Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:21-25

Autosomal dominant late onset cerebellar ataxia withmyoclonus, peripheral neuropathy and sensorineuraldeafness: a clinicopathological reportM BARAITSER,* W GOODDY,t AM HALLIDAY,t AE HARDING,: P RUDGE,tF SCARAVILLIt

From the Hospital for Sick Children, Great Ormond Street, * The National Hospital for Nervous Diseasestand The Institute ofNeurology, t Queen Square, London, UK

SUMMARY Three members of a family were affected by an autosomal dominant disorder compris-ing cerebellar ataxia, sensorineural deafness, myoclonus, and peripheral neuropathy. This is thesecond kindred with this syndrome reported to date. Necropsy of the proband showed loss of cellsin the dentate nuclei, a reduced amount of cerebellar white matter, and pallor of the gracile tractsin the spinal cord.

The combination of cerebellar ataxia and myoclonuswas first described by Ramsay Hunt in 1921.1 Therehas since been a tendency to apply the label of "theRamsay Hunt syndrome" to any patient demonstrat-ing this combination of clinical features.2 This is con-fusing, as such cases are both clinically and geneti-cally heterogeneous. Hunt's' patients clearly fellinto two groups. Four were single cases who hadmyoclonic epilepsy before the age of 20 years andlater developed progressive cerebellar ataxia.Another two, twin brothers, had a neurological syn-drome resembling Friedreich's ataxia from earlychildhood. Myoclonus did not occur until the thirddecade. Necropsy in one patient showed degenera-tion of the spinocerebellar tracts and posterior col-umns in the spinal cord, and atrophy of the dentatenucleus. Myoclonus and cerebellar ataxia occurtogether in a number of autosomal recessive storagedisorders, including Lafora body disease, some ofthe lipidoses, sialidosis and ceroid lipofuscinosis.3Other recessive cases of cerebellar ataxia and myoc-lonus are more difficult to classify. It is likely thatmany of the patients reported from Scandinavia,with Unverricht-Lundborg disease or "Baltic myoc-lonus" 34 are examples of a disorder which is distinctfrom the majority considered to have the RamsayHunt syndrome.56One striking feature of dominantly inherited late

Address for reprint requests: Dr AE Harding, the National Hospi-tal for Nervous Diseases, Queen Sq, London WCIN 3BG, UK.

Received 17 June 1983Accepted 17 July 1983

onset cerebellar ataxia is the wealth of associatedfeatures which may be found in addition to ataxia.These include ophthalmoplegia, optic atrophy,extrapyramidal signs, pigmentary retinal degenera-tion, dementia and amyotrophy.7 Myoclonus occur-ring in combination with cerebellar ataxia of domin-ant inheritance is rare. Bonduelle and colleagues8described a family in which ataxia developed in thethird decade and was associated with areflexia,myoclonus and ophthalmoplegia. Post-mortemexamination of one patient revealed olivopon-tocerebellar atrophy with degeneration of thespinocerebellar tracts, posterior columns andanterior hom cells in the spinal cord. Gilbert et a19reported a similar, but more slowly progressive dis-order in which the age of onset was earlier and tre-mor more prominent. May and White'0 describedthe association of deafness, ataxia and myoclonuswhich was dominantly inherited in six members of afamily. The subject of this paper is a kindred similarto that of May and White, with a description of thenecropsy findings in one case. The pedigree of thefamily is shown in fig 1.

Case reports

1. 1. This man died in his seventies from an accident (typeunknown) but had no neurological symptoms.I.2. This female died at the age of 52 years from a stroke.She was said to be "mentally unstable" and was known tohave had difficulty in hearing.11.3. This female, who died at the age of 74 years in 1978,was first admitted to University College Hospital in 1973.She gave a seven year history of involuntary jerky move-

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2 T

II8

IVl 2 3

Fig 1 Pedigreee offamily (square = male, circle = female,oblique line = deceased, filed in symbols = affected, arrow= index case).

ments of the face, arms and trunk, and mild hearingdifficulties. The movements were nearly always provokedby bright light and had been associated with brief episodesof unconsciousness on two occasions. For five monthsbefore admission she had noticed increasing ataxia of gait.On examination there was irregularity of volume and pitchin her speech and marked ataxia of all four limbs. The gaitwas also ataxic. The tendon reflexes and sensation werenormal. She had bilateral sensorineural deafness which wasmore severe on the right. There were irregular myoclonicmovements of all four limbs and the face which occurredapproximately six to ten times per minute. These weremore severe and generalised when the patient was exposedto sudden bright lights. A resting electroencephalogram(EEG) was normal. Repetitive flash stimulation inducedgeneralised polyspike-slow wave complexes in the EEG.Neuro-otological examination in 1973 (Dr MR Dix)revealed a moderately severe sensorineural loss bilaterallythat was rather greater on the right. Recruitment was fullas judged by the loudness discomfort levels." Vestibularfunction was abnormal. The caloric responses demons-trated a marked directional preponderance to the rightwith a superimposed canal paresis. Pursuit and saccadicmovements were normal without nystagmus. Optokineticnystagmus was deranged. There was no positional nystag-mus.

In early 1974 the patient was readmitted because ofincreasing unsteadiness and memory loss. On examinationthen she was mildly demented. Her speech was scanningand explosive. There was generalised myoclonus with strik-ing photosensitivity, and marked cerebellar ataxia in thelimbs and of gait. The ankle jerks were absent but theother tendon reflexes were normal. Her somatosensoryevoked responses to electrical stimulation of the digitalnerves in the index and middle finger of either hand wereof extremely large amplitude, showing the characteristicenhanced second surface negative wave typically found inmyoclonic epilepsy. The early positivity (P32 component)measured approximately 21 ,uV for the left hemisphere

and 32 ,uV for the right hemisphere, in contrast to thenormal response, which has an upper limit of 8 ,uV in thehealthy population. In spite of her photosensitivity, shetolerated repetitive flash stimulation well, although theflash-evoked response was also abnormally large. She was,however, exquisitely sensitive to the black and white chec-kerboard pattern reversal stimulus used to test the patternvisual evoked response, and had a partial seizure within afew seconds of the stimulus being presented. During thisattack she jerked violently all over and both eyes rolled upand to the left. She was inaccessible at this time, althoughshe became responsive within a few seconds of the stimulusbeing turned off. The seizure was accompanied by a con-tinuous train of high voltage, bilateral, polyspike-slowwave complexes in the EEG. She was treated withclonazepam which led to considerable improvement of hermyoclonus. Recorded again two weeks later, bothsomatosensory and visual evoked responses were greatlyreduced in amplitude.

In December 1974 she developed intermittent drowsi-ness and a progressive left hemiparesis over a period ofthree weeks. Investigations confirmed the clinical diagnosisof a sub-dural haematoma and this was evacuated. Thepatient made a good recovery from this but her ataxiacontinued to deteriorate. She was last seen in early 1978when she was only just able to walk. Later that year shehad a series of generalised seizures which culminated instatus epilepticus and the patient died. At post-mortemexamination, apart from collapse of the left lung with anassociated large pleural effusion, the pathological findingswere confined to the nervous system. Macroscopic exami-nation of the brain after fixation showed mild atrophy ofthe dentate nuclei of the cerebellum, and small areas of oldsoftening in the left basis pontis involving the pyramidaltract. Blocks were taken from several regions of the cere-bral and cerebellar hemispheres, brain stem, spinal cordand dorsal root ganglia, and embedded in paraffin wax.Sections were stained with haematoxylin-eosin,haematoxylin-van Gieson, Glees' silver impregnation foraxons and luxol fast-blue-cresyl violet.

In order to establish the severity of nerve cell loss in thegrey matter, the relevant areas were enlarged and meas-ured. Using a grid applied to the eyepiece, all neurons withrecognisable nucleoli contained within randomly chosenfields were counted; the area of a single unit of the grid wascalculated using a stage micrometer and the total numberof cells in the area was estimated. The results were expre-ssed as a percentage of the number of cells in comparableareas of an age-matched control brain.

Histological examination of the cerebral hemispheresshowed circumscribed foci of laminar necrosis in the rightpericallosal gyrus; most of the pyramidal cells of theAmmon horn had disappeared while the remaining oneswere shrunken. In the brain stem the presence of an area ofold softening with cavitation in the left basis pontis wasconfirmed. In the cerebellum, the folia of the vermis andcerebellar hemispheres appeared moderately shrunken;there was a mild decrease in density of Purkinje cells andthe white matter was considerably reduced in volume. Theribbon of the dentate nucleus was thiner than normal andthe number of nerve cells in it showed a 40% decrease innumber compared with an age and sex matched control (fig

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Autosomal dominant cerebellar ataxia with myoclonus, peripheral neuropathy and deafness

Fig 2 The dentate ribbon ofcase I.3 (A) is thinner than that in a control brain (B) and contains a fewshrunken nerve cells. (Luxol Fast Blue-Nissl x 100)

i d ll .0;----- 4

F

Fig 3 Case 11.3: Transverse section ofthe cervical spinalcord showing pallor ofboth gracile tracts. (Luxol FastBlue-Nissl)

2 A and B). No abnormalities were found in the basalganglia, thalamus, red and sub-thalamic nuclei, substantianigra and medulla, including the cochlear nuclei, apartfrom pallor of the pyramidal tract below the site of thelesion in the pons and some gliosis of the inferior olive. Inthe spinal cord, the gracile tract showed moderate pallor ofthe myelin stain throughout its length (fig 3). The dorsalroot ganglia were normal.11.5. This female was noted to have a somewhat cyc-

lothymic personality during the fifth decade of life; she firstbecame unsteady and had involuntary jerking movementsof the limbs at about the age of 50 years. She was diag-nosed as having Huntington's chorea eight years later. Onexamination aged 68 there was no definite evidence ofdementia. She had severe dysarthria and mild bilateral sen-sorineural deafness. There were prominent myoclonicjerks involving the eyes, palate, head and all four limbs. Itwas virtually impossible to assess cerebellar functionbecause of the myoclonus. The tendon reflexes were nor-mal and the plantar responses flexor. There was no sensoryloss. Her somatosensory and visual evoked potentials wererecorded at a time when she was showing minimal involun-tary twitchings of the intrinsic muscles of the left hand.Neither of the cortical potentials were abnormally enlargedat this time, nor was there any cortical wave detected byjerk-locke,d averaging triggered from the abnormal move-ments of the left abductor digiti quinti muscle. The patientdied at the age of 60; no necropsy was performed.III.8. This 40-year-old man first noticed a tendency tospill full cups of coffee in his late teens but was only awareof ataxia of gait at the age of 32. This had since been mildlyprogressive and he had difficulty in running and turningquickly. He had not noticed any disturbance of speech. Hehad been aware of mild bilateral deafness for about tenyears and wore a hearing aid in the right ear. On examina-tion he was dysarthric and had mild bilateral sensorineuraldeafness. The jaw-jerk was brisk. There was moderatecerebellar ataxia in all four limbs. Power was normal. Thetendon reflexes in the upper limbs were normal, but theknee and ankle jerks were absent. The plantar responseswere flexor. Sensation was normal. His gait was ataxic.

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There were no involuntary movements.Haematological and biochemical investigations, includ-

ing serum thyroxine and glucose tolerance test, were nor-mal. CT scan showed an area of iow attenuation in theregion of the left sylvian fissure which was thought to be anarachnoid cyst. EEG with photic stimulation was normal.Electromyography of the right abductor pollicis brevismuscle was normal. Motor nerve conduction velocity,(MNCV) in the right median nerve was normal at 52 ms- 'but that in the peroneal nerve was slightly reduced at 44ms- Median, ulnar, and sural sensory action potentials(SAP) were reduced in amplitude (3,3 and 5 ,IV) and hadlatencies to peak of 4.4, 4-2 and 5-3 ms respectively.On neuro-otological examination there was a moder-

ately severe bilateral sensorineural hearing loss, symmetri-cal below 1 kHz (30 dB, 35 dB and 50 dB at 250, 500 and1 kHz respectively) and greater in the right ear above this(50 dB, 40 dB, 40 dB in the left ear and 60 dB, 60 dB and70dB in the right ear at 2, 4 and 8 kHz respectively).Recruitment was full, there was no significant tone decay atany frequency and the speech audiogram was not worsethan anticipated from the pure tone thresholds. The stap-edius reflex thresholds were normal at all frequencieswithout significant decay. Brainstem auditory evokedpotentials (BSAEP) to a 95 dB click (peak sound pressurelevel) were not consistently recorded from the left ear, buta small component V (0-2 AV) was obtained to right earstimulation at slightly increased latency (6.6 ms, upperlimit of normal 6 5 ms). Vestibular function was deranged.There was no response either in the light or the dark toconventional Fitzgerald and Hallpike caloric testing. Pur-suit was a little irregular, optokinetic nystagmus deranged(small drum) and saccadic movements normal. There wasno nystagmus in the present of fixation or in the dark.Microsaccadic oscillations were present both in the lightand the dark in all positions of gaze. There was no posi-tional nystagmus.

Discussion

The clinical and genetic features of this family arevery similar to those of the kindred described byMay and White'0 and it is highly likely that affectedindividuals from both families suffered from theeffects of the same rare mutant gene. May andWhite'0 described three patients in detail and therewas a history of similar symptoms in three relativeswho were dead. The proband was a 32-year-old manwho was noted to be deaf at the age of four yearsand developed generalised myoclonus, dysarthriaand ataxia when he was 14. He had six generalisedmajor seizures one year later. All his symptomswere slowly progressive apart from the major seiz-ures which did not recur. His mother was clumsyduring adolescence and later became progressivelyataxic and dysarthric. She had no myoclonus but hadone major seizure during the third decade of life.Deafness developed in early adult life. Her brotherhad an almost identical clinical picture. He had nomyoclonic jerks and had never had any seizures.

The pedigree shown in fig 1 indicates that the dis-order here is dominantly inherited, as it was in Mayand White's'° family despite the presence of consan-guineous marriages in two generations. It is prob-able, from the details available, that case 1.2 in ourfamily was affected, but died before fully manifest-ing the disease.

In both families perceptive deafness and cerebel-lar ataxia occurred in all the affected individualswhereas the presence of myoclonus was variable.Deafness preceded other symptoms by a number ofyears in some instances. In two of our cases a formalassessment of this was made (case 111.8 and II.3) andit appears that the deafness was probably of cochlearorigin rather than due to a more central disturbance.The presence of full recruitment, some asymmetryof the thresholds between the ears, normal stapediusreflex, absence of significant tone decay and rela-tively normal speech audiometry all favour such anorigin as does the preserved BSAEP in the presenceof moderately severe deafness at 1-2 kHz. At nec-ropsy there was no evidence of involvement of thecentral auditory pathways in the one case examinedbut unfortunately the temporal bones were notobtained.May and White'0 did not examine the vestibular

system in their cases but in the present patients itappears that the semicircular canal system wasinvolved. It is not possible to say whether the sen-sory epithelium, eighth nerve, or vestibular nucleiwere the seat of the abnormality. The extra-ocularmovement abnormalities are compatible with thepresence of a cerebellar disorder, with derangedpursuit and small drum optokinetic nystagmus, butthe exact site of the disturbance, that is brainstempathways or cerebellum itself, is unclear.One additional clinical feature in case 111.8, which

may also have been present in his mother, was thatof a sensory peripheral neuropathy. The patient hadno symptoms resulting from this although the kneeand ankle jerks were absent and his sensory nerveaction potentials were reduced in amplitude. Case11.3 had absent ankle jerks, but she was aged 70years at the time of examination so this may nothave been significant. None of the patients describedby May and White'0 had -any clinical featuresattributable to a peripheral neuropathy;neurophysiological investigations were not per-formed. It would seem reasonable to suggest thatthe neuropathy found in case 111.8 was part of hisinherited disease; no other cause for this was foundand he was not diabetic.The pathological findings in the necropsied case

reported here were confined to loss of neurons in thedentate nuclei, gliosis of the inferior olives, mild lossof Purkinje cells in the cerebellum, loss of cerebellar

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Autosomal dominant cerebellar ataxia with myoclonus, peripheral neuropathy and deafness

white matter and reduced myelin staining of the fas-ciculus gracilis in the spinal cord. As in manyhereditary ataxic disorders, clinicopathological cor-relation in cases of cerebellar ataxia and myoclonusis not high. The pathological findings in previouslyreported cases have varied considerably. Neverthe-less, the dentate nucleus is nearly always abnormal,with severe neuronal loss and gliosisl 512-15 althoughexceptions have occurred.'6 Involvement of theinferior olives and posterior columns of the spinalcord, as were seen in our case, is almost as frequent.It is of interest that the abnormalities in the brain ofcase II.3 were relatively mild, and cell counting wasnecessary to establish neuronal loss in the dentatenucleus. The circumscribed areas of laminar necrosisseen in the cerebral hemispheres, together with thelesion in the pons, were considered to be ischaemic,or possibly traumatic due to repeated falls, in origin,rather than degenerative as suggested by Bird andShaw.5

It should be stressed that the disorder present inmembers of the family reported here, and that ofMay and White, is genetically and clinically distinctfrom that described in most cases of cerebellarataxia and myoclonus and also from the other auto-somal dominant late onset cerebellar ataxias. Theexistence of this disease illustrates the heterogeneityof the hereditary ataxias generally, and particularlyof what has been called the Ramsay Hunt syndrome.

AEH thanks the Friedreich's Ataxia Group forfinancial support, and the secretarial assistance ofMiss S Jenner is gratefully acknowledged.

References

'Hunt JR. Dyssynergia cerebellaris myoclonica-primaryatrophy of the dentate system. Brain 1921;44:490-538.

2 Greenfield JG. The Spino-cerebellar Degenerations.Oxford: Blackwell, 1954.

3 Marsden CD, Hallett M, Fahn S. The nosology andpathophysiology of myoclonus. In: Marsden CD andFahn S, eds. Movement Disorders, London: Butter-worths International Medical Reviews 1982:196-248.

4 Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R.Progressive myoclonus epilepsy. A clinical and his-topathological study. Acta Neurol Scand1974;50:307-32.

Bird TD, Shaw CM. Progressive myoclonus and epilepsywith dentatorubral degeneration. J Neurol NeurosurgPsychiatry 1978;41:140-9.

6 Jacobs H. Myoclonus and ataxia occurring in a family. JNeurol Neurosurg Psychiatry 1965;28:272-5.

Harding AE. The clinical features and classification ofthe late onset autosomal dominant cerebellar ataxias:a study of eleven families, including descendants ofthe 'Drew family of Walworth'. Brain 1982;105: 1-28.

Bonduelle M, Escourolle R, Bouygues P, Lormeau G,Gray F. Atrophie olivopontoc6rebelleuse familialeavec myoclonies. Rev Neurol (Paris) 1976;132:113-24.

Gilbert GJ, McEntee WJ, Glaser GH. Familial myoc-lonus and ataxia. Pathophysiologic implications.Neurology (Minneap) 1963;13:365-72.

10 May DL, White HH. Familial myoclonus, cerebellarataxia and deafness. Specific genetically determineddisease. Arch Neurol 1968;19:331-8.

"Dix MR. Loudness recruitment and its measurementwith especial reference to the loudness discomfortlevel test and its value in diagnosis. Ann Otol RhinoLaryngol 1968;77:1131-5 1.

12 Louis Bar D, Van Bogaert L. Sur la dyssynergie cerebel-leuse myoclonique (Hunt). Monat fur PsychiatNeurol 1947;113:215-47.

'3 Christophe J, Gruner J. La dyssynergie cerebelleusemyoclonique de Ramsay Hunt. ttude anatomiqued'un cas. Rev Neurol (Paris) 1956;95:297-309.

4 Roger J, Soulayrol R, Hassoun J. La dyssynergie cere-belleuse myoclonique (syndrome de Ramsay Hunt).Rev Neurol (Paris) 1968;119:85-106.

,s De Barsy T, Myle G, Troch C, Matthys R, Martin JJ. Ladyssynergie cerebelleuse myoclonique (R Hunt):affection autonome ou variante du type degeneratif del'dpilepsie-myoclonie progressive (Unverricht-Lundborg). Approche anatomo-clinique. J Neurol Sci1968;8: 111-127.

16 Choteau P, Gray F, Warot P, Dereux JF. Syndrome deRamsay Hunt. etude anatomique d'un cas. RevNeurol (Paris) 1980;136:837-52.

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