trigeminal-neuralgia version 2- sept 2014

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163

Trigeminal Neuralgia: Diagnosis and Nonoperative Management

Marlon S. Mathews n Devin K. Binder n Mark E. Linskey

Neuropathic facial pain (NFP) is defined as pain around the mouth or face that arises from a primary lesion or dysfunction of the nervous system.1 The management of NFP can be a frustrat-ing as well as rewarding experience in neurosurgical practice because facial pain is often a difficult problem with a wide variety of potential causes. It is therefore important for neurosurgeons to have a broad understanding of the underpinnings of facial pain syndromes. NFP can be primary (with no recognizable underly-ing pathology) or secondary, such as following traumatic nerve injury. NFP includes a heterogeneous group of entities and can be broadly considered in two categories: paroxysmal and continu-ous.2 Paroxysmal neuropathies such as trigeminal neuralgia (TN) are characterized by short electrical shock-like or sharp pain. Continuous pain often has a burning characteristic and is a common feature of conditions such as postherpetic neuralgia (PHN). NFP can vary in severity and also commonly presents with thermal or mechanical allodynia.

HISTORICAL PERSPECTIVEOne of the earliest known descriptions of paroxysmal facial pain was by the Arab physician Jurjani in the 11th century. He described a type of pain which affects the teeth on one side and the whole of the jaw on the side which is painful.3 The 17th century physician John Locke described the symptoms of TN in the wife of the English ambassador to France. Faced with limited treatment options for the patients excruciating pain, the physi-cian opted for eight rounds of cleansing of the gastrointestinal tract, which reportedly resulted in remission of symptoms.4

In the era preceding the description of TN, studies of the anatomy of the cranial nerves led to a better understanding of facial pain. In 1829, the Scottish anatomist Sir Charles Bell (1774-1842) described the anatomy of the fifth cranial nerve and its motor and sensory functions, establishing the trigeminal nerve as the cranial nerve responsible for subserving facial sensation as well as motor innervation to the masticator muscles.5 Previously, it was widely believed that the seventh cranial nerve was the source of facial pain syndromes. Bells discovery shifted the focus of investigation of facial pain syndromes from the seventh to the fifth cranial nerve.3

An important breakthrough in the management of TN occurred fortuitously in 1942 when Bergouignan administered his patients the then new anticonvulsant diphenylhydantoin (phe-nytoin).6 Before this, the condition was referred to as neuralgia epileptiform owing to a prior hypothesis by Trousseau in 1853 that TN being paroxysmal was related to abnormal impulse conduc-tion, analogous to epilepsy.7 When carbamazepine, a new medi-cation for epilepsy was introduced in 1962, it was soon found to be useful in patients with TN.8,9 It had greater efficacy and less toxicity than the hydantoins and remains to this day the mainstay of medical therapy.10

GENERAL PRINCIPLES IN THE MEDICAL MANAGEMENT OF FACIAL PAINThe initial treatment of most facial pain syndromes is medical. The differential diagnosis of facial pain includes pathology involving nerves, teeth and jaw, sinuses, the aerodigestive tract, and blood vessels and is summarized in Table 163-1. Treatment must be driven by proper diagnosis and the characteristic features of the pain (Fig. 163-1). Pain due to head or neck neoplasm is best treated by treatment of the lesion. Similarly, psychogenic pain is best managed by treatment of the underlying psychiatric condition. It is important to distinguish nociceptive from neuro-pathic pain. Nociceptive pain is caused by normal and appropri-ate neural activity in the setting of local tissue injury (e.g., trauma, malignancy, infection). Nociceptive pain is typically constant and aching and only occasionally paroxysmal. Besides appropriate management of the underlying condition, nociceptive pain is best managed by opioid medications.

In contrast, neuropathic pain results from abnormal or inap-propriate neural activity and frequently occurs in the absence of obvious organic pathology. Neuropathic pain is thought to arise from aberrant regeneration or conduction following injury to the nervous system. Neuropathic pain can be paroxysmal or constant and is frequently described as electrical, burning, itching, or crawling. Neuropathic pain is thought to be opioid resistant. Medical treatment of neuropathic pain focuses on reducing abnormal neural activity through the use of various anticonvul-sant medications.

Nonsteroidal anti-inflammatory drugs may have a role in the treatment of facial pain with an inflammatory component. Topical applications of salicylates and capsaicin may be used as adjunctive therapy in facial pain syndromes especially in the treatment of PHN.

TRIGEMINAL NEURALGIATN, a neuropathic pain syndrome, is defined by the Interna-tional Association for the Study of Pain (ISAP) as a sudden and usually unilateral severe brief stabbing recurrent pain in the dis-tribution of one or more branches of the fifth cranial nerve. It is an excruciating, short-lasting (

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elination lead to hyperexcitability of injured afferents, which results in after discharges large enough to result in a non- nociceptive signal being perceived as pain.11 One theory to explain TN is the one proposed by Devor and colleagues,12 called the ignition theory, which can be explained as follows. The trig-gering of pain in TN may follow innocuous stimuli, a phenom-enon that is probably explained by postinjury changes in neuronal function. After nerve injury, there is an increased proportion of A-beta fibers with subthreshold oscillations that ultimately gen-erate ectopic discharges.13-15 These produce a transient depolar-ization in neighboring passive C neurons in the same ganglion.16 These findings favor a mechanism whereby afferent nociceptors could be stimulated by activity in injured low-threshold mecha-noreceptors. It is likely that both central and peripheral changes occur, which would explain why not all patients with a treated compression of the nerve get permanent relief. There are likely

Most TN patients (>85%) have classic TN. Diagnosis in typical cases is often straightforward; however, most TN patients suffer from misdiagnosis. Common conditions that mimic TN as well as their presenting features are listed in Table 163-2.

Etiology and PathophysiologyConsiderable progress has been made in elucidating the etiology of TN. In most patients with classic TN, the pain is generated because of compression of the trigeminal nerve most commonly at the root entry zone by an artery or vein. Observations support-ing this are summarized in Table 163-3. The plaques of demy-

Facial pain

DiagnosisTreat underlyingcause

Nociceptive Neuropathic

Paroxysmal

Anticonvulsants Psychotropics(TCAs/neuroleptics)

ConstantOpioids

FIGURE 163-1 General principles in themedical management offacialpain.tcAs,tricyclicantidepressants.

Seconds, no after pain

Periods of complete remissionweeks, months

Seconds, dull after painfor minutes

Provoking

Character

Relieving

AssociatedTrigger points

May be sensory change

Drugs

Sometimes sleep

Spontaneous

Light touch

Washing

Talking

EatingSeverity

Site

Unilateral 97%

Trigeminal nerveRight up to 60%

First division rare

Moderate to severe

Unbearable

Terrifying, exhausting

Shooting, sharp

Clinical features oftrigeminal neuralgia

TimingAttacks

FIGURE 163-2 Majorclinicalfeaturesoftrigeminalneuralgia.(From Zakrzewska JM, Linskey ME. Trigeminal neuralgia. In: Zakrzewska JM, ed. orofacialPain. New York: Oxford University Press; 2008, pp 119-134.)

TABLE 163-1 Differential Diagnosis of Facial Pain

LOCATION OF LESION

CONDITION

nerve trigeminalneuralgia,postherpeticneuralgia,

trigeminalneuropathicpain,

glossopharyngealneuralgia,

sphenopalatineneuralgia,geniculate

neuralgia(RamsayHuntsyndrome),

multiplesclerosis,cerebellopontineangle

tumor

teethandjaw Dentinal,pulpal,orperiodontalpain;

temporomandibularjointdisorders

Sinusesand

aerodigestivetract

Sinusitis,headandneckcancer,

inflammatorylesions

eyes opticneuritis,iritis,glaucoma

Bloodvessels Giantcellarteritis,migraine,cluster

headache,tolosa-Huntsyndrome

Psychological Psychogenic,atypicalfacialpain

Winn_Ch 163_main.indd 2 3/29/2010 6:47:20 PM

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c H A P t e R 163 Trigeminal Neuralgia: Diagnosis and Nonoperative Management 163-3

AdaptedfromBennettoL,PatelnK,FullerG.trigeminalneuralgiaanditsmanagement.BMJ.2007;334:201-205.

TABLE 163-2 Common Conditions that Mimic Trigeminal Neuralgia

DIAGNOSIS IMPORTANT FEATURES

Dentalinfectionorcrackedtooth Welllocalizedtotooth;localswellinganderythema;appropriatefindingsondentalexamination

temporomandibularjointpain oftenbilateralandmayradiatearoundearandtoneckandtemples;jawopeningmaybelimitedandcan

produceanaudibleclick

Persistentidiopathicfacialpain

(previouslycalledatypical facial

pain)

oftenbilateralandmayextendoutoftrigeminalterritory;painoftencontinuous,mildtomoderatein

severity,andachingorthrobbingincharacter

Migraine oftenprecededbyaura;severeunilateralheadacheoftenassociatedwithnausea,photophobia,

phonophobia,andneckstiffness

Postherpeticneuralgia Historyofherpeszosterorvesicularoutbreak

temporalarteritis commoninelderlypeople;temporalpainshouldbeconstantandoftenassociatedwithjawclaudication,

fever,andweightloss;temporalarteriesmaybefirm,tender,andnonpulsatileonexamination


TABLE 163-3 Evidence of Neurovascular Compression as Causative for Trigeminal Neuralgia

Anaberrantloopofartery,orlesscommonlyvein,isfoundtobe

compressingtherootentryzoneofthetrigeminalnervein80%to

90%ofpatientsatsurgery.

thetrigeminalnerveisdemyelinatednexttothecompressing

vessel.

eliminatingthecompressionbysurgeryprovideslong-termrelief

inmostpatients.

intraoperativeassessmentsreportimmediateimprovementin

trigeminalconductionondecompression.

Sensoryfunctionrecoversafterdecompression.

othercauses,suchascompressionbytumorsorthedemyelinatingplaquesofmultiplesclerosis,producesimilarlesionsoftheroot

entryzoneofthetrigeminalnerve.

other factors involved given the rarity of the disease, and there are reports of genetic and familial forms.17,18

EpidemiologyTN is considered a rare condition with the following features:

Annual incidence of 5.7 per 100,000 in women and 2.5 per 100,000 in men

Peak incidence in the 50- to the 60-year-old group, increas-ing with age

A recent study using general practice research databases in the United Kingdom and very broad diagnostic criteria that may have allowed inclusion of neuropathic facial pain syndrome other than TN suggested a higher prevalence of 26 per 100,000.19

Risk FactorsThe major risk factor for TN is multiple sclerosis.11 Hyperten-sion may play a role but is common in the age group at risk. Familial tendency is rare but has been reported.17,18 Bilateral involvement is present in only 5% of cases, and sensory deficits

are usually subtle and partial and are associated with either chro-nicity of the syndrome or a history of prior surgical interven-tion.20,21 In a retrospective study by Pollock and colleagues,21 patients with bilateral TN were more commonly females (74% versus 58%; P < .1), had a higher rate of familial TN (17% versus 4.1%; P < .001), and had a greater increased incidence of additional cranial nerve dysfunction (17% versus 6.6%; P < .05) and hypertension (34% versus 19%; P < .05). Early, significant, and nonsurgical sensory loss, in addition to bilateral involvement, should trigger a thorough investigation for symptomatic (i.e., secondary) TN.

Clinical FeaturesDiagnostic criteria for classic TN have been described in the International Classification of Headache Disorders (Table 163-4). These include paroxysmal attacks of pain, characterized by intense, sharp, superficial, or stabbing precipitated from trigger areas or by trigger factors, similar attacks in a patient, absence of neurological findings, and absence of other demonstrable cause. However, these criteria have not been validated.22 The most problematic feature of the diagnostic criteria is a requirement for absence of sensory deficit in the absence of prior surgical inter-vention history. There is abundant evidence that subtle clinically detectable sensory deficits are present in the setting of typical TN as well as evidence that electrophysiologic abnormalities may


TABLE 163-4 Diagnostic Criteria for Classic Trigeminal Neuralgia

Paroxysmalattacksofpainlastingfromafractionofasecondto2

minutesthataffectoneormoredivisionsofthetrigeminalnerve

Painthehasatleastoneofthefollowingcharacteristics:

intense,sharp,superficial,orstabbingprecipitatedfromtrigger

areasorbytriggerfactors.

Attacksthataresimilarinindividualpatients

noclinicallyevidentneurologicaldeficitisclinicallyevident

notattributedtoanotherdisorder

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clear evidence of the effectiveness of other drugs, the choice among other agents can be made on the basis of adverse effects and ease of use.

Oxcarbazepine is a prodrug of carbamazepine with similar efficacy of pain control.30 Although it is of similar efficacy to carbamazepine, it is much better tolerated and results in fewer drug interactions.31 Long-term follow-up has also shown that the drug is safe but gradually loses its efficacy because of either development of tolerance or increase in severity of the disease.32

Lamotrigine and baclofen have been suggested as second-line agents for TN on the basis of small studies. In practice, lamotrig-ine needs to be titrated over many weeks and has limited value in severe pain. Other drugs to consider are phenytoin, clonaze-pam, valproate, mexiletine, and topiramate.

Gabapentin is widely used for neuropathic pain, although it lacks evidence in TN. Use of gabapentin therefore relies on the similarities between TN and other neuropathic pain syndromes, rather than their obvious differences.10 A recent randomized con-trolled trial suggests that gabapentin, combined with repeated topical injections of ropivacain, gives better pain control than gabapentin on its own.33 Familiarity with use of gabapentin in other neuropathic pain syndromes has led many clinicians to choose this as second-line for TN.34

Pregabalin has been licensed for use in neuropathic pain and has been reported to be effective in a cohort series in TN.35 Clonazepam, valproate, and phenytoin are often used. There are no high-quality studies on the use of polypharmacy as often practiced in epilepsy. Topical injections of lidocaine into trigger points can give some temporary relief. Drugs such as tocainide, tizanidine, and pimozide are ineffective or their side-effect profile is severe enough to exclude their use.36-38

The fear, loneliness, and depression associated with TN may require psychological, social, or other nonmedical help. Support groups can help to reduce feelings of isolation and despair and can also provide high-quality information.

PrognosisUntreated, TN becomes gradually more severe with fewer remis-sion periods, but the rate at which this occurs is unpredictable. Spontaneous remission periods of up to 6 months are common, yet the syndrome remains predominantly progressive in nature.29,32 Up to 44% of patients when followed for up to 16 years will fail to get complete pain relief with medical therapy.29

TABLE 163-5 Key Points in the Management of Patients with Trigeminal Neuralgia

Acomprehensivehistoryandexamination,includingbaseline

measureofpainandqualityoflife,isessential.

Magneticresonanceimagingisusedfordiagnosisofsymptomatic

trigeminalneuralgiaandevaluationofneurovascularcompression.

Medicalmanagementstartswithcarbamazepineandthentrialof

otherdrugs.

Referearlyforaneurosurgicalopinion.

Ablativesurgeryresultsinsomedegreeoftrigeminalnerveinjury

andgivespainrelieffor3to5years.Microvasculardecompression

offersthelongestpain-freeperiodwithlittlesensorylossbutrisk

formortality.

Psychologicalsupportisimportantandincludestheneedtoprovide

accesstowritteninformation.

Patientisprovideddetailsofasupportgroup.

antedate detectable sensory loss on examination.23-27 There are other forms of TN that most frequently have been called atypical trigeminal neuralgia and trigeminal neuropathy. Because there are no long-term cohort studies, it is not possible to determine whether these atypical forms are in fact the same condition but further on in the natural history or whether they may represent a distinct condition.

The timing of the attacks and remission periods, as well as the character of the pain, are the distinguishing features for classic TN. Many patients with increased pain severity during the day and only one third of patients will report nocturnal pain resulting in awakening.11 Patients with atypical TN often describe a burning, dull, aching after pain that is persistent with a com-pletely pain-free interval.11

Quality of life in TN can be severely impaired. Because the attacks are usually spontaneous and provoked when eating or talking, this reduces the ability to relax and enjoy social activity. Depression is common, and suicides have been reported.11

Although on routine examination most patients have no sensory deficit, existing minor sensory deficits may be very subtle and may increase in frequency with chronicity of the syndrome. Abnormalities in neurophysiologic testing may identify subclini-cal deficits.25-27 Patients may exhibit tactile trigger areas within the trigeminal distribution, which will precipitate an attack when stimulated. There are no autonomic features.

Ancillary TestsThe diagnosis of TN is purely clinical. However, hematologic and biochemical monitoring is important in patients on drug therapy (see later). Radiologic investigations are important to differentiate between symptomatic and idiopathic TN. Magnetic resonance imaging (MRI) is useful to rule out secondary TN (e.g., neoplasms, cysts, vascular pathologies, multiple sclerosis plaques, lacunar infarctions). MRI does not have sufficient posi-tive or negative predictive value to assess vascular compression as an etiology for the syndrome. Sensory testing is not done routinely, but quantitative sensory testing (QST) and evoked potentials may play an important role in differentiating between symptomatic and idiopathic TN.26-27

Medical ManagementAll patients with TN are initially managed medically. Medical management begins with a comprehensive history and physical examination, including baseline measure of pain and quality of life. Psychological support is important, and patients should be provided information about support groups. Key points in the management of patients with TN are summarized in Table 163-5. Commonly used drugs are carbamazepine, oxcarbazepine, gabapentin, lamotrigine, and baclofen. The evidence for their use is summarized in Table 163-6. Patients should keep pain diaries and change their drug levels to adjust to the changing severity of the pain and tolerability of side effects. Most of the drugs need to escalated and withdrawn slowly to avoid side effects.

Carbamazepine is the drug of choice, with good evidence to show that this drug is highly effective.1 Common adverse effects such as drowsiness, dizziness, constipation, ataxia, and syndrome of inappropriate diuretic hormone (NNH, 3; 95% confidence interval, 2 to 4), although most can continue taking the drug.28 Other adverse effects include rashes, leucopenia, and abnormal liver function tests. The efficacy of the drug may diminish with long-term use.29 The pharmacokinetics of the drug also result in numerous drug interactions, and one of special note is that with warfarin. If the patient responds well, a controlled-release prepa-ration can be substituted, and the dose can gradually be reduced. What is less clear is what to do if a patient is intolerant or allergic to carbamazepine, or if the drug is ineffective. In the absence of

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TABLE 163-6 Drugs Used in the Medical Management of Trigeminal Neuralgia

DRUGLEVEL OF EVIDENCE EFFECT ADVERSE EFFECTS SUGGESTED DOSE COMMENT

carbamazepine

(theonly

first-lineagent)

Systematicreviewof

fourrandomized

controlledtrials

(n=160)

nntforpainreliefis

1.9;72%ofpatients

hadexcellentor

goodresponse

Drowsiness,ataxia,

nausea,constipation

(minor);nnt3.7

100mgtwicedaily;

increaseas

necessaryby

50-100mgevery3-4

days;targetrange

400-1000mg/day

Dosemayneedtobe

adjustedafter3weeks

becauseofenzyme

induction

Baclofen onecontrolledtrial

compared

baclofenwith

placebo(n=10)

Sevenof10patients

improvedwith

baclofen;0of10

improvedwith

placebo(P=.05)

Drowsiness,hypotonia;

avoidabrupt

withdrawal

10mg3timesdaily;

increaseas

necessaryby10mg/

day;targetdose

50-60mgdaily

Maybeusefulinpatients

withmultiplesclerosis

whenitsantispasticity

effectscanbeharnessed

Gabapentin Fiveuncontrolled

studies(n=123)

Goodtoexcellent

painreliefin40%,

anypainreliefin

53%

Drowsiness,ataxia,

diarrhea(minor);

nnt2.5.

300mgoncedaily;

increaseas

necessaryby

300mgevery3days

individeddoses(3

timesdaily);target

dose900-2400mg

daily

Widelyusedfortrigeminal

neuralgiaalthough

evidenceisweak;evidence

baseinothertypesof

neuropathicpainsmuch

stronger

Lamotrigine onerandomized

controlledtrial

withlamotrigine

asaddonto

carbamazepineor

phenytoin(n=14)

tenof13patients

improvedon

lamotrigine;8of14

improvedon

placebo;(nS)

Drowsiness,dizziness,

constipation,nausea

(nodifferentfrom

placebo)

25mgtwicedaily;

increaseby50mg

weekly;targetdose

200-600mgdaily

Probablybettertolerated

thancarbamazepinebut

needsslowtitration;may

thereforehavearoleinthe

elderlypatientsorpatients

withmultiplesclerosiswho

havelessseveredisease

oxcarbazepine twouncontrolled

studies(n=21)

Painreliefinall21

patients

Dizziness,fatigue,

rash,hyponatremia

300mgtwicedaily;

increaseby600mg

weekly;targetdose

600-2400mgdaily

evidenceweak;structurally

similartocarbamazepine

althoughprobablybetter

tolerated

Phenytoin threeuncontrolled

studies(n=30)

About77%ofpatients

reportedsomepain

relief

Drowsiness,ataxia,

dizziness,gum

hypertrophy

300mgaday;dose

alteredtoachieve

therapeuticplasma

concentration

Firstdrugusedinthe

successfulmanagementof

trigeminalneuralgia;little

evidencebutrapiddose

titrationandonce-daily

dosingareadvantages

nnt,numberneededtotreat;nS,notstatisticallysignificant.AdaptedfromBennettoL,PatelnK,FullerG.trigeminalneuralgiaanditsmanagement.BMJ.2007;334:201-205.

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WYN_163

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1. AU: Please define NNH here.

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trigeminal-neuralgia version 2- sept 2014

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