Review Article

Cranial Neuralgias
Address correspondence to
Dr William P. Cheshire Jr,
Mayo Clinic, 4500 San Pablo
Road, Jacksonville, FL 32224,
cheshire@mayo.edu. William P. Cheshire Jr, MD, FAAN
Relationship Disclosure:
Dr Cheshire has received
personal compensation
for manuscript preparation ABSTRACT
from Turner White Purpose of Review: Pain arising from cranial neuralgias represents a significant health
Communications, Inc.
Unlabeled Use of
burden. Successful treatment depends on accurate diagnosis, which requires knowledge
Products/Investigational of neuroanatomy and pathophysiology as well as familiarity with the varied clinical
Use Disclosure: presentations encountered in neurologic practice. This article delineates the relevant
Dr Cheshire discusses the
unlabeled/investigational use
anatomy, clinical features, and management of the most common primary and secondary
of oxcarbazepine, baclofen, cranial neuralgias.
phenytoin, fosphenytoin, Recent Findings: Trigeminal neuralgia, which can result from neurovascular compres-
gabapentin, botulinum toxin,
tizanidine, pimozide, and
sion or demyelination, is a particularly severe form of facial pain. Herpes zoster virus is a
motor cortex stimulation for common cause of neuralgia that causes herpes zoster ophthalmicus acutely and post-
the treatment of trigeminal herpetic neuralgia chronically. Rarer facial pain syndromes arising from a single nerve
neuralgia; tricyclics, pregabalin,
opioids, tramadol, and capsaicin
include glossopharyngeal neuralgia, nervus intermedius neuralgia, and paratrigeminal
for the treatment of postherpetic oculosympathetic syndrome.
neuralgia; carbamazepine, Summary: In patients presenting with a cranial neuralgia, unless the etiology is
gabapentin, lamotrigine, and
tricyclics for the treatment of
apparent (eg, herpes zoster), cranial imaging studies should be undertaken to look
nervus intermedius neuralgia; for structural abnormalities such as neoplasm, granulomatous disease, demyelin-
and nonsteroidal anti-inflammatory ating disease, or vascular malformations. Management of both common and rare
drugs, muscle relaxants, tricyclics,
gabapentin, and occipital nerve
cranial neuralgias is often challenging and is best guided by the most recent
stimulators for the treatment available evidence.
of occipital neuralgia.
* 2015, American Academy Continuum (Minneap Minn) 2015;21(4):10721085.
of Neurology.

INTRODUCTION neuralgias involve the trigeminal nerve,

Cranial neuralgias encompass some of
the most debilitating forms of neuro-
pathic pain that come to the attention
of neurologists. One reason may be that
the face, which is disproportionately rep-
resented on the homunculus of the pri-
mary somatosensory cortex, is the main
portal through which the nervous sys-
tem encounters the world. Facial pain
also impacts patients psychologically and
socially, as the face is integral to inter-
personal communication and ones sense
of personal identity.
NEUROANATOMICAL BASIS
Nociceptive pain can arise from any area
of the scalp, face, or deeper cranial struc-
tures in response to injury. Neuropathic
pain, which occurs in the absence of
an ongoing tissue injury, can arise from
any of the sensory nerves that innervate
these structures. The majority of cranial
1072 www.ContinuumJournal.com
which comprises ophthalmic, maxillary,
and mandibular divisions (Figure 9-11).
The trigeminal nerve also mediates pain
arising from co-innervated structures, such
as the optic nerve and ocular motor mus-
cles. The sensory branches of the facial
and glossopharyngeal nerves and the
second cervical nerve can also transmit
pain (Table 9-12).
CLINICAL APPROACH TO
DIAGNOSIS
The clinical evaluation of the patient
with facial pain requires an organized ap-
proach beginning with localization. Is
the pain unilateral or bilateral? Can it be
traced to a single cranial nerve, or is
it more broadly distributed, which may
indicate a central or multiple cranial
nerve pain syndrome? Are colocalizing
neurologic deficits present?
August 2015

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 KEY POINTS
h Most cranial neuralgias
involve the trigeminal
nerve; however, the
sensory branches of
the facial and
glossopharyngeal nerves
and the second cervical
nerve can also
transmit pain.
h An organized clinical
approach is key to
reaching the correct
diagnosis in patients
with facial pain.
h Trigeminal neuralgia is
the most intensely
painful of the
cranial neuralgias.
h The pain of trigeminal
neuralgia is paroxysmal
FIGURE 9-1 Sensory innervation of the face by the trigeminal nerve. The trigeminal nerve root and classically sharp
exits the pons and gives rise to the trigeminal (gasserian or semilunar) ganglion, which
divides into ophthalmic, maxillary, and mandibular divisions of the trigeminal nerve. or electrical in quality.

Reprinted from Gray H, Lea & Febiger.1

The next question to address is etiol-
ogy. Can the onset of the pain be traced
to an identifiable insult, such as trauma,
a viral rash, an infectious or inflammatory
process, or a structural intracranial lesion?
The temporal profile, quality of pain,
and associated features are also helpful to
narrow the diagnosis. Is the pain paroxys-
mal or continuous? How long do episodes
last? What factors trigger, worsen, or re-
lieve the pain? Does the pain correlate
with the menstrual cycle, time of day, spe-
cific activities, or certain types of physical
stimulation of the painful area or remote
facial areas? Is the pain dull, aching, throb-
bing, pulsing, sharp, stinging, prickling,
burning, or electrical in quality? Are there
autonomic accompaniments? What types
of medications have been effective? Are
imaging abnormalities present?
TRIGEMINAL NEURALGIA
The most common cranial neuralgia
involves the trigeminal nerve (cranial
nerve V). Trigeminal neuralgia is also the
most intense of the cranial neuralgias.
Also known as tic douloureux, its prev-
alence is estimated at between 5 and 29 per
100,000 person-years.3Y6 Onset is most
often after the age of 50, and its incidence
increases with advancing age. Women are
affected 1.7 times more often than men.
The International Headache Society
(IHS) defines trigeminal neuralgia as a
disorder characterized by recurrent uni-
lateral brief electric shock-like pains, abrupt
in onset and termination, limited to the
distribution of one or more divisions of
the trigeminal nerve and triggered by
innocuous stimuli.2 The maxillary and
mandibular branches are most often af-
fected at about equal frequency. The sharp
or electrical paroxysms last seconds to
minutes and may occur in rapid succes-
sion. Painful attacks may be followed by
a brief refractory period.
Patients may notice a sensitive trig-
ger zone, which, although on the same

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 Cranial Neuralgias

TABLE 9-1 International Headache Society Classification of Cranial Neuralgias Organized

Neuroanatomicallya

International Headache
Level Nerve Society Classification
Cranial nerve II Optic nerve Headache associated with optic neuritis
Cranial nerves III, Oculomotor, trochlear, Headache attributed to ischemic oculomotor nerve palsy
IV, VI and abducens nerves
Cranial nerve V Trigeminal nerve Classical trigeminal neuralgia, purely paroxysmal
Classical trigeminal neuralgia with concomitant persistent
facial pain
Trigeminal autonomic cephalalgias
Painful trigeminal neuropathy attributed to acute herpes zoster
Painful trigeminal neuropathy attributed to postherpetic neuralgia
Painful trigeminal neuropathy, posttraumatic
Painful trigeminal neuropathy attributed to space-occupying lesion
Persistent idiopathic facial pain
Burning mouth syndrome

Cranial nerve VII Facial nerve Nervus intermedius neuralgia

Cranial nerve IX Glossopharyngeal nerve Glossopharyngeal neuralgia
Cervical nerve 2 Occipital nerve Occipital neuralgia

CNS Central neuropathic pain Painful trigeminal neuropathy attributed to multiple sclerosis
a
Data from Headache Classification Committee of the International Headache Society (IHS), Cephalalgia.2 www.ihs-classification.org/
_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf.

side of the face, does not always coincide
with the location of pain. The trigger
zone may be located near the nasolabial
fold; on the lateral aspect of the nares;
or along the lip, gum line, or tongue. The
slightest touch of the trigger zone during
routine daily activities, such as brushing
or flossing the teeth, shaving, washing
the face, applying facial cosmetics, smil-
ing, speaking, or eating, will unleash ex-
cruciating pain (Case 9-1). In severe cases,
patients may lose weight from not eat-
ing. Pain triggered by exposure to wind
or a cool breeze may confine the pa-
tient indoors.
Although many patients will experi-
ence spontaneous remissions, not all do,
and severe pain may return suddenly
months or years later. For most patients,
pain frequency and intensity progres-
sively increase over time. When tri-
geminal neuralgia is active, patients are
usually asymptomatic between attacks,
although in a minority of cases, contin-
uous dull or burning background pain
may precede or linger after the more
severe paroxysms. The IHS terms this
classical trigeminal neuralgia with con-
comitant persistent facial pain.2 The
continuous component is presumably
owing to central sensitization and may
respond poorly to treatment.
Neurologic examination in trigeminal
neuralgia is usually normal or may dis-
close a subtle trigeminal sensory def-
icit. The patient presenting with newly

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 Case 9-1
A 67-year-old man presented with a 2-year history of paroxysmal pain affecting his right cheek. The first
time he experienced this pain was while shaving, and he wondered if his electric razor had a short circuit,
because the pain felt like an electric shock shooting through his face. The pain had increased in frequency,
occurring numerous times during the day, and although each episode lasted only a few seconds, he described
the pain as excruciating and rated it as 10 times more severe than the pain he had experienced from a
kidney stone years earlier. Episodes of pain were easily triggered by the slightest breeze against his face,
by brushing his teeth, and at times by speaking or eating. Sneezing was particularly painful, although
he had no sinus discharge. He had been thoroughly evaluated by his dentist, who assured him that the pain was
not coming from his teeth. Whereas treatment with ibuprofen and oxycodone failed to prevent or reduce the
pain, carbamazepine at 200 mg 3 times a day had almost eliminated it. Neurologic examination was normal,
except that touching a wisp of cotton to his right nasolabial fold provoked the patients pain, causing him to
wince and withdraw. MRI of the brain disclosed a large prepontine mass (Figure 9-2). The diagnosis was
trigeminal neuralgia affecting the right maxillary division secondary to a prepontine epidermoid cyst.
Comment. Although the majority of patients with trigeminal neuralgia will have normal cranial
imaging results, a structural cause may be found in up to 15% of cases of trigeminal neuralgia.7

FIGURE 9-2 Axial brain MRI disclosing a large nonenhancing T1 hypointense (A) and T2
hyperintense (B) prepontine epidermoid cyst causing posterior displacement of
the brainstem and deforming the anterior aspect of the right brachium pontis. The
mass encases the cisternal portion of the right trigeminal nerve, which is not visualized, whereas at the
same level, the left trigeminal nerve root is seen as a linear structure just lateral to the basilar artery.

diagnosed trigeminal neuralgia should un-
dergo gadolinium-enhanced MRI of the
brain with fine cuts through the trigem-
inal nerves. A structural cause may be
found in up to 15% of cases of trigem-
inal neuralgia.7 When unmistakable or
progressive facial sensory loss is detected,
unless explained by prior trigeminal nerve
surgery, or if other cranial nerve or focal
neurologic deficits are present, a careful
search should be undertaken for an KEY POINT
underlying tumor, including repeated h The patient presenting
cranial imaging with attention to the en- with newly diagnosed
trigeminal neuralgia
tire course of the trigeminal nerve. The
should undergo
differential diagnosis for trigeminal neu-
gadolinium-enhanced
ralgia includes invasive squamous cell MRI of the brain with
carcinoma of the face, meningioma, ves- fine cuts through the
tibular schwannoma, epidermoid cyst or trigeminal nerves.
other skull base tumor, Chiari malforma-
tion, or saccular aneurysm or arteriovenous

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 Cranial Neuralgias
KEY POINTS
h Neurovascular malformation compressing the trigeminal
compression, which is nerve root.8
believed to be the basis Many cases of trigeminal neuralgia,
for pain in most cases of if not the majority, result from trigem-
trigeminal neuralgia, is inal neurovascular compression. Ac-
usually not visible by cording to this model, a redundant or
standard MRI. tortuous vascular loop, most often the
h Trigeminal neuralgia that superior cerebellar artery, impinges on
occurs bilaterally or in the trigeminal nerve root in the poste-
younger patients may rior fossa. Over time, pulsatile indenta-
suggest a diagnosis of tion induces a focus of demyelination,
multiple sclerosis. which leads to aberrant discharge of the
h Carbamazepine is the drug nerve spontaneously or in response
of first choice in treating to normally innocuous afferent traffic.
trigeminal neuralgia. Ephaptic spillover to adjacent fibers
within the trigeminal nerve reaches a
critical threshold, which ignites a pain-
ful crescendo of maximal discharge. Cur-
rently, routine MRI techniques lack the
resolution to identify neurovascular com-
pression with sufficient sensitivity or spe-
cificity.9 Neurovascular compression may,
however, be visualized in some cases by
high-resolution imaging, including con-
structive interference in steady state (CISS)
coronal imaging.10
Compared to the general population,
patients with multiple sclerosis have a
20-fold increased risk of developing tri-
geminal neuralgia, with a prevalence of
2% to 5%.11,12 Whereas idiopathic or neu-
rovascular trigeminal neuralgia is almost
always (97%) unilateral, when trigeminal
neuralgia occurs in multiple sclerosis, it
may be bilateral in up to 30% of pa-
tients.8,11 Thus, it is important to con-
sider a diagnosis of multiple sclerosis
in the patient who presents with bilateral
trigeminal neuralgia, particularly if the
patient is relatively young or has other
neurologic signs or symptoms. Ultrastruc-
tural studies have shown demyelination
in the proximal centrally myelinated por-
tion of the trigeminal root.13
The first line of therapy in the treat-
ment of trigeminal neuralgia is carbamaz-
epine, which carries Level A evidence
(Table 9-214Y16). Resolution of pain within
a few days of beginning carbamaze-
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pine is considered one of the diagnos-
tic features of trigeminal neuralgia as
distinguished from other types of facial
pain.8 A low dose, 100 mg 2 to 3 times
daily, may be effective initially, as the
lowest effective dose is preferable to
minimize side effects, particularly in pa-
tients with multiple sclerosis, some of
whom may have dizziness, ataxia, or im-
paired coordination at baseline. Un-
fortunately, over time larger doses are
typically required to maintain pain con-
trol, and eventually carbamazepine may
not be effective. Level B evidence exists
for oxcarbazepine, and Level C evidence
exists for baclofen and lamotrigine.7
Gabapentin or, for acute crisis, phe-
nytoin or fosphenytoin may be useful
in some patients.17,18 Several small short-
term studies have indicated that intra-
dermal injection of onabotulinumtoxinA
may be effective in the treatment of
trigeminal neuralgia.19,20 Limited, low-
quality evidence suggests that tiza-
nidine and pimozide may be helpful in
some patients.21
For patients with severe, debilitat-
ing pain refractory to medical therapy,
surgical options should be considered.
The choice of procedure often depends
on the neurosurgeons preference and
experience.22 Level C evidence exists for
microvascular decompression, gasserian
ganglion percutaneous techniques, and
gamma knife radiation therapy.7 The
level of evidence for comparative effi-
cacy and durability of these surgical pro-
cedures is low, as they have not been
subjected to randomized trials or well-
designed long-term studies.23
Microvascular decompression is the
one procedure that uniquely addresses,
with the aim of reversing, the underly-
ing neurovascular pathology, and it
appears to lead to the most enduring long-
term outcomes. This procedure carries
potential complications of cranial neu-
ropathies, cerebellar hematoma or con-
tusion, meningitis, or CSF leakage.8,24,25
August 2015
 Percutaneous procedures reach the niques include radiofrequency thermoco-
gasserian ganglion via the foramen ovale agulation, injection of neurotoxins such as
and induce a partial injury. Available tech- alcohol or glycerol, or compression of the

a
TABLE 9-2 Pharmacologic Treatment of Trigeminal Neuralgia

Level of Common Adverse Serious Adverse

Evidenceb Drug Initial Dose Typical Dose Effectsc Effectsc
A Carbamazepined,e 100 mg 100Y200 mg Dizziness, nystagmus, Atrioventricular block,
2 times/d 3 times/d nausea, constipation, hepatotoxicity, bone
ataxia, fatigue, marrow suppression
drowsiness, blurry vision including aplastic anemia
or agranulocytosis,
Stevens-Johnson
syndrome, toxic epidermal
necrolysis, hyponatremia,
hypocalcemia, pancreatitis,
nephrotoxicity, multiorgan
hypersensitivity,
angioedema, suicidal
thoughtsc
B Oxcarbazepined,e 300 mg 600Y1200 mg Dizziness, nystagmus, Hyponatremia, erythema
2 times/d 2 times/d nausea, ataxia, fatigue, multiforme, Stevens-
drowsiness, blurry vision Johnson syndrome, toxic
epidermal necrosis,
anaphylaxis, bone marrow
suppression, suicidal
thoughts, angioedema
C Baclofen 5 mg 10Y20 mg Drowsiness, hypotension, Gastrointestinal
3 times/d 3 times/d constipation, nausea, hemorrhage, pneumonia,
hypotonia or muscle drug withdrawal seizures
weakness, fatigue, if stopped abruptly
dizziness
Gabapentind 100 mg 100Y900 mg Peripheral edema, Stevens-Johnson
3 times/d 3 times/d fatigue, drowsiness, syndrome, suicidal
dizziness, nausea, ataxia thoughts
Lamotrigined 25 mg every 50Y200 mg Rash, abdominal pain, Erythema multiforme,
other day 2 times/d diarrhea, nausea, Stevens-Johnson
dizziness, ataxia, syndrome, toxic
diplopia, insomnia, epidermal necrolysis,
headache, blurry vision, anemia, leukopenia,
anxiety, tremor, eosinophilia,
depression, rhinitis, disseminated intravascular
dysmenorrhea coagulation,
hepatotoxicity, aseptic
meningitis, drug
hypersensitivity syndrome,
neuroleptic malignant
syndrome, angioedema,
suicidal thoughts
Continued on page 1078

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 Cranial Neuralgias

a
TABLE 9-2 Pharmacologic Treatment of Trigeminal Neuralgia Continued from page 1077

Level of Common Adverse Serious Adverse

Evidenceb Drug Initial Dose Typical Dose Effectsc Effectsc
C Phenytoind 50 mg 300Y400 mg at Rash, gingival hyperplasia, Stevens-Johnson
3 times/d bedtime (single ataxia, dizziness, syndrome, toxic epidermal
nightly dosing refers nystagmus, nausea, necrolysis, systemic lupus
to the extended slurred speech, erythematosus, bullous
release form) confusion, drowsiness, dermatosis, bone
hirsutism, vitamin D marrow suppression
deficiency, blurred including agranulocytosis
vision/double vision or aplastic anemia,
hepatotoxicity,
nephrotoxicity, suicidal
thoughts
a
In general, the same pharmacologic strategy may be utilized when treating glossopharyngeal neuralgia and nervus intermedius neuralgia.
b
A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in
the specified population. (Level A rating requires at least two consistent Class I studies.) (In exceptional cases, one convincing Class I
study may suffice for an A recommendation if 1) all criteria are met, 2) the magnitude of effect is large [relative rate improved outcome 95
and the lower limit of the confidence interval is 92].)
B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified
population. (Level B rating requires at least one Class I study or two consistent Class II studies.)
C = Possibly effective, ineffective or harmful (or possibly useful predictive or not useful/predictive) for the given condition in the
specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
c
Lists of potential adverse affects are incomplete and the prescribing physician should refer to the Physicians Desk Reference or its equivalent
for a complete list.
d
In 2008, on the basis of a meta-analysis, the US Food and Drug Administration (FDA) issued an alert warning that antiepileptic drugs in
general carry an increased risk for suicidality. Uncertainty whether those studies controlled adequately for relevant comorbidities has
caused some to question the strength of that association.14Y16 Since trigeminal neuralgia itself carries an increased risk for suicide, when
prescribing antiepileptic drugs for cranial neuralgia, the physician should inform the patient of the possible increased risk of suicidality
and assess the overall benefits versus risks of the drug.
e
The risk of serious and sometimes fatal dermatologic reactions to carbamazepine may be tenfold higher in patients of Asian ancestry who
have the HLA-B*1502 genotype.

ganglion with an inflatable balloon.22,26 radiation facial paresthesia and dyses-

All result in some degree of facial numb-
ness or paresthesia and, especially follow-
ing multiple procedures, can potentially
cause deafferentation pain, which is
termed anesthesia dolorosa. The bal-
loon compression technique appears
to have efficacy similar to that of the
others with less risk of corneal anes-
thesia or anesthesia dolorosa.26
Gamma knife stereotactic radiation
therapy may be an appropriate inter-
vention for patients unable to tolerate a
surgical procedure. This technique targets
the trigeminal nerve root entry zone at
the level of the pons with ionizing radia-
tion. Reported outcomes have varied
greatly, and a high incidence of post-
thesia exists.27
Motor cortex stimulation has shown
initial promise in treating selected pa-
tients, not with trigeminal neuralgia but
with severe medically intractable trigemi-
nal deafferentation pain, which can be
quite severe and, unlike the brief
paroxysmal pain of trigeminal neuralgia,
is typically continuous and dull, aching, or
burning in quality.28 The procedure in-
volves an open craniotomy and implan-
tation of a strip of electrodes over the
motor cortex, connected to a subcutane-
ously tunneled stimulator.
The role of surgical intervention in
treating trigeminal neuralgia in patients
with multiple sclerosis is less certain,

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especially when neurovascular com-
pression is not demonstrated.7,8
PARATRIGEMINAL
OCULOSYMPATHETIC SYNDROME
(RAEDER SYNDROME)
Paratrigeminal oculosympathetic syn-
drome consists of constant unilateral
pain in the distribution of the ophthal-
mic division of the trigeminal nerve
along with ipsilateral ptosis and miosis
(Horner syndrome). The pain is wors-
ened by eye movement and may ex-
tend also to the maxillary division. This
clinical presentation is indicative of a
lesion in the carotid artery or middle
cranial fossa and should alert the neu-
rologist to the possibility of a carotid
artery dissection.29,30
GLOSSOPHARYNGEAL
NEURALGIA
Similar in quality to the pain of trigem-
inal neuralgia but less severe, glossopha-
ryngeal neuralgia affects the auricular
and pharyngeal branches of the vagus
nerve (cranial nerve X) and branches of
the glossopharyngeal nerve (cranial nerve
IX). The incidence of glossopharyngeal
neuralgia is 0.2 to 0.8 per 100,000 person-
years.2,5,31 It may coexist with trigem-
inal neuralgia.
Patients report unilateral pain deep
in the pharynx, posterior aspect of the
tongue, or ear that is triggered by swal-
lowing.32 Paroxysms of pain may cause
reflex bradycardia or syncope. Some pa-
tients will also manifest coughing, diffi-
culty with swallowing, or hoarseness.
Pharmacologic treatment is similar to that
for trigeminal neuralgia.
In some cases, MRI has shown vagal
neurovascular compression, which re-
sponded to microvascular decompres-
sion.33 Recurrent refractory syncope may
require placement of a cardiac pacemaker
in some patients.34
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KEY POINTS
HERPES ZOSTER h Unilateral eye pain
Varicella-zoster virus (VZV) is a ubiq- accompanied by Horner
uitous and highly neurotropic herpes- syndrome can be a clue
virus that causes varicella (chickenpox) to carotid artery dissection.
infection in children, after which the h Glossopharyngeal
virus remains latent for decades in tri- neuralgia causes
geminal, dorsal root, and autonomic pharyngeal pain with
ganglia. With age-related decline in cell- swallowing and may
mediated immunity or in immunocom- trigger reflex bradycardia
promised patients, VZV may reactivate or syncope.
as herpes zoster (shingles), which pre- h Herpes zoster frequently
sents with a painful vesicular cutaneous involves the trigeminal
eruption typically in the distribution of nerve, 80% of the time
a single dermatome. Pain may precede involving the ophthalmic
the emergence of rash by several days. division of this nerve,
Occasionally, herpes zoster may cause with the potential for
dermatomal neuropathic pain in the visual impairment.
absence of a rash (zoster sine herpete).
In such cases, evidence in support of a
viral basis has included the detection of
VZV DNA or intrathecal synthesis of anti-
VZV IgG in CSF and pathologic findings
of active viral ganglionitis.35 The inci-
dence increases with age: 70% to 80%
of herpes zoster occurs after the age of
50. Groups at particular risk are patients
with transplanted organs, human immu-
nodeficiency virus (HIV), lymphoma, or
tuberculosis. The age-adjusted incidence
of herpes zoster is approximately 3.9 and
3.2 per 1000 person-years for women and
men, respectively, and the lifetime risk of
herpes zoster is estimated at 30%.36,37
Herpes zoster affects the trigeminal
nerve in 8% to 28% of cases, 80% of
which occur in the ophthalmic division
(herpes zoster ophthalmicus). This is in
contrast to trigeminal neuralgia, which
involves the ophthalmic division in less
than 5% of cases.37,38 In addition to pain,
herpes zoster eye involvement can lead
to ptosis, keratitis, uveitis, iritis, conjunc-
tivitis, or acute retinal necrosis with the
potential for permanent visual loss in
nearly 7%.39
The pain of herpes zoster ophthalmicus
is typically multimodal, with burning,
shooting, stabbing, aching, tingling, prick-
ling, and itching components (Case 9-2).
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 Cranial Neuralgias

KEY POINTS
h Postherpetic neuralgia
occurs in more than
40% of patients older
than 60 years of age
following acute
herpes zoster.
h Nervus intermedius
neuralgia typically
causes sharp pain felt
deep in the ear canal.
Case 9-2
A 72-year-old woman sought neurologic evaluation for pain in the forehead.
Symptoms began 1 month previous with a burning sensation that she initially
thought was sunburn, but it affected only the right side. Two days later, blisters
erupted in the same area, and the headache intensified with sharp, throbbing,
stinging, and tingling components. She was seen at an urgent care clinic and
given valacyclovir 1 g orally 3 times a day for 1 week and hydrocodone 10 mg
4 times a day. Her pain gradually subsided from 10/10 to 6/10 in intensity, but
was worsened by wearing reading glasses or by anything that touched the right
eyebrow, forehead, or lateral aspect of the nose. Her past medical history was
remarkable only for hypertension. She reported that she had been under some
stress recently, caring for a terminally ill family member. Neurologic examination
showed 20/20 visual acuity in each eye. Facial sensory examination was abnormal
with patchy hyperesthesia involving the ophthalmic division of the right
trigeminal nerve.
Comment. This is a typical presentation for herpes zoster ophthalmicus.
It is important to consider herpes zoster ophthalmicus in the differential
diagnosis of new-onset unilateral frontal or temporal headache in the
elderly patient, as a rash may not be present initially.

Cutaneous allodynia is frequently pres- of the trigeminal nerve that persists or

ent. Antiviral drugs, such as valacyclovir
or famciclovir, have been shown to accel-
erate healing of the rash and shorten the
duration of pain and are US Food and
Drug Administration (FDA) approved for
treatment of acute herpes zoster. Severely
affected or neurologically complex pa-
tients may require IV acyclovir.35 Whereas
antiviral agents have been shown to de-
crease zoster-associated pain during the
first few weeks,40 strong evidence indi-
cates that antiviral agents do not reduce
the incidence of postherpetic neuralgia.41
Geniculate zoster involving cranial
nerve VII presents with ipsilateral facial
palsy and sometimes painful vesicles in
the external auditory canal, anterior two-
thirds of the tongue, or hard palate
(Ramsay Hunt syndrome). Herpes zos-
ter can involve any of the other cranial
nerves acutely or in the days and weeks
that follow the rash.35
More than 40% of patients older than
60 years of age with acute herpes zoster
will experience chronic pain. Postherpetic
trigeminal neuropathy is a form of post-
herpetic neuralgia defined as pain caused
by herpes zoster in one or more branches
recurs for at least 3 months.2 This pain can
be difficult to treat. First-line treatments
include tricyclics, gabapentin, pregabalin,
and topical lidocaine. Second- and third-
line treatments include opioids, tramadol,
and topical capsaicin (Table 9-3).42
Preventive efforts by vaccination are
showing promise. Herpes zoster vaccine
administered to adults older than 60 years
of age is 51% effective for prevention of
zoster and 66% effective for prevention
of postherpetic neuralgia, although ef-
ficacy beyond 5 years is uncertain.43,44
NERVUS INTERMEDIUS
NEURALGIA
Also known as geniculate neuralgia, ner-
vus intermedius neuralgia is a very rare
disorder in which pain arises from the
sensory branch of the facial nerve (cra-
nial nerve VII), which innervates the
external auditory meatus, pinna, and a
small area of skin below the ear lobe.
Patients present with paroxysmal unilat-
eral sharp or stabbing pain deep in the
auditory canal triggered by swallowing,
speaking, or stimulation of the posterior
wall of the auditory canal. The pain may

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TABLE 9-3 Pharmacologic Treatment of Postherpetic Neuralgia

Level of Common Adverse Serious Adverse

Evidencea Drug Typical Dose Effectsb Effectsb
A Lidocaine 5% 1Y3 patches Paresthesia or skin Systemic effects such as
applied topically irritation at the hypotension or bradycardia
for up to 12 out application site are unlikely with appropriate
of 24 hours use of the patch
Nortriptyline or 10Y75 mg at Constipation, dry mouth, Prolonged QT interval,
amitriptyline bedtime weight gain, dizziness heart block, myocardial
infarction, paralytic ileus,
hyponatremia, bone
marrow depression,
increased intraocular
pressure, depression,
urinary retention
Gabapentin 100Y900 mg Peripheral edema, Stevens-Johnson
3 times/d fatigue, drowsiness, syndrome, suicidal
dizziness, nausea, ataxia thoughts
Pregabalin 75Y300 mg Peripheral edema, weight Hepatotoxicity, increased
2 times/d gain, constipation, dry creatine kinase, suicidal
mouth, fatigue, dizziness, thoughts, angioedema
ataxia, blurry vision,
disturbance in thinking,
nasopharyngitis
B Opioids (eg, hydrocodone, Oral or topical, Constipation, nausea, Confusion, hypotension,
oxycodone, morphine, titrate based on pruritus, dizziness, peripheral edema,
hydromorphone, pain response somnolence, headache, prolonged QT interval
methadone, fentanyl) and side effects difficulty swallowing, (particularly for
tremor methadone), respiratory
depression, urinary
retention, serotonin
syndrome (when combined
with other drugs that
increase serotonin levels)
Tramadol 25Y100 mg Flushing, pruritus, Myocardial infarction,
4 times/d constipation, nausea, pancreatitis, anaphylaxis,
dizziness, headache, seizure, dyspnea,
insomnia, somnolence serotonin syndrome
C Capsaicin Single 1-hour Erythema, pain, nausea Hypertension, blistering
application of
8% patch every
3 months
a
A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in
the specified population. (Level A rating requires at least two consistent Class I studies.) (In exceptional cases, one convincing Class I
study may suffice for an A recommendation if 1) all criteria are met, 2) the magnitude of effect is large [relative rate improved
outcome 95 and the lower limit of the confidence interval is 92].)
B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified
population. (Level B rating requires at least one Class I study or two consistent Class II studies.)
C = Possibly effective, ineffective or harmful (or possibly useful predictive or not useful/predictive) for the given condition in the specified
population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
b
Lists of potential adverse affects are incomplete and the prescribing physician should refer to the Physicians Desk Reference or its equivalent
for a complete list.

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 Cranial Neuralgias
KEY POINTS
h Persistent idiopathic
facial pain (formerly
termed atypical facial
pain) may be difficult to
treat because of central
sensitization and
psychological comorbidity.
h Granulomatous
inflammation of the orbit,
superior orbital fissure,
or cavernous sinus presents
with unilateral orbital pain
with ophthalmoplegia.
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also extend to the auricle, facial mus-
culature, and over the parieto-occipital
region, as well as to the palate and
tongue, but unlike the pain of glos-
sopharyngeal neuralgia is not triggered
by swallowing.2,38 Nervus intermedius
neuralgia may develop as a complication
of herpes zoster. Impaired lacrimation,
salivation, or taste may occur.
Treatment is similar to that for tri-
geminal neuralgia, with the first line
of treatment being carbamazepine.
Gabapentin, lamotrigine, and tricyclics
have brought improvement to some pa-
tients. For patients in whom medical
therapy has failed, anecdotal reports of
successful surgical treatments include
transection of the nervus intermedius,
microvascular decompression of the
nervus intermedius, and extracranial in-
fratemporal division of the cutaneous
branches of the facial nerve.45,46
PERSISTENT IDIOPATHIC
FACIAL PAIN
Previously termed atypical facial pain,
persistent idiopathic facial pain refers to
the clinical syndrome of continuous or
daily recurring facial or oral pain in the
absence of a clinical neurologic deficit.
Its presentations are highly variable.
The pain may be unilateral or bilateral,
regional, diffuse, superficial, deep, or
poorly localized. Patients may report pain
that is dull, nagging, burning, or aching.
This pain may follow minor or insignifi-
cant facial trauma or dental procedures
and frequently is associated with psycho-
logical comorbidity and psychosocial
disability.2 Clinical management can
be very difficult.
The evaluation of persistent idiopathic
facial pain should assess for a possible
underlying connective tissue disorder,
such as mixed connective tissue disorder,
scleroderma, sarcoidosis, or Sjogren syn-
drome. Cranial imaging is required when
focal neurologic deficits are found.
BURNING MOUTH SYNDROME
Related to persistent idiopathic facial
pain is burning mouth or burning tongue
syndrome. This condition occurs in 5 to
10 per 100,000 population, most commonly
in middle-aged and elderly women.47
Burning mouth syndrome is frequently
idiopathic, although some patients have
chronic hyposalivation, which may be
induced by anticholinergic medication
or Sjogren syndrome. The differential
diagnosis also includes vitamin B12 de-
ficiency, oral candidiasis, and lichen planus.
Lubricating oral rinses may be helpful.
HEADACHE WITH
OPHTHALMOPLEGIA
(TOLOSA-HUNT SYNDROME)
Unilateral orbital pain accompanied by
ocular motor (cranial nerve III, IV, or VI)
paresis should arouse strong suspicion
for a structural lesion. This is the char-
acteristic presentation of Tolosa-Hunt
syndrome, which is caused by granulo-
matous inflammation in the orbit, su-
perior orbital fissure, or cavernous sinus,
and may be the presenting symptom of
neurosarcoidosis.48 MRI may disclose a
focal enhancing mass.49 The granulo-
matous inflammation typically responds
well to corticosteroids. Other potential
etiologies include orbital tumors, cavern-
ous carotid aneurysm, carotid-cavernous
fistula, carotid dissection, vasculitis, men-
ingitis, and diabetes mellitus.2,50
OPTIC NEURITIS
Pain behind one or both eyes, which may
be worse with eye movement, accompa-
nied by impaired visual acuity may signal
optic neuritis, which is caused by demy-
elination of the optic nerve. Optic neuri-
tis can occur as an isolated syndrome
or as a manifestation of either multiple
sclerosis51 or neuromyelitis optica.52
Diagnostic evaluation includes dilated
funduscopic examination, MRI of the
brain and orbits, and CSF analysis. Op-
tical coherence tomography is useful to
August 2015

measure retinal axonal loss. Treatment
with high-dose corticosteroids shortens
the time of acute visual impairment but
does not affect the final visual outcome.53
OCCIPITAL NEURALGIA
Occipital neuralgia can arise from the
greater occipital nerve, which originates
from the dorsal ramus of C2, or from
the lesser occipital or third occipital nerves,
which originate from C2 and C3 in the
cervical plexus.54 The pain is unilateral
in 85% of patients, who may present with
paroxysmal pain associated with dyses-
thesia or allodynia in the posterior scalp.
The paroxysms are shooting or stabbing
in quality and last from seconds to min-
utes. In some cases the pain may radiate
to the ipsilateral fronto-orbital region be-
cause of trigeminocervical interneuro-
nal connections in the trigeminal spinal
nuclei. Physical examination may disclose
tenderness over the affected nerve
branches, in which case the diagnosis
is confirmed by temporary relief of pain
by injection of local anesthetic.2,55,56
Anesthetic block of the greater or lesser
occipital nerves combined with injection
of a corticosteroid is efficacious in the
majority of patients.55 Conservative in-
terventions, such as warm or cold com-
presses, massage, and physical therapy
directed to improving posture, may also
be helpful. Nonsteroidal anti-inflammatory
medications, muscle relaxants, tricyclics,
and gabapentin have been reported to
be helpful.55 Limited evidence suggests
that implanted occipital nerve stimula-
tors may be effective in some patients
refractory to standard treatments.57
CONCLUSION
Cranial neuralgias can be very challeng-
ing problems. A thorough organized clin-
ical approach is essential to reaching a
specific diagnosis, on which depend ef-
fective disease-specific pharmacologic or,
when indicated, surgical interventions.
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