasticity can give rise to an increased risk of exteroceptive pain and pain in turn may exacerbate spasticity. So patients with spasticity and related pain can enter a vicious circle of increased pain and increased spasticity (fig. 1). This chapter will present an overview on the botulinum toxin type A (BTX-A) treatment of peripheral nociceptive musculoskeletal pain associated with spasticity. Discussion will centre on typical syndromes of the upper and lower limb like the painful clenched fist or painful curled toes. There will be no specific discussion of central pain syndromes like thalamic pain syndrome or central post-stroke pain or pain associated with syringomyelia or incomplete spinal cord lesions. The effect of oral drug treatment on spasticity-related pain is often limited due to systemic side effects, therefore local approaches offer an attractive alternative. Intramuscular injections of BTX-A have been reported to alleviate pain associated with various conditions with and without excess muscle contractions [2] and studies in patients with cervical dystonia being treated with BTX-A suggest that pain relief exceeds the motor benefit [36]. BTX-A injections in spastic muscles have been shown to be effective in reducing spasticity and seem to represent the first-line treatment option in the management of focal spasticityrelated pain syndromes.
Spasticity
Botulinum toxin ROM Pain
Contractures
Fig. 1. Vicious cycle of spasticity-related pain and suggested mechanisms of action of BTX treatment in spasticity-related pain: The vicious circle describes the situation when increased spasticity or spastic dystonia leads to a decrease in ROM (ROM decreased range of motion) of involved joints which result in contractures and lead to focal pain. Suggested mechanisms of BTX action in the treatment of spasticity-related pain: Flash with *: intramuscular injection of BTX exerts its effect at the neuromuscular junction by blocking the release of acetylcholine on intrafusal and extrafusal muscle fibres which result in reduction of spastic muscle tone, compression of the muscles own vascular and subsequent increased oxygen supply of the muscles. Flash with : BTX is blocking the release of co-localized Substance P which can result in decrease or blocking of local SubstanceP-mediated sensitization reaction of nociceptors in the muscle.
Clinical Syndrome and Treatment of Spasticity-Related Pain
Definition Spasticity is the leading symptom of the UMNS and is characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex [7]. According to Young [8], several positive symptoms in addition to spasticity such as exaggerated cutaneous reflexes with painful spasms, mass reflexes, abnormal postures and negative symptoms such as paresis, lack of dexterity and fatigability form the UMNS. Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [9]. In patients with lesions of the central nervous system (CNS) who develop pain it is crucial for further management to make a clear distinction between peripherally induced nociceptive pain or a central pain pattern. Spasticity-related pain is characterized as nociceptive musculoskeletal pain of variable intensity in combination with increased muscle tone classified
127
as spasticity. Typically intensity of spasticity-related pain increases with intensity of spasticity and vice versa. Nociceptive pain is defined as pain resulting from normal operation of peripheral and central pain sensory system whereas central pain results from abnormal operation of the nervous system. The IASP defines central pain as pain initiated or caused by a primary lesion or dysfunction in the central nervous system [9]. Therefore in patients with CNS lesions (e.g. subcortical infarct in the territory of the left middle cerebral artery) either central pain (e.g. thalamic pain syndrome: spontaneous burning pain in the right upper extremity) or peripheral nociceptive pain (e.g. spasticity-related pain: painful spastic clenched fist on the right) or a combination of central and peripheral pain may be present. Furthermore, it is known that peripherally induced nociceptive pain may invoke central mechanisms like plasticity, sprouting or central sensitization which can also modify quality and quantity of pain perception [1012]. Additionally, in many patients spasticity-related pain may occur in body segments which are affected by other disabling symptoms, e.g. sensory loss, neglect or apraxia. Aetiology and Diagnosis Aetiology of CNS lesions resulting in UMNS with spasticity-related pain includes stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), encephalomyelitis disseminata (ED), hypoxic brain injury, cerebral palsy (CP) and other lesions of the CNS. Apart from these different aetiologies, some typical clinical syndromes of upper and lower limb spasticity-related pain can be characterized (see below: Recommendations for BTX Treatment in Typical Spasticity-Related Pain Syndromes). To make a reliable clinical diagnosis it is important to take into account the patients report on quality, frequency, occurrence and provoking factors of pain as well as the clinical investigation of muscle tone. Spasticity-related pain often presents with pulling or pressing quality, intensity typically varies and has a positive correlation to the degree of spastic muscle tone, velocity of passive joint motion and passive stretch of the muscles involved. On the other hand, central pain most commonly presents as spontaneous constant pain with burning, aching, pricking or lancinating quality without correlation to muscle tone, passive stretching of muscles or motion of the joints involved [9, 13]. However, some degree of evokable pain such as allodynia or hyperalgesia is typical in central pain syndromes [13]. As previously mentioned, diagnosis of spasticity-related pain requires a positive correlation between increasing velocity of muscle stretch and increasing amplitude of motion with increasing intensity of focal pain localized in the muscles or joints affected. Therefore, increasing pain during passive stretch is the typical clinical sign that could be used to identify muscles responsible for spasticity-related pain [14]. Additionally, in some patients a
Wissel
128
spontaneous tonic muscle activity classified as spastic dystonia [15] may lead to abnormal joint postures with secondary soft tissue changes resulting in fixed contractures and permanent limb disfigurement with severe spasticityrelated pain. Pathogenetic Mechanisms Pathogenesis of spasticity-related pain has not been fully established, but several hypotheses are under discussion. Spasticity-related pain seems largely due to the so-called vicious circle of spasticity (fig. 1). This vicious circle describes the situation when increased muscle tone or spastic dystonia leads to a decrease in range of motion (ROM) of the involved joint or movement segments which result over time in contractures and leads to focal pain. Additionally, pain by itself is a major factor to increase spasticity and vice versa (fig. 1). The term spastic dystonia is used to describe abnormal posture of a limb or body segment. Spastic dystonia can give rise to an increased risk of musculoskeletal pain. Abnormal postures may be produced by continuous muscle activity, dependent upon continuous supraspinal drive to the spinal -motoneurone pool but also by consecutive soft tissue and joint capsula changes [15]. According to physiological and histological investigations, peripheral structural changes in chronic spasticity consist of alterations in tendon compliance, changes in muscle fibres and connective tissue viscosity [1618]. Based on the ability of prolonged tonic muscle contraction and unphysiological stretch to elicit activity of muscle nociceptors, one hypothesis dedicates the development of muscle pain in spasticity to mechanical compression of nociceptors in the muscle itself. This hypothesis is based on recordings of the electrical activity of single muscle afferent units in cats which have shown activity of nociceptors in the muscle while unphysiological muscle stretching and prolonged contractions [19]. Another hypothesis dedicates spasticity-related pain under prolonged contraction to the compression of the muscles own vasculature and consume of large amounts of oxygen. Thus the muscle is forced to perform contractions under ischaemic conditions [20, 21]. Ischaemic muscle contractions activate nociceptors that are able to initiate muscle contraction (e.g. the flexor reflex [22]), most likely by release of inflammatory substances [23]. These inflammatory substances in turn lead to further pain and reflex spasm and might be able to contribute to the vicious cycle of spasticity-related pain. Secondary peripheral and central mechanisms in the nervous system (plasticity, sprouting and peripheral as well as central sensitization mechanisms) may also be relevant in generating and promoting spasticity-related pain.
129
Treatment Options Treatment should be considered when spasticity is causing harm, especially when patients complain about pain and related functional decline or disability. Physical measures (e.g. local application of cold, ultrasound and electrical stimulation) are helpful as first-line treatment. An important factor in management of spasticity-related pain is adequate handling and positioning of the painful spastic limb: (a) the limb should be placed in a physiological position using comfortable pillows or adjustable splints as long as possible, and (b) each passive motion of the limb should only be carried out at very slow velocities in order not to induce spasticity, spasms and consecutive pain. Daily physical treatment is sufficient to modify spasticity, reflex excitability and may contribute to the maintenance of the optimal muscle length as well as joint and connected soft tissue conditions in the movement segment involved. In particular, all methods to prevent contractures (e.g. positioning, day and night splinting), physiotherapy, sports and occupational therapy seem to be effective but the antispastic and analgesic effect of these treatment modalities are short-lived and have not been clearly established in controlled studies [24]. Beside recommended drug treatment of pain (see recommendations by the World Health Organisation) the management of spasticity and related pain involves drugs with specific antispastic potency. Antispastic drugs with clearly established efficacy in controlled studies can be broadly divided into those acting peripherally (e.g. dantrolen, phenol, alcohol or BTX-A) or in the CNS (e.g. baclofen, tizanidine, tetrazepam or diazepam). Those drugs acting in the CNS-mimicking effects of neurotransmitters utilized in descending, regulatory systems (e.g. 2-adrenergic receptor agonist tizanidine) or those which are used as neurotransmitters in spinal circuits (GABA-A receptor agonist diazepam or GABA-B receptor agonist baclofen) [25]. Controlled clinical trails showed antispastic efficacy of systemic oral treatment regimens with baclofen and tizanidine. However, in oral treatment regimens with recommended dosing regimens side effects like tiredness, sedation, generalized muscle weakness and hypotonia (baclofen, tizanidine, tetrazepam, diazepam) or diarrhoea (dantrolene) and dry mouth (tizanidine) limit their clinical use [25, 26]. Beside oral drug treatment, intrathecal baclofen, clonidine or morphine administration, nerve, spinal cord and cortex stimulation and destructive peripheral and central surgical procedures are effective in selected cases with severe generalized or widespread segmental spasticity-related pain and otherwise unresponsive pain and spasticity [2729]. Neurolytic and chemodenervation procedures are further elements of spasticity-related pain management, especially in localized focal spasticity-related pain syndromes. Besides alcohol and phenol nerve
Wissel
130
blocks with the risk of permanent necrosis and painful dysaesthesias [26, 30], local treatment with intramuscular injections of BTX appears to be safe and effective [3135].
Botulinum Toxin in Spasticity-Related Pain Syndromes
In controlled trials, BTX-A has been shown to decrease focal spasticity, increase ROM of affected joints, facilitate hygiene and reduce spasticityassociated disability [3135]. Treatment of spasticity-related pain with BTX-A should be considered when spasticity and pain occur in the same body region and a positive correlation between the degree of spasticity and pain can be established [14]. To identify muscles for BTX treatment in spasticity-related pain management, clinical investigation of the body segment affected is crucial. Increasing pain while passive stretching of spastic muscles is the clinical sign to identify muscles responsible for spasticity-related pain [14]. In some patients the development of spasticity-related pain parallels the occurrence of spastic dystonia with the development of limb disfigurement and consecutive contractures. Biomechanical analysis of the joint position or limb disfigurement resulting from spastic dystonia also allows identifying the muscles responsible for pain in this condition [36]. Muscles that often contribute to the common spasticityrelated pain syndromes and dose ranges recommended for treatment are summarized in tables 13. Once identified, an adequate dose of BTX should be placed in the muscles targeted (recommendations: maximum dose in adults per session: 400 units Botox, 1,500 units Dysport, 15,000 units NeuroBloc; maximum dose in children per session: 12 units Botox per kilogram body weight or 300 units Botox, 1,000 units Dysport, 10,000 units NeuroBloc; maximum dose per injection site: 50 units Botox, 200 units Dysport, 2,500 units NeuroBloc). Correct placement in the muscle selected for treatment is crucial, therefore in case of difficult anatomical situation with deep and small muscles sonographic or electrophysiological (electromyographical/electrical stimulation) guidance of BTX injection is recommended whereas in superficially located and anatomically welldefined muscles straightforward injection without guidance is sufficient [36]. Intramuscular injection of BTX exerts its primary effects at the neuromuscular junction by blocking the release of acetylcholine (ACH) with subsequent reduction of muscle tone and spasms 314 days following injection (fig. 1). Recently, Ishikawa et al. [37] have shown in an animal experiment that besides blocking the release of ACH, the release of co-localized Substance P may also be inhibited by BTX-A injections. Inhibition of Substance P release in a painful
131
Table 1. Spasticity-related pain syndromes in upper limb Syndrome Muscles Dose range recommended, IU Botox Internally rotated and adducted shoulder Flexed elbow and pronated forearm Flexed wrist Clenched fist Thumb-in-palm Pectoralis major Teres major Latissimus dorsi Biceps brachii Brachialis Pronator teres Flexor carpi radialis Flexor carpi ulnaris Flexor digitorum spf. Flexor digitorum prf. Flexor pollicis longus Thenar muscles Adductor pollicis 5075 2550 5075 75125 5075 5075 3075 3060 3060 3060 3060 2030 1020 Dysport 200300 100200 200300 300600 200300 200300 120300 100200 100200 100200 100200 60120 4080 NeuroBloc 2,5004,000 1,5003,000 2,5004,000 4,00010,000 2,5004,000 2,5004,000 2,0004,000 1,5003,000 1,5003,000 1,5003,000 1,5003,000 1,0001,750 7501,500
Spasticity-related pain syndromes, muscles responsible and starting dose range recommended for treatment (maximum dose in adults per session: 400 units Botox, 1,500 units Dysport, 15,000 units NeuroBloc; maximum dose per child per session: 12 units Botox per kilogram body weight or 300 units Botox, 1,000 units Dysport, 10,000 units NeuroBloc; maximum dose per injection site: 50 units Botox, 200 units Dysport, 2,500 units NeuroBloc). Table 2. Spasticity-related pain syndromes in head and neck region Syndrome Muscles Dose range recommended, IU Botox Head deviation (tonic neck reflexes) Trapezius Splenius capitis Levator scapulae Sternocleidomastoid Temporalis Masseter Pterygoid medialis 3040 3060 3060 2030 2030 2030 2030 Dysport 120160 120240 120240 80120 80120 80120 80120 NeuroBloc 1,7503,000 1,7504,000 1,7504,000 1,5002,000 1,5002,000 1,5002,000 1,5002,000
Clenched jaw (bruxism)
Spasticity-related pain syndromes, muscles responsible and starting dose range recommended for treatment (maximum dose in adults in head/neck region per session: 200 units Botox, 1,000 units Dysport, 10,000 units NeuroBloc; maximum dose per child in head/neck region per session: 6 units Botox per kilogram body weight or 150 units Botox, 500 units Dysport, 5,000 units NeuroBloc; maximum dose per injection site: 50 units Botox, 200 units Dysport, 2,500 units NeuroBloc).
Wissel
132
Table 3. Spasticity-related pain syndromes in lower limb Syndrome Muscles Dose range recommended, IU Botox Flexed hip and adducted thighs (adductor spasm) Iliopsoas Rectus femoris Adductor longus Adductor magnus Adductor brevis Gracilis Semitendinosus Semimembranosus Gracilis Biceps femoris Gastrocnemius Quadriceps: Rectus femoris Vastus medialis Vastus lateralis Vastus intermedius Medial gastrocnemius Soleus Tibial posterior Extensor hallucis longus Extensor hallucis long Flexor digitorum longus Flexor digitorum brevis Flexor hallucis longus 75150 50100 5080 50100 5080 5080 50100 50100 50100 50100 50100 200300 50100 5080 5080 5080 50150 50150 50150 2550 2550 5080 2550 2550 Dysport 300750 200500 200300 200500 200300 200300 200500 200500 200500 200500 200500 8001,200 200500 200300 200300 200300 200500 200500 200500 100200 100200 200300 100200 100200
Flexed knee (flexor spasm)
Extended knee (extensor spasm)
Equinovarus foot
Hitchhikers grand toe Curled/claw toes
Spasticity-related pain syndromes, muscles responsible and starting dose range recommended for treatment (maximum dose in adults per session: 400 units Botox, 1,500 units Dysport; maximum dose per child per session: 12 units Botox per kilogram body weight or 300 units Botox, 1,000 units Dysport; maximum dose per injection site: 50 units Botox, 200 units Dysport).
spastic muscle may additionally result in decrease or blocking of local sensitization reaction of nociceptors in the muscle (fig. 1). Recent studies demonstrated higher affinity of activated muscle fibres to BTX-A in patients with hemifacial spasm [38] and following local electrical stimulation [39] the toxin is most likely to act in active muscle fibres mainly involved in generating muscle spasms and spastic hypertension. Furthermore, BTX-A acts
133
on intrafusal and extrafusal muscle fibres [40] and therefore removes facilitation from the treated and inhibition from the antagonistic muscle [41]. Adjunctive to local BTX injections, passive stretching of the muscles injected is necessary to gain maximum treatment effect. Splints or casts are helpful to regain or maintain the optimal muscle length as well as joint and soft tissue conditions in the movement segment treated. Daily physical or occupational therapy is also sufficient to enhance the effect of BTX injections to modify spasticity-related pain and seems to prolong the antispastic and analgesic effets of BTX [24]. Up to now only two studies focussing on local BTX-A treatment of spasticity-related pain syndromes have been published. Therefore, more placebo-controlled and dose-ranging studies are necessary to further evaluate and elaborate this promising method. Beside these challenges for further trails it can be concluded that local BTX-A injections are effective and well tolerated in reducing spasticity-related local nociceptive pain. BTX may serve as firstline treatment especially in patients with focal spasticity-related pain syndromes or in case of poor response or intolerable side effects to oral or intrathecal drug treatment.
Published Data
In five open trails, pain relief was mentioned as an additional benefit of local BTX-A spasticity treatment [4246]. Recent published controlled studies confirm the efficacy of BTX-A in focal spasticity treatment of the upper and lower limbs [3235], but none of the trials showed a significant decrease of pain following BTX-A treatment. However, these results might partially be explained by the design of these studies for the following reasons: (1) not all patients included had pain as major complaint; (2) pain reduction did not serve as primary efficacy measure in most studies, and (3) pain was not defined with respect to the aetiology of pain (central and/or spasticity-related pain). Up to now, only two trials focused on spasticity-related pain or painful spasms as a primary outcome measure in the evaluation of local BTX-A treatment are published. Wissel et al. [14] included 60 adults with acute or chronic spasticityrelated pain and cerebral palsied children with spasticity-related pain in an open prospective multicentre study. Local intramuscular BTX-A injections were targeted in muscles which exhibiting increased spastic muscle tone in combination with local pain during passive joint movement. Muscle selection and dosing were individualized and patients received a mean total dose of 165 (range 30400) units Botox in a mean of 34 muscles per treatment session.
Wissel
134
Baseline and follow-up measures included a patient self-assessment of pain and function on a five-level scale. This instrument showed that 90% of the patients experienced a decrease in severity of pain following BTX-A. Relief of spasticityrelated pain started about 1 week following injection and lasted about 412 weeks. Only mild reversible side effects (local pain, haematoma, oedema, mild weakness) were observed in 4 patients. Barwood et al. [47] reported antinociceptive effects of intramuscular BTX-A upon administration of 6 units Botox per kilogram body weight in spastic adductor muscles on both sides 12 weeks prior to a standardized procedure of adductor-release surgery under standardized anaesthesia in children with spastic CP. In a standardized postoperative setting a reduced need for analgesics (morphine and other analgesics) was reported in children treated with BTX-A compared to the children receiving placebo. Children receiving BTX-A prior to surgery were also discharged earlier and had lower pain scores in a doubleblind, placebo-controlled study design. No child showed side effects following placebo or BTX-A injections. The positive effect of BTX-A on postoperative spasticity-related pain and spasm management was so dramatic in the pilot phase of the study that the trial was terminated prematurely.
Recommendations for Botulinum Toxin Treatment in Typical Spasticity-Related Pain Syndromes
This chapter and tables 13 summarizes key information about frequently observed spasticity-related pain syndromes that are associated with spastic movement pattern or posturing of the upper and lower limb and head and neck region. Common spastic muscle activation pattern (spasticity, spastic synergies and spastic dystonia) resulting in spasticity-related pain and recommendations for BTX treatment are summarized (see tables 13). Nevertheless, it should be remembered that not all muscles mentioned in the tables as relevant for specific spasticity-related pain syndromes will be involved in a painful spastic limb in a particular patient. Therefore, clinical investigation of the muscles listed in the tables for identification of the relevant spastic muscles contributing to spasticity-related pain in the particular patient offers a useful evaluation strategy to develop an adequate individualized treatment plan for BTX treatment [14, 24]. In syndromes due to supratentorial brain lesions (e.g. stroke in the region of the anterior or middle cerebral artery), spasticity-related pain often occur when passive movement is directed against the typical post-stroke spastic movement pattern called Wernicke-Mann pattern with a dominant flexor synergy in the upper and an extensor synergy in the lower limb. In the upper limb
135
these typical movement patterns consist of internally rotated and adducted shoulder with flexed elbow, pronated forearm, flexed wrist and clenched fist, occasionally in combination with thumb-in-palm deformity or tonic activation of the intrinsic hand muscles. In the lower limb the Wernicke-Mann pattern leads to a flexed adducted hip and stiff-knee pattern (decreased ROM, often combined with recurvation of the knee) with equinovarus foot position, frequently combined with flexor spasms of the toes (claw toes) and hitchhikers grand toe [24, 48]. Painful muscle spasms are rare in patients with supratentorial brain lesions with dominant Wernicke-Mann spasticity. On the other hand, patients with spasticity due to brainstem lesions, SCI or in chronic stages of MS often suffer from typical combination of spontaneous or stimulus-triggered painful muscle spasms (extensor, flexor or adductor spasms) with severe attacks of spasticity-related pain. In patients with tetraspastic pattern due to midbrain or brainstem lesions, head and neck as well as limb positions often are dominated by vestibular or tonic neck reflexes which result in spastic posturing (e.g. lateroflexion and rotation) of the head/neck and typical asymmetric tonic neck reflex synergies of the limbs which could lead to painful spastic dystonia syndromes. Typicially, in patients with large lesions in the pontine area spastic trismus with painful clenched jaw and difficulties in oral hygiene and nutrition occur. Also patients with multiple or diffuse lesions of the CNS (e.g. following severe TBI or hypoxic brain injury) suffer from clenched jaw and bruxism with pain and discomfort in the preauricular and lower face area. In patients with diffuse lesions of the CNS the lower limbs typically develop a disabling and painful flexed-knee pattern in combination with slide internal rotation, severe adduction and flexion of the hips and equinus position of the ankle with clawed toes.
Acknowledgements
To Jrg Mller, MD, Department of Neurology, University of Innsbruck; Klemens Fheodoroff, MD, Neurological Rehabilitation Centre Hermagor, Austria, and Urban Fietzek, MD, Child & Brain Bonn-Berlin GmbH, Germany, for review of the manuscript.
References
1 Barnes MP: An overview of the clinical management of spasticity; in Barnes MP, Johnson GR (eds): Upper Motor Neurone Syndrome and Spasticity. Cambridge, Cambridge University Press, 2001, pp 111. Aoki KR: Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001; (suppl 1):310.
Wissel
136
3 4 5
7 8 9 10 11
12
13 14 15 16 17 18 19
20 21 22 23 24 25
26 27
Jankovic J, Schwartz K: Botulinum toxin injections for cervical dystonia. Neurology 1990;40: 277280. Tsui JKC, Eisen A, Stoessl AJ, Calne S, Calne DB: Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;ii:245247. Jankovic J, Schwartz K, Donovan DT: Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633639. Wissel J, Kanovsky P, Ruzicka E, Bares M, Kortova H, Streitova H, Jech R, Roth J, Brenneis C, Mller J, Schider P, Auff E, Richardson A, Poewe W: Efficacy and safety of a standardised 500 unit dose of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: Results of a prospective, multicentre, randomised double-blind, placebo-controlled parallel group study. J Neurol 2001;248:10731078. Lance JW: Symposium synopsis; in Feldman RG, Young RR, Koella WP (eds): Spasticity: Disordered Motor Control. Chicago, Year Book Medical, 1980, pp 485494. Young RR: Spasticity: A review. Neurology 1994;44 (suppl 9):1220. Merskey H, Bogduk N (eds): Classification of Chronic Pain, ed 2. Seattle, IASP Press, 1994. Millan MJ: The induction of pain: An integrative review. Progr Neurobiol 1999;57:1164. Mailis A, Bennett G: Painful neurological disorders: From animals to humans; in Aronoff GM (ed): Evaluation and Treatment of Chronic Pain, ed 3. Baltimore, Williams & Wilkins, 1998, pp 8192. Dougherty PM, Lenz FA: Plasticity of the somatosensory systems following neural injury; in Boivie J, Hansson P, Lindblom U (eds): Progress in Pain Research and Management. Touch Temperature and Pain in Health and Disease: Mechanisms and Assessments. Seattle, IASP Press, 1994, vol 3, pp 439459. Nicholson K: An overview of pain problems associated with lesions, disorders or dysfunction of the central nervous system. Neurol Rehabil 2000;14:313. Wissel J, Mller J, Dressnandt J, Heinen F, Naumann M, Topka H, Poewe W: Management of spasticity associated pain with botulinum toxin A. J Pain Symptom Manage 2000;20:4449. Sheean GL: Pathophysiology of spasticity; in Sheean G (ed): Spasticity Rehabilitation. London, Churchill Communications Europe Ltd, 1998, pp 1738. Dietz V, Berger W: Normal and impaired regulation of muscle stiffness in gait: A new hypothesis about muscle hyertonia. Exp Neurol 1983;79:680678. Thilmann AF, Fellows SJ, Garms E: The mechanism of spastic muscle hypertonus: Variation in reflex gain over the time course of spasticity. Brain 1991;114:233244. Dwyer NJ, Ada L, Neilson PD: Spasticity and muscle contracture following stroke. Brain 1996;119:17371749. Simone DA, Caputi G, Marchettini P, Ochoa JL: Slowly conducting, high threshold mechanoreceptors microrecorded from human striatal muscle: Receptor responses, axonal conduction velocity and projected pain. Soc Neurosci 1991;17:1368. Alo KM, Yland MJ, Kramer DL, Charnov JH, Redko V: Botulinum toxin in the treatment of myofascial pain. Pain Clin 1997;10:107116. Travell J, Rinzler SH: The myofacial genesis of pain. Postgrad Med 1952;11:425434. Emre M, Mathies H: Muscle Spasms and Pain. London, Parthenon, 1988. Mense S: Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993;54: 241289. Ward AB: A summary of spasticity management A treatment algorithm. Eur J Neurol 2002; 9(suppl 1):4852. Emre M: New developments in the medical treatment of spasticity; in Thilmann AF, Burke DJ, Rymer WZ (eds): Spasticity: Mechanisms and Management. Berlin, Springer, 1993, pp 372383. Abbruzzese G: The medical management of spasticity. Eur J Neurol 2002;9(suppl 1):3034. Kasdon KL, Abromovitz JN: Neurosurgical approaches; in Glenn MB, Whyte J (eds): The Practical Management of Spasticity in Children and Adults. Philadelphia, Lea & Febiger, 1990, pp 259267.
137
28 29 30
31 32
33
34
35
36
37
38
39
40 41
42 43 44 45 46
Lazorthes Y, Sol JC, Sallerin B, Verdie: The surgical management of spasticity. Eur J Neurol 2002;9(suppl 1):3541. Albright AL, Barron WB, Fasick MP, Polinko P, Janosky J: Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993;270:24752477. Kirazli Y, On AY, Kismali B, Aksit R: Comparison of phenol block and botulinus toxin type A in the treatment of spastic foot after stroke: A randomised, double-blind, placebo-controlled trial. Am J Phys Med Rehabil 1998;77:510515. Snow BJ, Tsui JKC, Bhatt MH, Varelas M, Hashimoto SA, Calne DB: Treatment of spasticity with botulinum toxin A: Double-blind study. Ann Neurol 1990;28:512515. Simpson DM, Alexander DN, OBrien CF, Tagliati M, Aswad AS, Leon JM, Gibson J, Mordaunt JM, Monaghhan EP: Botulinum toxin type A in the treatment of upper extremity spasticity: A randomised, double-blind, placebo-controlled trial. Neurology 1996;46:137 13061310. Hyman N, Barnes M, Bhakta B, Cozens A, Bakheit M, Kreczy-Kleedorfer B, Poewe W, Wissel J, Bain P, Glickman S, Sayer A, Richardson A, Dott C: Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: A prospective, randomised, doubleblind, placebo-controlled, dose-ranging study. J Neurol Neurosurg Psychiatry 2000;68: 707712. Bakheit M, Thilmann AF, Ward AB, Poewe W, Wissel J, Mller J, Benecke R, Collin C, Mller F, Ward CD, Neumann C: A randomised, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke 2000;31:24022406. Brashear A, Gordon MF, Elovic E, Kassicieh VD, Marciniak C, Do M, Lee CH, Jenkins S, Turkel C: Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after stroke. N Engl J Med 2002;347:395400. Wissel J, Mller J, Poewe W: Electromyography for identification of dystonic and spastic muscles and techniques for guidance of injections; in Moore AP, Naumann M (eds): Handbook of Botulinum Toxin Treatment, ed 2. Oxford, Blackwell Science, 2002. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, Shimizu K: Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscle. Jpn J Ophthal 2000;44:106109. Glocker FX, Guschlbauer B, Lcking CH, Deuschl G: Effects of local injections of botulinum toxin on electrophysiological parameters in patients with hemifacial spasm: Role of synaptic activity and size of motor units. Neurosci Lett 1995;187:161164. Hesse S, Reiter F, Konrad M, Jahnke T: Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: A randomised, doubleblind, placebo-controlled trial. Clin Rehabil 1998;12:381388. Rosales RL, Arimura K, Takenaga S, Osame M: Extrafusal and intrafusal effects in experimental botulinum toxin A injection. Musc Nerve 1996;19:488496. Wissel J, Mller J, Baldauf A, Ung SC, Ndayisaba JP, Stckl B, Frischhut B, Haberfellner H, Poewe W: Gait analysis to assess the effects of botulinum toxin type A treatment in cerebral palsy: An open-label study in 10 children with equinus gait pattern. Eur J Neurol 1999; 6(suppl 4):6367. Dunne JW, Heye N, Dunne SL: Treatment of chronic limb spasticity with botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;58:232235. Grazko MA, Polo KB, Jabbari B: Botulinum toxin A for spasticity, muscle spasms and rigidity. Neurology 1995;45:712717. Pierson SH, Katz DI, Tarsy D: Botulinum toxin A in the treatment of spasticity: Functional implications and patient selection. Arch Phys Med Rehabil 1996;77:717721. Memin B, Pollak P, Hommel M, Perret J: Treatment of spasticity with botulinum toxin. Rev Neurol 1992;148:212214. Bhakta BB, Cozens JA, Bamford JM, Chamberlain MA: Use of botulinum toxin in stroke patients with severe upper limb spasticity. J Neurol Neurosurg Psychiatry 1996;61:3035.
Wissel
138
47
48
Barwood S, Baillieu C, Boyd R, Brereton K, Low J, Nattrass G, Graham HK: Analgetic effects of botulinum toxin A: A randomised placebo-controlled clinical trail. Dev Med Child Neurol 2000;42:116121. Moore AP: Botulinum toxin A for spasticity in adults. What is the evidence? Eur J Neurol 2002;9(suppl 1):4247.
Ao. Univ.-Prof. Dr. Jrg Wissel Neurologische Rehabilitationsklinik, Kliniken Beelitz GmbH, Paracelsusring 6a, D14547 Beelitz-Heilsttten (Germany) Tel. 49 33 204 21140, Fax 49 33 204 22309, E-Mail wissel@gesundheitspark.com
139
Treatment of Piriformis Syndrome with Botulinum Toxin

Gerhard Reichel
Paracelsus Clinic, Zwickau, Germany
The first report of the piriformis syndrome (PS) was published 75 years ago [1]. Although it is mentioned in relevant monographs, in clinical practice it is not always taken into account adequately well in the differential diagnosis of back-buttocks-leg pain [2, 3]. Apart from a few exceptions, only isolated case records are found in the literature [4, 5]. The incidence of PS in the United States is estimated at 4.86.4 million cases annually [6].
Definition
According to several authors, the pathogenic mechanism underlying PS is a myofascial pain syndrome caused by contraction of the piriform muscle [79]. Most investigators, however, define it as bottleneck syndrome or irritation syndrome of the sciatic nerve (or portions of it) at the level of the infrapiriform foramen [1016]. In most cases, definition as myofascial pain syndrome requires but the presence of typical trigger points and the appropriate area for pain radiation (referred pain). By contrast, definition as bottleneck syndrome requires the presence of typical subjective and objective symptoms (table 1).
Etiology/Pathogenesis
In general, the medical literature assumes that PS, in most cases, is a bottleneck syndrome, primarily involving the sciatic nerve [17]. The piriform muscle originates from the anterior wall of the sacral bone (at the level of the 2nd to 4th anterior sacral foramina), runs through the greater sciatic foramen and inserts into the greater trochanter. It abducts the flexed thigh and rotates the
Table 1. Clinical definition of PS Subjectively 1. Pain in buttocks radiating into the coccygeal bone and/or thigh 2. Increase in pain while sitting on hard mattress, during bending and prolonged walking 3. Facultatively: gluteal trauma in the history Objectively 1. Trigger point at typical location 2. Increase in pain a) By passive forced hip adduction b) During impairment of active hip abduction 3. Pain relief on lateral rotation of the foot in end position with positive Lasgues sign
extended leg laterally. The piriform muscle does not fill the entire lumen of the greater sciatic foramen. Anatomical structures such as the pudendal and inferior gluteal nerves (and the homonymous arteries and veins) as well as the posterior cutaneous femoral nerve and the sciatic nerve run through this free space below the muscle (infrapiriform foramen) (fig. 1). The infrapiriform foramen is the only physiologic narrow pass for the latter two nerves. Analogous to other bottleneck syndromes (e.g., carpal tunnel syndrome), this clinical picture should correctly be termed syndrome of infrapiriform foramen. Passive local hyperemia occurs by pressure of the muscle on vascular network abundantly surrounding the sciatic nerve [18]. In addition, in the presence of myositis of the piriform muscle, a biochemical alteration of the nerve is discussed [19, 20]. An alteration of the mechanical muscle-nerve situation may occur during atrophy of the muscle, hypertrophy and spasm of the muscle, but also, if the range of excursion of the sciatic nerve is limited because of inflammatory changes at lumbosacral roots or due to spondylolisthesis with lumbar lordosis. Sciatic and posterior cutaneous femoral nerves may directly be damaged by blunt gluteal traumas. Such instances pose less diagnostic problems. In addition, however, traumatic lesions of the piriform muscle and adjacent tissues may not lead to stenotic changes of the infrapiriform foramen until cicatricial tissue shrinkage occurs. Hence, years may pass by between trauma and clinical manifestation of the PS, and many a patient will no longer recall the traumatic event. The vulnerability of the nerve increases if portions or all of the sciatic nerve run through the piriform muscle or through the tendons of a partitioned piriform muscle [2125] (fig. 2). In the latter case the posterior cutaneous femoral nerve may also be partitioned: One branch accompanies the tibial portion of the sciatic nerve below the piriform muscle and supplies sensory areas of the perineum and the medial posterior aspect of the thigh; the other
Piriformis Syndrome
141
N. glutaeus sup.
M.p F. ip N. glutaeus inf. N. pudendus
N. cut. fem. post
N. ischiadicus
Fig. 1. Schema of infrapiriform foramen. F. ip form muscle.
Infrapiriform foramen; M. p
piri-
branch accompanies the peroneal portion of the sciatic nerve, runs through the piriform muscle and supplies the lower sensory regions of the buttocks (nervi clunium inferiores) and the lateral posterior aspect of the thigh. In approximately 15%, the inferior gluteal nerve extends through the piriform muscle as well [26]. Of note is the fact that in most cases the PS is not associated with significant motor deficits of the sciatic nerve. In other bottleneck syndromes of peripheral nerves containing sensory fibers, however, pain at least in the beginning is also the predominant symptom (e.g., carpal tunnel syndrome). The question arises whether or not, in many a case, all symptoms of the PS are attributable to the painful contraction of the muscle and to the irritation of the
Reichel
142
78%
21%
1%
Fig. 2. Schematic representation of course variants of the sciatic nerve [according to 25]. a Entire sciatic nerve running through the infrapiriform foramen. b Portion of the sciatic nerve running through the piriform muscle. c Portion of the sciatic nerve running through the suprapiriform foramen.
posterior cutaneous femoral nerve. In such a case, it should be regarded as bottleneck syndrome of the posterior cutaneous femoral nerve rather than the sequel of a lesion of the sciatic nerve. Since the autonomic cutaneous area of innervation is relatively small, a sensory deficit may be missing if the posterior cutaneous femoral nerve is damaged, whereas pain may radiate into the entire area supplied by this nerve (table 2). Gluteal atrophy is occasionally observed in the setting of a PS [27]. In these cases Dyck et al. [28] found endometriotic tumors as the cause for the
Piriformis Syndrome
143
Table 2. Causes of piriformis syndrome (references and own experience) 1. 2. Gluteal trauma (possibly years ago) [31] (fig. 3) Predisposing anatomical variants: double piriform [32], superior gemellus or gluteal [33] muscles, course variants of sciatic [23, 34], posterior cutaneous femoral and inferior gluteal nerves and passage through the piriform muscle or its tendons Hypertrophy of the piriform muscle due to 3.1. Exercise (track-and-field sports) [35] 3.2. Chronic contraction due to psychic causes 3.3. Dystonia musculorum deformans [36] 3.4. Coxarthrosis or subsequent to hip arthroplasty [37, 38] (fig. 7) 3.5. Scoliosis [39] 3.6. Abnormal psoas primordium (fig. 4) Abscess [40, 41], myositis [42], hematoma [4345], bursitis [46] of piriform muscle Neoplasms in the area of the infrapiriform foramen [47], colorectal [29], neurinoma of sciatic nerve (fig. 6) Limitation of excursion of sciatic nerve (inflammatory changes of roots, postlaminectomy syndrome, sacroiliac arthritis, spondylolisthesis and lumbar lordosis [48, 49] Femoral nailing [5052] Myositis ossificans of piriform muscle [53] Gluteal abscess [40] Thrombosis of iliac vein Pseudoaneurysm of inferior gluteal artery following gynecologic surgery [54] Intragluteal injections [55] Klippel-Trnaunay syndrome (fig. 8)
3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
narrowing of the infrapiriform foramen. LaBan et al. [29] described the occurrence of neuropathy of the inferior gluteal nerve in 5 patients with recurrent rectal carcinoma. The complete syndrome of the infrapiriform foramen, i.e., lesion of all four nerves running through this narrow pass, should only have to be expected in case of severe traumatic damage, large regional neoplasm and as a result of incorrect intramuscular injection. Hence, deficit symptoms of the sciatic, pudendal and inferior gluteal nerves should always be grounds for intensive etiologic search. In addition, an upper PS has been described: Pressure of the anterior upper portion of the muscle causes a bottleneck syndrome of the superior gluteal nerve [30] (fig. 39).
Symptoms and Signs
In the majority of cases the PS occurs in middle-aged patients (mean age 38 years [31]) and markedly more frequent (about 6 times [54]) in females than
Reichel
144
in males. In addition to complaints listed in the definition, objective findings obtained without technical assistance are relevant for the establishment of the diagnosis. Deep leg vein thrombosis with leg swelling may occasionally occur as a result of PS [56] (fig. 1017). In the supine position at rest a slight lateral rotation of the foot is detectable as manifestation of spasm or shortening of the piriform muscle (fig. 13). The piriform muscle is palpable from the outside, rectally or vaginally. Palpation through the gluteal muscle is executed as follows [57]: The junction is located between the middle and lower third of the line between the anterior superior iliac spine and the end of the coccygeal bone. A bimanual approach is advised on rectal or vaginal examination: The right index finger deeply inserted towards the coccygeal bone is advanced to the greater sciatic foramen. At the same time the left index finger is pressed on the aforementioned external point of projection. The piriform muscle is now felt between both index fingers. In PS a change in muscular consistency is sometimes palpable. Pain is regularly triggered radiating into the buttocks, posterior aspect of the thigh or lumbar region [58]. In addition, authors considering PS a myofascial pain syndrome have described trigger points and pain reference zones [8, 59, 60]. Sensory defects may be completely missing in PS. If present, they are consistent with the supply area of the posterior cutaneous femoral nerve: nervi clunium inferiores (lower border of buttocks) and posterior cutaneous branches of femoral nerve (posterior aspect of the thigh down to the popliteal cavity or below) (fig. 11). Sensory defects may also affect areas supplied by the sciatic nerve and, very rarely, even may mimic a lesion of the sural nerve [61]. Lasgues sign may be positive in PS. A typical finding is pain relief on lateral rotation of the leg once the trigger point is reached [according to 62] (fig. 14). Beattys maneuver [63] (fig. 15) consists in the elevation of the flexed leg on the painful side while lying on the asymptomatic side. In PS this maneuver causes deep-seated gluteal pain. In lumbar spine syndromes, pain occurs in the back and legs; in hip-joint affections, pain is present in the trochanter, not, however, in the buttocks. Paces sign [64] (fig. 16) is characterized by an increase in symptoms on passive prolonged flexion, adduction and medial rotation of the hip. Freibergs sign [65] is characterized by pain due to prevention of active hip abduction while sitting (fig. 17). Of all these tests, tenderness on rectal palpation of the piriform muscle is said to be the most reliable diagnostic tool [2].
Piriformis Syndrome
145
6 3
7a
4a
7b
4b
Reichel
146
9 Fig. 39 Examples of PS. 3 PS in a 46-year-old woman: CT: side difference of the piriform muscles following blunt gluteal trauma 3 years ago. 4 Full-blown clinical picture of PS in a 37-year-old man. a Hypertrophy of the left-sided piriform muscle. b Cause: missing leftsided psoas muscle. 5 PS with hypertrophy of the piriform muscle and atrophy of the left-sided middle gluteal muscle (bottleneck lesion of the inferior gluteal nerve). Cause: left-sided ovarian cyst. 6 Sciatic neurinoma with atrophy of the piriform and gluteal muscles in a 42-year-old man. 7 A 67-year-old female patient with typical PS following left-sided hip arthroplasty. a Hypertrophy of left-sided piriform muscle. b Pronounced right-sided coxarthrosis with hipjoint ankylosis. The left-sided piriformis hypertrophy is due to the overload of the left-sided hip joint. 8 A 43-year-old woman with PS in the presence of Klippel-Trnaunay syndrome (triad: cutaneous capillary hemangiomas, circumscribed hypertrophy of connective tissue, varicosis) with enlargement of the left-sided buttocks and large hemangiomas in uterus and bladder. 9 A 37-year-old woman: no clinical signs or findings of PS in imaging studies following gluteal trauma: isolated scar of the gluteal muscle without irritation of nerve structures.
Not infrequently, the presence of PS is overlooked. PS is often diagnosed as postlaminectomy syndrome, coccygodynia or pseudoradicular S1 syndrome [66]. On average, five different physicians are consulted, and 32 months go by until PS is eventually diagnosed [31]. More rarely, PS is erroneously presumed if another cause of pain has been established which is most likely if PS is presumed and incorrectly treated without adequate diagnostic evidence, solely based on trigger points or reference zones. In addition, pure lesions of the gluteal muscle (fig. 9) without narrowings of the infrapiriform foramen and without the mentioned signs of PS, unrecognized pelvic fractures or undiagnosed stones of the kidney [67] may lead to the erroneous diagnosis of PS. Ever since modalities of patient information have been improved via the media and the Internet, more and more patients with somatization disorders
Piriformis Syndrome
147
12
10
13
11
14
Reichel
148
15
17
16 Fig. 1017. Clinical piriformis test. 10 Schematic representation of the piriform muscle with trigger point. 11 Area of sensory impairment in PS. 12 Trigger point. 13 Slight lateral rotation of foot. 14 Complemented Lasgues sign [according to 62]: once the painful angle is reached, the foot is rotated laterally, thereby relieving the pain. 15 Test according to Beatty: in the lateral position on the normal side the flexed leg is actively elevated. Pain occurs: in PS in the buttocks, in hip-joint affections in the trochanter, in lumbosacral root lesions in the back and leg. 16 Test according to Freiberg: the leg flexed in the knee and hip joint is passively rotated medially in the hip joint, thereby provoking pain. 17 Test according to Pace: pain occurs if active abduction in the hip joint is prevented while sitting.
Piriformis Syndrome
149
show up who refuse to be talked out of their self-established diagnosis of PS and who demand invasive treatment modalities. Neurophysiologic test methods primarily serve to rule out other illnesses. The diagnostic scope of electromyography is limited to the detection of spasms of the piriform muscle or signs of denervation [57]. Similarly limited is the validity of electroneurography. The presence of normal electroneurographic findings of the sciatic nerve does not rule out PS. Specific test methods will find out if the inferior gluteal nerve and the posterior cutaneous femoral nerve, respectively, are involved [68]. If abnormal findings are present prolonged reflex time elicitation of the H-reflex may corroborate the tentative diagnosis of PS [69]. The FAIR test is an elective means of diagnosis PS and assessing clinical improvement. This test compares posterior tibial and peroneal H-reflexes elicited in the anatomical position, with H-reflexes obtained in flexion, adduction and internal rotation (FAIR test; normal mean prolongation: 0.01 0.62 ms). Electrophysiological criterion for diagnosis of PS is a 1.86-ms prolongation of the FAIR test. This test is well correlated with visual analogue estimates of pain [6]. Somatosensoryevoked cortical potentials are said to objectivize sensory abnormalities of innervation [70], although an adequate body of evidence in PS is not yet available. The ninhydrin sweat test reveals sudorimotor abnormalities on the soles and thus is able to rule out sympathetic abnormalities of innervation (e.g., paraaortic metastases) as the cause of pain. In PS the sudorimotor function is intact. Only in exceptional circumstances will the plain x-ray film of the pelvis, among the imaging modalities, show calcification of the piriform muscle or its tendon [71]. Contrary to former assumptions, exostoses are irrelevant for PS [72]. However, if PS is presumed, a CT examination of the pelvis should at any rate be conducted in order to detect side differences of the piriform muscle [20] or other causes for the narrowing of the infrapiriform foramen. If uncertainties remain, MRT examination of the sciatic nerve and its vicinity in particular with regard to structural changes of the piriform muscle is indicated [73]. Coronary visualization has proved successful. Former attempts of scintigraphic demonstration of PS [74] are obsolete. Infiltrations of procaine into the piriform muscle have diagnostic and therapeutic relevance. Prompt pain relief for at least 2 h is evidence for the presence of PS. The problem encountered in this procedure is the correct position of the injection needle which, because of the marked variability of the structures surrounding the piriform muscle, can only be verified under CT monitoring. Since such an approach, however, is expensive in terms of technical equipment and time, it will only be employed in conjunction with a planned injection of botulinum toxin (BTX) [8].
Reichel
150
Presence of subjective and objective PS Etiologically treatable causes excluded
Physical therapy, rules of behavior successful after 4 weeks? No Yes
Local anesthetic successful? Yes
Continue No
Repeat Sustained effect? No Yes
Probatory BTX administration successful? Yes No
BTX administration successful? Yes No
Continue
Repeat
Surgical revision
Repeat
Surgical revision
Fig. 18. Treatment of PS (flow chart).
Therapy
If etiologically treatable causes of PS are ruled out, mode of behavior and physical therapy should be the first therapeutic step (fig. 18). The patient is advised to stand up every 30 min on prolonged sitting, to change the sitting position, and to put on trousers and socks only while sitting. The patient should sleep with the tender side up. A big cushion should be placed between the legs to support thigh, lower leg and foot. As for physical therapy, relaxation exercises of pelvic floor muscles, stretching exercises of gluteal muscles, massages of the piriform muscle [75, 76] and exercises to mobilize the iliosacral articulation and lumbar spine should be performed. Self-massages of the muscle are possible by lying on a tennis ball. In most cases, these measures alone will not suffice to achieve sustained pain relief. In part of the patients, permanent improvement is attained with repeated infiltrations of local anesthetics into the piriform muscle. Opinions
Piriformis Syndrome
151
about the additional administration of corticosteroids [77, 78] are divided. Our own experiences including other bottleneck syndromes tend to be negative. Trigger point infiltrations with local anesthetics are said to exert a certain effect in PS [79], not, however, in true bottleneck syndromes. Optimal results are attained by injections with BTX into the piriform muscle. Even if this treatment method is of no avail, operative severance of the piriform muscle and its tendon, respectively, and neurolysis of the sciatic nerve may be considered [27, 49, 80]. Mere severance of the tendon is not always successful [81]. Since the introduction of the BTX therapy, however, surgical interventions in PS have rarely been necessary.
Therapy with Botulinum Toxin (fig. 1924)
Although a double-blind randomized study has already been conducted on the treatment of back pain with BTX injections into paravertebral muscles [79], there are only three as yet unfinished studies in the literature, in addition to individual case records, on the treatment of PS with BTX [82, 83]. In 1997, Alo et al. [84] studied 3 patients with PS who were treated with BTX. Porta [9, 85] published a study on the results comparing injections of BTX with injections of methylprednisolone into the piriform muscle in 23 patients with PS. While pain relief was comparable in both groups after 30 days, BTX exhibited clearly better effects after 60 days. Among the patients receiving corticoids, the compliance for physical therapy (muscle stretching) was significantly worse which, according to the author, was attributed to less pain in the BTX group. In 30 patients with PS, Fanucci et al. [8] initially injected 3 ml of 2% lidocaine under CT-assisted monitoring. After removal of the needle, standard clinical tests were performed. The patients were now free of pain. Once the diagnosis had been confirmed, 200500 mU Botox were injected with a fresh needle under CT monitoring into the posterior portion of the piriform muscle. The dose was defined according to the muscle diameter. In 26 patients, symptoms
Fig. 1924. Technique of BTX therapy of PS. 19 Injection syringe (1 ml) marked with the CT-measured puncture depth by sterile strip and sterile tape measure (mm grading). 20 CT measurement of the distance of the puncture site (B) from the midline of the back (A) and the puncture depth of the skin (C) to the middle of the piriform muscle (D). 21 Needle with mandrin injected into the piriform muscle. 22 CT monitoring of needle position. 23 Examples for CT documentation of the position of BTX in the piriform muscle. a BTX located in the middle of the muscle venter. b BTX located in the anterior portion of the piriform muscle. 24 CT following third injection of BTX in right-sided PS: the female patient is free of complaints for 6 months. Marked atrophy of the piriform muscle is discernible.
Reichel
152
19
20
23a
21 23b
22
24
Piriformis Syndrome
153
receded within 57 days. In the remaining 4 patients the injection was repeated after 2 months, thereafter these were also free of complaints. The follow-up MRT performed in 9 of the patients 3 months later revealed in 7 cases a signal change of the muscle tissue, in 2 patients muscle atrophy. In 1985 we have started imaging diagnostic procedures in PS, and in 1997 BTX injections were instituted; thereafter, standardized techniques were developed. All injections are carried out under CT monitoring, since blind injections and those controlled by electromyography reach the piriform muscle in only about 60% [86] and the effect of BTX depends on whether or not the endplate region of the muscle is reached [60]. Use of a nerve stimulator to locate the sciatic nerve is reported to improve that percentage [87]. The safest method, however, is the imaging technique [88]. Technique of BTX Injection in PS Once etiologially treatable causes of PS have been ruled out and physical therapy or mode of behavior have been of no avail, 5 ml of 2% lidocaine are injected into the piriform muscle. If the injection is ineffective or no sustained effect is attainable after three injections, BTX injection is advised. The patient is informed about the effect and potential side effects as well as about the fact that the preparation is not approved for this indication. Written informed consent and confirmation of information is obtained, and the patient receives a patient ID card containing information for attending physicians in case of emergency, in case of necessary surgical interventions, administration of local anesthetics and antibiotics. In addition, the ID card contains a phone number for the patient to contact a physician of the clinic 24 h/day who is familiar with BTX. The patient is lying in the prone position in the computerized tomograph. A shadow-casting marker is fixed over the palpation site of the piriform muscle. Thereafter, the position of the marker is checked in the computed tomographic scan and corrected, if necessary, so that it is located directly above the largest diameter of the piriform muscle. The distances of the marker to the midline (spinous processes) and to the middle of the muscle venter of the piriform muscle are measured (fig. 20). Subsequently, the puncture site is marked with iodine solution and disinfected. The necessary puncture depth is marked with a sterile strip on a 9- or 15-cm long sterile needle (fig. 21). Five milliliters of 2% procaine solution are injected into the selected puncture site and puncture channel. Thereafter, the needle is inserted and forwarded to the marked site. The position of the needle tip is verified by CT film and, if necessary, corrected (fig. 22). Two milliliters of BTX solution (equivalent to Botox 100 U, Dysport 400 U) are then injected, and the needle is removed. A final CT film shows the BTX in the muscle venter (fig. 23).
Reichel
154
In all patients, onset of action occurs within 12 weeks after the first injection and persists for about 34 months. The duration of action is prolonged after multiple injections. The majority of patients remain free of complaints after the third injection. Follow-up CT or MRT films show marked atrophy of the piriform muscle (fig. 24). Side effects such as distant effects or leg weakness have never been observed. The latter is unlikely since, in terms of strength, the piriform muscle only ranks fourth among the short lateral hip rotators [27]. The positive effect of BTX in PS is mainly attributed to the direct muscle relaxation by blockade of extrafusal neuromuscular synapses. Furthermore, an additional relaxation effect is presumed by inhibition of intrafusal muscle fibers and an effect on pain receptors [85, 89]. In conclusion, BTX is the first treatment modality in PS offering a noninvasive therapeutic option with sustained action. The treatment of PS with BTX in combination with physical therapy, like the treatment of other chronic pain syndromes, is not only more effective but also cheaper than systemic continuous therapy with analgesic drugs [90].
References
1 2 3 4 5 6 Yoeman W: The relation of arthritis of the sacroiliac joint to sciatica. Lancet 1928;11191122. Durrani Z, Winnie AP: Piriformis muscle syndrome: An underdiagnosed cause of sciatica. J Pain Symptom Manage 1991;6:374379. Silver JK, Leadbetter WB: Piriformis syndrome: Assessment of current practice and literature review. Orthopedics 1998;21:11331135. Huber HM: Das Piriformissyndrom eine mgliche Ursache fr Ischialgien. Schweiz Rundschau Med 1990;79:235236. Pfeifer T, Fitz WF: Das Piriformis-Syndrom. Z Orthop Ihre Grenzgeb 1989;127:691694. Fishman LM, Dombi GW, Michaelsen C, Ringel S, Rozbruch J, Rosner B, Weber C: Piriformis syndrome: Diagnosis, treatment and outcome A 10-year study. Arch Phys Med Rehabil 2002;83: 295301. Childers MK: Use of Botulinum Toxin Type A in Pain Management. Columbia/MO, Academic Information Systems, 1999. Fanucci EA, Masala SA, Sodani GA, Varrucciu VA, Romagnoli AA, Squillaci EA, Simonetti GA: CT-guided injection of botulinic toxin for percutaneous therapy of piriformis muscle syndrome with preliminary MRI results about denervative process. Eur Radiol 2001;11:25432548. Porta M: A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain 2000;85:101105. Goldner JL: Piriformis compression causing low back and lower extremity pain. Am J Orthop 1997;26:316318. Hallin RP: Sciatic pain and the piriformis muscle. Postgrad Med J 1983;74:6972. McCrory P, Bell S: Nerve entrapment syndromes as a cause of pain in the hip, groin and buttock. Sports Med 1999;27:261274. Parziale JR, Hudgins TH, Fishman LM: The piriformis syndrome. Am J Orthop 1996;25:819823. Reichel G: Das Piriformis-Syndrom. Zentralbl Neurochir 1988;49:178184. Retzlaff EW, Berry AH, Haight AS, Parente PA, Lichty HA, Turner DM, Yezbick AA, Lapcevic JS, Nowland DJ: The piriformis muscle syndrome. J Am Osteopath Assoc 1974;73:799807. Robinson DH: Piriformis syndrome in relation to sciatic pain. Am J Surg 1947;73:355358.
7 8
9 10 11 12 13 14 15 16
Piriformis Syndrome
155
17 18 19 20 21 22 23 24
25 26 27 28 29
30 31 32 33 34 35 36 37 38 39 40 41 42 43
44
Kopell HP, Thompson WAL: Peripheral entrapment neuropathies of the lower extremity. N Engl J Med 1960;262:5660. Freiberg AH: The fascial elements in associated low-back and sciatic pain. J Bone Jt Surg 1941;23:478480. Steiner C, Staubs C, Ganon M, Buhlinger C: Piriformis syndrome: Pathogenesis, diagnosis and treatment. J Am Osteopath Assoc 1987;87:318323. Ueno K: Sup 6sup 7Ga imaging of gluteal muscle inflammation secondary to pyogenic sacroiliitis. Jpn J Clin Radiol 1985;30:319322. Beaton LE, Anson BJ: The sciatic nerve and the piriform muscle. Their interrelation a possible cause of coccygodynia. J Bone Jt Surg 1938;20:686688. Misra BD: The relation of the sciatic nerve to the piriformis in Indian cadavers. J Anat Soc India 1954;3:44. Pecina M: Contribution to the etiological explanation of the piriformis syndrome. Acta Anat 1979; 105:181187. Charamza J, Machalek L, Holibkova A, Cach A: A contribution to the anomalous penetration of the sciatic nerve through the greater sciatic foramen. Acta Univ Palacki Olomuc Fac Med 1998; 141:5759. Tiel RL: The surgical treatment of entrapment neuropathies of the lower extremity. Semin Neurosurg 2001;12:109123. Tillmann B: Verlaufsvarianten des N. gluteus inferior. Anat Anz 1979;145:293302. Solheim LF, Siewers P, Paus B: The piriformis muscle syndrome. Sciatic nerve entrapment treated with section of the piriformis muscle. Acta Orthop Scand 1981;52:7375. Dyck PJ, Thomas PK, Bunge R (eds): Peripheral Neuropathy. Philadelphia, Saunders, 1984. LaBan MM, Meerschaert JR, Taylor RS: Electromyographic evidence of inferior gluteal nerve comprise: An early representation of recurrent colorectal carcinoma. Arch Phys Med Rehabil 1982;63:3335. Rask MR: Superior gluteal nerve entrapment syndrome. Muscle Nerve 1980;3:304307. Benson ER, Schutzer SF: Posttraumatic piriformis syndrome: Diagnosis and results of operative treatment. J Bone Joint Surg Am 1999;81:941949. Arifoglu Y, Surucu HS, Sargon MF, Tanyeli E, Yazar F: Double superior gemellus together with double piriformis and high division of the sciatic nerve. Surg Radiol Anat 1997;19:407408. Kirici Y, Ozan H: Double gluteus maximus muscle with associated variations in the gluteal region. Surg Radiol Anat 1999;21:397400. Ozaki S, Hamabe T, Muro T: Piriformis syndrome resulting from an anomalous relationship between the sciatic nerve and piriformis muscle. Orthopedics 1999;22:771772. Julsrud ME: Piriformis syndrome. J Am Podiatr Med Assoc 1989;79:128131. Gandhavadi B: Bilateral piriformis syndrome associated with dystonia musculorum deformans. Orthopedics 1990;13:350351. Uchio Y, Nishikawa U, Ochi M, Shu N, Takata K: Bilateral piriformis syndrome after total hip arthroplasty. Arch Orthop Trauma Surg 1998;117:177179. Uluutku MH, Kurtoglu Z: Variations of nerves located in deep gluteal region. Okajimas Folia Anat Jpn 1999;76:273276. Rossi P, Cardinali P, Serrao M, Parisi L, Bianco F, De Bac S: Magnetic resonance imaging findings in piriformis syndrome: A case report. Arch Phys Med Rehabil 2001:82:519521. Arai Y, Kawakami T, Soga H, Okada Y: Psoas abscess associated with iliac vein thrombosis and piriformis and gluteal abscesses. Int J Urol 1999;6:257259. Kinahan AM, Douglas MJ: Piriformis pyomyositis mimicking epidural abscess in a parturient. Can J Anaesth 1995;42:240245. Chusid MJ, Hill WC, Bevan JA, Sty JR: Proteus pyomyositis of the piriformis muscle in a swimmer. Clin Infect Dis 1998;26:194195. Katati MJ, Vilchez R, Pinar L, Abdulha O, Horcajadas A, Ros B, Arraez MA, Castaneda M: Haematoma of the piriformis muscle simulating a giant presacral tumour: Unusual case of lumbosacral radiculopathy. Acta Neurochir (Wien) 1998;140:403404. Ku A, Kern H, Lachman E, Nagler W: Sciatic nerve impingement from piriformis hematoma due to prolonged labor. Muscle Nerve 1995;18:789790.
Reichel
156
45 46 47 48 49 50 51 52 53 54 55 56 57
58 59 60
61 62 63 64 65 66 67
68 69 70
Stevens KJ, Banuls M: Sciatic nerve palsy caused by haematoma from iliac bone graft donor site. Eur Spine 1994;3:291293. Peh WC, Reinus WR: Piriformis bursitis causing sciatic neuropathy. Skeletal Radiol 1995;24: 474476. Hockel M: Laterally extended endopelvic resection: Surgical treatment of infrailiac pelvic wall recurrences of gynecologic malignancies. Am J Obstet Gynecol 1999;180:306312. De Jong PJ, van Weerden TW: Inferior and superior gluteal nerve paresis and femur neck fracture after spondylolisthesis and lysis: A case report. J Neurol 1983;230:267270. Mizugucchi T: Division of the piriformis muscle for the treatment of sciatica. Arch Surg 1976; 111:719722. Dora C, Leunig M, Beck M, Rothenfluh D, Ganz R: Entry point soft tissue damage in antegrade femoral nailing: A cadaver study. J Orthop Trauma 2001;15:488493. Townsend DR, Hoffinger S: Intramedullary nailing of femoral shaft fractures in children via the trochanter tip. Clin Orthop 2000;376:113118. Winquist RA: Locked femoral nailing. J Am Acad Orthop Surg 1993;1:95105. Beauchesne RP, Schutzer SF: Myositis ossificans of the piriformis muscle: An unusual cause of piriformis syndrome. A case report. J Bone Joint Surg Am 1997;79:906910. Papadopoulos SM, McGillicuddy JE, Albers JW: Unusual cause of piriformis muscle syndrome. Arch Neurol 1990;47:11441146. Obach J, Aragones JM, Ruano D: The infrapiriformis foramen syndrome resulting from intragluteal injection. J Neurol Sci 1983;58:135143. Bustamante S, Houlton PG: Swelling of the leg, deep venous thrombosis and the piriformis syndrome. Pain Res Manag 2001;6:200203. Kipervas IP, Ivanov LA, Urikh EA, Pakhomov SK: Kliniko-elektromiograficheskaia kharakteristika sindroma porazhenija grushevidnoi myshtzy. Z Nevropatol Psichiatr Korsakowa 1976;76: 12891292. Zeigermann JH: Piriformis vaginal syndrome. J Abdom Surg 1984;26:100102. Simons DG, Travell JG: Myofascial origins of low back pan. 3. Pelvic and lower extremity muscles. Postgrad Med 1983;73:99105. Childers MK, Kornega JN, Aoki R, Otaviani L, Bogan DJ, Petroski G: Evaluating motor endplate-targeted injections of botulinum toxin type A in a canine model. Muscle Nerve 1998;21: 653655. Murphy BP: Piriformis syndrome mimics sural nerve entrapment. J Am Podiatr Med Assoc 1997; 87:183184. Kopell A, Thompson W: Peripheral entrapment neuropathies of the lower extremity. N Engl J Med 1960;26:5660. Beatty RA: The piriformis muscle syndrome: A simple diagnostic maneuver. Neurosurgery 1994;34:512514. Pace JB: Commonly overlooked pain syndromes responsive to simple therapy. Postgrad Med 1975;58:107113. Freiberg AH: Sciatic pain and its relief by operations an muscle and fascia. Arch Surg 1937;34: 337350. Rodrigue T, Hardy RW: Diagnosis and treatment of piriformis syndrome. Neurosurg Clin N Am 2001;12:311319. Mller M, Mller-Mattheis V, Seitz RJ, Ackermann R: Piriformis-Syndrom ein ungewhnlicher Weg bis zur Diagnose eines Nierenbeckensteins in einer kaudal dystopen Niere. Aktuel Urol 2001;52:3841. Dumitru D, Nelson MR: Posterior femoral cutaneous nerve conduction. Arch Phys Med Rehabil 1990;71:979982. Fishman LM, Zybert PA: Electrophysiologic evidence of piriformis syndrome. Arch Phys Med Rehabil 1992;73:359364. Nainzadeh N, Lane ME: Somatosensory-evoked potentials following pudendal nerve stimulation as indicators of low sacral root involvement in a postlaminectomy patient. Arch Phys Med Rehabil 1987;68:170172.
Piriformis Syndrome
157
71 72 73 74 75 76
77 78 79 80 81 82 83 84 85 86 87 88
89 90
Stark P, Hildebrandt-Stark HE: Calcific tendinitis of the piriform muscle. Fortschr Rntgenstr 1983;138:111112. Huber H: ber die Irritation des N. ischiadicus durch eine im Bereich Tuber ossis ischii vorkommende Exostose. Klin Med 1959;14:383386. Almanza MY, Poon-Chue A, Terk MR: Dual oblique MR method for imaging the sciatic nerve. J Comput Assist Tomogr 1999;23:138140. Karl RD, Yedinak MA, Hartshorne MF, Cawthon MA, Baumann JM, Howard WH, Bunker SR: Scintigraphic appearance of the piriformis muscle Syndrome. Clin Nucl Med 1985;10:361363. Sinaki M, Merritt JL, Stillwell GK: Tension myalgia of the pelvic floor. Mayo Clin Proc 1977;52: 717722. Thiele GH: Coccygodynia and pain in the superior gluteal region and down the back of the thigh: Causation by tonic spasm of the levator ani, coccygeus and piriformis muscle and relief by massage of these muscles. JAMA 1937;109:12711275. Hanania M, Kitain E: Perisciatic injection of steroid for treatment of sciatica due to piriformis syndrome. Reg Anesth Pain Med 1998;23:223228. Barton PM: Piriformis syndrome: A rational approach to management. Pain 1991;47:345352. Foster L, Clapp L, Erickson M, Jabbari B: Botulinum toxin A and chronic low back pain: A randomized, double-blind study. Neurology 2001;56:12901293. Chen WS, Wan YL: Sciatica caused by piriformis muscle syndrome: Report of two cases. J Forms Med Assoc 1992;91:647650. Spinner RJ, Thomas NM, Kline DG: Failure of surgical decompression for a presumed case of piriformis syndrome. Case report. J Neurosurg 2001;94:652654. Chesire WP, Abashian SW, Mann JD: Botulinum toxin in the treatment of myofascial pain syndrome. Pain 1994;59:6569. Seddigh S, Nagel B, Gerbershagen HU: Botulinumtoxin-Injektionen zur Therapie eines Piriformis-Syndromes. Klin Neurophysiol 2000;31:184. Alo KM, Yland MJ, Kramer DL, Charnov JH, Redko V: Botulinum toxin in treatment of myofascial pain. Pain Clin 1997;10:107116. Porta M, Perretti A, Gamba M, Luccarelli G, Fornari M: The rationale and results of treating muscle spasm and myofascial syndromes with botulinum toxin type A. Pain Digest 1998;8:346352. Fishman SM, Caneris OA, Bandman TB, Audette JF, Borsook D: Injection of the piriformis muscle by fluoroscopic and electromyographic guidance. Reg Anesth Pain Med 1998;23:554559. Hanania M: New technique for piriformis muscle injection using a nerve stimulator. Reg Anesth 1997;22:200202. Jankiewicz JJ, Hennrikus WL, Houkom JA: The appearance of the piriformis muscle syndrome in computed tomography and magnetic resonance imaging. A case report and review of the literature. Clin Orthop 1991;262:205209. Rosales RL, Arimura K, Takenaga S, Osame M: Extrafusal and intrafusal muscle effects in experimental botulinum toxin A injection. Muscle Nerve 1996;19:488496. Porta M: Treatment of Myofascial Pain by Injection with Botulinum Toxin. Rationale, Procedure and Outcomes. Bollington/UK, Adelphi Communications Ltd, 1997.
Prof. Dr. Gerhard Reichel Paracelsus-Klinik, Werdauer Strasse 68, D08060 Zwickau (Germany) Tel. 49 375 5901301, Fax 49 375 5901306, E-Mail prof.reichel@t-online.de
Reichel
158
Botulinum Toxin in Low Back Pain

Wolfgang H. Jost a, Peter Reilichb, Dieter Pongratz b
a Department of Neurology and Clinical Neurophysiology, German Clinic of Diagnostics, Wiesbaden, and bFriedrich-Baur-Institute, Ludwig-MaximiliansUniversity, Munich, Germany
Presentation of the Clinical Picture
Backaches are the most common complaints at the general practitioners. Seventy to 90% of the population are believed to develop backaches in the course of their lives [1]. Under nonspecific management of pain, symptoms remit in the majority of the patients [2]. Approximately 37% suffer from chronic backaches [3]. The lumbar spine is affected in two thirds of this pain syndrome. Onset of backaches is associated with dysfunction of the musculoskeletal support system in most patients but not with any causative disorder in need of treatment. An organic cause, e.g. disk prolapse with root compression, is involved in merely 1015% [4]. The burden on the healthcare system is tremendous. Costs in the USA are estimated to be about USD 50 billion [5]. After experimental manipulation during surgeries of the lumbar spine under a specific form of regional anesthesia [6], the longitudinal ligaments, the external annulus fibrosus of the disk, the facet joints (lancinating pain) and the deckplates of the vertebral bodies (dull pain) were identified to be the structures sensitive to pain. Traction to a healthy uncompressed root will evoke malaise but no pain. Roots under tension already at the levels of a slipped disk for instance, are, on the other hand, highly sensitive to pain due to pressure or traction their electrical stimulation produces pain in approximately 90%. Irritation of the facet joints or disk [7] by injection of hypertensive saline solution leads to typical lumbago transmitting to the dorsal thigh as well in absence of radicular irritation. Pathogenetically we distinguish three types of different pain topically generated pain, pain referred from another region of the body, and radicular pain. In view of the therapeutic approach with botulinum toxin (BTX), the muscular system is presented separately in addition to locally generated pain.
Locally Generated Pain
Locally generated pain is caused by pressure on pain-sensitive structures, by pressure on sensitive paravertebral branches of the spinal nerves or by local release of pain-mediating substances, e.g. in inflammatory processes (arthritis). Pain enhanced by movement or position is typical of a diseased locomotor segment, the vertebral joints that is, the vertebra or ligamentous system. Acute backaches are frequently associated with paravertebral hardening which may, in turn, generate pain again (see also below). The possibility of tumor or infection (osteomyelitis, epidural abscess) should be taken into account with well-localized backache not affected by change of position. In severe osteoporosis, spontaneous compression fractures can occur especially from the midthoracic spine down in the caudal direction. Locally generated pain may radiate from the lower lumbar spine to the backside of the thigh, from the upper lumbar spine to the inguinal region and to the anterior side of the thigh (see above). This kind of pain transmission is termed pseudoradicular by some authors. Whether and inasmuch as degenerative changes of the spine, evidenced on imaging examinations, are involved in the genesis of chronic pain states remains obscured, as there is no or just minor correlation between them and the degree of pain.
Referred Pain
Visceral abdominal and pelvic diseases may lead to lumbar pain. Disorders of the chest organs can project to the neck region. Pain typical for the organs affected may simultaneously be present but not always. Backaches are usually not position-related, they are frequently dull or boring in character. Isolated backache is found in 1520% of patients with rupture of an abdominal aneurysm. The classical triad of abdominal pain, shock and backache is only seen in about 20% of the patients. Abdominal examination is indispensable in such cases to identify the pulsatile resistance present in the majority of the patients.
Radicular Pain
This pain is typically stabbing, griping or partly electrifying. It radiates from the back to the affected extremity along the sensitive territory of the compressed root(s). Pain is enhanced by cough, sneezing or straining on defecation, which is another typical feature. It results in increased intrathecal pressure aggravating
Jost/Reilich/Pongratz
160
compression of the root afflicted. Pain is in addition worsened by certain positions, with a distending effect on the affected root Lasgues sign is positive in root compression of L5 and S1, i.e. there is a pain reflectory blockade when trying to flex the affected leg beyond 80 in the hip while the knee is stretched. Reversed Lasgues sign (hip extension in prone position) turns positive in root compression of the upper lumbar spine (L2L4). Pain associated with paresthesias or other malaise usually confirms the radicular irritation suspected by their regional distribution. Lesion-induced sensomotor deficits and attenuated deep tendon reflexes are definite signs of radicular lesion. They are basic in the assessment for surgical intervention as may be indicated from the imaging examinations. When checking on power we must be careful not to confuse pain reflectory inhibition of innervation with actual paresis. Contrary to true paresis, pain-induced hypoinnervation is no indication for surgery.
Lumboischialgia
Degenerative changes of the disk are most commonly responsible for disk herniation with root compression in segments L4/5 and L5/S1 mostly of the root one level further down L5 or S1. The reason may be trivial, such as a clumsy movement, cough or sneezing. This is a cue to degenerative changes which have obviously preceded the prolapse resulting in weakness of the annulus fibrosus among others. We often find signs of osseous chronic degenerative changes like sclerosis of the deckplates (osteochondrosis) osteophytic deformities (retrospondylosis) and hypertrophy of the facet joints. The combination of radicular pain, careful positions and painfully restricted mobility of the spine (on flexion in particular) in conjunction with disturbed sensibility in a dermatoma, attenuated reflex and segmental paresis eventually, is typically permitting the definite clinical assignment to root involvement. Although in most cases the level of the disk prolapse is located congruently with radicular syndrome, there are always exceptions to the rule since the lumbosacral roots in particular pursue a long course in the spinal canal from the origin of the conus at the level of T12L1 to the corresponding intervertebral foramen. MRI with sagittal longitudinal views thus facilitates the detection of lesions higher up, even when only caudal roots are clinically involved. Table 1 gives an overview on deficiency symptoms evident in lesions of single roots. As opposed to paresis in peripheral nerve lesions, reduced power due to radiculopathy is always partial since the muscles of the extremities are all innervated by several segments each. When definite clinical assessment of power is impossible because of pain-reflectory inhibition, the EMG might help to furnish
BTX in Low Back Pain
161
Table 1. Neurologic deficits in radicular lesions Segment Sensibility Muscle involved M. iliopsoas Reflectory attenuation DD
L12
L3
L4
L5
Inguinal region, prox. anterior side of the thigh Dist. 2/3 of anterior side of thigh, ant. knee Outer side of thigh, inner side of lower leg to mall. med. Outer side of leg to dorsum of the foot and hallux
M. quadriceps
Patellar reflex
Femoral nerve lesion Femoral nerve lesion Peroneal nerve lesion
M. quadriceps, M. tib. ant. M. ext. hallucis, M. peronei, M. tib. post. M. glut. med. M. triceps surae
Patellar reflex
(Tib. post. refl.)
S1
Flexor side thigh, calf, sole of the foot, outer side of the foot
Achilles jerk
proof of neurogenic lesion of the anterior root by evidence of pathologic spontaneous activity. There is, however, a latency period of about 2 weeks between the point of lesion and the evidence of spontaneous activity, examination during the acute state may thus not be too helpful. Occasionally, after remission of acute pain, there may be indolent paresis which is usually consistent with severe root compression to the point of radicular death necessitating quick surgical intervention. Whereas unilateral symptoms are induced by the majority of slipped disks, a large median prolapse can result in cauda syndrome, causing sensibility disorder in the breeches region (S2S4) by compression of the median sacral roots, as well as impaired bladder and bowel evacuation with urinary retention or overflow incontinence. Acute cauda syndrome is always regarded as an emergency requiring immediate imaging examinations and surgical treatment depending on the findings. As to the indication of surgical exploration, we refer to table 2. The greater the match between clinical picture and imaging findings, the more favorable the expected outcome of surgical intervention will be. Surgical intervention is advised against when there is no definite evidence of radicular syndrome. Postoperative discomfort in such cases is going to increase rather than decrease,
162
Table 2. Indications for surgical treatment of prolapsed Nc. pulposus 1. 2. 3. 4. 5. Progressive motor paresis within the framework of radicular lesion Progressive deterioration of electrophysiologic findings (EMG, NCS, EPs) Bladder and bowel evacuation disturbance or other signs of myelonic affection Severe, functionally disabling radicular pain for at least 4 weeks (relative indication) Recurrent severe, functionally impairing pain despite conservative treatment (relative indication)
and prospects are dim that the patient will be fit for work again afterwards. Conservative treatment is to be given preference when there is no compelling reason for surgery (see table 2, items 13). Application of nonsteroid antiphlogistics, back education supervised by a physiotherapist and other active physiotherapeutic measures such as hydrotherapy have been successfully evaluated. From our experience, short-term steroid pulse treatment in acute lumboischialgia can afford clinical stabilization, too (e.g. 500 mg methylprednisolone i.v. on 3 days). Immobilization of more than 2 days duration is not wise according to a randomized study [8].
Spinal Canal Stenosis
Additional narrowing of the lumbar medullary space occurs predominantly in the later years of life, primarily consecutive to a constitutionally narrow spinal canal, by degenerative changes developing with almost infallible regularity. These will typically lead to stress-related backaches and leg pain, often accompanied by mostly sensible radicular deficiency symptoms. Pain subsides completely on anteflexion or when sitting down (intermittent spinal claudication). Persistent neurologic deficits are rare. Unlike in peripheral arterial occlusive disease (AOD), symptoms may just be provoked by standing. Severe forms of spinal canal stenosis can be encountered in a few primary skeletal disorders such as achondroplasia, frequently also involving the thoracic region. Spondylolisthesis and other vertebral affections, too, may reduce the total diameter of the dural sac to the degree of creating a similar clinical picture. Conservative therapy by NSAIDs and exercises should be carried on as long as possible. Sixty-five to 80% of the patients operated do benefit from the intervention, up to 25% of the patients who had surgery, however, develop a relapse at the same level or in the adjacent segment.
163
Chronic Lumbar Syndrome
Backaches lasting for more than 3 months are considered to be chronic. Although patients with chronic lumbago/lumboischialgia just make up for 5% of all patients presenting with such symptoms, they produce nearly 50% of the costs incurred. This is a mixed group of patients, frequently with an earlier history of multiple surgeries. Multiple operations lead to increased cicatrization compatible with adhesive arachnoiditis, and the condition is refractory to any further treatment. Unfortunately, the limitations of our therapeutic scope of intervention are quickly unveiled. As a rule we are not dealing with a purely somatic problem psychosomatic components and defective coping with the disease are increasingly involved with prolonged duration of pain. Pharmacotherapy with thymoleptics is certainly worth trying in patients with depressive moods and phobias. On the other hand it is unrealistic to be striving for analgesia. We rather feel that a multimodality pain therapy program is going to make more sense by getting the patient to adopt a more active lifestyle, thereby raising his pain tolerance.
Muscle Ache Accounting for Low Back Pain
The place value of the muscular system as primary source of chronic backache still remains disputable. The assertion that the musuclature is the substantial constituent of the vicious circle pain leading to muscular spasm with consecutive generation of additional pain is not supported by scientifically valid data. Muscular spasticity in that model is believed to trigger off a spinal reflex with increased -motoneuron activity. This theory is controversial though, and certainly simplified. Secondary dysfunction of the musculoskeletal support system is regularly found in chronic backache. The inducing mechanical irritation leads to increased muscle tone and shortening of the muscle. The painful segment is protectively fixed in response to that irritation, and this is maintained when the irritation is gone. This makes for painful muscular spasm with correlated dysfunction despite varying possible causes. In a more complex model, chronic muscle pain is generated by release of neuropeptides such as Substance P and CGRP (calcitonin gene-related peptide) from the endings of pain fibers (A - and C-fibers) due to pathologically increased muscle tone [9]. This may set off a cascade of alterations, i.e. release of vasoneuractive substances, sensitization of nociceptors, vasodilation and edema, local ischemia, ATP deficiency and muscle contraction ensuing from
164
Table 3. Muscles as myofascial origins that may cause or contribute to low back pain [from 11] Erector spinae Erector longissimus Erector iliocostalis Multifidi Rotatores Rectus abdominis Quadratus lumborum Iliopsoas Gluteus medius Gluteus maximus Levator ani Piriformis
that (see Gbel, pp. 1422). Short of these effects in the muscle, Substance P also acts on the spinal level by sensitizing the neurons of the posterior horn, and by involving adjacent spinal neurons [9] within the framework of complex processes. The innervation density of the muscle may perhaps even increase in neuropeptide nerve fibers. This feedback control system can be influenced accordingly by BTX (see Gbel, pp. 1422), with the result of pain relief and direct inhibition of Substance P release in addition [10]. Generally speaking, we will have to reconsider whether muscular dysfunction in chronic backache has to be integrated in the concept of myofascial pain [11]. Myofascial pain syndrome is a regional pain defined by the presence of hyperirritable active trigger points in a taut band of muscle fibers associated with local tenderness and referred pain into welldefined areas remote from the trigger points (see chapter Myofascial Pain Syndrome). Dejung [12] observed that lumbosacral pain of unknown origin is frequently caused by trigger points and can be reduced by trigger point therapy. Even other authors identified the importance of a myofascial source of low back pain [13, 14]. Of 250 consecutive patients with chronic low back pain, 94 subjects (37.6%) were diagnosed as having myofascial pain whereas only 57 subjects (22.8%) as having herniated disc syndrome [15]. In a systematic examination among 283 patients with idiopathic low back pain (chronic intractable benign pain) with no objective findings on routine physical examination, 96.7% met the criteria of underlying myofascial pain syndrome caused by trigger points [16]. Potential muscles that may harbor trigger points and may work as an origin of low back pain are listed in table 3. Occasionally only one muscle will be responsible for the pain as presented but it is much more common for several muscles to contribute to overlapping pain patterns (fig. 1). According to the chapter Myofascial Pain Syndrome in this book, BTX may result in substantial pain relief in this condition owing to both its muscle relaxant and analgesic properties, established physiotherapeutic approaches apart.
165
lliocostalis lumborum
lliopsoas
Composite
Deep quadratus lumborum
S1 multifidus
Fig. 1. Individual pain patterns of several trigger points (indicated with crosses) that refer to the lumbosacral region and that may superimpose on each other. The composite pain pattern (middle) represents the summated pain. The individual pain patterns of the iliocostalis lumborum, iliopsoas, deep quadratus lumborum and the S1 multifidus are shown around the composite picture [24].
State of Data
Only one relevant study has been published to date on the use of BTX in chronic low back pain [18]. Thirty-one patients were enrolled in that study. Fifteen of them received BTX-A, 16 patients were given placebo. The study
166
was completed with 14 patients from each group. Fifteen patients got injections of 200 units Botox each, 40 units/site at five lumbar paravertebral levels on the side of maximum discomfort, while 16 patients received normal saline. Data were collected via VAS (visual analogue scale) and OLBPQ (Oswestry Low Back Pain Questionnaire). Follow-up was carried out after 3 and 8 weeks. Considerable differences were seen in both groups after only 3 weeks. 25% of patients in the placebo group (4 out of 16) indicated pain relief versus 11 of 15 (73.3%) in the BTX group. This result became even more distinctive after 8 weeks. Nine of 15 patients in the BTX group (60%) and merely 2 of 16 patients (12.5%) in the placebo group reported pain relief. Similar results were depicted in the OLBPQ. Improvement was described by 66.7% (10 of 15) in the BTX group but only in 18.8% (3 of 16) in the placebo group. Side effects were not observed.
Indications for BTX
Considering the scarce data, we must refrain from recommending BTX injections in low back pain for the time being. This treatment should only be administered by expert users, preferably in controlled studies. Uncritical application must be avoided. BTX may possibly be used in chronic low back pain. Prior to its application we will have to exclude any tractable symptomatic origin (see above). Physical examination should include the search for trigger points in specific muscles (table 3). Recognized therapies should be applied prior to anything else, and only after those have failed consider BTX as an additional element in the multimodal therapeutic approach. Mind the contraindications!
Technique
Owing to the scarce data again, we cannot come up with recommendations what technique to employ. Pursuant to the principle of follow the pain, injections these days are applied to the paravertebral muscles which are most commonly affected. The majority of users prefer to inject the trigger points. Common injection techniques are described in the chapter Myofascial Pain Syndrome. Injection under needle-EMG guidance can be helpful in some cases. The ideal dose has not yet been defined, although we must assume that the dose better be individually set. 2040 units Botox and/or 80160 units Dysport are suggested per injection site. The total dose mostly varies between one or two vials of the toxin, and it may either be higher or lower depending on the
167
individual case. Injections are usually applied to the painful side but the opposite side can be treated as well as may seem wise in that case. Final conclusions as to instabilities, faulty posture and imbalance due to weakness of the unilateral muscles are still pending with a number of larger studies going on.
Additional Indications
BTX is used in various indications at present. We cannot outline the entire spectrum of applications. Some case studies have supplied interesting approaches, further studies are, however, required to warrant a general statement. Use of BTX in backaches related to stiff person syndrome [18] has been exemplary, the same holds true for the analysis of BTX applications after back surgery [19]. Within this context, mention should be made of a study on chest pain due to spastic esophageal motility disorders that included 29 patients [20]. 72% of these patients reported pain relief by at least 50%. The duration of action was rated between 7.3 4.1 months [20]. Reference is also made to the great number of studies regarding BTX treatment of achalasia describing pain relief as well [21]. The tennis elbow might become another important indication in the future [22, 23]. The study of Keizer et al. [22] compared the results of BTX injections with those of an operation (both collectives contained 20 patients each). The outcome of surgery tended to be better but this was statistically insignificant. After 1 year, good results were reported in 65% (BTX) versus 75% (operation), after 2 years in 75% (BTX) versus 85% (operation).
References
1 2 3 4 5 6 Wipf JE, Deyo RA: Low back pain. Med Clin North Am 1995;79:231246. Frymoyer JW: Predicting disability from low back pain. Clin Orthop Rel Res 1992;279:101109. Schrank B, Jost WH: Rckenschmerzen aus Sicht des Neurologen; in Beck H et al (eds): Schmerztherapie. Stuttgart, Thieme, 2002, pp 379382. Frymoyer JW: Back pain and sciatica. N Engl J Med 1988;318:291300. Nachemson A: Newest knowledge of low back pain. Clin Orthop Rel Res 1992;279:820. Kuslich SD, Ulstrom CL, Michael CJ: The tissue origin of low back pain and sciatica: A report of pain response to tissue stimulation during operations on the lumbar spine using local anesthesia. Orthop Clin North Am 1991;22:181187. Mooney V, Robertson F: The facet syndrome. Clin Orthop 1976;115:149156. Deyo RA, Diehl AK, Rosenthal M: How many days of bed rest for acute low back pain? N Engl J Med 1986;315:10641070. Mense S, Simons DG: Muscle pain: Understanding its nature, diagnosis, and treatment. Philadelphia, Lippincott Williams & Wilkins, 2001.
7 8 9
168
10 11 12 13 14 15
16 17 18 19
20
21 22
23 24
Aoki KR: Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001; 248(suppl 1):I3I10. Simons DG, Travell JG: Myofascial origins of low back pain. 13. Postgrad Med 1983;73:66105. Dejung B: Manuelle Triggerpunktbehandlung bei chronischer Lumbosakralgie. Schweiz Med Wochenschr 1994;124(suppl 62):8287. Gerwin RD: Myofascial aspects of low back pain. Neurosurg Clin North Am 1991;2:761784. Rosen NB: The myofascial pain syndromes. Phys Med Rehabil Clin North Am 1993;4:4163. Cassisi JE, Sypert GW, Lagana L, Friedman EM, Robinson ME: Pain, disability and psychological functioning in chronic low back pain subgroups: Myofascial versus herniated disc syndrome. Neurosurgery 1993,33:379385. Rosomoff HL, Fishbain D, Goldberg M, Santana R, Rosomoff RS: Myofascial findings in patients with chronic intractable benign pain of the neck and/or back. Pain Management 1990;3:114118. Foster L, Clapp L, Erickson M, Jabbari B: Botulinum toxin A and chronic low back pain. Neurology 2001;56:12901293. Davis D, Jabbari B: Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. Mov Disord 1993;8:371373. Indahl A: Botulinum toxin type A in the treatment of patient after back surgery; in Raj P (ed): Botulinum Toxin Type A in Pain Management. Hamburg, Wissenschaftsverlag Wellingsbttel, 2002, pp 4348. Miller LS, Pullela SV, Parkman HP, Schiano TD, Cassidy MJ, Cohen S, Fisher RS: Treatment of chest pain in patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using botulinum toxin injection into the gastrointestinal. Am J Gastroenterol 2002;97:16401646. Jost WH: Pelvic floor and gastrointestinal uses; in Moore P, Naumann M (eds): Handbook of Botulinum Toxin Treatment. Oxford, Blackwell, 2002, in press. Keizer SB, Rutten HP, Pilot P, Moore HH, van Os JJ, Verburg AD: Botulinum toxin injection versus surgical treatment for tennis elbow: A randomised pilot study. Clin Orthop 2002;401: 125131. Moore HH, Keizer SB, van Os JJ: Treatment of chronic tennis elbow with botulinum toxin. Lancet 1997;349:1746. Simons DG, Travell JG, Simons LS: Travell & Simons Myofascial Pain and Dysfunction: The Trigger Point Manual, vol I: Upper Half of Body, ed 2. Baltimore, Williams & Wilkins, 1999.
Prof. Dr. med. Wolfgang H. Jost Department of Neurology and Clinical Neurophysiology, Deutsche Klinik fr Diagnostik, Aukammallee 33, D65191 Wiesbaden (Germany) Tel. 49 611 577321, Fax 49 611 577311, E-Mail jost.neuro@dkd-wiesbaden.de
169
Subject Index
Achalasia, botulinum toxin therapy 168 Anal fissure, botulinum toxin A treatment 21 Axial dystonia, botulinum toxin management 72 Backache, see Low back pain Botulinum toxin complexes 1, 3 degradation 5 endocytosis 3, 4 ganglioside binding 3 indications, see specific conditions lethal dose 8, 9 mechanism of action 3, 1420 proteolytic activity and substrates 5, 6 retrograde neural uptake, central nervous system 16 serotypes 9 structure 1 translocation and priming 4, 5 Cervical dystonia course and prognosis 56 definition 54 degenerative changes 58 diagnosis 56 epidemiology 54 etiology 54, 55 pain origins and role 5760 symptoms 55
treatment botulinum toxin antibody development and resistance 66, 67 botulinum toxin A 14, 15 dose equivalence 65 injection technique and assessment 64, 65 mechanisms of pain reduction 63 pain response 5963, 66, 71 side effects 63, 66 pharmacotherapy 56, 57 surgery 57 Chronic lumbar syndrome, see Low back pain Complex regional pain syndrome (CRPS), botulinum toxin management of dystonia 76, 77 Corticobasal degeneration (CBD), botulinum toxin management of dystonia 75, 76 Degradation, botulinum toxin 5 Dopamine, migraine 107 Dosing, see specific conditions Dystonia, see also Axial dystonia; Cervical dystonia; Complex regional pain syndrome; Focal dystonia; Limb dystonia; Oromandibular dystonia; Parkinsons disease botulinum toxin injection technique 79, 80
170
pain, primary dystonia 71 pharmacotherapy 78, 79 Endocytosis, botulinum toxin 3, 4 Facial pain, see Myofascial facial pain and dysfunction Fibromyalgia, myofascial pain syndrome, comparison 24 Focal dystonia atypical parkinsonian syndromes and botulinum toxin management 75, 76 botulinum toxin A treatment 14, 15 botulinum toxin injection technique 79, 80 Ganglioside, botulinum toxin binding 3 Gluteal atrophy, piriformis syndrome 143, 144 Headache, see Migraine; Tension-type headache Inflammation, botulinum toxin A inhibition 17, 18 Infrahyoid muscle, botulinum toxin injection 64 Levator scapulae muscle, botulinum toxin injection 64 Limb dystonia, botulinum toxin management 72 Low back pain botulinum toxin therapy clinical trial 166, 167 indications 167 injection technique 167, 168 chronic lumbar syndrome 164 epidemiology 159 locally generated pain 160 lumboischialgia 161163 muscular dysfunction 164, 165 pathogenesis 159 radicular pain 160, 161 referred pain 160 spinal canal stenosis 163 Lumboischialgia, see Low back pain
Masseter muscle, botulinum toxin injection 46, 47, 117 Migraine clinical features 102104 definition 102 differential diagnosis 90, 91 epidemiology 104 pathophysiology dopamine, role 107 heredity 107, 108 neuronal theory 105 serotonin, role 106, 107 sympathetic nervous system, role 107 trigeminovascular system, role 105, 106 vascular theory 104, 105 treatment attack therapy 110 botulinum toxin clinical studies 112115 dosing 116 formulations 116 injection technique 117, 118 onset of action 115, 116 prospects 118 rationale, prophylaxis 110112 side effects 116 prophylactic medication 108, 109 trigger factor avoidance 108 Myofascial facial pain and dysfunction muscle groups, pain and dysfunction 42, 43 pain pathogenesis 42, 43 treatment adjuvant medical measures 44 botulinum toxin A clinical trials 45, 46 injection technique 50, 51 lateral pterygoid muscle injection 49 masseter muscle injection 46, 47 mechanism of action 51, 52 medial pterygoid muscle injection 48, 49 temporalis muscle injection 48 dental measures 43
Subject Index
171
Myofascial pain syndrome (MPS) clinical findings 23, 24 definition 23 diagnostics needle electromyography 28 ultrasound 28 epidemiology 23 treatment adjuvant drug therapy 30 botulinum toxin clinical trials 3135 dose 38 formulations 38 indications 30, 31 injection technique 3539 mechanism of action 15, 16, 1820, 23 prospects 39 muscle stretching 29, 30 needling methods 30 trigger point botulinum toxin effects 1820, 23 clinical features 23 histopathological findings 26, 27 pathophysiology 2426 Needle electromyography, myofascial pain syndrome diagnosis 28 Neuromuscular spindle activity, botulinum toxin A effects 15, 16 Neuronal theory, migraine 105 Occipitofrontal muscle, botulinum toxin injection 117 Oromandibular dystonia, botulinum toxin management 73 Parkinsons disease, botulinum toxin management of foot dystonia 74, 75 Piriformis syndrome bottleneck syndromes 141, 142 definition 140 diagnostics 150 etiopathogenesis 140144 gluteal atrophy 143, 144 piriform muscle anatomy 140, 141 symptoms and signs 144, 145, 147, 150
treatment botulinum toxin advantages 155 clinical trials 152, 154 injection technique 154 onset and duration of action 155 side effects 155 pharmacotherapy 151, 152 physical therapy 151 Pterygoid muscle, botulinum toxin injection lateral muscle 49 medial muscle 48, 49 Radicular pain, see Low back pain Semispinalis capitis muscle, botulinum toxin injection 64 Serotonin, migraine, role 106, 107 SNAP-25, botulinum toxin cleavage 5, 6 SNAREs botulinum toxin cleavage 5, 6 functions 68 Spasticity-related pain clinical presentation 127, 128 definition 127 diagnosis 128, 129 etiology 128 pathogenesis 129 treatment botulinum toxin A clinical trials 134, 135 dosing 131 indications 131 mechanism of action 131, 133, 134 muscle identification 131 overview 126 recommendations 135, 136 pharmacotherapy 130, 131 physical therapy 130, 134 Spinal canal stenosis, see Low back pain Splenius capitis muscle, botulinum toxin injection 64, 118 Sternocleidomastoid muscle, botulinum toxin injection 64
Subject Index
172
Stroke, botulinum toxin management dystonia 77, 78 spasticity, see Spasticity-related pain Substance P, botulinum toxin A inhibition of release 16, 17, 110, 111 Suprahyoid muscle, botulinum toxin injection 64 Synaptobrevin, botulinum toxin cleavage 5, 6 Synaptotagmin, function 8 Syntaxin, botulinum toxin cleavage 5, 6 Temporalis muscle, botulinum toxin injection 48, 117 Temporomandibular joint dysfunction, see Myofascial facial pain and dysfunction Tennis elbow, botulinum toxin therapy 168 Tension-type headache (TTH) classification of headache disorders 82, 83 definition 83 diagnosis 89, 90 differential diagnosis 90, 91 epidemiology 83, 84 etiopathogenesis chronification and aggravating factors 87, 88 emotional factors 85 genetics 84 muscular causes 8587 neurotransmitters 85
socioeconomic aspects 98 subgroups 89 symptomatology 89 treatment analgesics 93 antidepressants 93 botulinum toxin clinical trials 9497 costs and reimbursement 98 dilution and dosing 97 indications 94 injection technique 97 multimodal therapy 98 exercises 92, 93 stress management 91 Translocation, botulinum toxin 4, 5 Trapezius muscle, botulinum toxin injection 64, 118 Trigger point botulinum toxin A effects 1820 myofascial pain syndrome, see Myofascial pain syndrome Ultrasound, myofascial pain syndrome diagnosis 28 Upper motor neurone syndrome, see Spasticity-related pain Vascular theory, migraine 104, 105 Wrinkles, botulinum toxin treatment 9
Subject Index
173

Botulinum Toxin in Painful Diseases

Enviado por

Dados do documento

Descrição original:

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Botulinum Toxin in Painful Diseases

Enviado por

Direitos autorais:

Formatos disponíveis

Botulinum Toxin in Painful Diseases

Pain and Headache

Botulinum Toxin in Painful Diseases

57 figures and 31 tables, 2003

Prof. Dr. med. Wolfgang H. Jost

Art. No. 16594

Pharmacology of Botulinum Neurotoxins

H N Limited proteolysis (clostridial proteases) Nicking

223 HELIH 227 2 Zn

Toxicokinetics of Clostridial Neurotoxins

Pharmacology of Botulinum Neurotoxins

Binding and endocytosis

Enzymatic Action of Clostridial Neurotoxins

Pharmacology of Botulinum Neurotoxins

Calcium binding site Synaptotagmin v-SNAREs Synaptobrevin SNAP-25 Ternary complex

Neurexin Syntaxin t-SNAREs

Synaptic vesicle Plasma membrane

Active zone Nerve ending Synaptic cleft

Pharmacology of Botulinum Neurotoxins

Clinical Use of Clostridial Neurotoxins

Pharmacology of Botulinum Neurotoxins

Pharmacology of Botulinum Neurotoxins

Pharmacology of Botulinum Neurotoxins

Botulinum Toxin A Usage in Pain Therapy

Botulinum Toxin A in Pain Management

Botulinum Toxin A in Pain Management

Relaxed muscle fibers

Local twitch of band

b Fig. 1. a, b Characteristics of muscular trigger points.

b Fig. 2. ac Palpation of muscular trigger points.

Botulinum Toxin A in Pain Management

Normalization of muscle spindle activity

Retrograde uptake in CNS

Inhibition of sterile inflammation

Elimination of muscular trigger points

Botulinum Toxin A in Pain Management

Myofascial Pain Syndrome

Definition and Clinical Signs

The Pathophysiologic Concept: Integrated Trigger Point Hypothesis

Diagnostic criteria Clinical findings

Local injections Outcome

Uncertain Usually chronic

72% also have active trigger points

Myofascial Pain Syndrome

Muscular overload Dysfunctional endplate

Vasoneur. substances (Bk, 5-HT)

Nociceptive nerve fibers (SP)

Autonomic nerve fibers Motor nerve terminal Excessive acetylcholine release

Energy crisis Depolarization Decreased energy supply Increased energy demand

SR Muscle fiber Calcium release

Fig. 1. Integrated trigger point hypothesis [modified after 8].

Myofascial Pain Syndrome

Established Therapeutic Possibilities

Myofascial Pain Syndrome

Indications for Botulinum Toxin Therapy

Published Clinical Data

Myofascial Pain Syndrome

Wheeler, 2001 [30] negative Foster, 2001 [29] positive

Randomized plc-controlled double-blind Randomized plc-controlled double-blind

Porta, 2000 [28] positive

Freund, 2000 [27] positive

Randomized plc-controlled double-blind

Wheeler, 1998 [26] negative