Brief Communication

Familial Trigeminal Neuralgia: Case Reportsand Review of the Literature

Paul Smyth, MD; Glen Greenough, MD; Elijah Stommel, MD, PhD

The paroxysmal facial pain of trigeminal neuralgia is usually idiopathic, but familial cases have been described.We describe a family with apparent autosomal dominant transmission of trigeminal neuralgia. Our cases and areview of the literature suggest that the etiology of trigeminal neuralgia may be vascular compression of the fifthcranial nerve. Autosomal dominant vascular and epileptic disorders are reviewed, and possible relationships tofamilial trigeminal neuralgia are considered.

Key words: trigeminal neuralgia, facial pain, familial syndrome

Abbreviations: TGN trigeminal neuralgia, AD autosomal dominant

(Headache 2003;43:910-915)

Trigeminal neuralgia (TGN) is paroxysmal facialpain resulting from compressive, ischemic, or demyeli-nating lesions. Most cases are sporadic. A familial vari-ant of TGN has been described, but the nature of theinherited predisposition is unknown.1-3 We describea family with 4 cases of TGN in 3 generations, andconsider possible mechanisms for the familial form ofTGN.

CASE HISTORIESPatient C. B. developed left-sided pain character-

istic of TGN at aged 45 years in the second divisionof the fifth cranial nerve. She had no other pain syn-dromes and aside from the uncomplicated births of herdaughters, no significant medical history. Carbamaza-pine provided about 80% relief of pain, but made herfeel sleepy and drugged. Physical examination showedonly guarding behavior in the area of the facial pain,and perhaps a slight reduction in temperature andtouch sensations in that region as well. Imaging hasnot been done. She is still contemplating surgery.

From Dartmouth Medical School, Hanover, NH.

Address all correspondence to Dr. Elijah Stommel, Departmentof Neurology, Dartmouth Hitchcock Medical Center, Lebanon,NH 03756.

Accepted for publication May 6, 2003.

Both of C. B.’s daughters have facial pain con-sistent with TGN, and both have been helped con-siderably by microvascular decompressive surgery. Agranddaughter of C. B. also has TGN.

A daughter of C.B., D. S., began having left-sidedfacial pain at aged 45 years in the second and third di-visions of the fifth cranial nerve. Her medical historywas significant for the uncomplicated birth of a daugh-ter, A. G., who also developed TGN (see below), andsurgery to her left eye for macular degeneration yearsbefore her facial pain began. Carbamazapine, gatrap,mexiletine, and amitriptyline caused no diminution inthe pain. Physical examination was significant for un-willingness to allow the painful area to be touched.She underwent microvascular decompressive surgery.Intraoperatively, a compressive vascular loop formedby the superior cerebellar artery (SCA) was seen ad-jacent to the root of the fifth cranial nerve. A Teflonspacer was used to separate the nerve root and thelooped vessel. Postoperatively, the lancinating facialpain was gone, though she did have intermittent facialdysesthesias including the sensation of insects crawl-ing on her face at night. This has gradually diminishedwith amitriptyline.

The other daughter of C. B., D. R., began havingright-sided facial pain at aged 32 years. The pain con-sisted of a constant pain in the second division of the

910

Headache 911

fifth cranial nerve with superimposed ice-pick jabs in-volving her nose and up to the vertex of her head.Light touch, eating, or even gusts of wind initiatedthese pains. At first, the pain was only occasional andseemed to respond to over-the-counter medications,but over the next 10 years, the pain became progres-sively worse and less amenable to treatment. Mag-netic resonance imaging (MRI) showed only sinusi-tis. Tegretol no longer affected the symptoms, nor didthe removal of several teeth. Three alcoholic bever-ages one weekend reduced the pain, but did not elim-inate it. Medical history included a hiatal hernia, mi-graine headaches, and occasional hand numbness andtingling. She had microvascular decompression, andseveral small vessels were found near the trigeminalnerve by its take-off from the brain stem. Teflon wasused to separate the vessels and nerve. Following thesurgery, the constant pain and lancinating componentwere gone. She did complain of a “buglike” pressurebehind her right eye, worse with rest, and she contin-ued to have weekly migraines that responded to med-ication as before.

The daughter of D. S., A. G., developed attacksof right facial pain in the second division of thefifth cranial nerve at aged 24 years, which she de-scribed as “electrocuting” and “stabbing.” The painwas worse with teeth brushing, chewing, cold wind,and touch. She also experienced numbness and tin-gling in the first and second divisions of the fifth cra-nial nerve for minutes to hours following the attacksof pain. Ibuprofen was mildly helpful, while amitripty-line, nortriptyline, sumatriptan, and gabapentin hadno effect. An MRI/magnetic resonance angiography(MRA) showed no fifth cranial nerve pathology or vas-cular abnormality to explain the pain, but a follow-upfat-saturation image suggested a right SCA loop con-tacting the cisternal segment of the fifth cranial nerve.She is contemplating surgery.

COMMENTSOur cases and the literature on familial TGN re-

viewed below suggest that familial TGN is charac-terized by autosomal dominant (AD) transmission,an etiology of vascular compression, and a modestfemale predominance. Anticipation, or onset earlierin succeeding generations, may also be a feature.

These properties may be clues that can help identifythe locus of the inherited predisposition and clarifythe mechanism of familial and sporadic TGN. Twoof our patients developed anesthesia dolorosa, rais-ing the intriguing possibility of a familial predispo-sition to this condition; however, a literature searchrevealed no extant reports. Following a review ofthe literature on familial TGN, possible links to ADdisorders with vascular or epileptic involvement isconsidered.

Review of Familial Trigeminal Neuralgia.—Harrissummarized clinical observations suggesting a hered-itary component to bilateral trigeminal pain in 1936,and followed in 1940 with a series of 1433 cases ofTGN and outcomes after alcohol injection of the gasse-rian ganglion to relieve pain.4,5 The earlier articledescribed a family with ever-earlier onset (anticipa-tion), and the latter series found 30 (2%) of 1433 in-dex cases that had family members with similar facialpain. These reports by Harris, along with those of Al-lan and Castaner-Vendrell and Barraquer-Bordas,6,7

were consistent with AD inheritance; the family stud-ied by Allan also appeared to show anticipation. Morerecent case reports by Herzberg and Duff et al are alsoconsistent with AD transmission.1,2

Coffey and Fromm, reviewing an association be-tween familial TGN and Charcot-Marie-Tooth (CMT)neuropathy, also found evidence for AD transmis-sion.3 Charcot-Marie-Tooth disease (hereditary sen-sorimotor neuropathy type I) is AD and results fromperipheral demyelination. Sporadic cases of TGN-like pain have been associated with multiple sclerosisplaques as well. Including cases described by Coffeyand Fromm, the number of reported patients with bothCMT and TGN is 15. For familial TGN alone, Coffeyand Fromm report a female to male ratio of 1.5:1, con-sistent with the 39-year survey of TGN incidence byKatusic and colleagues.8

In 1979, Knuckney and Gubbay proposed an asso-ciation between trigeminal and glossopharyngeal neu-ralgia based on a family in whom a grandfather hadTGN; his son developed both TGN and glossopharyn-geal neuralgia and his granddaughter had glossopha-ryngeal neuralgia.9 Twenty years later, Duff et al pre-sented a single case of a woman with contralateralhemifacial spasm, possibly due to a tumor, along with

912 September 2003

TGN; her mother had TGN as did 5 of the patient’ssiblings.2

Thus, the clinical syndrome of TGN has been as-sociated with several disease processes and rarely withconcurrent cranial and noncranial neuropathies.

Etiologies of Trigeminal Neuralgia.—Conce-ptually, pain in the distribution of the fifth cranial nervecould be a result of irritating stimulus to the nerve pe-ripherally; another possibility is that neuronal mem-brane instability (peripherally or centrally) generatesaberrant signals experienced as pain.

The notion that mechanical (usually vascular)compression causes TGN may have originated withDandy, who also proposed resection of the fifth cranialnerve root at the pons as a surgical cure.10,11 More re-cently, the concept has been discussed by Jannetta.12,13

Reviewing a series of 30 patients with evidence of com-pression at surgery found the SCA alone involved in79%; the SCA with the anterior inferior cerebellarartery (AICA) in an additional 10.5%, and the pet-rosal vein in a final 10.5%.14

Not all patients with TGN show grossly visible ev-idence of nerve deformation, though, and some withsuch visible grooves at surgery have no history of TGN.Conditions reported as associated with or causingTGN include tumors,15 stroke,16 and both central andperipheral demyelinating disorders (eg, multiple scle-rosis and CMT disease).3,17 Vascular disorders associ-ated with TGN include ateriovenous malformation.18

Nonetheless, vascular compression is consideredthe most common cause of sporadic TGN (reviewedin Rosenkopf and Kaye),19,20 and microvascular de-compression eliminates symptoms immediately after-ward in over 80% of those undergoing the procedure.Those with persistent relief at 10 years falls to 64%.21

Whether this is due to removal of an extrinsic me-chanical compression (ie, a vessel making contact) ortraumatic interruption of aberrant nerve functioningat the nerve root or pontine entry zone is unclear. In aseries of 41 patients, similar results were found in theoutcomes in 26 patients with (and 15 without) evidenceof vascular compression at surgery.22 At autopsy, onestudy found that 3% of subjects without TGN hadobvious evidence of vascular compression,23 while anMRA study found an 8% incidence of asymptomaticvascular compression of the fifth cranial nerve.14

Membrane instability as a primary cause of TGN isless well-characterized. That carbamazepine, a sodiumchannel blocking drug, stabilizes membranes and isefficacious in treating TGN symptomatically does notprove that membrane instability causes TGN.

Autosomal Dominant Vascular Disorders.—Sincefamilial TGN appears to be AD and may be relatedto patterns of vascularity, known AD vascular disor-ders may help guide the search for a genetic locus forfamilial TGN. Moreover, familial TGN appears withother cranial nerve dysfunctions including those of theseventh and eighth cranial nerves.24-26

Autosomal dominant disorders with primary orsecondary vascular involvement include hereditaryhemorrhagic telangiectasia ([HHT] former eponym,Osler-Weber-Rendu disease), neurofibromatosis type1 (NF1), cerebral AD arteriopathy with subcorti-cal infarcts and leukoencephalopathy (CADASIL),von Hippel-Lindau disease (VHL), polycystic kidneydisease (PKD), several ophthalmologic syndromes,and a variety of vascular malformations includingcavernous angioma and venous and arteriovenousmalformations.

The Table summarizes AD disorders with vascu-lar involvement by chromosome; all of these disordersper se can be eliminated as a direct cause of famil-ial TGN because they involve widespread systemic orother pathognomonic features that are not known tobe present in the family reported here or in other ac-counts of familial TGN. For example, venous malfor-mations involve pain due to bleeding in skin and mus-cle, and HHT involves multisystem vascular dysplasiawith mucocutaneous bleeds. Cerebral AD arteriopa-thy with subcortical infarcts and leukoencephalopathyinvolves a characteristic history of migraine headachesand cumulative cognitive decline in middle age due torecurrent stroke, usually in the absence of typical car-diovascular risk factors. Polycystic kidney disease andNF1 also have typical clinical presentations not presentin reported cases of TGN.

Further examination of the genes involved andtheir functions sheds little light on the putative vas-cular cause of TGN. There is no obvious connec-tion between transforming growth factor (TGF)-beta receptor (HHT; chromosome 3), the reduc-tion of 5-HT and tryptophan (hereditary vascular

Headache 913

Autosomal Dominant Vascular Disorders by Known Chromosome∗

Chromosome Disorder Comment Reference

1 p21-p22 Venousmalformation

• Any organ system, usually skin and muscle with pain/bleeding;often linked to chromosome 9, but with glomus cells, may beautosomal dominant with linkage to chromosome 1

Boon et al, 199927

3 p22 HHT† • 3p22 with HHT; multisystem vascular dysplasia withmucocutaneous bleeds; 3p22 associated with TGF-beta receptor

Vincent et al, 199528

p21 HVR • HVR also includes cerebral ischemia, Raynaud syndrome, andmigraine; 5-HT and precursor tryptophan reduced

Ophoff et al, 200129

7 q Cavernousmalformation

• Of CNS and retina; seizure, hemorrhage, focal CNS deficit,migraine; CCMI gene encodes Krit1=?tumor suppressor

Marchuk et al, 199530

Davenport et al, 200131

9 q33-34 HHT‡ • As above in chromosome 3; associated pulmonary AVMs McDonald et al, 199432

p Venousmalformation

• α and β interferon; ?tumor suppressor genes mts-1 and -2in this region

Boon et al, 199433

12 HHT§ • Pulmonary AVMs absent here Vincent et al, 199528

19 CADASIL • Strokes and headaches; Notch3 gene; doesn’t involvehypertension or other cardiovascular risk factors; arterial

Reviewed in Thomaset al, 200034

∗Disorders may be more commonly idiopathic. Some disorders map to more than one chromosome. HHT indicates hereditaryhemorrhagic telangiectasia; TGF, transforming growth factor; HVR, hereditary vascular retinopathy; CNS, central nervoussystem; AVMs, arteriovenous malformations; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy.†See also chromosomes 9 and 12.‡See also chromosomes 3 and 12.§See also chromosomes 3 and 9.

retinopathy [HVR], associated with unknown genemutation on p21), the putative tumor supressor geneCCM1 (chromosome 7, cavernous malformation), in-terferons α and β (venous malformations associatedwith possible tumor supressor genes mts-1 and -2 onchromosome 9), or the Notch3 protein.

Thus, cases of familial TGN of putative vascu-lar etiology and AD transmission bear no obviousrelationship to known AD-transmitted conditions in-volving vascular malformation or dysplasia. Vascularchange, if present, seems isolated to the vasculature ofthe posterior fossa. In contrast to the systemic condi-tions discussed above, several relatively restricted vas-cular conditions are known to cause retinopathy andinvolve vascular tortuosity.

Autosomal Dominant Epilepsies.—Inheritedepilepsies include partial seizures involving the tem-poral lobe (auditory symptoms with rare generaliza-tion) linked to chromosome 10q24 and AD nocturnalfrontal lobe epilepsy (ADNFLE).35 ADNFLE isassociated with childhood onset of partial frontal

seizures in clusters with multiple attacks per night,36

and has been linked to mutations in the neuronalnicotinic acetylcholine receptor (CHRNA4) gene,mapping on chromosome 20q13.37 Further study hasidentified ADNFLE linkage to chromosome 15q24and chromosome 1.38,39 The region on chromosome1 codes for the β2 subunit of the neuronal nicotinicacetylcholine receptor (CHRNB2) which assembleswith the α4 subunit to form a functional nicotinicreceptor. As with the vascular disorders discussedabove, there is no evident connection between thesedisorders and TGN, and no reported increase in facialpain in families with AD epilepsies.

CONCLUSIONKnown AD vascular and epileptic conditions show

no evident relationship to TGN, yet genetic influenceon vascular growth patterns and membrane stabilitymay still be involved. Anatomic (spatial) constraintsmay also shed light on the etiology of familial TGN—morphometric data suggest that men with cluster

914 September 2003

headache have narrower middle and anterior cranialfossae than matched controls,40 and if a spatial con-straint were found in familial TGN, this would helpexplain a familial predisposition to pain of the fifthcranial nerve. Further study of familial TGN kindreds,including clinical, anatomical, and molecular biologi-cal information may help identify an AD-transmittedgene or trait that can provide insight into the mecha-nisms of idiopathic and familial TGN.

REFERENCES

1. Herzberg L. Familial trigeminal neuralgia. Arch Neu-rol. 1980;37:285-286.

2. Duff JM, Spinner RJ, Lindor NM, Dodick DW,Atkinson JL. Familial trigeminal neuralgia and con-tralateral hemifacial spasm. Neurology. 1999;53:216-218.

3. Coffey RJ, Fromm GH. Familial trigeminal neuralgiaand Charcot-Marie-Tooth neuropathy. Surg Neurol.1991;35:49-53.

4. Harris W. Bilateral trigeminal tic: its association withhereditary and disseminated sclerosis [letter]. AnnSurg. 1936;103:161.

5. Harris W. An analysis of 1,433 cases of paroxysmaltrigeminal neuralgia and the end results of gasserianalcohol injection. Brain. 1940;43:209-244.

6. Allan W. Familial occurrence of tic douloreaux. ArchNeurol Psychiatry. 1938;40:1019-1020.

7. Castaner-Vendrell E, Barraquer-Bordas L. Six mem-bers de la meme familie avec tic douloureux detrijemeau. Monatassche Psych Neurol. 1949;118:77-80.

8. Katusic S, Beard CM, Bergstralh E, Kurland LT. In-cidence and clinical features of trigeminal neural-gia, Rochester, Minnesota, 1945-1984. Ann Neurol.1990;27:89-95.

9. Knuckey NW, Gubbay SS. Familial trigeminaland glossopharyngeal neuralgia. Clin Exp Neurol.1979;16:315-319.

10. Dandy WE. Concerning the cause of trigeminal neu-ralgia. Am J Surg. 1934;24:447-455.

11. Dandy WE. An operation for the cure of ticdouloureaux: partial section of the sensory root atthe pons. Arch Surg. 1929;18:687-734.

12. Jannetta PJ. Arterial compression of the trigeminalnerve at the pons in patient with trigeminal neuralgia.J Neurosurg. 1967;26:159-162.

13. Jannetta PJ. Observations on the etiology of trigem-inal neuralgia, hemifacial spasm, acoustic nerve dys-function and glossopharyngeal neuralgia. Definitivemicrosurgical treatment and results in 117 patients.Neurochirurgia. 1977;20:145-154.

14. Meaney JM, Miles JB, Nixon TE, WhitehouseGH, Ballantyne ES, Eldridge PR. Vascular con-tact with the fifth cranial nerve at the pons in pa-tients with trigeminal neuralgia. Am J Roentgenol.1994;163:1447-1452.

15. Ikeno S, Mitsuhata H, Furuya K, Shimizu R. Painfultic convulsif caused by a brain tumor undiagnosedpreoperative. Anesthesiology. 1995;83:643-644.

16. Kim JS, Kang JH, Lee MC. Trigeminal neuralgia afterpontine infarction. Neurology. 1998;51:1511-1512.

17. Hartmann M, Rottach KG, Wohlgemuth WA,Pfadenhauer K. Trigeminal neuralgia triggered byauditory stimuli in multiple sclerosis. Arch Neurol.1999;56:731-733.

18. Figueiredo PC, Brock M, De Oliveiro AM Jr, Prill A.Arteriovenous malformation in the cerebellopontineangle presenting as trigeminal neuralgia. Arq Neu-ropsiquiatr. 1989;47:61-71.

19. Rosenkopf KL. Current concepts concerning the eti-ology and treatment of trigeminal neuralgia. Cranio.1989;7:312-318.

20. Kaye AH. Trigeminal neuralgia: vascular compres-sion theory. Clin Neurosurg. 2000;46:499-506.

21. Barker FG, Jannetta PJ, Bissonette DJ, Larkins MV,Jho HD. The long-term outcome of microvascular de-compression for trigeminal neuralgia. N Engl J Med.1996;334:1077-1084.

22. Canavery S, Bonicalz V, Ferroli P. Can trauma aloneto the trigeminal root relieve trigeminal neuralgia?The case against the microvascular compression hy-pothesis. J Neurol Neurosurg Psychiatry. 1997;63:411-412.

23. Hamlyn PJ, King TJ. Neurovascular compression intrigeminal neuralgia: a clinical and anatomical study.J Neurosurg. 1992;76:948-954.

24. Coad JE, Wirtschafter JD, Haines SJ, Heros RC,Perrone T. Familial hemifacial spasm associated witharterial compression of the facial nerve. Case report.J Neurosurg. 1991;74:290-296.

25. Sorenson TT. Familial recurrent cranial nerve palsies.Acta Neurol Scand. 1988;78:542-543.

26. Verhagen WI, Huygen PL, Theunissen EJ, JoostenEM. Hereditary vestibulo-cochlear dysfunction andvascular disorders. J Neurol Sci. 1989;92:55-63.

Headache 915

27. Boon LM, Brouillard P, Irrthum A, Karttunen L,et al. A gene for inherited cutaneous venousanomalies (“glomangiomas”) localizes to chromo-some 1p21-22. Am J Hum Genetics. 1999;65:125-133.

28. Vincent P, Plauchu H, Hazan J, Faure S, WeissenbachJ, Godet J. A third locus for hereditary haemorrhagictelangiectasia maps to chromosome 12q [erratum ap-pears in Hum Molec Genet. 1995;4:1243]. Hum MolecGenetics. 1995;4:945-949.

29. Ophoff RA, DeYoung J, Service SK, et al. Hereditaryvascular retinopathy, cerebroretinal vasculopathy,and hereditary endotheliopathy with retinopathy,nephropathy, and stroke map to a single locus onchromosome 3p21.1-p21.4. Am J Hum Genetics.2001;69:447-453.

30. Marchuk DA, Gallione CJ, Morrison LA, et al. Alocus for cerebral cavernous malformations mapsto chromosome 7q in two families. Genomics.1995;28:311-314.

31. Davenport WJ, Siegel AM, Dichgans J, et al. CCM1gene mutations in families segregating cerebralcavernous malformations. Neurology. 2001;56:540-543.

32. McDonald MT, Papenberg KA, Ghosh S, et al. Adisease locus for hereditary haemorrhagic telangiec-tasia maps to chromosome 9q33-34. Nature Genetics.1994;6:197-204.

33. Boon LM, Mulliken JB, Vikkula M, et al. Assign-ment of a locus for dominantly inherited venous mal-

formations to chromosome 9p. Hum Molec Genetics.1994;3:1583-1587.

34. Thomas NJ, Morris CM, Scaravilli F, et al. Heredi-tary vascular dementia linked to notch 3 mutations.CADASIL in British Families. An NY Acad Sci.2000;903:293-298.

35. Michelucci R, Passarelli D, Pitzalis S, Dal Corso G,Tassinari CA, Nobilc CA. Autosomal dominant par-tial epilepsy with auditory features: description of anew family. Epilepsia. 2000;41:967-970.

36. Scheffer IE, Bhatia KP, Lopes-Cendes I, FishDR, Marsden CD, Andermann E, Andermann F,Desbiens R, Keene D, Cendes F, et al. Autosomaldominant nocturnal frontal lobe epilepsy. A distinc-tive clinical disorder. Brain. 1995;118(pt 1):61-73.

37. Phillips HA, Scheffer IE, Berkovic SF, Hollway GE,Sutherland GR, Mulley JC. Localization of a gene forautosomal dominant nocturnal frontal lobe epilepsyto chromosome 20q13.2. Nat Genet. 1995;10:117-118.

38. Phillips HA, Scheffer IE, Crossland KM, et al. Au-tosomal dominant nocturnal frontal-lobe epilepsy:genetic heterogeneity and evidence for a second locusat 15q24. Am J Hum Genet. 1998;63:1108-1111.

39. Gambardella A. A new locus for autosomal dominantnocturnal frontal lobe epilepsy maps to chromosome1. Neurology. 2000;55:1467-1471.

40. Afra J, Cecchini AP, Schoenen J. Craniometricmeasures in cluster headache patients. Cephalalgia.1998;18:143-145.