Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Menu

Peripheral Neuropathy
Robert W. Shields, Jr.
Published: August 2010

Contents

Definition and Etiology

Peripheral neuropathy, in the broadest sense, refers to a range of clinical syndromes affecting a variety of
peripheral nerve cells and fibers, including motor, sensory, and autonomic fibers (Box 1). Most peripheral
neuropathies affect all fiber types to some extent. However, a single fiber type may be predominantly or
exclusively affected in some disorders. For example, in small-fiber neuropathy (SFN) (Table 1), smallcaliber, unmyelinated, or only thinly myelinated autonomic fibers and somatic sensory fibers that subserve
pain and thermal receptors are predominantly involved.1 Thus, patients with SFN present primarily with
pain and autonomic dysfunction. Peripheral neuropathies are also defined by the pattern of nerve-fiber
involvement. For example, some disorders involve single individual peripheral nerves
mononeuropathiesand some involve numerous individual peripheral nerves, the mononeuritis
multiplex syndrome. In addition, peripheral nerve disorders can involve the brachial plexus, lumbosacral
plexus, or a single root, resulting in signs and symptoms in one limb.
Box 1 Peripheral Neuropathy Syndromes
Acute-Subacute Generalized Polyneuropathies
Sensorimotor
Acute motor and sensory axonal neuropathy syndrome
Alcohol or nutritional deficiencies
Toxins (metals)
Motor More than Sensory
Acute motor axonal neuropathy syndrome
Diphtheria
Guillain-Barr syndrome
Porphyria
Toxins (dapsone, vincristine)
Sensory
Human immunodeficiency virus
Paraneoplastic/autoimmune (anti-Hu-associated)
Toxins (cisplatin)
Vitamin B6 toxicity

1 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Chronic Generalized Symmetrical Polyneuropathies

Sensorimotor
Alcohol or nutritional deficiencies
Connective tissue diseases
Diabetes
Dysproteinemias
Uremia
Motor More than Sensory
Chronic inflammatory demyelinating
polyradiculoneuropathy
Dysproteinemias
Hypothyroidism
Toxins (amiodarone, cytosine arabinoside, metals,
tacrolimus)
Sensory
Paraneoplastic or autoimmune (anti-Hu-associated)
Sjgren's syndrome
Vitamin B6 toxicity
Vitamin E deficiency
Inherited Generalized Symmetrical Sensory and Motor
Polyneuropathies
Charcot-Marie-Tooth disease types 1, 2, 3, and X
Familial amyloidosis
Hereditary predisposition to pressure palsies (focal and
symmetrical)
Asymmetrical Generalized Sensory and Motor
Polyneuropathies
Diabetes
Lyme disease
Sarcoidosis
Vasculitis
Mononeuropathies
Compression and entrapment neuropathies
Diabetes
Vasculitis

2 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Most generalized disorders conform to a polyneuropathy syndrome, which usually implies both sensory
and motor fiber involvement in a relatively symmetrical fashion and typically with a distal-to-proximal
gradient of involvement. These disorders are termed generalized sensorimotor polyneuropathies, and they
represent the most common form of peripheral neuropathy. This review focuses primarily on this form of
peripheral neuropathy.
Table 1 Drugs that Can Induce Polyneuropathies

Drug

Clinical Features of Polyneuropathy

Antibiotic
Chloramphenicol

Sensory, optic neuropathy

Chloroquine

Sensory

Dapsone

Motor

Didanosine

Sensory

Ethambutol

Sensorimotor

Ethionamide

Sensory

Isoniazid

Sensory (vitamin B6 deficiency)

Metronidazole

Sensory

Nitrofurantoin

Sensorimotor

Savudine

Sensory

Suramin

Suramin

Sensorimotor
Zalcitabine

Sensory

Chemotherapeutic
Cisplatin

Sensorimotor, ototoxicity

Cytarabine

Sensory

Docetaxel

Sensorimotor

Paclitaxel

Sensorimotor

Procarbazine

Sensorimotor

Vinblastine

Sensorimotor

Vincristine

Sensorimotor

Cardiovascular

3 of 16

Amiodarone

Sensorimotor, ototoxicity

Captopril

Sensorimotor

Enalapril

Sensorimotor

Flecainide

Sensory

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Hydralazine

Sensory (vitamin B6 deficiency)

Perhexiline

Sensorimotor

Rheumatologic
Allopurinol

Sensorimotor

Colchicine

Sensory

Gold

Sensorimotor

Indomethacin

Sensorimotor

Miscellaneous
Disulfiram

Sensory

Interferon alfa

Sensorimotor

Lithium

Sensorimotor

Lovastatin

Sensorimotor

Phenytoin

Sensorimotor

Pyridoxine

Sensory

Simvastatin

Sensorimotor

Thalidomide

Sensorimotor

The peripheral nervous system can be involved in a wide range of medical disorders with various
pathophysiologies (see Box 1). It may be affected by numerous toxins, drugs (Table 2), and industrial
agents (Table 3) and by a variety of chronic infections, including human immunodeficiency virus (HIV). A
number of apparently immune-mediated disorders result in peripheral neuropathies, including
Guillain-Barr syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and
multifocal motor neuropathy with conduction block syndrome (MMNCB). A host of hereditary
polyneuropathies can cause a wide range of peripheral neuropathy syndromes (Box 2).
Table 2 Environmental and Industrial Toxins That Cause Polyneuropathy

4 of 16

Toxin

Clinical Features of the Polyneuropathy

Acrylamide

Sensorimotor, ataxia

Allyl chloride

Sensory

Arsenic

Sensorimotor

Carbon disulfide

Sensorimotor

Ethylene oxide

Sensorimotor, ataxia

Hexacarbons

Sensorimotor

Lead

Sensorimotor, motor > sensory

Mercury

Sensorimotor, motor > sensory

Organophosphorus esters

Sensorimotor, autonomic (cholinergic)

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Thallium

Sensorimotor

Trichloroethylene

Cranial neuropathies

Table 3: Heredofamilial Polyneuropathies

Disorder

Inheritance

Clinical

Pathology

CMT type 1

AD

Common, childhood onset, S/M

CMT type 2

AD

Rare, later onset than type 1, EM

CMT type 3 (DejerineSottas disease) AD

Rare, infantile onset,

severe S/M, D

CMT, X-linked

XR

Second-most common, S/M, earlier

onset, more severe D

HNPP

AD

Variable onset, compression

neuropathies, S/M

Familial amyloidosis

AD

Variable onset, autonomic and S/M

Refsums disease

AR

Variable onset, ataxia, retinitis

pigmentosa

Tangier disease

AR

Very rare, variable onset,

splenomegaly, orange tonsils

Fabrys disease

XR

Childhood onset, SFN

AD, autosomal dominant; AR, autosomal recessive; A, axon loss; CMT, Charcot-Marie-Tooth disease; D,
demyelinating; HNPP, hereditary neuropathy with liability to pressure palsies; S/M, sensorimotor; SFN,
small-fiber neuropathy; XR, X-linked recessive.

Box 2 Small-Fiber Neuropathies

Diabetes mellitus
Alcohol or nutritional deficiency
Amyloidosis (familial and primary)
Drugs or toxins
Cisplatin
Disulfiram
Isoniazid
Metals (gold, arsenic, thallium)
Metronidazole
Primary biliary cirrhosis

5 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Hypothyroidism
Heredofamilial
Hereditary sensory and autonomic neuropathy types I, III, and IV
Fabry's disease
Tangier disease
Dominantly inherited burning foot neuropathy
Sjgren's syndrome
Human immunodeficiency virus
Hyperlipidemia
Monoclonal gammopathy of uncertain significance
Idiopathic neuropathies
This diverse array of possible etiologies can make the diagnosis of peripheral neuropathies challenging.
Nevertheless, the diagnosis can be facilitated with a systematic approach that classifies the peripheral
neuropathy on the basis of clinical features, taking into account the type of peripheral nerve fiber that may
be involved (i.e., sensory, motor, or autonomic), the distribution or pattern of peripheral nerve fiber
involvement (generalized and symmetrical versus asymmetrical and multifocal), and the mode of evolution
(acute, subacute, or chronic).
Back to Top

Prevalence and Risk Factors

Peripheral nerve disorders are relatively common conditions that affect 2.4% of the population.2 However,
the prevalence increases to 8.0% with advancing age.
The most common generalized polyneuropathy is diabetic sensorimotor polyneuropathy, which may be
present in as many as 66% of type 1 diabetes patients and in nearly 59% of type 2 diabetes patients.3 Even
higher prevalence rates have been reported depending on the criteria used to diagnose polyneuropathy.
Considering that the prevalence rate of diabetes is approximately 1.3%, this common complication of
diabetes could affect nearly 1% of the general population.
The most common genetic sensorimotor polyneuropathy is Charcot-Marie-Tooth disease type 1a, which
has a prevalence of approximately 30 per 100,000 population. Carpal tunnel syndrome, caused by chronic
entrapment of the median nerve in the carpal tunnel, is the most common mononeuropathy, with a
prevalence estimated to be between 3% and 5% of adults.
Back to Top

Pathophysiology and Natural History

Despite the diverse array of medical disorders that cause peripheral neuropathies, peripheral nerves exhibit
only a few distinct pathologic reactions to an insult or disease: wallerian degeneration, axonal
degeneration, and segmental demyelination. The specific mechanisms by which the various disorders
affecting peripheral nerves induce these pathologic changes are largely unknown.

6 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

In wallerian degeneration, the axon degenerates distal to a focal lesion that interrupts the continuity of the
axon. This reaction often occurs in focal mononeuropathies that result from trauma or nerve infarction.
Axonal degeneration, sometimes referred to as the dying-back phenomenon, results in axonal degeneration
at the most distal extent of the axon. Axonal degenerative polyneuropathies are usually symmetrical, and as
the disorder progresses, the axons typically degenerate in a distal-to-proximal gradient. Axonal
degeneration is the most common type of pathologic reaction in generalized polyneuropathies, and it is
often attributed to a metabolic cause.
Segmental demyelination refers to focal degeneration of the myelin sheath with sparing of the axon. This
reaction can be seen in focal mononeuropathies and in generalized sensorimotor or predominantly motor
neuropathies. Acquired segmental demyelinating polyneuropathies are often immune-mediated or
inflammatory in origin. However, segmental demyelination can also occur in some hereditary
polyneuropathies.
In peripheral nerve disorders that are characterized by either wallerian degeneration or axonal
degeneration, prognosis is less favorable because the axon must regenerate and reinnervate muscle, the
sensory organ, blood vessels, and other structures before clinical recovery is noted. Recovery may be more
rapid with segmental demyelination because remyelination is accomplished more quickly, thereby
re-establishing normal conductivity of the axon and return of function.
Back to Top

Symptoms and Signs

A host of symptoms and signs that reflect sensory, motor, and autonomic nerve fiber dysfunction are typical
of peripheral neuropathies, and some combinations of symptoms and signs may be recognized as specific
syndromes of peripheral nerve disease. Sensory symptoms include sensory loss, often described by patients
as a sense of numbness or a Novocain-like feeling. In most generalized polyneuropathies, these
symptoms begin in the most distal extent of the longest sensory fibers (i.e., those that subserve sensation in
the toes and feet). The pathologic changes in most of these polyneuropathies are those of a distalto-proximal axonal degeneration that have been referred to as distal axonopathies or dying-back
neuropathies. Similar symptoms may be seen in hereditary or acquired demyelinating polyneuropathies.
Sensory Symptoms
Typically, all sensory modalities are affected to some extent, including light touch, pain, thermal sensation,
vibratory sense, and joint position sense. As the disease progresses, sensory loss ascends the lower
extremities, typically in a symmetrical fashion. When the sensory loss is at or above the level of the knee,
the axons supplying the distal fingertips begin to be involved, and the length-dependent process then begins
in the upper extremities. In addition to sensory loss, patients often complain of paresthesias and
dysesthesias, often characterized by a sense of numbness, tingling, prickling, and pins-and-needles
sensations. They might also complain of intense bandlike sensations and feelings of pressure.
The sensory examination often discloses a distal-to-proximal loss of the various sensory modalities. In
certain polyneuropathies, pain predominates in the clinical picture, and the sensory examination tends to
disclose deficits predominantly of pain and thermal sensation, conforming to an SFN. On occasion, when
significant proprioceptive deafferentation occurs, patients are found to have altered joint position sense that
can manifest as an ataxia or tremor of the affected limbs and an imbalance of gait and station.
Pain is a serious symptom for many patients. It may be described as a dull aching sensation, an intense
burning sensation or, occasionally, as intermittent lancinating pulses of pain. On occasion, patients notice
that their skin is hypersensitive to tactile stimulation such as from the touch of bed sheets or clothing or
from standing on their feet. Some patients note an exaggerated painful sensation resulting from any
7 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

stimulus to the affected area, a form of pain termed allodynia.

Weakness
Impairment of motor function typically produces weakness in a distal-to-proximal gradient consistent with
a length-dependent axonal degeneration. As with sensory loss, weakness begins in the toes, and as the
polyneuropathy progresses, it ascends up the distal lower extremities to the level of the knees, at which
time motor involvement in the hands may be observed. Similar patterns of weakness may be seen in
demyelinating polyneuropathies. However, in the acquired segmental demyelinating polyneuropathies such
as CIDP and related disorders, proximal muscle weakness resulting from root involvement may be
observed outside the proximal-to-distal gradient of the dying-back mechanism. This pattern of involvement
is termed a polyradiculoneuropathy.
Axonal degenerative polyneuropathies tend to produce weakness along with muscle atrophy, but atrophy is
much less conspicuous in segmental demyelinating polyneuropathies because in these disorders the axon
remains in continuity with the muscle, preventing denervation atrophy. The most common symptom in
polyneuropathy is weakness in dorsiflexion of the feet at the ankles. This can result in a partial or complete
foot drop that typically causes the feet to slap while walking and predisposes the patient to stumble and fall
when the toes catch on an uneven surface.
Tendon reflexes are usually depressed or absent in a distal-to-proximal pattern of involvement, with the
lower extremities affected more than the upper extremities. An exception to this is in SFN, in which the
large-caliber sensory afferent fibers from muscle spindles are relatively preserved and the tendon reflexes
might remain intact.
Autonomic Symptoms
In some polyneuropathies, typically in SFN, autonomic fibers are also affected. In these disorders, a variety
of autonomic symptoms may be present, although certainly the most dramatic and incapacitating is
orthostatic hypotension, which causes postural light- headedness, syncope, or both. However, orthostatic
hypotension typically occurs only with advanced autonomic involvement.
Earlier in the course of autonomic neuropathy, patients might notice reduced or absent sweating (i.e.,
anhidrosis) often in a distal-to-proximal gradient. Some patients complain of excessive sweating confined
to the head and neck region. This is most often secondary to anhidrosis in the limbs and thorax and reflects
compensatory hyperhidrosis in the restricted areas that maintain normal sweating.
Other autonomic symptoms include dryness of the eyes and mouth and gastrointestinal dysmotility, often
manifested by alternating constipation and diarrhea or by early satiety from gastroparesis. In addition,
patients may have urinary bladder dysfunction caused by an atonic bladder, which results in overflow
incontinence. In men, erectile dysfunction can represent an early autonomic symptom, reflecting
parasympathetic autonomic nervous system involvement.
Other Symptoms and Signs
Various limb deformities and trophic changes may be observed in chronic polyneuropathies. Pes cavus,
characterized by high arches and hammer toes and the clawfoot deformity, are typical foot deformities in
hereditary polyneuropathies with childhood onset. These deformities are a result of progressive weakness
and atrophy of intrinsic foot muscles. A similar claw-like deformity may be observed in the hand.
Autonomic involvement of a limb may, at times, cause the affected area to appear warm, red, and swollen
and at other times pale and cold because of abnormal regulation of small vessels as a result of autonomic

8 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

denervation. Various trophic changes can occur including tight, shiny skin.
In patients who have had severe sensory loss in the limbs, the affected areas may be subject to incidental
traumas, including burns, pressure sores, and other injuries that are not perceived by the patient. In these
patients, repeated injuries and traumas can result in chronic infections, sometimes leading to osteomyelitis.
In peripheral nerve disorders that are focal and asymmetrical, sensory and motorand occasionally
autonomicsymptoms and signs may conform to a specific peripheral nerve distribution. For example, in
carpal tunnel syndrome, patients might complain of intermittent numbness and tingling in the median nerve
distribution in the hand or, as the entrapment progresses, atrophy and weakness of the thenar muscle group.
In the mononeuritis multiplex syndrome, multiple individual peripheral nerves may be affected, and the
sensory, motor, and autonomic symptoms and signs will be distributed in a multifocal pattern conforming
to numerous individual peripheral nerve lesions. On occasion, some peripheral nerve disorders cause
generalized sensory and motor fiber involvement with asymmetrical and focal features (see Box 1).
Back to Top

Diagnosis
Diagnosis begins by recognizing typical symptoms of peripheral nerve disease and identifying the pattern
of peripheral nerve involvement. For example, if the symptoms are highly restricted and focal, they might
conform to the distribution of an individual peripheral nerve or, possibly, to an individual root.
More-diffuse involvement of an entire limb might be caused by involvement of the brachial or lumbosacral
plexus. Alternatively, if generalized symptoms are distributed in an asymmetrical and focal fashion, they
may be consistent with a mononeuritis multiplex picture or possibly a polyradiculoneuropathy or
polyradiculopathy syndrome. Most often, peripheral neuropathies produce symptoms that are generalized
and relatively symmetrical, conforming to a distal-to-proximal gradient typical of a distal axonopathy.
History and Physical Examination
As soon as their distribution is recognized, the symptoms should be analyzed to determine which fiber
types appear to be involved (i.e., sensory, motor, autonomic). In addition, the temporal profile of the
disorder (i.e., chronic, subacute, acute) is noted. The neurologic examination is then helpful in confirming
signs of sensory, motor, or autonomic dysfunction and in documenting the pattern and fiber type involved.
These clinical features, which can be derived solely from the history and physical examination, are
valuable for characterizing the nature of the peripheral nerve syndrome, which is essential in constructing a
differential diagnosis (see Box 1 and Table 3).
Electrodiagnostic Studies
Another important component to the evaluation of peripheral nerve disease is electrodiagnostic studies,
primarily nerve conduction studies and the needle electrode examination. Electrodiagnostic testing can
document the presence of peripheral nerve disease, define the distribution and pattern of various sensory
and motor fibers, and characterize the underlying pathologic processes (i.e., wallerian degeneration, axonal
degeneration, segmental demyelination, or some mixture of these pathologic reactions). Characterizing the
electrodiagnostic features, particularly whether the process is axonal or demyelinating, adds additional
information.4
Medical Studies
Other special studies include lumbar puncture for cerebrospinal fluid analysis, which may be useful in
diagnosing inflammatory or infectious causes of polyneuropathy, in evaluating acquired demyelinating

9 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

polyneuropathies such as those in GBS and CIDP, and in a variety of immune-mediated polyneuropathies.
Nerve biopsy, typically sural nerve biopsy, is most often recommended in patients with asymmetrical or
focal polyneuropathies in whom a diagnosis of vasculitis is being considered. In addition, biopsies may be
used to assist in the diagnosis of some inflammatory, infectious, and metabolic polyneuropathies. Nerve
biopsy can help to establish the pathologic basis of the polyneuropathy when electrodiagnostic studies
cannot conclusively distinguish an axonal from an acquired segmental demyelinating disorder.
Special autonomic studies, particularly those that measure cardiovascular autonomic reflexes (including
heart rate response to deep breathing, heart rate and blood pressure responses to the Valsalva maneuver, and
heart rate and blood pressure responses to head-up-tilt) may also be valuable in documenting autonomic
cardiovascular involvement. Various tests of sudomotor function including the sympathetic skin response,
quantitative sudomotor axon reflex test, and thermoregulatory sweat testing can provide valuable
information regarding the extent and distribution of sudomotor impairment in polyneuropathy.
Skin biopsy to measure epidermal nerve fiber density is also a helpful test for the diagnosis of SFN.
Quantitative sensory testing is a technique that allows precise measurement of sensory perception
thresholds of various fiber types, which can also be helpful in assessing peripheral neuropathy, especially
SFN, in which the electrodiagnostic studies are often normal.
Laboratory Studies
By recognizing the peripheral nerve syndrome and appreciating the potential differential diagnosis, one
may systematically perform appropriate medical tests to explore the various possible causes. The most
common peripheral nerve syndrome is the generalized sensorimotor polyneuropathy with electrodiagnostic
features of a distal axonopathy. For this disorder, it is usually appropriate to pursue a history of toxin
exposure (see Tables 2 and 3) and alcoholism with nutritional deficiency. It is also reasonable to perform
routine laboratory screening studies including a complete blood cell count; erythrocyte sedimentation rate;
a blood chemistry panel encompassing hepatic function, renal function, and electrolytes; thyroid function
studies; and vitamin B12 level.
It is important to screen patients for diabetes mellitus. In the past, a fasting blood sugar or hemoglobin A1c,
or both, was often performed, but recent reports suggest that impaired glucose tolerance detected on a
glucose tolerance test might provide more meaningful information regarding diabetes as a potential cause
for polyneuropathy.5
Screening the serum and urine with protein electrophoresis with immunofixation is also important in
assessing patients with generalized polyneuropathy. In one series, the only laboratory tests that were
helpful in establishing a precise cause for the polyneuropathy were vitamin B12, serum protein
electrophoresis with immunofixation, and serum glucose.6 Additional laboratory and radiographic studies
may be considered pending the specific clinical features, and may include chest radiograph, skeletal bone
survey, antinuclear antibodies, rheumatoid factor, and angiotensin-converting enzyme level.
In patients with an aggressive, evolving polyneuropathy or a specific paraneoplastic syndrome, additional
testing for an occult malignancy is often performed, usually in conjunction with autoantibodies, especially
anti-Hu. A variety of autoantibodies have been associated with different polyneuropathy syndromes. The
most useful of these include anti-GM1 antibodies in the setting of MMNCB, anti-Hu antibodies in the
context of a sensory neuronopathy, and anti-myelin-associated glycoprotein antibodies in acquired
demyelinating polyneuropathy with predominately sensory features and with a distal pattern of
involvement.7,8 Most of the other antibodies are much less specific, and their roles in the mechanism of the
polyneuropathies are less certain. Thus, the precise value of performing panels of antibody tests is unclear
at this time.9

10 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Lumbar puncture is often reserved for patients with possible immune-mediated polyneuropathies,
particularly those with demyelinating features on electrodiagnostic testing. However, CSF studies are also
often assessed in cryptogenic axonal degeneration polyneuropathies and in patients with possible infectious
or inflammatory disorders.
Additional Tests
In patients with electrodiagnostic features suggesting acquired segmental demyelination, a variety of tests
are indicated to assess for CIDP and related disorders (Box 3), including serum and urine for protein
electrophoresis with immunofixation, skeletal bone survey for myeloma or osteosclerotic myeloma, and
HIV testing in patients at risk.
Box 3 Autonomic Neuropathies and Polyneuropathies with Prominent Autonomic Features
Acute
Acute pandysautonomia (paraneoplastic and idiopathic)
Botulism
Guillain-Barr syndrome
Porphyria
Toxins (vincristine, amiodarone, cisplatin, organic solvents, metals)
Chronic
Amyloidosis
Chronic pandysautonomia (paraneoplastic and idiopathic)
Diabetes
Riley-Day syndrome
In patients with SFN, various hereditary diseases must also be considered if the more common acquired
disorders are not present (see Table 1). In the asymmetrical polyneuropathies, particularly those of acute or
subacute evolution, the differential diagnosis includes various connective tissue disorders associated with
vasculitis. Appropriate laboratory studies must be obtained to investigate these disorders.
The acute polyneuropathies are a special category that includes GBS, although variants and other
less-common causes must also be considered. The inherited polyneuropathies are, of course, identified by a
typical chronic course, often with onset in childhood and a family history of similar illness. Some of the
hereditary polyneuropathies, in particular Charcot-Marie-Tooth disease, may be confirmed with genetic
tests performed on blood.
Despite comprehensive testing and assessments, an etiologic diagnosis is not determined in nearly 25% of
patients with polyneuropathy.10 In this group, particularly those with chronic sensorimotor
polyneuropathies, careful assessment of first-degree relatives may be helpful in identifying an unrecognized
familial disorder. In addition, in patients with idiopathic polyneuropathy, judicious reassessment of their
laboratory investigations should be performed periodically, particularly if symptoms and signs progress.
Back to Top

Treatment

11 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Medical Treatment
Specific therapies for polyneuropathy are based on the precise etiologic diagnosis. In disorders attributed to
underlying medical conditions, management is focused on the medical disorder. For example, optimizing
glycemic control in diabetic polyneuropathy often stabilizes or improves the polyneuropathy.
In patients with idiopathic immune-mediated polyneuropathies, including GBS, CIDP, and MMNCB,
specific immune-modulating therapies are often recommended.8,11 For GBS, intravenous gamma globulin
(IVIg), typically administered at a dosage of 400 mg/kg daily for 5 consecutive days, is initiated early in
the patients course. Alternatively, plasmapheresis may also be instituted as initial therapy.
Treatment of CIDP may begin with corticosteroid therapy. However, chronic IVIg or plasmapheresis, or
both, are usually effective and obviate the need for long-term steroid therapy. Alternative therapies
including azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, methotrexate, and
rituximab have also been used in patients who have not responded to initial standard therapies.
Toxic polyneuropathies are managed by discontinuing the offending drug or removing the industrial toxin
from the patients environment.
Management of hereditary polyneuropathies includes education of the affected family members regarding
the nature and genetic features of the disorder and judicious screening of family members at risk.
Supportive Therapy
For all patients, and particularly for those without a specific or treatable cause, therapy focuses on
supportive measures. This may include the use of various physical therapy and occupational therapy
modalities including bracing and aids to ambulation. An ankle-foot orthosis may be effective in improving
ambulation in a patient with foot drop. In patients with severe sensory loss in the feet and lower
extremities, careful daily foot inspection for signs of trauma and infection are essential to prevent serious
infections and other complications.
Pain Management
In patients who have associated pain, particularly patients with SFN, specific neuropathic pain management
is instituted. Neuropathic pain typically does not respond to simple analgesics, and its potential chronicity
precludes narcotic therapy as a first choice. Typically, patients with SFN and other painful polyneuropathies
respond to drugs known to be effective for neuropathic pain, including tricyclic antidepressants and a
variety of antiepileptic drugs and membrane stabilizers (Table 4).1,6,12
Table 4 Drug Therapy for Neuropathic Pain

Drug

Daily Dosage,
Range

Comments

Antidepressants

12 of 16

Amitriptyline

10-150 mg

Sedation, anticholinergic side effects, weight gain,

arrhythmia

Nortriptyline

10-150 mg

Similar to amitriptyline but less sedating

Imipramine

10-300 mg

Similar to amitriptyline but less sedating

Desipramine

10-300 mg

Similar to amitriptyline but least sedating

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Duloxetine

60-120 mg

Nausea, dry mouth, constipation

Venlafaxine XR

37.5-225 mg

Asthenia, nausea, sweating, ejaculatory dysfunction

Gabapentin

300-3600 mg

Sedation, dizziness

Pregabalin

150-300 mg

Sedation, dizziness

Carbamazepine

200-1200 mg

Sedation, dizziness, nausea, bone marrow suppression

Oxycarbazepine

600-2400 mg

Fatigue, nausea, dizziness, leukopenia

Lamotrigine

50-500 mg

Serious rash, dizziness, nausea, sedation

Topiramate

25-400 mg

Sedation, weight loss, nephrolithiasis, myopia, angle closure

glaucoma

Mexiletine

150-750 mg

Dyspepsia, dizziness, tremor, arrhythmia

Tramadol

50-400 mg

Dizziness, nausea, constipation, seizures

Capsaicin
0.075%

Topical tid-qid

Burning, erythema

Antiepileptics

Miscellaneous

The choice for each patient must be individualized, taking into account potential side effects and drug
interactions, among other factors. For patients requiring sedation because of disturbed sleep from the pain,
a sedating tricyclic drug taken at bedtime, such as amitriptyline, is a good choice. However, the
anticholinergic side effects of the tricyclic antidepressants make them a poor choice in patients with
prominent dysautonomia because they are likely to worsen gastrointestinal dysmotility and bladder
dysfunction.
Because most of these drugs can potentially cause sedation, it is customary to begin therapy with small
doses and gradually escalate as needed and tolerated. However, it is important to increase a drug to a
reasonable dosage before determining its clinical efficacy. Drugs with little efficacy despite high doses
should be tapered and discontinued before starting an alternative drug. Alternatively, drugs that provide
some relief but are not controlling the pain adequately may be maintained in some circumstances, and
another drug may be added to the regimen.
Back to Top

Outcomes
Peripheral neuropathies are common disorders associated with a wide range of medical conditions and
immune-mediated mechanisms. With a systematic approach to the evaluation of these disorders,
approximately 75% of patients have a specific etiologic diagnosis. Despite comprehensive evaluations, the
peripheral nerve disorder must be regarded as cryptogenic or idiopathic in nearly 25% of patients. In most
patients with a peripheral neuropathy related to a medical disorder or immune-mediated mechanism,
specific therapies directed at the underlying mechanism are usually effective in controlling the peripheral
neuropathy. Despite these therapies, the symptoms and signs of the peripheral neuropathy remain a chronic
problem in most patients. Even in the absence of a specific treatable cause, the symptoms of
polyneuropathy can be treated with a variety of supportive measures including medications for neuropathic
pain, physical therapy modalities, and orthotic devices. Fortunately, for most of these patients, the
peripheral nerve disorder does not result in serious disability.

13 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

Back to Top

Summary
Peripheral neuropathy encompasses a wide spectrum of clinical disorders affecting sensory, motor,
and autonomic peripheral nerve fibers.
Generalized peripheral neuropathy often manifests with symptoms and signs of sensory and motor
deficits distributed symmetrically in a distal-to-proximal gradient, with the lower extremities more
affected than the upper extremities.
The diagnosis of peripheral neuropathy depends on the recognition of the symptoms and signs of
peripheral nerve dysfunction. Electromyography can be helpful in confirming the diagnosis and in
defining the nature and extent of the peripheral neuropathy.
The etiologic diagnosis of peripheral neuropathy can be challenging and depends on a careful and
methodologic assessment for underlying medical conditions that can cause peripheral neuropathy, as
well as other causes including hereditary, toxic, and primary autoimmune peripheral nerve disorders.
Management of the peripheral neuropathy is directed first at the specific cause if it is treatable and
second at the alleviation of symptoms, including managing neuropathic pain and bracing and
physical therapy for weakness.
Back to Top

Suggested Readings
Donofrio PD, Albers JW: Polyneuropathy: Classification by nerve conduction studies and
electromyography. AAEM Minimonograph #34. Muscle Nerve 1990;13:889-903.
England JD, Asbury AK: Peripheral neuropathy. Lancet 2004;363:2151-2161.
Lacomis D: Small-fiber neuropathy. Muscle Nerve 2002;26:173-188.
Lindenbaum Y, Kissel JT, Mendell JR: Treatment approaches for Guillain-Barr syndrome and
chronic inflammatory demyelinating polyradiculoneuropathy. Neurol Clin 2001;19:187-204.
Mauermann ML, Burns TM: The evaluation of chronic axonal polyneuropathies. Semin Neurol
2008;28:133-151.
Pourmand R: Evaluating patients with suspected peripheral neuropathy: Do the right thing, not
everything. Muscle Nerve 2002;26:288-290.
Saperstein DS: Chronic acquired demyelinating polyneuropathies. Semin Neurol 2008;28:168-184.
Sindrup SH, Jensen TS: Pharmacologic treatment of pain in polyneuropathy. Neurology
2000;55:915-920.
Singleton JR, Smith AG, Bromberg MB: Painful sensory polyneuropathy associated with impaired
glucose tolerance. Muscle Nerve 2001;24:1225-1228.
Wolfe GI, Barohn RJ: Cryptogenic sensory and sensorimotor polyneuropathies. Semin Neurol
1998;18:105-111.

References
1. Lacomis D: Small-fiber neuropathy. Muscle Nerve 2002;26:173-188.
2. Hughes RAC: Peripheral neuropathy. BMJ 2002;324:466-469.

14 of 16

01/12/2015 23:33

Peripheral Neuropathy

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

3. Dyck PJ, Kratz KM, Karnes JL, et al: The prevalence by staged severity of various types of diabetic
neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic
Neuropathy Study. Neurology 1993;43:817-824.
4. Donofrio PD, Albers JW: Polyneuropathy: classification by nerve conduction studies and
electromyography. AAEM Minimonograph #34. Muscle Nerve 1990;13:889-903.
5. Singleton JR, Smith AG, Bromberg MB: Painful sensory polyneuropathy associated with impaired
glucose tolerance. Muscle Nerve 2001;24:1225-1228.
6. Barohn RJ: Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18:7-18.
7. Kissel JT: Autoantibody testing in the evaluation of peripheral neuropathy. Semin Neurol
1998;18:83-94.
8. Saperstein DS, Katz JS, Amato AA, Barohn RJ: Clinical spectrum of chronic acquired demyelinating
polyneuropathies. Muscle Nerve 2001;24:311-324.
9. Pourmand R: Evaluating patients with suspected peripheral neuropathy: Do the right thing, not
everything. Muscle Nerve 2002;26:288-290.
10. Wolfe GI, Barohn RJ: Cryptogenic sensory and sensorimotor polyneuropathies. Semin Neurol
1998;18:105-111.
11. Lindenbaum Y, Kissel JT, Mendell JR: Treatment approaches for Guillain-Barr syndrome and
chronic inflammatory demyelinating polyradiculoneuropathy. Neurol Clin 2001;19:187-204.
12. Sindrup SH, Jensen TS: Pharmacologic treatment of pain in polyneuropathy. Neurology
2000;55:915-920.

Back to Top

15 of 16

01/12/2015 23:33

Peripheral Neuropathy

16 of 16

http://www.clevelandclinicmeded.com/medicalpubs/diseasem...

01/12/2015 23:33