trigeminal neuralgia - stony brook school of medicine · trigeminal neuralgia reflect successive...

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Trigeminal NeuralgiaGiorgio Cruccu, MD

ABSTRACTPurpose of Review: Although trigeminal neuralgia is well known to neurologists,recent developments in classification and clinical diagnosis, new MRI methods, and adebate about surgical options necessitate an update on the topic.Recent Findings: Currently, a worldwide controversy exists regarding the classification,diagnostic process, and surgical treatment of trigeminal neuralgia. This controversy hasbeen caused on one side by the recognition that some 50% of patients with trigeminalneuralgia, apart from characteristic paroxysmal attacks, also have continuous pain inthe same territory, which results in greater diagnostic difficulties and is associated witha lower response to medical and surgical treatments. In contrast, recent developmentsin MRI methods allow differentiation between a mere neurovascular contact and aneffective compression of the trigeminal root by an anomalous vessel, which impliesmore difficulties in the choice of surgical treatment, with the indication formicrovascular decompression becoming more restricted.Summary: This article proposes that the diagnosis of trigeminal neuralgia, with orwithout concomitant continuous pain, must rely on clinical grounds only. Diagnostictests are necessary to distinguish three etiologic categories: idiopathic trigeminal neu-ralgia (nothing is found), classic trigeminal neuralgia (an anomalous vessel producesmorphologic changes of the trigeminal root near its entry into the pons), andsecondary trigeminal neuralgia (due to major neurologic disease, such as multiplesclerosis or tumors at the cerebellopontine angle). Carbamazepine and ox-carbazepine (ie, voltage-gated, frequency-dependent sodium channel blockers)are still the first-choice medical treatment, although many patients experiencesignificant side effects, and those with concomitant continuous pain respond lesswell to treatment. The development of sodium channel blockers that are selectivefor the sodium channel 1.7 (Nav1.7) receptor will hopefully help. Although all thesurgical interventions (percutaneous ganglion lesions, gamma knife radiosurgery,and microvascular decompression) are very efficacious, precise MRI criteria fordifferentiating a real neurovascular compression from an irrelevant contact will beof benefit in better selecting patients for microvascular decompression.

Continuum (Minneap Minn) 2017;23(2):396–420.

INTRODUCTIONFacial pain is easily misdiagnosed.When the pain is intense and recurrentand the underlying etiology is elusive,the condition is often labeled trigem-inal neuralgia, although other condi-tions are much more likely to be thecause. The prevalence of trigeminalneuralgia in the population is 0.07%,compared to approximately 2% inpatients with facial pain in general.1,2

Conversely, trigeminal neuralgia (also

known as tic douloureux) is frequentlymistaken for dental pain, leading toredundant diagnostic procedures suchas x-rays of the jaw and, in more thana few cases, unnecessary extractionsof teeth.3

Accurate diagnosis of trigeminalneuralgia depends critically on thepatient’s description of its characteris-tic features. Clarification of the char-acteristics of the pain is thereforenecessary to guide clinical diagnosis

Address correspondence toGiorgio Cruccu, Departmentof Neurology and Psychiatry,Viale Universita 30, Rome,Italy 00185,[email protected].

Relationship Disclosure:Dr Cruccu has receivedpersonal compensation forserving on the advisory boardof and as a consultant forAngelini and Biogen,Inc and has received personalcompensation for serving onthe advisory board of and as aspeaker for Sigma TauPharmaceuticals, Inc.Dr Cruccu has receivedresearch/grant supportfrom Sapienza University ofRome and Sigma TauPharmaceuticals, Inc.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Cruccu discusses theunlabeled/investigational useof BIIB074 for the treatmentof elderly patients withtrigeminal neuralgia.

Supplemental digital content:Direct URL citations appear inthe printed text and are in-cluded in the HTML, PDF, andapp versions of this article.

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and management. Successful diagnosticcriteria must account for establishedvariants of the phenotype (eg, typicalversus atypical trigeminal neuralgia),incorporate symptoms or signs thatcorrelate with different etiologies (pri-mary trigeminal neuralgia versus trigem-inal neuralgia secondary to a majorneurologic disease), and identify painfeatures that indicate underlying patho-physiologicmechanisms (peripheral ver-sus central), as they are relevant to directfurther investigations or treatment de-cisions (pharmacologic therapy versussurgery). Physicians should be awarethat the literature on trigeminal neural-gia has been hampered by a terminolog-ical dishomogeneity, which must besolved to the benefit of researchers,clinicians, and, ultimately, patients.

Although tic douloureux is fre-quently used as a synonym for trigem-inal neuralgia, the term was originallyintroduced to describe the involuntarywincing associated with the occur-rence of pain. Other diagnostic labelshave been proposed to indicate differ-ences in the etiology or clinical pre-sentation of trigeminal neuralgia.

Variable use of seemingly inter-changeable labels, such as classic andidiopathic or secondary and symp-tomatic, has been a major source ofconfusion. To differentiate idiopathictrigeminal neuralgia from manifesta-tions of neuralgia that are secondaryto an identified disease, in 1973Strandjord4 established the term pri-mary trigeminal neuralgia, whichcontradicts the notion of trigeminalneuralgia as a condition of neuropathicpain. MRI shows neurovascular contactin 70% to 83% of patients with typicaltrigeminal neuralgia.5,6 In neurosurgicalcase series, this frequency increasesto 89%.7 Hence, primary trigeminalneuralgia was loosely used by manyauthors to describe both trigeminalneuralgia without identifiable cause

and trigeminal neuralgia secondaryto neurovascular contact. To solvethis problem, the International Clas-sification of Headache Disorders(ICHD) endorsed the term classic,specifying that classic trigeminal neu-ralgia should be diagnosed when nocause other than neurovascular contactis apparent.8

The author agrees with this solu-tion because it avoids confusion.However, the author favors additionaldifferentiation of idiopathic trigeminalneuralgia from classic trigeminal neu-ralgia. Even after surgical explorationof the posterior fossa at the base ofthe skull for microvascular decom-pression, approximately 11% of pa-tients with trigeminal neuralgiaremain without diagnosis of an appar-ent cause.7,9 The frequency of caseswithout an etiology justifies theirdesignation as idiopathic. For trigem-inal neuralgia caused by a neurologicdisease other than neurovascular com-pression, the author prefers the termsecondary rather than symptomaticbecause it is less ambiguous. The termsymptomatic may also indicate thepainful side of the face or the affectedtrigeminal root on MRI.

CLINICAL DIAGNOSIS OFTRIGEMINAL NEURALGIAThe International Association for theStudy of Pain (IASP) defines trigeminalneuralgia as ‘‘sudden, usually unila-teral, severe, brief, stabbing, recurrentepisodes of pain in the distribution ofone or more branches of the trigem-inal nerve.’’10 The ICHD, Third Edi-tion, beta version (ICHD-3 beta)describes trigeminal neuralgia in sim-ilar terms, ‘‘as a disorder characterizedby recurrent unilateral brief electricshocklike pains, abrupt in onset andtermination, limited to the distribu-tion of one or more divisions of thetrigeminal nerve and triggered by

KEY POINTS

h Although trigeminalneuralgia isstill frequentlymisdiagnosed, itspeculiar clinical featuresare unmistakable.

h A neurovascularcompression isacknowledged asthe most frequentcause of trigeminalneuralgia (classictrigeminal neuralgia).

h Notwithstanding themost accurate andadvanced investigations,no cause can be foundin about 11% ofpatients with trigeminalneuralgia (ie, idiopathictrigeminal neuralgia).

397Continuum (Minneap Minn) 2017;23(2):396–420 ContinuumJournal.com



innocuous stimuli.’’ According to theInternational Headache Society (IHS)definition, trigeminal neuralgia ‘‘maydevelop without apparent cause orbe a result of another diagnosed dis-order. There may or may not be,additionally, persistent background fa-cial pain of moderate intensity. Classictrigeminal neuralgia develops withoutapparent cause other than neurovas-cular compression.’’11 Although thesedescriptions are certainly correct, theydo not allow for evaluating the strengthof the diagnostic criteria.

The starting points for a diagnosisof trigeminal neuralgia include unilat-eral facial pain, pain that cannot be feltoutside the trigeminal territory, andpain that is paroxysmal. Trigeminalneuralgia must be considered whenepisodes of orofacial pain exhibit thecharacteristics laid out in the defini-tions provided by IASP and IHS.11,12

Pain episodes in trigeminal neuralgiaoccur and end abruptly, are short andsevere, and are felt on only one side ofthe face within the innervation terri-tory of the trigeminal nerve. Thesensory characteristics of the pain areusually described as stabbing or com-parable to an electric shock. Bilat-eral trigeminal neuralgia is very rare,except for secondary trigeminal neu-ralgia in multiple sclerosis (MS). Oc-casional reports of bilateral classictrigeminal neuralgia reflect successiveepisodes of unilateral pain that moveto the opposite side of the face ratherthan pain episodes that occur simulta-neously on both sides.13 A recentmeta-analysis of clinical studies didnot find any report of truly bilateraltrigeminal neuralgia in 234 patientswith classic trigeminal neuralgia andfound only one case of bilateral painout of 74 patients with secondarytrigeminal neuralgia.6 This meta-analysis included mixed causes ofsecondary trigeminal neuralgia. In

their recent meta-analysis, Cruccuand colleagues14 reviewed studies ofMS associated with trigeminal neural-gia and identified a total of 24 cases ofbilateral trigeminal neuralgia out of252 MS patients with trigeminal neu-ralgia (ie, a frequency of slightly lessthan 10%).

POSSIBLE TRIGEMINALNEURALGIAA patient’s history must fulfil tworequirements for the identification ofpossible trigeminal neuralgia: the painmust be paroxysmal, and its distribu-tion must be consistent with theinnervation territory of the trigeminalnerve (Figure 3-1).

The paroxysmal characteristic oftrigeminal neuralgia, with its abruptonset and termination, is unmistak-able, even if the verbal descriptorsvary from patient to patient. Typicaldescriptions of temporal and sensoryqualities of trigeminal neuralgia in-clude brief, sudden, stabbing, or elec-tric shockYlike. Although the durationof trigeminal neuralgia paroxysms maylast up to 2 minutes, in most patientsthey are only a few seconds long. Thenumber of paroxysms per day mayrange from zero to more than 50.15

Refuting earlier assumptions,16 a re-cent study of 200 patients with classictrigeminal neuralgia did not find evi-dence that frequency or duration oftrigeminal neuralgia paroxysms in-crease with duration of the disease.17

Unlike other neuropathic pains, tri-geminal neuralgia may enter intoperiods of complete pain remissionin up to 63% of patients.15 Theseperiods may last from weeks to years,but most often last a few months.15,18

Previous definitions of trigeminal neu-ralgia emphasize a stereotypic charac-ter of the pain. Stereotypy, however, isnot a unique feature of trigeminalneuralgia. Stereotypic pain character

KEY POINT

h Paroxysmal pain intrigeminal neuralgia isa very abrupt andshort-lasting painusually described asstabbing or similar toan electric shock.


Trigeminal Neuralgia



FIGURE 3-1 New classification and diagnostic grading system for trigeminal neuralgia (TN).

a Trigeminal neuralgia is typically a unilateral condition. Few patients developtrigeminal neuralgia on both sides of the face over the course of a disease (eg, inmultiple sclerosis), but they almost never present with simultaneous bilateral pain.

b The pain strictly follows the distribution of the trigeminal nerve branches. It doesnot extend to the posterior third of the scalp, the posterior part of the externalear, or the angle of the mandible (Figure 3-2).

c Paroxysmal pain is the most noted symptom, but may be accompanied bycontinuous pain.

d Triggermaneuvers include innocuousmechanical stimuli, facial or oral movements, orcomplex activities such as shaving or applying makeup. Confined trigger zones and acommon combination with brisk muscle contractions (tics) help distinguish triggeredtrigeminal neuralgia from allodynia in other conditions of neuropathic pain. Triggermaneuvers may be tested by the examiner.

e MRI readily identifies major neurologic diseases, such as tumors of thecerebellopontine angle or multiple sclerosis. Other investigations may includethe neurophysiologic recording of trigeminal reflexes and trigeminal evokedpotentials, which become necessary in patients who cannot undergo MRI.

f Advanced MRI techniques can demonstrate neurovascular compression withmorphologic changes of the trigeminal nerve root.

Reprinted with permission from Cruccu G, et al, Neurology.14 B 2016 American Academy of

Neurology. neurology.org/content/87/2/220.short.



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may be observed with other forms ofneuropathic and non-neuropathicpain. In addition, it is not uncommonfor trigeminal neuralgia to producepain of variable sensory characteristicsover the course of the disease.14,16,19,20

Pain should be felt in one or moredivisions of the trigeminal nerve(Figure 3-2). The examining physicianshould ascertain that the pain does notextend to the posterior third of thescalp, the posterior part of the externalear, or the skin overlying the angle ofthe mandible, as these territories areinnervated by cervical nerves. Theterritory of the mandibular divisionextends up to the temple: a patientwith trigeminal neuralgia in the man-dibular branch of the trigeminal nervemay therefore describe pain at thetemple and the lower lip (Figure 3-2).If trigeminal neuralgia involves two

trigeminal divisions, they should becontiguous (most frequently a combi-nation of the maxillary and mandibularbranches of the trigeminal nerve).Trigeminal neuralgia in the ophthalmicdivision or the tongue has long beenconsidered an indication of secondarytrigeminal neuralgia. However, this no-tion has not been adequately scruti-nized in clinical studies.5,6 Of note, theaffected division of the trigeminal nerveand the side of the face may change,before or after surgery.14,16,19,20

TRIGGERED PAIN AS ACRITERION OF CLINICALLYESTABLISHED TRIGEMINALNEURALGIAStimulus dependence is one of themoststriking features of trigeminal neuralgia.In most patients, pain is evoked bynon-noxious, light mechanical stimuli

KEY POINT

h Stimulus dependence isone of the most strikingfeatures of trigeminalneuralgia.

FIGURE 3-2 Innervation territories of the trigeminal nerve.Facial and intraoral territories of innervationof the three trigeminal branches: ophthalmic

(yellow), maxillary (green), and mandibular (orange).White areas are innervated by cervical nerves. Light grayareas in the back of tongue and throat are innervated by theglossopharyngeal nerve.

Reprinted with permission from Cruccu G, et al, Neurology.14 B 2016American Academy of Neurology. neurology.org/content/87/2/220.short.




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within the trigeminal territory, includ-ing the oral cavity (Figure 3-3).21

Subtlety of the trigger maneuvers isunique to trigeminal neuralgia. Thestimulus may simply be a touch or awhiff of air, although more complexmaneuvers involving both tactilestimuli and facial movement (eg,washing or shaving of the skin, appli-cation or removal of makeup, eatingor drinking) are also common. Move-ment alone (eg smiling, talking) maysuffice to provoke a pain attack. Thelocation of the evoked pain may differfrom the site of the stimulation, and thepain can be felt as radiating (similar tosciatica). These triggers are usuallyspontaneously reported by the pa-tient. However, they may also betested by the examiner, who shouldpay attention to the typical tic (ie, theinvoluntary facial movement in reac-tion to the evoked pain). The term ticrefers to the abruptness and shortduration of the movement. The pro-voked movement of the face is similarto other reactions to acute nocicep-tive pain (eg, after inadvertently bit-ing one’s tongue or a tooth with

pulpitis). In other diseases, this briskmovement is evoked by noxious orpotentially noxious stimuli.

Although pain paroxysms may orig-inate spontaneously, patients with ahistory of exclusively spontaneousattacks are very rare. It is possible thatin the few patients with no apparenttrigger, the pain attacks are evoked bymovements that the patients are un-aware of, such as eye blinking or atwitch of other facial muscles. Theauthor searched the literature forreports of pain with ‘‘no trigger’’or ‘‘without trigger’’ and did notfind these terms in any article. Thefew studies that looked specificallyinto the presence of trigger stimulior maneuvers in classic trigeminalneuralgia reported triggered pain in94% of patients.15,22,23 Hence, theauthor proposes that the presenceof triggered pain matching the abovedescription confirms the diagnosisof trigeminal neuralgia and qualifiesthe patient as having clinicallyestablished trigeminal neuralgia(Figure 3-1). Because triggered painparoxysms are a unique somatosensory

KEY POINT

h Trigger maneuversare unique totrigeminal neuralgia.

FIGURE 3-3 Mechanism of pain in trigeminal neuralgia. Distribution of 31 trigger zonesin 30 patients. Circles denote the typically small areas where light touch orother innocuous mechanical stimuli trigger the pain paroxysms. In somepatients, the trigger zones are larger (dashed areas) or intraoral (ovals).

Reprinted with permission from Kugelberg E, Lindblom U, J Neurol Neurosurg Psychiatry.21

B 1959 British Medical Journal. jnnp.bmj.com/content/22/1/36.short.



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phenomenon, it also increases thediagnostic certainty of neuropathicpain so that it should also be consid-ered probable neuropathic pain.24

Clinically established trigeminal neu-ralgia represents a sufficient degree ofdiagnostic certainty to implementtreatment or enroll patients in aclinical trial for trigeminal neuralgia.

TRIGEMINAL NEURALGIAWITH CONCOMITANTCONTINUOUS PAINSome patients with trigeminal neural-gia experience pain between attacks(Case 3-1). This pain is continuous ornearly continuous, but may vary inintensity and quality. Its sensory char-

acteristics differ from the paroxysmalpain and are commonly described asdull, burning, or tingling. The distri-bution of this continuous pain co-incides with that of the paroxysmalpain, and fluctuations of its intensityparallel in time those of the paroxys-mal pain.19,25 A recent cross-sectionalstudy in 158 patients with trigeminalneuralgia has well defined the charac-teristics of this other phenotype andhas brought far more attention to it,reporting a frequency of almost 50%.26

No generally agreed-upon termexists to describe the form of trigem-inal neuralgia in which concomitantcontinuous pain is present. It hasbeen known by several designations,

KEY POINTS

h In almost 50% ofpatients with trigeminalneuralgia, concomitantcontinuous painadds to the typicalparoxysmal pain.

h Diagnostic investigationsare needed to establishthe etiology in cases oftrigeminal neuralgia.

h Treatment of trigeminalneuralgia can beinitiated beforediagnostic investigationsare performed.

Case 3-1A 77-year-old woman presented to the neurology clinic for a 1-monthhistory of facial pain. She described the pain as being on the right sideonly and consisting of ‘‘a burning and stabbing pain’’ in her cheek thatsometimes lasted for hours. She also stated that when drying her face,she needed to slowly press the towel without brushing it up and down;otherwise, a lightninglike pain would go from her nose to her lip. Shehad already been treated with several pain killers and benzodiazepines byher primary physician with no improvement, but she had not triedvoltage-gated sodium channel blockers.

The neurologic examinationwas normal, apart from the patient grimacingwhen a cotton swab was touched to the right side of her face. The patientwas prescribed oxcarbazepine and titrated up to 300 mg 4 times a day.

MRI of her brain with contrast was ordered to rule out majorneurologic diseases. To look for a possible neurovascular compression,time-of-flight magnetic resonance angiography (MRA), three-dimensionalreconstruction, and constructive interference in steady state (CISS)sequences were also ordered. A baseline complete blood count andcomprehensive metabolic profile completed the investigations. After3 weeks, the patient returned, reporting resolution of her symptoms. Thepatientwas diagnosedwith trigeminal neuralgiawith concomitant continuouspain. Brain MRI showed a neurovascular compression that distorted andflattened the affected trigeminal root near its entry into the pons.

Comment. This patient’s symptoms were typical of trigeminal neuralgiawith concomitant continuous pain, including the presence of a triggermechanism (in this case the patient exhibited the ‘‘sign of the towel,’’ whereshe could pat a towel slowly to her face but could not brush the towel upand down because of the pain that was triggered.). Although diagnosticinvestigations to ascertain etiologymust be performed in all patients,medicaltreatment can be implemented early based on clinical information only.





including atypical trigeminal neural-gia and trigeminal neuralgia type 2.The author prefers the term trigemi-nal neuralgia with concomitantcontinuous pain because it directlyconveys the difference from typicalparoxysmal pain. The author prefersdescribing the pain as continuousrather than persistent because con-tinuous refers strictly to the temporalmanifestation of the pain, whereaspersistent may imply refractoriness totreatment (and can also be confusedwith persistent idiopathic facial pain,which is an unrelated painful condi-tion). Several authors have favoreddescribing the pain as constant, whichis nearly synonymous with continuousbut may also refer to unchangingintensity or sensory quality of the pain.Thus, continuous is the descriptionleast susceptible to confusion (Table 3-1).

The presence of continuous pain isnot related to etiology and may occurin idiopathic, classic, or secondary

trigeminal neuralgia. The mechanismsunderlying continuous as opposed toparoxysmal pain are not fully under-stood. Continuous pain may develop asa result of progressive root damage afterprolonged compression27 or reflectcentral mechanisms.28 Several authorshave suggested that continuous painis associated with poorer outcomeafter surgical intervention.20,29Y32 It isunclear to what extent these reportsreflect patient selection or differencesin nerve pathology. However, convinc-ing evidence exists that continuous andparoxysmal pain may improve differ-ently after microvascular decompres-sion, indicating that the mechanismsresponsible for the two pain compo-nents may be distinct.19,32,33

ETIOLOGYMRI is the most widely used diagnos-tic tool to assess for secondary tri-geminal neuralgia, because it is highlysensitive for detectingmajor neurologic

KEY POINTS

h The presence ofcontinuous pain is notrelated to etiology andmay occur in idiopathic,classic, or secondarytrigeminal neuralgia.

h MRI is the most widelyused diagnostic tool toassess for secondarytrigeminal neuralgia,because it is highlysensitive for detectingmajor neurologicdiseases such as a tumoror multiple sclerosis.

TABLE 3-1 Definition and Classification of Trigeminal Neuralgia

Definition Trigeminal neuralgia is orofacial pain restricted to one or moredivisions of the trigeminal nerve. Except for trigeminal neuralgiacaused by multiple sclerosis, the pain affects one side of theface. It is abrupt in onset and typically lasts only a few seconds(2 minutes at maximum). Patients may report their pain asarising spontaneously, but these pain paroxysms can always betriggered by innocuous mechanical stimuli or movements.

Patients usually do not experience pain between paroxysms.If they do report additional continuous pain, in the samedistribution and in the same periods as the paroxysmal pain,they are considered to have trigeminal neuralgia withconcomitant continuous pain.

Classification Trigeminal neuralgia is classified in three etiologic categories.Idiopathic trigeminal neuralgia occurs without apparent cause.Classic trigeminal neuralgia is caused by vascular compression ofthe trigeminal nerve root. Secondary trigeminal neuralgia is theconsequence of a major neurologic disease (eg, a tumor of thecerebellopontine angle or multiple sclerosis).

Either phenotype (purely paroxysmal pain or with additionalcontinuous pain) may occur with any of the three categories.




diseases such as a tumor or MS. MRImay reveal neurovascular contact of thetrigeminal nerve root, but the frequencyof mere contact between root andblood vessels in trigeminal nerves inasymptomatic patients cautions againstits use as a diagnostic criterion. Sup-ported by negative findings at opera-tion, recent studies have emphasizedthe importance of differentiating thetype of contact and its physical impacton the nerve, to the point that Cruccuand colleagues14 became convincedthat the reintroduction of the termidiopathic trigeminal neuralgia wasneeded.14 The degree of morphologictrigeminal root changes is therapeuti-cally relevant. The long-term outcomeafter surgical correction of simpleneurovascular contacts is poorer com-pared to the decompression of dis-located, distorted, or flattened nerveroots (Figure 3-4).31,33 Advanced MRItechniques now allow radiologic verifi-

cation of morphologic changes of thecompressed trigeminal root. Thesechanges of symptomatic nerve rootsare highly suggestive of physical alter-ation and have a high predictive valuefor pain relief after decompression.14

In a recent meta-analysis of ninehigh-quality blinded and controlledstudies, mere neurovascular contactwas found in 471 out of 531 symp-tomatic nerves and in 244 out of 681asymptomatic nerves, indicating highsensitivity but low specificity.7 Nervedislocation or signs of atrophy in-creased the specificity to 97%. Theseresults are corroborated by two pro-spective studies.34,35 Location of theneurovascular contact appears to berelevant. Compression of the trigemi-nal nerve at its entry into the brain-stem increased the specificity to 100%.It is important to acknowledge thatall the studies cited here rely on a clin-ical diagnosis of trigeminal neuralgia

KEY POINT

h MRI may revealneurovascular contactof the trigeminal nerveroot, but the frequencyof mere contactbetween root and bloodvessels in trigeminalnerves in asymptomaticpatients cautionsagainst its use as adiagnostic criterion.

FIGURE 3-4 Morphologic changes of the trigeminal rootshowing examples of classic righttrigeminal neuralgia. Two schematic drawings

show axial sections at the level of the trigeminal roots wheregray indicates nervous tissue, red indicates arteries, andblack indicates bone. Atrophy of the right trigeminal rootcaused by a crossing artery (A) and a downward loop of thesuperior cerebellar artery that provokes distortion of the righttrigeminal root at its entry into the pons (B) can be seen.





prior to MRI. Consequently, MRI find-ings alone cannot be used as bio-markers to diagnose trigeminalneuralgia unless the investigation ispreceded by an evaluation of clinicalsymptoms and signs that indicate thepresence of trigeminal neuralgia.However, a combination of clinicalsigns and morphologic changes causedby a vascular compression involving thesymptomatic trigeminal nerve providesstrong enough evidence to confirm theetiology of classic trigeminal neuralgia(Figure 3-1).

Detection of neurovascular compres-sion requires the use of specific imagingparadigms with three-dimensional re-construction MRI techniques. An in-creasing number of imaging optionsare available to depict the nerve andany blood vessels in proximity tothe posterior fossa. Typical imagingparadigms include sequences forthree-dimensional T2-weighted MRI(eg, constructive interference in steadystate [CISS]) for a detailed exami-nation of the cisternal and cavernoussegments of the nerve and three-dimensional time-of-flight magneticresonance angiography (MRA) forvisualization of arteries.34,36,37 The nec-essary but sufficient scope of the MRIevaluation to identify dislocation, dis-tortion, flattening, or atrophy of thetrigeminal root (ie, the morphologicchanges considered essential to distin-guish between a mere contact and areal compression)14 must still gainwide consensus.

Several studies suggest thatcompression-induced microstructuralchanges may be estimated usingdiffusion-tensor imaging (DTI) andtractography to measure focal demye-lination and edema.36,38 A recentreport suggests that effective treat-ment for trigeminal neuralgia reversesseveral DTI abnormalities at the tri-geminal root entry zone.38 Although

many believe that in the future DTIwill reliably demonstrate microstruc-tural damage in the trigeminal rootand thus become the ultimate inves-tigation, so far the available evidenceis still insufficient.

Trigeminal reflex testing is anestablished neurophysiologic assess-ment of nerve function (Figure 3-539).Trigeminal reflex testing requires onlystandard nerve conduction studyequipment; for stimulation, it usessurface electrodes placed over theemergence of the supraorbital, infra-orbital, and mental nerves and forrecording uses surface electrodesplaced over the orbicularis oculi andmasseter muscles. Allowing a between-side quantitative assessment of theophthalmic, maxillary, and mandibulardivisions, trigeminal reflex testing is areliable method to detect secondaryforms of trigeminal neuralgia and hasbeen recommended in guidelines forthe evaluation of neuropathic paininvolving the trigeminal nerve.40 In ameta-analysis of 629 patients withtrigeminal neuralgia, trigeminal re-flex testing achieved a sensitivity of94% and a specificity of 87% in iden-tifying patients with secondary trigem-inal neuralgia, comparable to thediagnostic accuracy of MRI.5,6 Trigem-inal reflex testing is particularly helpfulif a patient cannot undergo MRI or iftrigeminal neuralgia secondary to tri-geminal neuropathy is suspected inspite of a normal MRI result (refer tothe following section on secondarytrigeminal neuralgia).

Various evoked potentials afterelectric or thermal stimuli have beenstudied in trigeminal neuralgia. Incontrast to trigeminal reflex testing,which is normal in idiopathic orclassic trigeminal neuralgia, evokedpotentials may be altered, but theirmean specificity of 64% is low.5,12,28

Evoked potentials are adjuvant measures

KEY POINT

h Detection ofneurovascularcompression requiresthe use of specificimaging paradigmswith three-dimensionalreconstructionMRI techniques.




to demonstrate functional abnormalitiesin trigeminal neuralgia. It is worthemphasizing that all electric stimula-tions within the trigeminal territory arebound to elicit reflex responses that un-avoidably contaminate the scalp signals.Only electric stimulation via two fineneedle electrodes inserted into the in-fraorbital foramen provides a safe scalprecording of subcortical far-field poten-tials whose generation site has beenlocated near the trigeminal ganglion,root, or pons.12 In a clinical setting, thismethod of stimulation detailed byLeandri and Gottlieb41 is useful duringradiofrequency thermocoagulation ofthe ganglion because it allows the iden-tification of the affected trigeminaldivision under general anesthesia.

SECONDARY TRIGEMINALNEURALGIATrigeminal neuralgia caused by a ma-jor neurologic disease is readily iden-

tified by MRI or other appropriateinvestigations. In 15% of patientswith typical pain attacks, trigeminalneuralgia is caused by benign tumorsat the cerebellopontine angle or MS(Figure 3-642).5,6 Tumors causing tri-geminal neuralgia are mostly benignand compress the root near its entryinto the pons. They include meningi-omas, epidermoid cysts, acoustic neu-romas, and cholesteatomas. Localcompression induces focal demyelin-ation and may trigger paroxysmalectopic discharges, whereas infiltrativetumors lead to axonal degeneration.The different pathology of nerve dam-age by malignant tumors is commonlyassociated with hypesthesia and con-tinuous pain rather than trigeminalneuralgia. Evidence of tumors as acause of secondary trigeminal neural-gia comes from four main studies thatreported a total of 20 (8%) out of243 patients with trigeminal neuralgia.6

On the other hand, about 20% of

KEY POINT

h In some 15% ofpatients with trigeminalneuralgia, the cause isa major neurologicdisease, most oftenmultiple sclerosis orbenign tumors in thecerebellopontineangle (ie, secondarytrigeminal neuralgia).

FIGURE 3-5 Trigeminal reflex test to disclose secondary trigeminal neuralgia. Left, Schematicdrawing of the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions;stimulation sites at the supraorbital (V1), infraorbital (V2), and mental (V3)

nerves; and recording from the orbicularis oculi (A) and masseter (B) muscles. Right, Early (R1)and late (R2) blink reflex (V1-A), and early (SP1) and late (SP2) masseter inhibitory reflex (V2-Band V3-B). Calibration is 10 ms/100 2V.

Reprinted with permission from Cruccu G, et al, Neurology.39 B 2006 American Academy of Neurology.neurology.org/content/66/1/139.long.




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cerebellopontine angle tumors producetrigeminal neuralgia.43 All symptomatictumors compress the trigeminal nerveroot.44 Trigeminal neuromas almostnever produce trigeminal neuralgia.

Patients with MS have a 20-foldincreased risk of trigeminal neuralgia.18

The prevalence of trigeminal neuralgiain MS is 2% to 5%.18,45,46 The cause oftrigeminal neuralgia has conventionallybeen attributed to demyelinatingplaques in the pons.47,48 It has beenclearly shown, however, that the onsetage of the population with trigeminalneuralgia and MS is lower than that ofclassic trigeminal neuralgia but signifi-cantly higher than that of MS.49 Al-though trigeminal neuralgia in MS maybe one of several other common MSdisturbances, some patients have tri-

geminal neuralgia as their sole clinicalmanifestation for all their life, thusbeing classified as having clinicallyisolated syndrome.30 These patientstypically have multiple demyelinatedareas on MRI and strongly delayedresponses on neurophysiologic tests(trigeminal reflexes and evoked poten-tials), which are characteristic of MS. Ithas been hypothesized that the pontineplaque and a neurovascular compres-sion exert a dual, additive mechanism,in which inflammatory demyelination(the intraaxial plaque)48 and mechani-cal demyelination (the extraaxial neuro-vascular compression)50 create a doublecrush syndrome on the same primaryafferents near the root entry zone.51

Very recently, this theory has foundsound evidence.52

FIGURE 3-6 Common causes of symptomatic trigeminal neuralgia. A, Benign tumors along the extraaxial course of thetrigeminal root (arrows). B, Demyelinating plaques along the intraaxial course of the trigeminal afferents (arrows).

Reprinted with permission from Cruccu G, et al, Handb Clin Neurol.42 B 2010 Elsevier. sciencedirect.com/science/article/pii/S0072975210970565.



http://sciencedirect.com/science/article/pii/S0072975210970565

http://sciencedirect.com/science/article/pii/S0072975210970565


Because patients with MS-relatedtrigeminal neuralgia usually respondinsufficiently to pharmacologic treat-ment or must stay on high dosagesthat worsen their fatigue or may be-come toxic for the liver, microvasculardecompression or another surgicalprocedure for trigeminal neuralgiabecomes necessary sooner or later. Inthese patients, however, the benefityielded by any type of surgical treat-ment is shorter in duration than inclassic trigeminal neuralgia.53,54

A smaller group of patients maypresent with trigeminal neuralgia sec-ondary to a trigeminal neuropathy.These neuropathies may be dividedinto three subgroups in descendingorder of frequency: posttraumatic, as-sociated with connective tissue dis-eases, and idiopathic/genetic. Facialtrauma, dental procedures, or maxillo-facial or neurosurgical procedures maydamage branches of the trigeminalnerve. Although the primary symptomin trigeminal neuropathy is sensory loss,sometimes these focal neuropathiespresent with episodes of paroxysmalpain. The pain attacks are usually longerthan those associated with trigeminalneuralgia, and most patients also de-scribe continuous pain.55 The traumaor the intervention should not escapemedical history. Painful trigeminal neu-ropathy caused by a connective tissuedisease or genetic disorder is usuallybilateral but may begin asymmetricallyand occasionally present with parox-ysmal pain similar to trigeminal neu-ralgia.25,29,56,57 Indeed a paroxysmalpain similar to that of trigeminal neu-ralgia may be the first symptom of anunderlying connective tissue disease.58

The patients will eventually develop bilat-eral sensory deficits and continuouspain, which clarifies the diagnosis. MRIis normal, but trigeminal reflexes areinvariably delayed or absent.56

PATHOPHYSIOLOGY OFTRIGEMINAL NEURALGIAOne aspect of pathophysiology issupported by established neurophy-siologic, neuroimaging, and histologicevidence. Both in classic and second-ary trigeminal neuralgia, the primarymechanism is focal demyelination ofprimary afferents near the entry(extraaxial or intraaxial) of the trigem-inal root into the pons. Some investi-gators believe this area represents alocus minoris resistentiae (a site oflower resistance or higher susceptibil-ity to damage) because it is the sitewhere Schwann cells are substitutedby oligodendroglia in providing themyelin sheath.

A second pathophysiologic theory,admittedly more debatable, is that thedamaged primary afferents in the areaof focal demyelination become asource of ectopic generation of im-pulses. The author proposes that, be-cause mitochondria and the energeticapparatus necessary to pump sodiumoff are physiologically concentratedat the level of the nodes of Ranvier,when the demyelinating process allowsthe passage of ions in and out of theaxon, then the axons do not haveenough energy to promptly reestablishthe resting potential. Hence, the axonstend toward a depolarization level,which makes them hyperexcitable.Spontaneously, or because of a localdirect mechanical stimulus such asthe artery pulsation, ectopic activity isgenerated. More supported by evi-dence in animal models of focal demy-elination of the trigeminal root is theconcept of ephaptic transmission(cross talk) from close, healthy nervefibers and the generation of high-frequency discharges.59Y61

A third potential pathophysiologictheory, with almost no sound evi-dence at all at this time, is that the

KEY POINT

h Both in classic andsecondary trigeminalneuralgia, the primarymechanism is focaldemyelination of primaryafferents near the entry(extraaxial or intraaxial)of the trigeminal rootinto the pons.





hyperactivity of primary afferents sec-ondarily induces central sensitizationof wide dynamic range neurons in thespinal trigeminal nucleus or evenmore central changes.28,62

MEDICAL TREATMENT OFTRIGEMINAL NEURALGIAThe guidelines on trigeminal neuralgiamanagement that were agreed uponand jointly published by the AmericanAcademy of Neurology (AAN) and theEuropean Federation of NeurologicalSocieties (EFNS) are very clear asto medical treatment (SupplementalDigital Content 3-1, links.lww.com/CONT/A215).6 Based on evidence, thetreatment should begin either withcarbamazepine 400 mg/d to 1200 mg/dor with oxcarbazepine 900 mg/d to1800 mg/d. The author’s first-linechoice is oxcarbazepine because of itsbetter tolerability.17,63 If the patientreaches the dosages adequate for mostpatients (1200 mg/d to 1500 mg/d)without achieving the desired painrelief (ie, she or he is one of the rarecases of a real nonresponder), noother drug will be enough. Hencesurgery, being extremely efficaciousin trigeminal neuralgia, should beproposed.5,6

Aside from responders and non-responders, however, a third type ofpatient exists who requires someconsideration. Some patients cannottake either of the two choice drugsbecause of specific contraindications(most frequently cardiac conductionproblems or severe arrhythmias).Some other patients encounter seri-ous side effects and allergic dermatitis,which, unfortunately, tend to be cross-reactive (ie, the patients who had theallergic reaction to one of the twodrugs cannot be switched to theother) or, in the case of carbamaze-pine, a fall in blood elements (whitecells, red cells, or platelets) rarely

reaching aplastic anemia. Indeed, pa-tients on carbamazepine must under-go a complete blood count every 3 to4 months. Both drugs may causesodium depletion (Case 3-2). Bothdrugs, being antiepileptic drugs, in-duce central nervous system (CNS)depression, presenting as somno-lence, confusion, or imbalance. Thesecentral side effects, which are morefrequent with carbamazepine thanoxcarbazepine (Figure 3-7),17 mayprevent patients from maintainingadequate doses. Hence, in this thirdgroup of patients, who are neitherresponders nor nonresponders, otherdrugs can be tried. In this case, theAAN/EFNS guidelines suggest tryingother pharmacologic options asmonotherapy or add-on medications.In particular, analysis of the evidence-based trials led to the following sug-gestions: lamotrigine, baclofen, andpimozide.6 Lamotrigine is supportedby evidence if used as an add-on tocarbamazepine.64 Unfortunately, thecomparatively high risk of dermatitisimposes a very slow titration,63,65 and,naturally, this drug is not devoid ofside effects on the CNS, which wouldadd to those of carbamazepine oroxcarbazepine. Baclofen, an agonistof the ,-aminobutyric acid B (GABA-B)receptor, was believed to be very prom-ising because it was well supported byanimal experiments.66 Now it is knownthat unless baclofen is administeredintrathecally, the side effects restrict theoral dosage to a level lower than theone necessary to reach antinociceptiveeffects. Although pimozide was foundmore efficacious than carbamazepine ina small head-to-head clinical trial, it wasnever tried again.67 Some reports aboutthe efficacy of gabapentinoids and anti-depressants exist, but there have beenno adequate trials in trigeminal neuralgia.Both gabapentinoids and antidepres-sants, however, are expectedly more

KEY POINTS

h Medical treatmentof trigeminal neuralgiais based onfrequency-dependentsodium channelblockers, namelyoxcarbazepine andcarbamazepine.

h The adverse eventscaused by bothoxcarbazepine andcarbamazepine may oftenrequire discontinuation ofthese agents.



http://links.lww.com/CONT/A215

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Case 3-2A 67-year-old woman with a history of hypertension presented witha 6-month history of right-sided facial pain. The pain was paroxysmal(she described it as similar to an electric shock), and it was evoked by typicaltrigger maneuvers for trigeminal neuralgia: light touch on the foreheadand eyebrow, eyelidmovementwhen looking upward, and combing her hair.She had previously been prescribed carbamazepine 600 mg/d, and her painhad disappeared. Her problems were twofold: first, the carbamazepineinduced central nervous system side effects (eg, somnolence, dizziness,imbalance), which she found unbearable, and second, no investigation hadyet occurred to ascertain the etiology.

Neurologic examination was normal. She was switched to oxcarbazepine,with increasing doses up to 1200 mg/d. In addition, trigeminal reflextesting, a standard brain MRI, and a dedicated three-dimensional MRI andmagnetic resonance angiography (MRA) study were ordered to check fora neurovascular compression.

The patient returned for follow-up 3 weeks later, and she still had centralnervous system depression, although to a far lower degree, which she feltwas tolerable. The trigeminal reflex testing was normal, and the standardMRI showed some small ischemic lesions in the cerebral white matter;however, the dedicated MRI study for possible neurovascular compressionshowed a very rare compression by a wide-collar berry aneurysm of thesuperior cerebellar artery. The artery looped downward, and the aneurysmdistorted the trigeminal root. The possibility of an endovascular interventionwas discussed, but its efficacy was considered uncertain.

One week later, the patient suddenly developed severe weakness andconfusion and was seen in a local emergency department, where she wasdiagnosed with severe hyponatremia (120 mEq/L) and was begun onsaline infusions. She was also seen by another neurologist, who quicklytapered and stopped oxcarbazepine, as well as an interventionalneuroradiologist who, as soon as the electrolyte abnormality resolved,proceeded with endovascular intervention first with a coil in the aneurysmand then with a stent in the artery. Within 24 hours after the intervention,she had complete disappearance of the neuralgic pain attacks and continuedto have no further symptoms when seen in follow-up 6 months later.

Comment. With oxcarbazepine, sodium depletion occurs in 6% to 8% ofpatients. Regarding medication side effects, although oxcarbazepine by nomeans requires the three to four checks per year of blood elements that aremandatory for thedurationof therapy for patients on carbamazepine,monitoringof serum sodium is necessary at least once. In this case, in retrospect, thispatient’s cardiologist had recently introduced adiuretic to her antihypertensiveregimen that probably added to oxcarbazepine in depleting sodium.

Regarding the etiologic classification of this patient, althoughsecondary trigeminal neuralgia is usually attributed to tumors or multiplesclerosis, other major neurologic diseases (eg, the rare trigeminal isolatedsensory neuropathy or aneurysms) should be kept in mind whensomething in the history or symptoms suggests a secondary origin. In thiscase, the only unusual clinical factor was the location of her pain, whichexclusively involved the ophthalmic division (this was long considered a

Continued on page 411





efficacious in continuous than parox-ysmal pain and are often tried as an add-on to oxcarbazepine or carbamazepinein patients with the atypical form oftrigeminal neuralgia with concomitantcontinuous pain. A dedicated clinicaltrial has never been reported in trigem-inal neuralgia with concomitant contin-uous pain, nor has the safety of thesecombinations been verified.

Often, this third group of patientsis eventually referred for surgery. Many

patients, however, may not acceptsurgery that easily. The author believesthat in those patients who do not wantto undergo any kind of surgical in-tervention, botulinum toxin injec-tions of the trigger areas should betried.68Y71 The amount of publishedevidence is growing day by day, andthe safety profile is very high. Reportedly,the pain relief lasts several months,and the main side effect is a transientweakness of the facial muscles in the

FIGURE 3-7 Trigeminal neuralgia (TN) treatment algorithm.

MRI = magnetic resonance imaging.

sign of probable secondary trigeminal neuralgia, although this associationwas not confirmed by the American Academy of Neurology [AAN] and theEuropean Federation of Neurological Societies [EFNS] 2008 guidelines6).

Regarding pathophysiology, it is well known that microvasculardecompression relieves neuralgic pain far before a remyelinatingprocess might take place. This case suggests the need for a pulsatingstimulus on the demyelinated nerve fibers to induce the ectopic generationof high-frequency discharges. In microvascular decompression, theneurosurgeon leaves a tiny sponge to keep the artery and the nerve rootseparate. In this case, the artery pulsation was eliminated by the stent.

Continued from page 410




injected area.71 Naturally, botulinumtoxin injections should be performedby neurologists experienced in botu-linum toxin injections for other estab-lished indications. This treatment, soefficacious in other conditions, hasnot yet achieved US Food and DrugAdministration (FDA) indication fortrigeminal neuralgia.

Finally, BIIB074, a new voltage- andfrequency-dependent sodium channelblocker that has selectivity for the so-dium channel 1.7 (Nav1.7) subtype, hasbeen discovered.72 Nav1.7 is a majorsodium receptor in the nociceptivesystem, but no Nav1.7 receptors existin the brain. This absence of brainNav1.7 receptors promises to preventany side effects associated with depres-sion of CNS excitability. Nav1.7 hasbeen validated as a key pain target byhuman genetic linkage, as gain offunction mutations are linked to asevere chronic pain syndrome, whereasloss of function mutations lead to theinability to feel pain.73 Furthermore, itsefficacy and extreme tolerability hasalready been proved in patients in aphase 2 trial. Zakrzewska and col-leagues74 have now demonstrated thatBIIB074 can inhibit the firing of tri-geminal neurons, adding further mech-anistic support to the potential of thisnew molecule.

SURGICAL TREATMENT OFTRIGEMINAL NEURALGIAA first, difficult question is whethersome patients, according to theirinclination, should be offered the earlychoice between medical and surgicaltreatment. A study in patients whohad undergone surgery for trigeminalneuralgia found that many, afterexperiencing the long-lasting benefit,would have opted for surgery fromthe very beginning.75

Although trigeminal neuralgia is per-haps the neuropathic pain condition

where surgery is most effective, eachsurgical method entails its own poten-tial problems, thus the author believesthat the first treatment should beoxcarbazepine or carbamazepine. If thestandard dosages are not enough or theside effects are too severe, then surgeryshould at least be proposed and dis-cussed with the patient.

Surgical methods for treating trigem-inal neuralgia can be divided in fourgroups: lesions distal to the ganglion,lesions at the ganglion level, lesion ofthe root by gamma knife radiosurgery,and posterior fossa intervention ofmicrovascular decompression.

The first group of surgical methodsincludes all sorts of peripheral lesionsof the trigeminal terminal nerves attheir emergence from the facial bones:neurectomy, alcohol injections, radio-frequency lesions, or cryolesions. Noneof these methods has ever beensupported by adequate trials.6,70 Infact, these lesions were often thesource of anesthesia dolorosa (painin area of sensory loss).

The second group of surgicalmethods involve percutaneous gas-serian (ie, trigeminal) ganglion le-sions. In all cases, a long cannula orelectrode is inserted first through thecheek, then between the mandibulararch and the maxillary bone, to reachthe infratemporal fossa, and aimed atthe foramen ovale, through which itpenetrates the skull base reaching theMeckel cave, where the gasserianganglion lies. All these proceduresneed fluoroscopic guidance. When ontarget, three types of lesions can bedone: thermocoagulation by radio-frequency,76 chemical lesion by injec-tion of high-concentration glycerol,77

or mechanical compression by ballooninflation.78 Radiofrequency thermo-coagulation was conceived to prefer-entially damage the small pain fibers.Balloon compression and glycerol

KEY POINT

h Several surgicalprocedures for trigeminalneuralgia exist that arevery efficacious.





injection preferentially damage thelarge myelinated fibers; thus, therationale is that of blocking the trig-gering impulses. Whereas ballooncompression and glycerol injectioncan be performed under continuousgeneral anesthesia, radiofrequencythermocoagulation requires anesthe-sia when the electrode is moved tothe target and then again at themoment of the lesion. Hence, patientsmust be awakened in between be-cause they must report in what areasof the face they feel the paresthesiaevoked by electric impulses deliveredfrom the tip of the electrode to preventdamaging the wrong trigeminal divi-sion. The electrode is moved slightlyuntil the evoked paresthesia is coinci-dent with the painful division, and thenthe patient is anesthetized again beforethe actual thermocoagulation begins.Sophisticated methods have been de-veloped, including the intraoperativerecording of trigeminal evoked poten-tials.41 In any event, however, theelectrode cannot be aimed at the firsttrigeminal division because the dam-age to small fibers entails cornealdeafferentation and keratitis. Ballooncompression and glycerol injectionare devoid of the risk of cornealkeratitis because they damage largemyelinated fibers only. Regarding thegeneral pros and cons of the percuta-neous ganglion lesion techniques, thepain relief is immediate and completein a high percentage of cases, andfollow-up studies report a variableduration of pain relief, persisting inabout 70%, 60%, and 50% at 1, 3, and5 years, respectively.6,20 The successof ‘‘pulsed’’ radiofrequency, in con-trast, is not supported by evidence. Infact, one study reported that in allpatients submitted to pulsed radio-frequency, the original pain returnedby 3 months.79 Themajor risks of all per-cutaneous ganglion lesion procedures

are piercing of the maxillary artery(which is close to the trajectory towardthe foramen ovale), and that of the duramater covering the Meckel cave, withvarious possible consequences, fromburning of an oculomotor nerve toinfusion of glycerol into the CSF of themiddle cranial fossa. Almost unavoid-able are trigeminal sensory deficits,which are usually transient with ballooncompression and glycerol injectionand more severe and longer lastingafter radiofrequency (Figure 3-8).

Stereotactic radiosurgery (gammaknife) is the most recent type of in-tervention applied to trigeminal neu-ralgia and therefore the one with thefewest number of patients who havebeen treated. However, the amountof favorable evidence is increasingrapidly. Naturally, the main problemis the same as for all stereotacticradiosurgery interventions (ie, thereliabil ity and accuracy of themethods of finding the exact co-ordinates of the trigeminal root justbefore its entrance into the pons,where the radiation beams shouldcollimate). A randomized controlledtrial studied whether expanding theirradiated area more distally alongthe root would increase the rate ofresponders80: the total success ratewas 68% regardless of the length ofthe irradiated area. Only the occur-rence of facial numbness or pares-thesia correlated with the length ofthe irradiated area. This study (oneof the very rare randomized con-trolled trials of stereotactic radiosurgeryin trigeminal neuralgia) is very interest-ing because it conveys strong evidencethat the root entry zone is the key spotin the origin and maintenance of tri-geminal neuralgia. Unlike the othertypes of intervention, the pain-relieving effect of gamma knife therapyis not immediate and generally re-quires 6 to 8 weeks to develop.




According to the 2008 AAN/EFNSguidelines on trigeminal neuralgia,6 at1 year after gamma knife therapy,complete pain relief with no medica-tion occurs in up to 69% of patients.This falls to 52% at 3 years. Facialnumbness is reported in 9% to 37% ofpatients (although it tends to improvewith time), and troublesome sensoryloss or paresthesia is reported in 6%to 13%, whereas anesthesia dolorosais practically absent. No complicationsoutside the trigeminal nerve havebeen reported. The most recentCochrane Review81 does not add tothe 2008 guidelines.6 A recent meta-analysis of gamma knife interventions,however, found that, because about34% of patients do not reach 1 year ofpain relief, repeated administration ofradiations were necessary. With theincreasing number of interventions,the rate of success and the pain-freetime increase significantly. Unfortu-nately, toxicity also increases, with

facial hypesthesia persisting in 50% ofpatients at 1-year follow-up.82

Although microvascular decom-pression is the only causal cure andhuge numbers of patients have under-gone this procedure, no reported trialmeets the minimal criteria of evi-dence to be considered in a CochraneReview.81 Microvascular decompres-sion is the only type of surgery fortrigeminal neuralgia that cannot bedone as an outpatient surgical pro-cedure. It requires general anesthe-sia, intubation, craniotomy, cuttingthe dura mater, shifting the cerebellarhemisphere, and microscopy to ade-quately visualize the nerves emergingfrom the cerebellopontine angle. Theneurosurgeon may then disentanglethe looping artery and leave a smallsponge to keep the pulsating arteryseparated from the trigeminal root.Naturally, a placebo intervention orblinded operators are unthinkable.Importantly, in about 11% of patients

KEY POINT

h Microvasculardecompression requiresmajor surgery butis the only causalintervention oftrigeminal neuralgiaand offers longer-lastingpain relief.

FIGURE 3-8 Dropouts due to adverse events in 100 patients on carbamazepine and 100 patients on oxcarbazepine. Note that centralnervous system (CNS) disturbances affected patients on carbamazepine far more frequently than patients onoxcarbazepine, whereas hyponatremia only affected patients on oxcarbazepine.

Blood cells = white cells, red cells, or thrombocytes.





referred for this type of intervention,the surgeons do not find any neuro-vascular compression9,14 or they find amere contact that apparently is notdamaging the nerve. Most surgeons inthese latter cases interpose the separat-ing sponge anyway, but they report agreater rate of failure, hence the needto establish MRI criteria that ensurethat morphologic changes of the tri-geminal root are observed.14

Allowing for the lack of evidence-based data, still the meta-analyses ofthe largest studies make microvasculardecompression the most efficaciousof the surgical interventions for clas-sic trigeminal neuralgia: according tothe AAN/EFNS guidelines,6 90% ofpatients obtain pain relief. More than80% of patients will still be pain freeat 1 year, 75% at 3 years, and 73% at5 years. The average mortality associ-ated with the operation is 0.2%. Up to4% of patients incur major problemssuch as CSF leaks, infarctions, or hema-tomas. Aseptic meningitis is the mostcommon complication (11%). Diplopiais usually transient, and facial palsy israre. Sensory loss occurs in 7% of pa-tients. The major long-term complicationis ipsilateral hearing loss (Figure 3-9).

In conclusion, percutaneous gasserianganglion lesions, gamma knife, andmicrovascular decompression may allbe considered, with microvascular de-compression offering the longest dura-tion of pain relief.

When considering the choice of sur-gical treatment, the treating neurologistshould be involved in a collaborativefashion with our neurosurgical col-leagues and the patient. Specific char-acteristics should also be considered,such as how clear the neurovascularcompression is on MRI, whether thepatient also has involvement of thefirst division, and whether the patientis prepared to wait at least 1 month toget the pain relief from gamma knife.

When the decision is difficult, the bestoption is referral to a large center thatis led by experienced neurosurgeons.

Insufficient evidence exists to sup-port or refute the effectiveness of thesurgical management of trigeminalneuralgia in patients with MS. Theauthor, however, believes that MS pa-tients with evidence of drug-resistanttrigeminal neuralgia should be offeredthe surgical option. The recent demon-stration of the concurring pathophysio-logic role exerted by neurovascularcompression would seem to favor thechoice of microvascular decompres-sion in the posterior fossa.52 However,positive reports occur with all themain types of intervention, includingpercutaneous ganglion lesions andgamma knife.54

CONCLUSIONThe diagnosis of trigeminal neuralgia,with or without concomitant continu-ous pain, must rely on clinical groundsonly. Diagnostic tests are necessaryto distinguish three etiologic catego-ries: idiopathic trigeminal neuralgia(nothing can be found), classic tri-geminal neuralgia (an anomalousvessel produces morphologic changesof the trigeminal root near its entryinto the pons), and secondary trigem-inal neuralgia (due to major neurologicdisease such as MS or tumors at thecerebellopontine angle). Oxcarbazepineand carbamazepine are still the first-choice medical treatment, althoughmany patients experience significantside effects, and those with concomi-tant continuous pain respond less. Anew sodium channel blocker that isselective for the Nav1.7 receptor haspromise of efficacy without inducingside effects related to CNS depres-sion. Three categories of surgical in-terventions (percutaneous ganglionlesions, gamma knife, and microvas-cular decompression) are all very

KEY POINT

h Percutaneous ganglionlesions and gammaknife are efficacious inthe treatment oftrigeminal neuralgiaand can be repeated incases of relapse.




efficacious. Precise MRI criteria fordifferentiating a real neurovascularcompression from an irrelevant con-tact will be of benefit in betterselecting patients for microvasculardecompression. The treating neurol-ogist should work in a collaborativefashion with the patient and the

neurosurgeon to determine when andwhat type of surgical procedure to try.

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FIGURE 3-9 Complications of surgery for trigeminal neuralgia.

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