Cerebellar atrophy in epilepsy - BMJ · J. Neurol. Neurosurg. Psychiat., 1968, 31, 169-174...

J. Neurol. Neurosurg. Psychiat., 1968, 31, 169-174

Cerebellar atrophy in epilepsyPneumographic and histological documentation of a case with psychosis

ADEL K. AFIFI' AND MAURICE W. VAN ALLEN2

From the Neurosensory Center3 and the Department of Neurology, College of Medicine,University of Iowa, U.S.A.

Anoxia and the toxic effects of diphenylhydantoin(Dilantin) are the two most commonly cited causesfor the cerebellar atrophy which occasionally occursin epileptics. While the histopathology of thiscondition has been well documented (Spielmeyer,1930; Zimmerman, 1938; Meyer, Beck, and Shep-herd, 1955),few reports (Meurice, 1956; Minoque andLatham, 1965) have attempted a clinicopathologicalcorrelation. The case to be presented is that of ayoung woman, subject to convulsions since the ageof 5. Ataxia appeared and progressed at a time whenthe patient was free from seizures and not takingdiphenylhydantoin (Dilantin). Psychotic symptomsappeared before the onset of ataxia. There was nofamily history of cerebellar disease.

Three pneumoencephalograms gave graphic evi-dence of the temporal course of cerebellar atrophyand a biopsy of the cerebellum done at exploratorysurgery yielded tissue for microscopic studies.

CASE HISTORY

A 19-year-old white female, the eleventh of 14 livingsiblings was apparently normal at birth following anuneventful gestation. Two siblings had febrile convulsions.Both died, one during an attack of scarlet fever, the otherwith bronchopneumonia. A maternal first cousin is saidto have had convulsions for 47 years.The patient's neonatal history and subsequent develop-

ment were normal until the age of 5 years when she hada grand mal convulsion. She was first seen in theNeurology Department at the University Hospital inOctober 1951, at the age of 7 years. She had had by thena total of eight grand mal seizures. The results of physicaland neurological examinations were within normal limits.An electroencephalogram was abnormal with frequentspikes predominantly seen over the left temporal, frontal,'Present address: Department of Medicine (Neurology), AmericanUniversity of Beirut Hospitals, Beirut, Lebanon.'Reprint requests to Dr. M. W. Van Allen, Department of Neurology,University of Iowa Hospital, Iowa City, Iowa, U.S.A.'The Neurosensory Center is supported by Program-Project GrantNo. NB03354 of the National Institute of Neurological Diseases andBlindness, Bethesda, Maryland, U.S.A.

and motor areas. Spinal fluid examination was normal.Pneumoencephalogram was normal. She manifesteddifficulty in articulation with lateral emission of sibilantsincluding 's', 'sh', and 'ch'. The diagnosis of cryptogenicepilepsy was made and the patient was started on 90 mgphenobarbital daily.She was seen again in June 1952 and reported

occasional right-sided facial twitches but no majorconvulsions. The E.E.G. was unchanged. Phenobarbitaldosage was increased to 120 mg daily. In November 1952,because of an increase in frequency and severity of focalseizures, methyl phenylhydantoin (Mesantoin), 120mg/day, was added to her regimen. This drug wasineffective and was discontinued. Diphenylhydantoin(Dilantin), 200 mg/day, was started in February 1953.The facial twitching ceased.A Stanford-Binet test in November 1953 revealed an

I.Q. of 77. She performed best on verbal testing and didpoorly on motor coordination.

In May 1954 after 15 months of diphenylhydantoin(Dilantin), 200 mg/day, she was admitted because ofdiplopia, ataxia, incoordination, and nystagmus. She hadbeen seizure free since August 1953. All of these symptomssubsided 48 hr after discontinuing diphenylhydantoin(Dilantin). During this admission the haemoglobin level,white blood cell count, lumbar puncture, and radio-graphs of the skull were normal; an E.E.G. revealeddiffuse slow and fast activity. This acute episode wasattributed to drug toxicity, but because the seizures werewell controlled by diphenylhydantoin (Dilantin) it wasprescribed again in doses of 200 mg/day with pheno-barbital, 100 mg/day. Ataxia soon recurred anddiphenylhydantoin (Dilantin) was stopped. In August1954 she was seizure free and had some residual ataxia.She was admitted to the mental health facility at

Independence, Iowa, in August 1960 in an uncommunica-tive state and received 10 electroconvulsive treatments(E.C.T.). She had taken no medication since 1958 butdiphenylhydantoin (Dilantin), 200 mg/day, and pheno-barbital, 120 mg/day, were given during this hospital-ization.

She was readmitted to the mental health facility atIndependence a year later (August 1961). She wasnegativistic and mute. After a few days, she becameresponsive and communicative but remained emotionallyflat. During her stay in that hospital (August 1961 to

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Adel K. Afifi and Maurice W. Van Allen

October 1961) she had two grand mal seizures and re-current episodes of agitation necessitating restraint.There were no other abnormal physical or neurologicalfindings. In particular, there was no evidence of ataxia orincoordination. She was treated with 300 mg diphenyl-hydantoin (Dilantin), 750 mg primidone (Mysoline), and800 mg chlorpromazine hydrochloride (Thorazine) daily.She was readmitted to the Neurology Department in

October 1961. There were no specific physical findings;in particular there was no ataxia; laboratory examinationrevealed normal haemogram, spinal fluid, blood serology,fasting blood sugar, and serum calcium and phosphoruslevels. Roentgenograms of skull and chest were normal.Pneumoencephalogram was normal (Fig. la and b) andan E.E.G. revealed recurrent spike discharges withoccasional focal discharges from the left anteriortemporal region. During her stay, she was seizure free butmanifested episodes of agitated and combative behaviourand at times was withdrawn and catatonic. She wasdischarged on diphenylhydantoin (Dilantin) 200 mg/day.This was discontinued in December 1961 and for the restof her course.

In April 1962, four months after all medication exceptchlorpromazine hydrochloride (Thorazine) had beenstopped, she began to have difficulty in her gait. Ataxiawas progressive early but stabilized later. She wasadmitted to the Neurology Department a year later(April 1963) for evaluation of this new difficulty. She wasuncommunicative and resistive to examination. Her gaitwas unsteady and she needed support while walking.She was able to stand alone but swayed irregularly andtended to fall backward. Tendon stretch reflexes werenormal. There was no Babinski sign. Further evaluationof her neurological status was not possible because oflack of cooperation. The electroencephalogram wasunchanged except for absence of diffuse spiking. Lab-oratory examination revealed normal haemogram,calcium and phosphorus levels, and fasting blood sugar.She was readmitted in December 1963 at the age of

19 years for re-evaluation of her gait. She was morecooperative and permitted a more thorough examination.Positive findings on this admission included ataxia ofgait and extremities, mild temporal pallor of optic discs,decrease in alternate motion rate of tongue and all fourextremities, bilateral Babinski signs, and hyperactivereflexes in the lower limbs. Speech was mildly dysarthric.She was dull, moderately disoriented, and had difficultyin simple subtraction. The E.E.G. was abnormal withbilateral spike activity. Pupillography was normal. Thefinding of concentric constriction of visual fields wasbelieved to be due to the patient's mental state. A thirdpneumoencephalogram revealed evidence of advancedcerebellar atrophy (Fig. 2a and b), a striking change fromthe findings two years before.

Surgical exploration was undertaken on March 101964 because of the possibility of cerebellar compressionfrom a cyst. At exploration, the dura was found to beslack and not bulging. On incising the dura a very largecisterna magna and a small atrophic cerebellum wereencountered. The arachnoid appeared thickened and moreopaque than normal and was adherent to the pia.Numerous fibrous strands were seen between the arach-

FIG. lb

FIG. Ia and b. Normal pneumoencephalogram (October1961). There was no ataxia at this time. Psychoticsymptoms were present.

noid and pia. A portion of the arachnoid and underlyingcortex was taken for microscopic study. The patientrecovered well and was discharged with no change in hergait. She continues to be ataxic, hypotonic, and unable towalk alone. Sporadic seizures for which she has beenreceiving primidone (Mysoline) occur about twice yearly.Chlorpromazine hydrochloride (Thorazine), and thior-idazine (Mellaril) have been given for her schizophrenicstate. Figure 3 shows her clinical course and medication.

PATHOLOGY The tissue from the cerebellum was fixedin 10% formol saline and embedded in paraffin. Tenmicra thick sections were stained with haematoxylinand eosin and by Nissl, Weil, Bodian, and Heidenhain

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Cerebellar atrophy in epilepsy

FIG. 2a

FIG. 2b

FIG. 2a and b. Pneumoencephalogram (December 1963)showing massive accumulation ofair in the posterior fossa.Other views showed evidence of cortical atrophy ofmoderate degree.

methods. Light microscopy revealed almost completeabsence of Purkinje cells (Fig. 4a-c) with some degree ofrarefaction of the granule cell layer. No aetiologicalfeatures-for example, vascular changes, cellular in-filtrations, or cystic gliosis-were present. The arachnoidwas fibrotic.

DISCUSSION

The findings are consistent with those of 'parenchym-atous cortical cerebellar atrophy'. This is a syndromeof varied causal association. The commonly citedaetiologies are heredofamilial, metabolic, toxic,

infectious, traumatic, and ischaemic. The familyhistory of our patient is negative with regard tocerebellar disease. The convulsions in the siblingswere febrile, and deaths were attributable to non-neurological disease. The seizures in the firstmaternal cousin occurred over a period of 47 yearsand probably were cryptogenic. The onset of ataxiaat the age of 18 would appear to exclude the diagnosisof the late cortical atrophy of Marie, Foix, andAlajouanine.The association of convulsions, diphenylhydantoin

(Dilantin) administration, electroconvulsive therapy,and cerebellar degeneration bring to mind thepatients described by Thorpe (1935), Haberland(1962), Minoque and Latham (1965), and Meurice(1956). Their patients were also epileptic. Thepatients of Thorpe (1935), Haberland (1962), andMinoque and Latham (1965), like our patient, hadin addition prominent mental problems necessitatingE.C.T. in some (Haberland, 1962). Evidence ofcerebellar degeneration appeared in the course ofadministration of diphenylhydantoin (Dilantin)except in the case of Thorpe (1935). Cerebellardegeneration in their cases was progressive in natureand ended in incapacitation. Our patient can feedherself and take care of her own daily needs. Shewalks with support. Serial electroencephalogramsand cerebrospinal fluid examinations have notchanged substantially throughout the course of herillness.The aetiology of the cerebellar atrophy in our

case is speculative. Several possibilities should beconsidered.

CONVULSIONS The association of cerebellar degener-ation and epilepsy has been well documented. It isbelieved that anoxia is responsible. The patho-physiological changes in anoxia are not wellunderstood. Alexander and Lowenbach (1944), andScholz (1959) demonstrated evidence of anaemicand hypaemic areas in brains of animals submittedto convulsions induced by electroshock. These areasincreased in size during a series of seizures and per-sisted 40 min after the convulsions. Scholz (1959)considered these areas a manifestation of a cir-culatory disturbance associated with the seizure.Cerebellar changes similar to those occurring inepileptics were described by Lindenberg (1955) incases of increased intracranial pressure and wereattributed to compression of arteries which mightoccur during an epileptic attack.

In a study of alteration of cerebral dynamicsassociated with seizures, White, Grant, Mosier, andCraig (1961) found evidence of increase in cerebralblood flow and rise in cerebrospinal fluid pressure.Whether any of the above factors were operative in

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SYMPTOMS

l.Convulsions a,GM cb.FOC

2. Diplopia, atoxia, ny-stogmus (dilontin toxicity)3. Schizophrenic reaction4. Ataxia

TREATMENT

1. ECT (10)

F2. Phenobarbital 12tL

bt

60-

3. Mesontoin L60

4. Dilontin 300E(DiphIyl 100

Hydontoin)5. Mysoline

(Primidone) °

6. Thorazine 0(Chlorpromozin) °

7. Melloril 0(Thloridozio)

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LABORATORY STUDIE1. EEG2. PEG& CSF4 1.0.5. Skull Ro.ntgonogroms6. Biopsy (cerebellum)

xI x

x x x

x~~~~~~~~~~~

FIG: 3. Scheme of symptoms, treatment, and laboratory studies.

our case is difficult to say. The clinicopathologicalcorrelations of seizures and cerebellar degenerationin the literature are too few to permit a comparison.In contrast to the cases of Meurice (1966) andMinoque and Latham (1965), the seizures in ourpatient were at no time very severe, and at no timedid the patient go into status epilepticus. The totalnuinber known of grand mal seizures did notexceed 20. Ten convulsions were induced by E.C.T.Symptoms in our patient began several months aftershe was seizure free.

ELECTROCONVULSIVE THERAPY Our patient as wellas the two patients described by Haberland (1962)had E.C.T. sometime in their clinical course beforethe onset of cerebellar symptoms and signs. Thesame argument would hold here as discussed aboveunder convulsions for the role of E.C.T. in thegenesis of this state. If the E.C.T. is a factor in thisatrophy, it is strange that more cases of ataxia arenot encountered among the many patients receivingshock therapy.

DIPHENYLHYDANTOIN (DILANTIN) The associationof ataxia with diphenylhydantoin (Dilantin) has

been recognized since Merritt and Putnam (1939)noted ataxia, tremor, diplopia, drowsiness, andheadache during diphenylhydantoin (Dilantin)administration. These symptoms usually developwith large doses and generally subside after adecrease in the dosage or discontinuance of the drug.Utterback, Ojeman, and Malek (1958) and Rogerand Soulayrol (1959), however, described patientswho, having developed ataxia while taking diphenyl-hydantoin (Dilantin), experienced only incompleterecovery after the drug was discontinued. Utterbacket al. (1958) and Hofmann (1958) demonstratedselective Purkinje cell degeneration in patientsreceiving large doses ofdiphenylhydantoin (Dilantin),and Utterback et al. (1958) showed similar findingsin normal cats given diphenylhydantoin (Dilantin).In Hofmann's (1958) patients, the granule cell layerwas spared and in the cats of Utterback et al. (1958)granule cells were diminished after large doses ofdiphenylhydantoin (Dilantin).The contribution of diphenylhydantoin (Dilantin)

toxicity to the ataxia and cerebellar degeneration inour case is difficult to assess. Although our patienthad manifestations of diphenylhydantoin (Dilantin)toxicity, these were transitory and subsided on

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taking diphenylhydantoin (Dilantin) for severalmonths and was taking only chlorpromazine hydro-chloride (Thorazine). The evidence for the absenceof atrophy earlier in her course is seen in comparingthe air studies of 1951, 1961, and 1963. The rarefac-tion of the granule cell layer in our patients is atvariance with the observations in Hofmann's (1958)case who did not show this and the cats of Utter-back et al. (1958) which showed it only withrelatively high doses of diphenylhydantoin (Dilantin).The prominence of mental symptoms in our case

and in those of Thorpe (1935), Haberland (1962),and Minoque and Latham (1965) is of interest. Onewonders whether the psychiatric manifestations arenot part of a symptom complex of epilepsy, cerebel-lar degeneration, atnd organic psychosis reflecting

FIG. 4b

FIG. 4a. Nissl stain showing the striking absence ofPurkinje cells and rarefaction in the granule cell layer.x 77.

b. Nissl stain showing a solitary densely stainingPurkinje cell. x 165.

c. Bodian stain showing an empty basket (arrow)theformer site ofa Purkinje cell. x 286.

an unusual vulnerability of the cerebrum andcerebellum in such patients to the effects of seizure-induced anoxia. The role of diphenylhydantoin(Dilantin) in the development of such a symptomcomplex can be debated since Thorpe's (1935) casesnever received diphenylhydantoin (Dilantin).Our report confirms observations in the literature

on the existence of a syndrome of cerebellar degener-ation and ataxia in patients suffering from epilepsy.Our case differs from others in the occurrence ofataxia and cerebellar degeneration when the patientwas not taking anticonvulsive medication and whenshe was seizure free. The availability of serialpneumoencephalograms serves to confirm the timeof onset of cerebellar atrophy and helps to place thedifferent chronological events in perspective. Ourcase does not throw light on the pathophysiology ofthis syndrome. No vascular changes were seen. The

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unavailability of tissues from other areas known tobe vulnerable to anoxia (Ammon's horn, motorcortex) makes it difficult to be dogmatic aboutselective cerebellar damage versus diffuse damageinvolving other areas of the brain. Judging from theappearance of the pneumoencephalogram, thecerebellar atrophy is much more extensive than isatrophy elsewhere.

SUMMARY

The case of a young female epileptic who developedpersistent and disabling ataxia at the age of 18 ispresented. She had been treated by moderate dosesof phenobarbital diphenylhydantoin (Dilantin),primidone (Mysoline), and methyl phenylhydantoin(Mesantoin) at various times.Symptoms suggesting schizophrenia appeared

when she was 16 and were treated by 10 E.C.T. andchlorpromazine hydrochloride (Thorazine).

Three pneumoencephalograms documented thedevelopment of cerebellar atrophy. Tissue studiesshowed changes typical of 'parenchymatous cerebel-lar degeneration'.A syndrome of cerebellar degeneration, psychosis,

and epilepsy is discussed.

The senior author (A.K.A.) is indebted to the LebaneseResearch Council for a travel grant which made collabor-ation on this paper possible.

REFERENCES

Alexander, L., and Ldwenbach, H. (1944). Experimental studiet onelectro-shock treatment: the intracerebral vascular reaction asan indicator of the path of the current and the threshold ofearlychanges within the brain tissue. J. Neuropath. exp. Neurol., 3,139-171.

Haberland, C. (1962). Cerebellar degeneration with clinical manifest-ation in chronic epileptic patients. Psychiat. et Neurol. (Basel),143, 29-44.

Hofmann, W. W. (1958). Cerebellar lesions after parenteral Dilamninadministration. Neurology (Minneap.), 8, 210-214.

Lindenberg, R. (1955). Compression of brain arteries as pathogeneticfactor for tissue necroses and their areas of predilection.J. Neuropath. exp. Neurol., 14, 223-243.

Merritt, H. H., and Putnam, T. J. (1939). Sodium diphenyl hydantoin-ate in treatment of convulsive seizures. Arch. Neurol. Psychiat.(Chic.)., 42, 1053-1058.

Meurice, E. (1956). D'un syndrome c6r6bello-spasmodique progressifde longue dur6e dans l'epilepsie d'allure temporale. Actaneurol. Belg., 56, 396-401.

Meyer, A., Beck, E., and Shepherd, M. (1955). Unusually severelesions in the brain following status epilepticus. J. Neurol.Neurosurg. Psychiat., 18, 24-33.

Minoque, S. J., and Latham, 0. (1965). Cerebellar degeneration withepilepsy. Med. J. Aust., 1, 430433.

Roger, J., and Soulayrol, R. (1959). A propos des accidents neuro-logiques du traitement de l'6pilepsie par les hydantolnes.Rev. Neurol., 100, 783-785.

Scolz,W. (1959). The contribution of patho-anatomical research to theproblem of epilepsy. Epilepsia (Amst.), 4th ser., 1, 36-55.

Spielmeyer, W. (1930). The anatomic substratum of the convulsivestate. Arch. Neurol. Psychiat. (Chic.)., 23, 869-875.

Thorpe, F. T. (1935). Familial degeneration of the cerebellum inassociation with epilepsy. Brain, 58, 97-114.

Utterback, R. A., Ojeman, R., and Malek, J. (1958). Parenchymatouscerebellar degeneration with Dilantin intoxication. J.Neuropath. exp. Neurol., 17, 516-519.

White, P. T., Grant, P., Mosier, J., and Craig. A. (1961). Changes incerebral dynamics associated with seizures. Neurology(Minneap.), 11, 354-361.

Zimmerman, H. M. (1938). The histopathology of convulsive dis-orders in children. J. Pediat., 13, 859-890.

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