Chronic brainstem encephalitis with mental symptoms and ataxia · mm3, protein 0.7 g/l, Pandy (+3), and Nonne-Apelt (+). On the third occasion on 19 May, after steroid therapy, cell

Journal ofNeurology, Neurosurgery, andPsychiatry, 1978, 41, 516-524

Chronic brainstem encephalitis with mentalsymptoms and ataxiaReport of three cases with necropsy

TAKEJI UENO AND NAOHIKO TAKAHATA

From the Department of Psychiatry and Neurology,Hokkaido University School of Medicine, Sapporo, Japan

SUMMARY Three necropsied cases of chronic, sporadic brainstem encephalitis of unknownaetiology are presented. Since their outstanding symptoms were dementia and ataxia of a pro-gressive nature, a noninflammatory disease of the central nervous system was suspected.Neuropathological studies showed chronic inflammatory changes mainly in the brainstemwithout the presence of inclusion bodies or viral particles. Compared to cases previouslyreported as brainstem encephalitis, the clinical and pathological findings observed in thesecases have rather peculiar characteristics.

Many kinds of encephalitides have been known toshow localised or predominant lesions in thebrainstem-namely, encephalitis lethargica, thecerebral form of the Heine-Medin disease, rabies,and equine encephalitis which has been classifiedby Spatz (1930) as a type of polioencephalitis withpredominant involvement in the brainstem.Japanese B encephalitis (Haymaker and Sabin,1947) or Pette-Doring type of subacute sclerosingpanencephalitis (Pette and Doring, 1939) havealso been known to produce intense lesions in thediencephalon or brainstem.

In contrast to the above encephalitides, aeti-ologically obscure encephalitis has been called"brainstem encephalitis." Although a number ofbenign or fatal cases of this disease have beendescribed, the clinical and neuropathologicalfeatures have been too complicated to identifytheir aetiology (Moller, 1956; Bickerstaff, 1957;Moller and Nenzelius, 1961; lizuka, 1964; Tatetsuet al., 1964, 1968; Mukoyama et al., 1965, 1967;Gluszcz, 1966; Verhaart, 1966; Marsal, 1967;Minauf and Tateishi, 1969; Schain and Wilson,1971; Shirabe et al., 1971, 1972; Waxman et al.,1974; Yalaz and Tinaztepe, 1974).The cases with brainstem inflammation pre-

sented in this paper, had chronic and peculiar

Address for reprint requests: Dr Takeji Ueno, Department ofPsychiatry and Neurology, Hokkaido University School of Medicine,North 14 West 5, Sapporo, Japan.Accepted 25 January 1978

manifestations which have not been reportedpreviously. We have tried to describe their clinicaland pathological characteristics, as well as discussaetiology as compared with other encephalitides.

Case reports

CASE 1

This 39 year old male (SM) had been healthyuntil 30 years of age. There were no remark-able abnormalities in his family. From the ageof 31 years he gradually became indifferent,hypobulic, and eccentric. His manner of livingbecame disturbed; he suffered from insomnia andwas treated in a mental hospital. He was absentfrom work frequently, and became autistic withaffective flatness. He was admitted to mentalhospital in March 1961 with a provisionaldiagnosis of schizophrenia. During the admission,unsteadiness in walking, difficulty in speech, andhypersalivation appeared and worsened. At thattime, there were no abnormal findings in thecerebrospinal fluid and electroencephalogram(EEG). In October 1962, at the age of 37 years, hewas transferred to Hokkaido University Hospital.On examination consciousness seemed clear,

but he was indifferent and euphoric. There wasmoderate dementia. The visual acuity was re-duced to less than 20/200 without correction inboth eyes. The optic disc showed temporal pallor,and there was slight facial paresis on the right and

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Chronic brainstem encephalitis with mental symptoms and ataxia

deviation of the tongue to the right. Dysarthriawas noted, and his voice had a nasal quality. Thelimbs were hypertonic, and there was slight weak-ness on the right. Tests of co-ordination, such asdiadochokinesis, finger-nose, finger-finger, andheel-shin tests, were slow, unstable, and ataxic.Gait was also unstable, and ataxic. Tandem gaitwas impossible. Deep tendon reflexes were allhyperactive, especially on the right.There were no abnormalities in blood, urine,

liver function, serum electrolytes, basal urinaryexcretion of 17-KS and 17-OHCS, or serologicaltest for syphilis. No abnormal findings were notedin the skull radiograph or on the carotid angio-gram, but moderate dilatation of the third andlateral ventricles was observed on the pneumo-encephalogram. The EEG showed a diffuse basicalpha pattern with sporadic or random thetaactivity. At lumbar puncture on 9 October 1962,the CSF opening pressure was 90 mmH20, andclosing pressure 85 mmH,O after withdrawal of3 ml of clear, colourless fluid; 29 lymphocytes permm<, protein 0.5 g/l, chloride 111 mmol/l, sugar2.8 mmol/l, Pandy test (+), and Nonne-Apelt test(±). Electrophoresis of the protein revealed highvalues for beta and gamma globulin. The next teston 9 May, 1963, showed marked pleocytosis; 21lymphocytes and 289 polymorphonuclear cells permm3, protein 0.7 g/l, Pandy (+3), and Nonne-Apelt (+). On the third occasion on 19 May,after steroid therapy, cell count decreased to 22lymphocytes per mm3.Although some kind of cerebellar disease had

also been suspected, the CSF findings at a laterstage suggested an inflammatory disease in thecentral nervous system. Antibiotics and steroidswere administered, but with no effect. Thepatient's symptoms gradually worsened, and hefinally became bedridden. His general conditiondeteriorated with dysphagia. After about eightyears, he died of pneumonia on 5 August 1963.

Necropsy findingsGeneral pathology There was bronchopneumoniaof both lungs, erosion of the stomach, haemor-rhage of the gastrointestinal tract, parenchymatousdegeneration of the liver and kidney, ascites, andfibrinous pleurisy on the left.Neuropathology The brain weighed 1210 g.Macroscopically, turbidity of the meninges wasobserved on the convexity of the frontal lobeand the base of the brain. The frontal lobe, pons,and medulla were slightly atrophied. No grossabnormalities were noted in the basilar arteries,or on coronal sections of the brain.

Microscopically, the main pathological findings

were inflammatory changes localised in the brain-stem. Perivascular lymphocytic and plasmacyticinfiltration, and diffuse proliferation of glial cells,especially microglia, were prominent in the mid-brain and pons, and to a lesser degree in thethalamus, hypothalamus, medulla, and basalnucleus (Fig. 1). Only a few glial nodules werepresent in the parolfactory area, locus caeruleus,and inferior olive (Fig. 2). In addition, many smallsoftenings were observed in the tegmentum, cruscerebri, and inferior colliculus of the midbrain,ventral portions of the pons, and inferior olive onone side, where a number of gemistocytic astro-cytes and phagocytes appeared, and patchydemyelination and fibrous gliosis were observed(Fig. 3). Such changes were also present in thelateral geniculate body. Although slight ormoderate loss of the nerve cells was observed inthe pontine nucleus and inferior olive mentionedabove (Fig. 4), other areas of the brainstem were.,,,,* q;*. .--e

Fig. 1 Perivascular cell infiltration and diffuse glialproliferation in the pons. Case 1, H & E X55.

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Fig. 3 Small and patchy demyelination in the midbrain (a), pons (b), and medulla (c). In these areas,fibrous gliosis of varying degrees was observed. Case 1, Heidenhein-Woelke (H & W).

tion. Cellular infiltration was also present in themeninges of the base and brainstem. The struc-ture of the cerebral cortex and white matter was,however, relatively preserved with only glialincrease.

Electronmicroscopically, no viral particles couldbe observed in the nerve and glial cells in thelesions of the pons.

Fig. 4 Marked loss of nerve cells anastrocytes in the inferior olive. Case i

relatively well preserved. No neur

be observed. Moreover, inclusi(absent in the nerve cells or gllesions. In the cerebellum, a highof Purkinje cells was observed w

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CASE 2

A 26 year old male (KF) had been well except fora history of acute nephritis at 4 years of age, andfracture of the right thigh bone at 13. Familyhistory was noncontributory. He first began to

d increase of have occasional headaches and insomnia at the1, Nissl X55. age of 18 years. About one or two years later, he

became rather talkative and sensitive to his sur-

onophagia could roundings. He also became disoriented, restless,on bodies were and unkempt, and could not settle to an

lial cells of the occupation. In July 1962, at the age of 22 years,or moderate loss he was admitted to a mental hospital. Because of,ith a slight glial changes in his personality, he was thought to be(Fig. 5). More- schizophrenic and treated accordingly for three

iucleus showed a years. Neurological symptoms, however, such as

;h glial prolifera- dysphagia and momentary athetotic movementsof the extremities were noticed one year beforeadmission. Unsteadiness of gait and difficulty in

speaking were also evident at the time of ad-mission. Hypersalivation and a disturbance ofmicturition also appeared. In June 1965, at the

age of 25 years, he was transferred to our hospital.On examination, he seemed childish and

euphoric with slight dementia. The gag reflex was

absent, and dysarthria and a nasal voice were

observed. Muscular weakness of extremities was

.-;.<w-*eislight, atrophy was absent, and tone was reduced.i.S14'$'ti>Co-ordination tests were ataxic, particularly on

the right. Deep tendon reflexes were all hyper-s. Case 1, active especially at knee and ankle and on the right.

Involuntary movement appeared in the extremi-

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ties. Bladder and bowel function was disturbed.Gait was unstable and ataxic.There were no abnormalities found in blood,

urine, liver function, faeces, serum electrolytes,electrophoresis of serum protein, serological testfor syphilis, or skull radiograph. Marked dilatationof the third and lateral ventricles, and cortical atro-phy were demonstrated on the pneumoencepha-logram. On the EEG, alpha activity was poorin the occipital area with sporadic or randomtheta activity in the frontal and central areas.Lumbar puncture, in August 1965, showed anopening pressure of 117 mmH2O, a closing pres-sure of 80 mmH2O, with clear colourless fluid;8 lymphocytes per mm3, protein 0.5 g/l,chloride 124 mmol/l, Pandy test (+2), and Nonne-Apelt test (-). Electrophoresis of the proteinrevealed a high gamma globulin value (twice thenormal value).The patient was transferred to another hospital

in September, 1965 for rehabilitation. His neuro-logical and mental symptoms gradually becameworse, and after about eight years, he died ofpneumonia in February, 1966. He was suspectedof having a cerebellar disease.

Necropsy findingsGeneral Pathology There were no abnormalfindings in the visceral organs except for broncho-pneumonia in the lungs.Neuropathology The brain weighed 1300 g.Macroscopically, slight atrophy of the frontallobe, temporal lobe, pons, and cerebellum wasobserved. Leptomeninges in the central sulcusand parieto-occipital regions were remarkablyturbid. No other gross abnormalities wereobserved except for dilatation of the ventriclesystem.

Microscopically, inflammatory changes werenoted mainly in the brainstem. In the perivascularspace, there were various kinds of inflammatorycells. In addition to lymphocytes and plasma cellsthere were large round cells, phagocytes, such ashistiocytes, and fat- or iron-granule cells. A diffuseproliferation of glial cells, especially microglia,was also present. These findings were most pro-minent in the pons and medulla, and to a lesserdegree in the thalamus, hypothalamus, and mid-brain (Fig. 6). Such findings were also observedin the basal nucleus and internal capsule to aslighter degree. On the other hand, patchy ordiffuse demyelination and fibrous gliosis weredemonstrated in the crus cerebri of the midbrain,middle cerebellar peduncle, ventral portion of thepons, and pyramid of the medulla (Fig. 7). Therewas also a small infarct in the medial longitudinal

Fig. 6 Perivascular cuffing in the medulla. Case 2,Nissi X60

Fig. 7 Small and patchy demyelinating areas in thebrachium pontis and ventral portion of the pons.Fibrous gliosis was demonstrated in these areas.Case 2, H & W.

fasciculus on one side, where many gemistocyticastrocytes and phagocytes appeared. In spite ofthe above changes, the nerve cells in the brain-stem were relatively well preserved. Glial nodulesand neuronophagia were absent. In the cere-bellum, although no loss of Purkinje cells wasapparent, a slight or moderate loss of nerve cells,and a glial proliferation were observed in thedentate nucleus (Fig. 8). In the cerebrum, therewas slight loss of cortical nerve cells in the frontal,parietal, and temporal lobe with a few pen-vascular cellular cuffings in the frontal whitematter. The cervical and thoracic spinal cordshowed demyelination of lateral and anteriortracts without inflammatory changes (Fig. 9). Inthe meninges of the base and brainstem, inflam-matory cells similar to those in the perivascularspace were observed to some extent. There wereno inclusion bodies in the lesions.

Electronmicroscopically, no viral particles couldbe observed in the lesions of the hypothalamus.

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Fig.8 Moderate loss of nerve cells and diffuse glialproliferation in the dentate nucleus Case 2 Nissl

Fig. 9 Demyelination of lateral and anterior tract inthe cervical cord. Case 2, H & W.

CASE 3This 50 year old female (TN) had been well until47 years of age, when she began to show signs ofdifficulty in speech. The family history was notremarkable. Her voice became lower, and pro-nunciation obscure. Several months later, herfinger movement became clumsy, and she fre-quently dropped food and dishes while eating.Unsteadiness in walking also appeared. She alsobecame childish, and a decline in her intellectualfaculties was noticed. She visited KushiroMunicipal Hospital in April 1969.On examination, her face appeared apathetic

and dull. Comprehension was poor, and hermanner of speaking was circumstantial. Dementiaof moderate degree was observed. Neurologically,ophthalmoplegia, dysarthria, clumsiness of fingermovement, and ataxic gait were noted. She washypertensive (174/90 mmHg). There were noabnormal findings on the carotid angiogram andpneumoencephalogram. Lumbar puncture inApril 1969, showed an opening pressure of155 mmH20, a closing pressure of 105 mmH20,with clear, colourless fluid; Pandy test (-), and

Nonne-Apelt test (-), 4 lymphocytes per mm3,protein 0.175 g/l, sugar 3.3 mmol/l, chloride111 mmol/l.She was readmitted in May 1969, with suspected

cerebrovascular disease or presenile dementia. Onadmission, reacting to a trivial matter, she be-came negativistic and regressed. Suspected ofbeing in a hysterical state, electric convulsivetherapy was given, but it was ineffective in regardto the psychiatric and neurological symptoms. Inaddition, administration of various drugs andphysical therapy were not helpful. About oneyear later, dysphagia developed, and hernutritional state became worse. Muscular tone ofthe extremities became hypotonic, and theirmovement more ataxic. Finally, the patient couldnot stand and walk at all, and became bedridden.Facial paresis on the left, asymmetry of deeptendon reflexes, and Hoffman's reflex on the leftwere observed in the course of illness, but theywere slight and transient in their occurrence. Ata later stage, generalised tonic convulsions beganto occur once a month. In December 1972, afterabout four years, she died of pneumonia.There were no abnormal findings from examina-

tions of blood, urine, liver function, serum electro-lytes, serological test for syphilis, ECG, andskull or chest radiographs. Moderate dilatationof the third and lateral ventricles was revealed bypneumoencephalography in January 1971. AnEEG was carried out every year, but only lowvoltage and irregular alpha waves were observedwithout slow components or paroxysmal dis-charge. Cerebrospinal fluid, which was examinedin January 1971, revealed a cell count of 7 lympho-cytes per mm3, protein 0.25 g/l, sugar 4.0 mmol/l,chloride 120 mmol/l, with clear and colourlessfluid.

Necropsy findingsNecropsy was confined to the brain whichweighed 925 g. Macroscopically, it was small, andthe cerebral hemispheres showed marked corticalatrophy, especially in the frontal lobe. Pons andmedulla were also atrophied. Moderate athero-sclerotic changes were observed in the basilarartery. No other gross abnormalities were notedin the leptomeninges and coronal sections of thebrain.

Microscopically, inflammatory changes werelocated mainly in the grey matter of the brain-stem. Perivascular infiltration with lymphocytesand plasma cells, and diffuse proliferation of glialcells, especially microglia, were prominent in thethalamus, hypothalamus, and midbrain, and to alesser degree in the pons, medulla, and basal

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Fig. 10 Perivascular cuffing and diffuse proliferationof glial cells of high degree in the lateral nucleus ofthe thalamus. Case 3, H & E X60.

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nucleus (Fig. 10). In the dentate nucleus of thecerebellum, glial cells showed a moderate increase(Fig. 11). Slight diffuse demyelination and loss ofnerve cells were demonstrated in the lateralnucleus of the thalamus, tuber cinereum of thehypothalamus, and red nucleus and tegmentum ofthe midbrain (Fig. 12), where the inflammatorychanges were greatest. Relatively few glial nodules,light in appearance, were observed in the hypo-thalamus and dentate nucleus. Nerve cells in theother areas of the brainstem were relatively wellpreserved, and necrosis or neuronophagia were

absent. In the cerebellum there was no loss ofPurkinje cells or granular cells, although a slightloss in the dentate nucleus was observed. More-over, a slight degree of demyelination and fibrousgliosis were demonstrated in the superior cere-

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Fig. 11 Marked glial increase in the dentate nucleus.Case 3, H & E X80.

Fig. 12 Diffuse demyelination in the thalamus andcentrum semiovale. Case 3, H & W.

bellar peduncle. In the cerebral cortex, a slightloss of nerve cells was observed in the frontal andparietal lobe, although the structure of the nervecell layer was relatively preserved without senilechanges such as senile plaque or Alzheimer'sfibril. In the cerebral white matter, however,diffuse demyelination of the centrum semiovaleand temporal lobe was present with slight glialincrease (Fig. 12). Leptomeninges of the brain-stem showed slight cellular infiltration. There wereno arteriosclerotic changes of the small arteriesor arterioles in the meninges and parenchyma,and no inclusion bodies in the nerve cells andglial cells of the lesions.

Electronmicroscopically, no viral particlescould be found in the lesions of the midbrain.

Discussion

The cases presented in this paper have severalpoints in common.

1. The age of onset of the illness was in adultlife-from 21 to 47 years.

2. The occurrence was sporadic, and insidious.The course was chronic and slowly progressivewithout an acute stage or remission. The durationwas four to eight years.

3. The outstanding symptoms were progressivedementia and ataxia. In the initial stage, how-ever, personality change and abnormal behaviourwere so prominent, as in cases 1 and 2, that theywere suspected of schizophrenia, and treated inmental hospitals. Also, case 3 was suspected of a

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hysterical state, and treated with electric con-

vulsive therapy. As incidental symptoms todementia, there were euphoria in cases 1 and 2,and hypochondriacal mood or emotional inconti-nence in case 3. Neurologically, it is characteristicthat although bulbar signs such as dysarthria,dysphagia, and pyramidal signs were observed inall cases, other signs of brainstem lesions wererather poor or slight; only facial paresis or

ophthalmoplegia were noted to some extent incases 1 and 3, involuntary movement and bladder-bowel dysfunction in case 2, and generalised con-

vulsions in case 3.4. Medical and neurological symptoms or

signs, which suggested an inflammatory processof the central nervous system, were so inadequatethat making an exact diagnosis of "encephalitis"was difficult. Cases 1 and 2 were suspected of acerebellar disease, and case 3 of some preseniledementia or cerebrovascular disease. Headache atthe initial stage, and occasional slight fever dur-ing the fourth year after onset were notified incase 2 only.

5. Laboratory examinations also demonstratedminor inflammatory findings. Haematologicalexaminations revealed no abnormalities exceptduring the last stage of the illness, when pneu-monia was present. Cerebrospinal fluid showedpleocytosis of slight or moderate degree at a laterstage in case 1 only, and total protein was slightlyraised in cases 1 and 2.

6. Pathologically, chronic inflammatorychanges were observed, predominantly in thebrainstem, and to a lesser degree in the cerebellumor subcortical grey matter, but scarcely extendedto the cerebral cortex and white matter. In thebrainstem, white as well as grey matter was in-volved in cases 1 and 2, but changes in whitematter were not so prominent in case 3. Althoughperivascular cell infiltration and diffuse glial pro-liferation were prominent, only a few glial noduleswere observed in cases 1 and 3. Moreover, nervecells in the brainstem except for some regionswere relatively well preserved. Necrosis andneuronophagia were absent. No inclusion bodiesnor viral particles could be found in the nervecells and glial cells of the lesions.

It is clear from the above that clinical andpathological features of our cases differ fromencephalitides of known cause which were brieflymentioned in the introduction. Behcet's syndromealso shows inflammatory lesions in the brainstem(Rubinstein and Urich, 1963), but there were no

signs suggestive of this syndrome, such as cu-

taneous or ocular lesions, in our cases. In addition,similar inflammatory changes of the brainstem


have reportedly been induced by the remote effectsof cancer, particularly lung cancer (Russell, 1961;Henson et al., 1967; Henson and Urich, 1970). Inthis disease, a subacute course and symptoms ofmyeloradiculoneuropathy are commonly de-scribed, and it is said to be easily diagnosed ascancer before death. The necropsies of our cases1 and 2, however, clearly negate the possibility ofcancer. From clinical and radiological points ofview, case 3 can hardly be suspected of cancerand remotely induced brainstem lesions, althoughthere have been descriptions of a few chroniccases whose cancer was discovered only atnecropsy (Croft et al., 1967).

It is most probable that the inflammatorylesions in our cases were produced by chronicinfection of some yet undescribed virus which hada predilection for the brainstem region in thecentral nervous system. The biological properties,however, could not be clarified, since viralparticles could not be observed under electronmicroscopy. Moreover, virological studies werenot done because of our initial suspicion of a non-inflammatory disease. From the epidemiologicalpoint of view, it is of interest that this kind ofchronic encephalitis with these peculiar featureshas been observed only in the Hokkaido region,the northern part of Japan, where there has beenno epidemic of Japanese B encephalitis. Someendemic factors might have to be taken intoaccount in association with their occurrence, butthe details remain unclear.

Various neurological symptoms or signs havebeen described in brainstem encephalitis. Ataxiahas been observed in a relatively large number ofcases (Bickerstaff, 1957; Moller and Nenzelius,1961; Tatetsu et al., 1964; Mukoyama et al., 1965;Verhaart, 1966; Marsal, 1967; Minauf andTateishi, 1969; Schain and Wilson, 1971; Waxmanet al., 1974) though few showed ataxia as thepredominant symptom, or were suspected ofhaving cerebellar disease. Mental symptoms,except for disturbance of consciousness, werenoted in only a few cases, and were not soprominent as in our cases (lizuka, 1964; Tatetsuet al., 1964, 1968; Shirabe et al., 1972). On theother hand, it is interesting that the mentalsymptoms and the clinical course of our patientswere similar to those of chronic panencephalitisof unknown aetiology (Peters and Struck, 1959;Boudoresques et al., 1969; Ishino et al., 1971); atonset, they were in the fourth or fifth decade oflife, and had been suspected of mental diseasessuch as general paresis, presenile dementia, andschizophrenia, for they manifested dementia,euphoria, or dysarthria as the main symptoms.



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Pathologically, severe inflammatory changes hadbeen observed with numerous glial nodules in thegrey matter of the cerebrum and brainstem. Inour cases, however, only a few glial nodules wereobserved in the lesions of the brainstem. In ad-dition, inflammatory changes in our cases did notextend to the cerebral cortex, although severedamage of the cerebrum was suspected from theirmental changes and the abnormal findings ofpneumoencephalography and EEG. Kersting (1952)suggested that encephalitis of adult onset had atendency to show more intense changes in thebrainstem and subcortical grey matter. Accord-ing to his suggestion, our cases might be a typewith more localised lesions in the brainstem. Butour cases can hardly be considered the same as thetype of panencephalitis mentioned above, or to becaused by the same aetiology as that of pan-encephalitis, from the pathological point of view.

It is certain that the mental abnormalities inour three cases are closely correlated with involve-ment of the brainstem and diencephalon, whereseveral lesions were present, at the same time,without apparent changes in the cortex. Althoughthe aetiology is still obscure, we are sure that itwill be clarified in the near future by the develop-ment of virological and immunological studies.

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Chronic brainstem encephalitis with mental symptoms and ataxia · mm3, protein 0.7 g/l, Pandy (+3), and Nonne-Apelt (+). On the third occasion on 19 May, after steroid therapy, cell