Psychological Medicine, 1978, 8, 21—42 Printed in Great Britain

The late effects of necrotizing encephalitis of the temporal lobes and limbic areas: a clinico-pathological study of 10 cases R. HIERONS,1 I. JANOTA AND J. A. N. CORSELLIS From Brook General Hospital, London, and the Departments of Neuropathology, Institute of Psychiatry, London, and Runwell Hospital, Wickford, Essex

The clinical and neuropathological features are reported of 10 patients who had suffered, usually for several years, from the after effects of an acute or sub-acute necrotizing encephalitis of the limbic grey matter and of the adjacent temporal lobes. Emphasis is laid on the memory disturbance and on the behavioural and emotional aberrations that tended to occur and that are in some ways reminiscent of the Kliiver-Bucy syndrome.

SYNOPSIS

patients who survived for 3 and 39 years respectively are referred to more briefly (Table 1). In the subsequent section the clinical history of each case is followed by a summary of the localization of the pathological process. As a general indication, the areas most affected are illustrated in Figs. 1 and 2. They include the anterior part of the temporal lobe, the uncus and the amygdaloid nucleus, the hippocampus and dentate fascia, the insula and the parahippocampal, posterior orbital and cingular gyri. The damage is always bilateral but is usually more severe on one or the other side; at times the destruction spreads into the adjacent parts of the temporal, frontal and parietal lobes. The pathological process itself was studied in frozen and paraffin or nitrocellulose embedded sections stained by a variety of neuropathological techniques. It was essentially the same in all cases. It is therefore outlined at this point as a general statement and will only be referred to again in the subsequent individual reports when considered aberrant or essential. The process displayed the typical reaction of nervous tissue in the later stages of a 'necrotizing encephalitis'. In this the grey, and to a lesser extent, the white matter bordering areas of total loss of substance are scarred and may be inflamed. Perivascular infiltration by lymphocytes and fat phagocytes is sometimes marked and is usually accompanied by extensive neuronal loss, scattered microglial nodules and a more or less dense fibrous gliosis (Fig. 3). Loss of myelinated

INTRODUCTION There have been many reports during the last 35 years of an acute necrotizing encephalitis thought to be due to herpes simplex virus which selectively affects the limbic areas of the brain and the anterior parts of the temporal lobes. In the early stages the illness presents as an acute infection and occasionally even as a neurosurgical emergency. The outlook is then grave and death in the acute stage is common. Occasionally, however, the patient survives and is left severely incapacitated for months or even many years. In these circumstances the clinical picture takes on a psychiatric colouring: disorders of memory, of behaviour and of affect become prominent and some patients are stuporose, speechless or demented (Rose & Symonds, 1960; Friedman & Allen, 1969; Gascon & Gilles, 1973; Malamud & Hirano, 1974). In contrast, neurological signs are relatively slight or may be absent. Although uncommon, the condition deserves wider recognition. CASE MATERIAL The present report is a clinical and neuropathological study of 8 patients in whom the illness with its effects lasted up to 17 years; 2 further 1 Address for correspondence: Dr R. Hierons, Department of Neurology, Brook General Hospital, Shooters Hill Road, London SE18 4LW.

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Table 1. Sex, duration of illness and age at death

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

Case no.

Sex

Age at death (years)

MH.2505 MH.5857 RH.28/64 RH.213/73 RH.37/66 RH.234/70 RH.191/68 RH.9/72 BH.N4/76 MH.81/77

M M M F F F F F F M

39 49 53 63 28 25 33 67 27 39

Duration of illness (years) 2 3 3 17 * 16 1

4 From infancy

nerve fibres is severe in the gliosed zones between the absent and the surviving brain tissue. No inclusion bodies were identified in the present cases either within the nucleus or within the cytoplasm using both light and electron microscopy. Case 1 (MH.2505) A 37-year-old Englishman working in Canada was found confused one night in June 1961. In hospital he uttered a few inappropriate words. He had a fever of 38-8 °C and an indefinite right extensor plantar response. The CSF pressure was raised to 220 mm, the protein content was 0-85 g/1 and there were 180 white cells (90% lymphocytes) and 38 red cells per cmm. The sugar content was 3-2 meq/1. The EEG was markedly disturbed over the left side, with phase reversals of slow waves in the left temporal region. A less marked but similar abnormality was present over the right side. On biopsy purplish necrotic brain was aspirated in which there were haemorrhages, scattered polymorphs and histiocytes. A culture for bacteria was sterile. With the arrival of the man's sister from England it became known that the patient had begun to suffer from 2 or 3 convulsions a year at the age of 22. He had described the seizures as beginning with tingling in the fingers of both hands and lips, and a dry sensation in the throat, followed by a feeling of impending disaster. They occasionally awakened him from sleep. Examination in 1957 revealed no abnormal signs apart from a slight right-sided deafness, and several EEG recordings showed only an excess of theta

activity bilaterally. There was no family history of epilepsy. The level of consciousness gradually improved but the patient remained dysphasic, demented and incontinent. There was a mild right hemiparesis. He was returned to a hospital in London after 4 months. Apart from phrases like 'thank you' and 'that's better', he spoke unintelligible jargon and appeared not to understand simple questions. Most of the time he spent sitting motionless but if persuaded he could manage to walk. He smiled inappropriately, was often incontinent and needed to be fed, washed and dressed. He sucked his fingers for hours on end, and often put a blanket or some other object into his mouth. He was bad tempered when being shaved but showed no other emotional response even to his parents or friends. He would drink a cup of tea or eat an apple if they were put into his hand. He had a good appetite. Before the illness he had been a vegetarian but he would now eat anything. He slept normally. On examination a right homonymous hemianopia was suspected and signs of a mild right hemiparesis was found. It was doubtful whether he recognized familiar faces but he responded to speech and recognized his Christian name. Lumbar puncture 6 months after onset revealed a protein level of 1 -1 g/1,4 lymphocytes per cmm and a Lange curve of 5555321000. Air studies showed the third and lateral ventricles to be enlarged with greatly dilated temporal horns. The jargon dysphasia persisted. He remained doubly incontinent and unable to look after himself. He repeatedly rolled his tongue and beat his chest. A month before he died a series of epileptic fits occurred. Two years after the onset of the acute illness he died of a pulmonary embolism. All other pathological findings were confined to the nervous system. Brain-Localization of the pathological process Both temporal lobes were extensively damaged (Fig. 1 a). On the left, no part of the 3 temporal gyri, the fusiform gyrus and the amygdaloid nucleus could be identified. The hippocampus was represented by a scarred band in which only a few nerve cells had survived in the dentate fascia. The body of the fornix was demyelinated (Fig. 4). On the right side, at the rostral level of the uncus, no cortex or amygdaloid nucleus

The late effects oflimbic encephalitis in man

FIG. 1. Basal view of the cerebral hemispheres, (a) Case 1, (6) Case 3, (e) Case 4, (d) Case 5. The extent of destruction of the temporal lobes is varied and the 2 sides are unevenly affected. All photographs x i approximately.

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Fio. 2. Coronal slices at two levels through the cerebral hemispheres, (a), (6) Case 3; (c), (d) Case 4; (e), (/) Case 5. Note the destruction of the medial temporal regions and the insula in all three cases. The damage is most severe in (£)> (/) - Case 5 - where the cingular gyri and the middle and inferior temporal gyri on the right are also involved. Reduced x $ approximately.

The late effects oflimbic encephalitis in man

FIG. 3. (a) Case 7. Inflammatory reaction with gliosis and patchy destruction of the fusiform and parahippocampal gyri and in the hippocampus. Note also that the temporal horn of the lateral ventricle is dilated. Nissl, x 2-5. (6) Case 5. Swollen astrocytes in the border of complete destruction and lymphocytes and macrophages in the wall of the vessel. Haematoxylin Van Gieson, x 290. (c) Case 5. Low power view of the cavitated cortex with intense astrocytic gliosis deep to it. Haematoxylin Van Gieson, x 10. (d) Case 3. Round cell perivascular cuff in the white matter. Nissl, x290.

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could be seen (Fig. 5). More posteriorly, the gyri on the convexity and on the infero-lateral surface were spared. The parahippocampal gyrus, however, had been destroyed and the neuronal loss in the hippocampus was almost complete (Fig. 6). The right fimbria and the fornix were shrunken, with a few myelinated fibres surviving in the medial third of the latter (Fig. 4). In the cingular cortex on both sides there was considerable glial proliferation and nodule formation with slight cuffing. Neuronal loss was not severe but the sub-cortical white matter in the region of the cingulum was heavily gliotic. The posterior orbital cortex of both frontal lobes was necrotic, the lesions being confluent with the equally necrotic insular and temporal cortex. The frontal convexities showed only the mildest inflammatory reaction and the neuronal population was not apparently reduced. In the left hemisphere the necrosis had spread from the temporal surface back into the adjacent parietal and occipital convexity, the supramarginal gyrus being largely destroyed. More posteriorly the inferomedial cortex of the occipital lobe including the striate cortex was partly necrotic. The right parietal and occipital lobes were scarcely affected showing only a few glial nodules in the cortex. The left optic tract lay in a necrotic patch and showed an almost complete loss of nerve fibres. Intense neuronal loss and glial proliferation

FIG. 4. Case 1. Loss of myelin in the fornices and in the left medial thalamus. Luxol fast blue/Nissl, x 8.

affected the left lateral geniculate body while the left striate area, as mentioned above, was partly necrotic. The right optic pathways were intact; the integrity of the geniculate body on this side compared with the left is illustrated in Fig. la and b. In both corpora striata the ventral parts of the putamina were necrotic; the rest of the lentiform and of the caudate nuclei was preserved. The dorso-medial nuclei of the thalamus showed an intense inflammatory reaction and gliosis, with a streak of infarction on the left (Figs. 4, 8). Both anterior nuclei were shrunken and gliotic, the left more than the right. Only a slight patchy neuronal loss and gliosis was found in the lateral nuclear masses. In the hypothalamus both anterior columns of the fornix were lacking in myelin and heavily gliotic as they approached the mamillary bodies. These were both shrunken, and gliotic with a few cuffed vessels. Neuronal loss seemed slight. Similar but milder changes were scattered through the adjacent hypothalamic and subthalamic regions. The mid-brain showed mild cuffing and gliosis; the nerve cells of the substantia nigra were well preserved. There was a slight loss of myelin with gliosis in the lateral fifth of both cerebral peduncles. The pons, medulla and cerebellum were relatively unaffected with no more than a slight astroglial increase.

FIG. 5. Case 1. Right hemisphere - no temporal cortex or amygdaloid nucleus have remained. Luxol fast blue/Nissl, reduced x i approximately.

The late effects oflimbic encephalitis in man

Case 2 (MH.5857) A 46-year-old man developed pain behind the eyes and dizziness. A few days later he complained of nausea, anorexia and slight pyrexia. In the next 10 days he became unsteady on his feet, his hands were clumsy, his speech was slurred; later he developed diplopia and drowsiness. When admitted to hospital 2 weeks after the onset, he was confused and only able to answer simple questions. His temperature was 39-4 °C; he had a stiff neck. Both lateral rectus muscles were a little weak; mild cerebellar ataxia was more marked in the lower limbs than in the arms. The CSF contained 90 lymphocytes per cmm with a protein content of 0-38 g/1. The EEG showed a normal alpha rhythm with irregular 4-7 c/s in all areas and occasional high voltage slow waves at 2 c/s in both posterior temporal regions, but more marked on the right. He had frequent hiccups and over the course of a few days became stuporose responding only to painful stimuli. He ran an intermittent fever

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FIG. 7. Case 1. (a) Left lateral geniculate body showing gliosis and loss of distinction between the layers of nerve cells. (6) Normal-looking right lateral geniculate body. Nissl, xl4.

during the first 10 days in the hospital; the pulse rate persisted at about 140 for some months after the temperature had returned to normal. His level of consciousness improved but he remained restless and confused. A month after the onset he began to speak again; he was depressed and often noisy at night. He could do the 100 minus 7 test and simple money sums, but could retain neither the day, month, year, nor his present whereabouts for more than a minute. He was able to walk when helped. Initially his visual fields were full to confrontation and the optic discs were normal. The day after admission, however, he developed a small linear haemorrhage on the left sclera and later small haemorrhages on the floor of the mouth and one small ulcer on the tongue. He also

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FIG. 8. Case 1. Gliosis and patchy loss of nerve cells in the medial part of the left thalamus. The ependyma is on the left and a glial nodule is seen left of centre. Nissl, x 30.

developed several retinal haemorrhages and the disc margins became indistinct. After recovery from stupor he was totally blind with fixed dilated pupils and it became difficult to see the optic discs as the vitreous was filled with inflammatory exudate. Large patches of retinae, particularly around the periphery, were grey and bloodless. In other areas the red reflex of choroid could be made out, suggesting surviving retinal tissue. Towards the posterior pole there were patches of haemorrhage irregularly distributed; the retina did not appear elevated by choroidal exudate. Slit lamp examination showed no cells or flare in the anterior chamber and the retrolental space was clear. The iris and the ciliary body did not appear inflamed and it was considered that the uveal involvement was secondary; the ocular condition was attributed to an arteritis. There was defective conjugate gaze laterally and upwards. The right side of the face moved slightly less than the left. There was no detectable weakness of the limbs but the tendon reflexes were slightly brisker on the right. Both

plantar responses were extensor and slight ataxia was present on the heel-shin test bilaterally. During the first month he was treated with steroids without apparent benefit. In the sixth week the CSF cell count had fallen to 9 lymphocytes per cmm and the protein content was 0-51 g/1 with a moderate increase of globulin. The EEG showed a diffuse abnormality which was less marked than in the earlier records. Three months after the onset an air study revealed moderate ventricular dilatation with some excess of air over the cortical surface. After a few months the condition stabilized. He complained constantly of the cold and of aching pains. He knew that he was blind. He could do simple mental arithmetic and could converse on simple subjects sensibly and clearly. He could not retain a new fact for more than a minute, and had complete amnesia for the previous 15 years; he could not remember being married or having children. He had a fair knowledge of events that took place in the distant past but a patchy memory loss extended back to childhood. His personal habits were normal; he was able to feed and dress himself. Neurological examination, apart from blindness, was without abnormality; he could distinguish test odours in either nostril. He developed lens opacities but his condition remained otherwise unchanged. He spent the next few years partly at home, where he was unable to find his way about, and partly in a psychiatric hospital. He remained unable to store the simplest fact for a minute. He believed that his age was 36 instead of 48. He was often depressed and made many bizarre suicidal attempts, usually by throwing himself from a chair or hitting his head on the wall. He enjoyed his food. Three years after the onset of his illness he fell out of bed, banged his head and lapsed into coma. He died the following day with bronchopneumonia. Other significant pathological findings were confined to the central nervous system. Brain-Localization of the pathological process The fixed brain was small, weighing only 985 g. A long-standing necrotizing encephalitis has destroyed the anterior and medial parts of both temporal lobes (left side illustrated in Fig. 9 a) with almost total bilateral disruption of the unci, amygdaloid nuclei, hippocampi, para-

The late effects oflimbic encephalitis in man

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glial nodules. The remainder of the frontal and parietal lobes appeared unaffected. There was some patchy scarring in the cortical ribbon of parts of the occipital lobe. The striatum and pallidum were intact while the thalamus and hypothalamus contained patches of microglial and astrocytic gliosis and scattered particles of calcium. Similar patchy gliosis was seen in the mid-brain, pontine tegmentum, superior cerebellar peduncles and medulla. There was mild generalized proliferation of Bergmann glia in the cerebellum with some Purkyne cell loss in the tonsils.

(c) FIG. 9. (a) Case 2, (6) Case 4, (c) Case 5. Temporal lobe and basal ganglia. Note dilated temporal horn of the lateral ventricle and destruction of the medial temporal regions. Heidenhain/Woelcke, approximately natural size.

hippocampal gyri and fusiform gyri, while the more posterior parts of the 3 temporal gyri were soft and shrunken. The inferior horns of the lateral ventricles were dilated and their floor was reduced to a thin remnant of gliotic cortex covered by fibrous leptomeningeal tissue containing some perivascular infiltration. The damage extended into the claustrum and insula and towards the cingular gyri which were not necrotic but contained cuffs of lymphocytes and

Case 3 (RH.28/64) A leather dyer aged 50 had always been healthy apart from attacks of psoriasis. His mother was said to have had multiple sclerosis. For about 2 years he had had occasional severe and incapacitating headaches without vomiting. In April 1961 he was bitten by an adder on the left thumb. He went to a local hospital with a swollen hand. He was given 10 ml of antivenom serum and 150 units of hyaluronidase and was detained overnight. Afterwards he drove back to London, went to a football match and on the next day he resumed work. Five days later he complained of headache and during the night he sweated profusely. The next morning he was drowsy and confused and was admitted to hospital. His temperature was 38 °C and he had a fine erythematous rash. He became more confused and was pyrexial for the first 2 weeks. Both plantar responses were extensor. The CSF contained 160 cells per cmm, mainly lymphocytes, the protein content was 0-8 g/1 and the Lange curve 1232211000. The ESR was 27 mm in one hour. He remained confused and disoriented and he tended to confabulate. A month after admission the CSF contained 194 white cells per cmm (62% lymphocytes, 37% polymorphs), protein 1-6 g/1 and Lange curve 444433221. The WR was negative in the cerebrospinal fluid and in the blood. Two weeks later the CSF white cell count had fallen to 32 per cmm while the protein was 1-2 g/1; the paretic Lange curve persisted. Occasionally he was aggressive and after 2 months he was transferred to a psychiatric hospital. He could now play cards, draughts and table tennis; he was aware of being in a hospital but

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was never able to remember the date or the place. He had a severe amnesia for the previous 16 years. He tended to get lost and could not find his way to the toilet. His mood was flat; he often looked bewildered. He would collect in his pockets any small objects left lying about and if these were taken from him would say that they had been given to him or that he had bought them. He tended to meddle with things like flower pots, cups and saucers and toilet rolls. There was never any indiscriminate tendency to put objects into his mouth, but he had an extremely good appetite and gained about 20 kg in weight. He complained constantly about the cold even on a hot summer's day (as did Case 2) and he appeared to be hypersensitive to touch all over the body: even a reassuring hand on his shoulder might cause him to complain of pain. He sometimes had difficulty in recognizing familiar faces asking a ward orderly, for example, whether he was his father. At other times he could recognize old friends but it is not clear whether he recognized them from their faces or their voices. Psychological tests revealed a verbal IQ of 114 but the performance score was reduced to 87. On verbal subtests for comprehension and arithmetic he maintained a high level but he had considerable difficulty with digit symbols, picture arrangement, object assembly and block design tests. An EEG a month after the onset showed no significant abnormality but after 6 months there was a medium voltage alpha rhythm of about 10 c/s dominant in the post central areas, with paroxysms of mixed higher voltage slow components and sharp elements present symmetrically throughout both hemispheres but with greater amplitude in the frontal regions. Three years later the record was reported as having returned to normal. A year after the onset he began to suffer from attacks of sudden loss of consciousness lasting a minute or two, during which he would appear pale, often fall to the ground and occasionally sustain minor injuries. The slightly elevated cerebrospinal fluid protein persisted (0-7 g/1). Three years after the onset he developed status epilepticus, followed by a right hemiparesis and he died after a few days from broncho-pneumonia. Significant pathological

findings were confined to the central nervous system. Brain-Localization of the pathological process The brain weighed 1300 g. In both temporal lobes the uncus, the amygdaloid nucleus, the hippocampus, the parahippocampal gyrus and parts of the fusiform gyrus were absent or necrotic, the loss of tissue extending for 7 cm back from the temporal poles (Figs. \b,2a and b, 10). The insular cortex, the infero-medial cortical areas of both frontal lobes and the anterior part of the cingular gyrus were necrotic (Fig. 11). Both mamillary bodies were shrunken. Both lateral ventricles, and particularly the inferior horns, were enlarged. The bodies and the anterior columns of the fornices were grey and shrunken. No other abnormalities were noted in the cerebral hemispheres, apart from a slight generalized dilatation of the sulci. The brainstem and the cerebellum appeared normal.

_ < • • • .

(a)

FIG. 10. Case 3. Destruction of the medial parts of the right temporal lobe, (a) Nissl, (b) Heidenhain/Woelcke.

The late effects oflimbic encephalitis in man

FIG. 11. Case 3. Necrosis and gliosis in the cortex and white matter of the right cingular gyrus. Nissl, x 20.

Case 4 (RH.213/73) The clinical features of the first few years of this women's illness were described by Rose & Symonds (Case 3) in 1960. The disease began when she was aged 46 years. For a year she had complained of severe headaches every few days. In May 1956 she awoke feeling unwell with a temperature of 39-4 °C but recovered after a few days. A month later a similar febrile illness occurred and again she recovered; after a further month a third episode of fever was followed by confusion and delirium. On admission to hospital she was drowsy and delirious with a slight evening temperature. The CSF was under a normal pressure with a marked pleocytosis - 245 white cells per cmm (59% polymorphs, 4 1 % lymphocytes) and 0-9 g/1 of protein. The Lange curve was normal and the fluid was sterile on culture. A few days later the CSF had a faintly yellow tinge and contained 700 lymphocytes per cmm with a protein content of 4 0 g/1. Her mental state varied from inaccessibility to overactivity and after 2 weeks she was transferred

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to a psychiatric hospital. She was confused, disoriented and restless. She could recognize her husband but not other people whom she had known well. Several weeks later the cerebrospinal fluid was normal apart from a protein content of 0-75 g/1. She sat most of the time in silence and would answer questions with ' I don't know'. She had persistent anorexia, occasionally she vomited. She was unable to recognize family photographs. When taken for a drive she was very frightened of the speed even though the car was going slowly. She returned home after 9 months and spent most of the time in bed; she was very irritable. At first she did not seem to recognize her own home. Gradually she became able to knit again and play the piano from a score; she could wash dishes and cook a meal. In February 1957, there was a further episode of vomiting which continued for 3 days and she was readmitted to hospital. She was quiet and uncooperative and again no physical signs were found. The cerebrospinal fluid contained 9 lymphocytes per cmm and 0-65 g/1 of protein. Her state ranged from aggressive silence to rude behaviour of fulsome sentiment. During occasional weekends at home she did not recongize friends and she was apathetic. She had a good appetite and put on weight. The EEG was normal. She was transferred to a neurological hospital in September 1957, and again no abnormal neurological signs were found. She could distinguish test odours but could not name them. She was withdrawn, often uncooperative and antagonistic. She described events of her childhood, school and her work before marriage. There was a dense retrograde amnesia of approximately 20 years but at no time was there any tendency to confabulate. She could give the dates of the First World War but was unaware of the Second; she could repeat 6 digits forwards and 3 backwards at the first attempt but she refused to cooperate further. A number of mistakes was made in the 100 minus 7 test and she was extremely poor at similarities and proverbs. She could not retain simple facts for a minute. Under intravenous pentothal she answered questions. She was able to elaborate on her early life but her memory of the previous 30 years was extremely sketchy. She admitted that her memory

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had gone and she repeatedly said that she felt lost. An air encephalogram showed the left lateral ventricle to be more dilated than the right together with the anterior parts of both temporal horns. The CSF was normal except for a mildly paretic Lange curve. The EEG was within normal limits. She spent the next 13 years in psychiatric hospitals in which she was" solitary, withdrawn and often suspicious. Her memory remained severely impaired; she could not remember that her husband had died and often did not recognize her children. She only spoke when spoken to and had no spontaneous conversation. Her appetite was excessive and she took food from other patients' plates. She hoarded paper. Often during the day she undressed and got into bed. During the last few years of life she developed signs of congestive heart failure. Some months before death she developed a transient weakness of the left hand. She died aged 63, 17 years after the onset of the illness. No significant abnormalities, apart from broncho-pneumonia, were found outside the nervous system.

globus pallidus and the optic tract were normal. The cingular gyrus appeared normal. On the right side the damage was similar but less extensive, no amygdaloid nucleus, uncus or medial temporal structures having survived. The white matter of the superior, middle, and part of the inferior temporal gyri was grey. The inferior half of the insula was partly necrotic but the frontal lobe appeared normal. Both fornices were thin. Posteriorly, parts of the temporal gyri on both sides were preserved. The cingular gyri were intact. There was slight scarring in the right thalamus just lateral to the wall of the third ventricle. No further abnormalities were noted in the brainstem; the presence of a wedge-shaped area of recent haemorrhagic infarction in the cerebellum was confirmed.

Case 5 (RH.37/66) (Previously referred to by Heathfield et al. 1967) A schoolmistress aged 28 enjoyed excellent health until September 1967, when she developed headache, vomiting and a fever of 40 °C. When admitted to hospital 2 days later she was drowsy, irrational and she had a stiff neck. Examination of the CSF revealed a raised Brain-Localization of the pathological process pressure, no excess of cells; the protein content The fixed brain weighed 1077 g and was small. was 065 g/1. The fluid was sterile. Two days The leptomeninges over both convexities were later the fluid was cloudy with 180 white cells per slightly thickened and there was a generalized cmm (95% lymphocytes) and 0-55 g/1 of protein. slight widening of sulci. The striking abnormality Coxsackie B5 virus was cultured from the CSF was the virtual disappearance of the anterior but the level of neutralizing antibody in the serum parts of both temporal lobes (Figs. 1 c, 2c and d, during the course of the illness was not measured. and 9 b), the left temporal pole being reduced to An intermittent pyrexia continued for 2 weeks. a collapsed bag of thickened leptomeninges, During this time she became more responsive and whereas the left occipital lobe was intact. On the would look around when roused. She did not right side the distribution of the lesion in the speak or understand and failed to respond to medial temporal region was similar but only the people that she knew. There was weakness of the most anterior parts of the temporal gyri were left arm and leg, associated with slightly brisker destroyed. Both mamillary bodies were small. reflexes; both plantar responses were extensor. The aqueduct was slightly widened and the pons A week after admission the EEG showed a and medulla oblongata were normal. There was grossly asymmetrical record with almost coma patch of dark brown discoloration in the plete absence of activity on the right. A week leptomeninges, measuring about 1-5 cm across, later it revealed irregular slow activity of low in the left peritonsillar region of the cerebellum. amplitude, although the asymmetry was less Slicing of the brain at anterior levels confirmed marked. Occasional sharp waves were present in that on the left side almost the entire temporal the right temporal area. The highest white cell lobe was missing or necrotic with only a remnant count in the blood was 12600 per cmm and the of the superior temporal gyrus. The inferior ESR was 47 mm in one hour. Three weeks after the onset she deteriorated third of the insula and the amygdaloid nucleus were also necrotic and scarred. The putamen and with cyanosis and Cheyne-Stokes breathing so

The late effects oflimbic encephalitis in man that a tracheostomy and ventilation were necessary. She remained semiconscious and died 4 months after she had been first taken ill. No significant extra-cerebral abnormalities were found. Brain-localization of the pathological process The fixed brain weighed 1065 g. The right temporal lobe was soft and necrotic, consisting at the pole of a sac of thickened leptomeninges (Fig. Id). The superior, middle and inferior temporal gyri were partly spared but the uncus, the amygdaloid nucleus and hippocampus, the parahippocampal gyrus and the fusiform gyrus had been almost totally destroyed (Figs. 2e and/, and 9 c). The infero-medial gyri of the left temporal lobe were similarly affected but the 3 temporal gyri were much less affected than on the right. The necrosis had spread into the depths of the lateral fissures destroying the insula, claustrum and adjacent edge of the putamen on both sides. Anteriorly the posterior orbital cortex and subcallosal gyri were disintegrating while the cingular gyrus was necrotic back to the level of the splenium of the corpus callosum. The almost complete sparing of the frontal cortex on the convexity as well as all surfaces of the parietal and occipital lobes was striking. Both fornices and both mamillary bodies were brown and shrunken, more noticeably on the right. A few small cysts were present in the medial halves of both thalami. The substantia nigra was well pigmented and no further abnormality was found elsewhere in the brainstem or cerebellum. Case 6 (RH.234/70) The patient was a healthy girl until the age of 9 when she developed an upper respiratory infection with mild fever, listlessness and drowsiness. She improved and seemed well for some days until several generalized convulsions occurred. She was admitted to hospital in a state of coma with frequent seizures. The temperature was 38-8 °C. After the fits had subsided she did not move the left arm and leg as well as her right limbs. Examination of the CSF revealed a slightly turbid fluid containing 820 red cells and 364 white cells per cmm (16% polymorphs, 84% lymphocytes). The EEG revealed a marked abnormality over the right temporal area. The

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question of a cerebral abscess was raised and she was transferred to a neurosurgical unit. There was marked neck stiffness and a positive Kernig's sign. The retinal veins were engorged. The right side of the body moved briskly to painful stimuli but there were only very feeble movements on the left. Both plantar responses were extensor. X-rays of the skull showed no abnormalities. Air ventriculography showed the lateral ventricles to be displaced to the left and the anterior end of the third ventricle tilted to the left. A second ventriculogram a few days later showed an enlarged right temporal horn. Needling of the brain failed to reveal pus but soft, necrotic cortex herniated from the right temporal burrhole. Seven weeks after the onset, the EEG was grossly abnormal with high voltage slow waves and faster abnormal wave complexes on the right. Recordings from both temporal lobes were flat. Two months after the illness began she was mute, inaccessible and incontinent, with leftsided weakness. She lived for the next 16 years in a hospital for the mentally handicapped. During these years she was noisy, hyperactive, destructive and doubly incontinent. She tended to grasp any article and put it in her mouth; she chewed her clothes and seemed unable to recognize common objects. She watched TV, but was restless, at times aggressive and liable to temper tantrums. Occasionally she dressed herself but she needed almost constant supervision. The left hemiparesis remained; she was liable to generalized seizures. She died, aged 25, after a series of convulsions, and 16 years after her acute illness. Brain-Localization of the pathological process The fixed brain weighed 910 g. In the right hemisphere, which was smaller than the left, the temporal lobe was reduced to a thick, fibrous layer with scarred remnants of uncus, hippocampus and parahippocampal gyrus. There was also extensive destruction of the frontal and occipital lobes affecting the cortex and white matter. On the left side the ventro-lateral part of the temporal lobe, insula and frontal operculum were shrunken. The uncus was scarred but the posterior part of the hippocampus looked normal. PSM 8

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R. Hierons, I. Janota and J. A. N. Corsellis

simplex were detected at a titre of 1/1260 with neutralizing antibody titre of 1/320. Over the remaining 4 months she gradually deteriorated to a state of 'akinetic mutism'. She would follow with her eyes what went on around her. Uncomfortable stimuli led to her mumbling incoherently. Her jaw remained tightly clenched; all 4 limbs were rigid and there was a tremor of the left arm during attempts to move it. The tendon reflexes were difficult to elicit; the left plantar response was extensor and at times there were bilateral grasp reflexes. She only responded to loud stimuli by opening her eyes. There was no blink to menace; the optic discs were pale. Case 7 (RH.191/68) The neck was stiff. Bilateral facial weakness This woman had been healthy until the age of 32 seemed to be present and the jaw jerk was brisk. years. One night she became noisy and was Tone was increased in both arms and in the right found unconscious, frothing at the mouth and leg, while the left leg was flaccid with a sluggish incontinent. After admission to hospital she knee jerk; other tendon reflexes were brisk and recovered consciousness within a few hours and both plantar responses were extensor. She reno abnormal physical signs were found. The acted to pin prick over both sides of the body, CSF contained 0-8 g/1 of protein with no increase and to tendon pressure, by grimacing. The in cells. She was discharged after 3 weeks and muscles of the left side of the face and of the left seemed well until a second attack of unconscious- arm twitched almost continuously. ness 7 months later. The blood chemistry, haematology and seroOn admission she was drowsy and confused. logy were normal apart from an ESR of 23 mm For a few days she had a pyrexia up to 37-7 °C in one hour. The CSF contained 100 lymphocytes and a slight left-sided weakness. Tests of co- per cmm, and 0-65 g/1 of protein; bacteriological ordination were poorly performed, more especi- examinations of the fluid were negative. ally on the left. Examination of the CSF showed The EEG showed irregular theta and delta a protein content of 0-7 g/1 with 5 lymphocytes waves of low voltage in the fronto-central and 20 red cells per cmm. The EEG showed a regions. At times the delta activity was focal in poorly developed alpha rhythm disturbed in the the left anterior quadrant. The alpha rhythm was right parietal area by irregular slow activity. variable and better seen on the left side; auditory A cerebral abscess was suspected and she was stimulation produced no response. A gamma transferred to a neurosurgical unit. She was scan revealed a large, ill-defined area of irreguconscious and tried to cooperate but she was larly increased uptake centred in the right confused and disoriented. Apart from slight temporo-parietal region involving most of the incoordination of all 4 limbs there were no right hemisphere. Ventriculography showed neurological abnormalities. dilatation of the temporal horns, probably due Radiological investigations, including a brain to atrophy. The ventricular CSF contained 5000 scan and a right carotid angiogram, were normal. red cells, 35 lymphocytes, 8 polymorphs per She had occasional seizures involving mainly the cmm and 0-9 g/1 of protein. The Pandy reaction left side. Gradually she stopped speaking; tone was positive and the Lange curve was was increased in all 4 limbs. She had an inter- 5555432100. mittent pyrexia of 38-8 °C but this may have been Ten months after the onset the protein level in related to an indwelling catheter with urinary the lumbar CSF was 1-3 g/1 with increased infection. The CSF protein fell to 0-4 g/1. globulin but no excess of white cells. Her conNine months after the onset she was cheerful dition remained unchanged until shortly before and friendly; she knew the name of the hospital she died, 13 months after the onset. Virological but was disoriented in time. She became sus- studies on post mortem brain tissue were picious. Complement fixing antibodies to herpes negative.

The corpus callosum was thinned to 1-2 mm. The deep grey matter on both sides was relatively well preserved. The fornices were thin and grey. The aqueduct was patent. The substantia nigra was normally pigmented. The right basis pedunculi was atrophied and the right basis pontis and pyramid were much smaller than the left. There was a marked atrophy of the whole of the left cerebellar hemisphere, presumably secondary to the damage of the right cerebral hemisphere.

The late effects oflimbic encephalitis in man Brain-Localization of the pathological process The right and, to a slightly lesser extent, the left temporal lobes were reduced to cysts (Figs. 3 a and 12), which were lined by thin yellow tough leptomeninges, and extended posteriorly along the fusiform gyri to the level of the pineal gland. There was a cystic softening of the right gyrus rectus. The posterior part of the right paraolfactory gyrus was thin and yellow, as were the cortex of the insula and the white matter deep to it. There were patchy yellow, partly cystic lesions in the right superior and middle temporal convolutions and smaller lesions in the fusiform and parahippocampal gyrus anteriorly. A few minute cortical infarcts were present in the occipital lobe. The right mamillary body was yellow. Similar but less widespread lesions were present in the left hemisphere. They were most marked in the fusiform gyrus but involved the posterior orbital gyri, the amygdala, the superior, middle and inferior temporal gyri, and quite extensively the gyri of the posterior part of the parietal lobe. Small lesions were also present in

FIG. 12. Case 7. Basal view of the cerebral hemispheres. Note selective destruction of the medial temporal regions. Reduced x \ approximately.

35

the occipital lobe; none was recognized in the brainstem or cerebellum. Case 8 (RH.9/72) This patient, a retired social worker aged 63, was admitted to hospital in 1968. Some days before admission she had developed a high temperature and had become confused. She was restless, her speech was incoherent and she constantly muttered to herself. Apart from a temperature of 38-5 °C there were no other abnormal signs. X-rays of the skull and chest, blood count, ESR, examination of the urine, blood electrolytes and CSF did not reveal any abnormality. The EEG was polyrhythmic with a wide range of different frequencies: alpha components at 8, 10 and 12 c/s were present and slow activity was evident over both hemispheres but difficult to assess due to a great deal of artefact. Runs of intermediate slow waves, and sharp and slow wave complexes occurred periodically at 3-5 second intervals. A further examination of the CSF 6 days later revealed a normal pressure with a protein content of 0-35 g/1 and a positive globulin reaction. She was transferred to a neurosurgical unit. Both plantar responses were extensor. Ventriculography was normal. A week later the lumbar CSF contained 4 lymphocytes per cmm and the protein content was raised to 0-8 g/1. She gradually deteriorated and spent the rest of her life in a mental hospital. She was dysphasic, occasionally noisy and always confused; she was incontinent and often restless; she regressed to an infantile-like state. The EEG 5 months after the onset showed a prominent alpha rhythm at about 8 c/s but of greater amplitude on the right. No mention was made of her putting objects in her mouth. Only on isolated occasions was she able to feed herself. She died 4 years after the illness began. Brain-Localization of the pathological process The brain weighed 1270 g after fixation. The striking finding was the bilateral necrosis and virtual disappearance of 5-6 cm of the anteromedial parts of both temporal lobes, the remnants of which were covered by thick grey-white leptomeninges. The lateral fissure was exposed on both sides. The necrosis ran obliquely from the antero-lateral part of the temporal lobe back towards the parahippocampal gyrus. 3-2

36

R. Hierons, I. Janota and J. A. N. Corsellis

Coronal slices showed enlargement of both anterior horns of the lateral ventricles. The orbito-medial cortex was necrotic. At the level of the lamina terminalis there was necrosis of the ventral part of the pallidum on the right. The optic nerves did not appear affected. The anterior parts of both temporal lobes had been destroyed. More posteriorly there was marked necrosis of both medial temporal areas, including hippocampi, parahippocampal gyri and fusiform gyri. The temporal convexity, as well as the frontal, parietal and occipital lobes were spared. The corpus callosum was of normal thickness and neither it nor the cingular gyri appeared necrotic. The aqueduct in the midbrain was slightly dilated, the substantia nigra was well pigmented. The pons, medulla oblongata and cerebellum looked normal. The neurohistological features were similar to those seen in the previous cases. Case 9 (BH.N4/76) This 24-year-old woman became unwell and confused and had 3 seizures late in her first pregnancy. After 6 days she was taken to hospital. She continued having seizures and had a temperature of 38-8 °C. The CSF contained 0-77 g/1 of protein and no cells. A titre to herpes simplex antibodies rose from 1/256 to 1/1024. She became stuporose and while in stupor she gave birth to a normal child. About 4 weeks after the onset of her symptoms she recovered consciousness and began to scream. Three months later she was admitted to a mental hospital behaving like a baby. She would spit and would put objects, including rubbish off the floor, into her mouth. She kissed other patients indiscriminately and swore and threw things about. She improved when visited by her mother and her husband with whom she played cards. After 9 months she could sometimes help with washing up; her appetite was very good. An examination by a neurologist revealed no dysphasia, dyslexia or dysgraphia. She pried into everything within reach. There was a severe defect of recent memory and she was unable to repeat even 4 digits. She had a retrograde amnesia for several years. She denied having had a child; she signed her maiden name and said that she was 14 years old. After a year she was taken to live with her parents, and her condition did not change; she had occasional epileptic

fits and she died of broncho-pneumonia 3^ years after the onset of her illness. Brain-Localization of the pathological process There was an almost complete destruction of the temporal lobes on both sides. The damage spread posteriorly along the under surface of the lobes, involving the inferior and middle temporal gyri and sparing only the superior temporal gyri. The amygdaloid nuclei and the medial temporal gyri including the hippocampi were completely destroyed. Both fornices were thin and grey and the mamillary bodies were shrunken. The insular cortex on both sides was completely destroyed with the damage extending into the claustrum and the anterior tip of the Sylvian fissure. The cingulate gyri were lightly scarred posteriorly, whereas more anteriorly they had been reduced to a spongy fibrous strip which merged into similarly affected posterior orbital cortex; the adjacent white matter lying under the corpus striatum was soft and grey on both sides. The olfactory tracts were not identified but the optic nerves and tracts and the lateral geniculate bodies appeared to be well preserved. The remainder of the deep grey matter appeared to be normal apart from some gliosis in the medial parts of the thalami. The brainstem, including the midbrain and cerebellum, was not affected. Case 10 (MH.81/77) This 39-year-old man spent most of his life in a long-stay hospital. His birth and early development were said to have been normal but his mother could not cope with him at home indefinitely and at the age of 4 years he was admitted to an institution as an imbecile. He was often violent; he attacked patients and staff, and broke doors and windows sometimes with his head. He tried to eat things like buttons, pebbles, string, clothing and bed linen. There was some slight improvement in his general state as he grew up, so that from about the age of 15 years he could dress himself. At the age of 36 years his mental age was roughly that of a young child. He continued attacking other patients and staff. He did not speak and he could not feed himself. He died following a fall at the age of 39 years.

The late effects of limbic encephalitis in man Brain-Localization of the pathological process The brain weighed 1369 g. The salient abnormality was an almost total destruction of the anterior half of both temporal lobes, the right side being the more severely affected. The mamillary bodies were small. Slicing showed that the right anterior tip of the temporal lobe was destroyed together with the uncus, amygdaloid nucleus, hippocampus, and parahippocampal gyrus on both sides. Both fornices were wasted. No further lesions were seen in the rest of the cerebral hemispheres, or in the brainstem or cerebellum. Histological examination confirmed the gliosis and loss of nerve cells in the affected gyri. A few perivascular cuffs of round cells were found. DISCUSSION An acute cerebral disorder was identified some 30 years ago which had led to the destruction of both temporal lobes with an emphasis on the limbic parts of the cerebral hemispheres (Haymaker, 1949). The cause was at first obscure but the appearances under the microscope were those of a fulminating inflammatory reaction which was severe enough to lead to the total disintegration of the affected tissue. The disease therefore became known as 'acute necrotizing encephalitis' (van Bogaert etal. 1955). Virological studies in due course established that the condition was commonly associated with the presence of the herpes simplex virus (discussed by Drachman & Adams, 1962). There is still no explanation, however, why this, or any virus should prefer to attack the limbic structures of the brain in such a relatively selective way. The illness itself is not so uncommon. The outlook is usually grave and coma followed by death within a few days or a few weeks is the usual outcome. In such acute cases, the deterioration in the patient is too severe and too rapid for frank disturbances of behaviour and of intellect to become well established. These elements of the illness only dominate the picture if the initial attack is mild enough, or insidious enough, to be survived for months or years. Such long survival, however, would seem to be rare, for although the possibility is mentioned from time to time in the literature only 3 clinicopathological case reports have so far been traced.

37

Previous case reports The first was reported in detail by Friedman & Allen in 1969; the second by Gascon & Gilles in 1973, while Malamud & Hirano outlined a third in 1974. Friedman & Allen described 'complete limbic destruction' in the brain of a man of 50 who had survived an acute cerebral illness for 7 years. The damage had resulted in 'static behaviour abnormalities' described as 'failure of new memory recording, excessive motor activity, loss of sustained goal-directed activity, uninhibited sexual activity, impotence and docility'. Gascon & Gilles had encountered a woman of 26 who had lived for several months after 3 attacks of acute confusion. She had eventually developed an amnesic syndrome reminiscent of the previous case as well as a behavioural syndrome which the authors considered was similar to that reported by Kliiver & Bucy (1938). The neuropathological findings were much the same as those described by Friedman & Allen, and Gascon & Gilles proposed that the combination of a severe disorder of recent memory with the human counterpart of a Kliiver-Bucy syndrome together makes up what might be called 'limbic dementia'. They considered that this condition is prone to develop as a consequence of sub-acute or chronic necrotizing limbic encephalitis. Thirdly, Malamud & Hirano described a man who had lived for 2 years following an acute cerebral infection and whose chronic illness was characterized by marked confusion (memory was not mentioned), combativeness and oral tendencies, 'eating anything which he could lay his hands on'. Again, after death the limbic areas on both sides were found to have been selectively destroyed while, in addition, there had been positive evidence of an infection with herpes simplex. Malamud & Hirano also drew attention to the clinical picture being reminiscent in some ways of the KliiverBucy syndrome. Present cases Aetiology Although the diagnosis of sub-acute or chronic necrotizing encephalitis of the limbic areas had been suspected during life in several of the cases, it was first confirmed in all of them after death. In only two cases (Cases 7 and 9) was there

38

R. Hierons, I. Janota andJ. A. N. Corsellis

serological evidence of a herpes simplex infection. In Cases 1 and 6 a brain biopsy had shown evidence of an acute inflammatory reaction but no virological studies had been made. In Case 3 the encephalitis developed several days after an adder bite and the injection of anti-snake venom serum. It is conceivable that this may have activated a herpes infection but there is no positive evidence of this. Case 5 is curiously anomalous in that Coxsackie B5 virus had once been cultured from the cerebrospinal fluid in the early stages of the illness. The general conclusion is that the distribution of the pathological process makes it reasonable to suspect that most, if not all, the cases reported were the result of an infection with the herpes simplex virus, although in none had this virus been identified. The pattern of damage may be outlined as tending to focus on the anterior and medial parts of the temporal lobes including the uncus, amygdaloid nucleus, hippocampus, fusiform and parahippocampal gyri. The cingular gyrus, insula and posterior orbital frontal cortex, which are included in the limbic territories by Angevine & Yakovlev (1964), were also often involved. Sometimes, as in Cases 1 and 9, the damage extended beyond these areas and in Case 6 the whole of the right hemisphere was heavily scarred. The extent of the damage was always greater on microscopic examination than appeared to the naked eye and histological minutiae like the occasional cuffed vessel or glial star were often found well beyond the borders of the destroyed tissue. Changes secondary to the limbic destruction were frequent in the fornices, with loss of myelin, nerve fibres and with gliosis but in both the mamillary bodies and in the thalamus the changes usually seemed to be a mixture of primary and secondary involvement. Clinico-pathological aspects The role of the temporal lobes, and particularly of their more medial 'limbic' parts, has been discussed for over 150 years. Already in 1820 Treviranus had surmised that the hippocampus was 'probably involved with a higher mental function, perhaps that of memory'. A century ago Broca (1878) put forward the view that the 'great limbic lobe' of the brain, or as he called it, 'la partie brutale' served the 'lower faculties which predominate in the animal' in contrast to the rest of the cerebral mantle which to him was

'la partie intelligente'. Although strongly contested, these were imaginative ideas which have gained credence during the last 50 years and they foreshadow in a curious way the concept developed by Papez in 1937 of the medial wall of the hemisphere with its diencephalic connections, constituting a mechanism which may 'elaborate the functions of central emotion as well as participate in emotional expression'. Further interest was roused at around the same time by Kliiver & Bucy's (1938) account of the remarkable changes in behaviour that followed the removal of much of both temporal lobes in monkeys. It may therefore be worth while considering briefly the salient clinico-pathological features of bilateral destruction of the human limbic areas in relation first to memory and secondly to the behavioural and affective changes subsumed under the Kliiver-Bucy heading. Memory disorder One of the earliest reports on man was made by Bechterew in 1900 when he mentioned briefly a disturbance of memory that had lasted for 20 years in a patient with 'destruction of the anterior and inner parts of the cortex of both temporal lobes'. The most striking observation, however, came in 1954 when Scoville resected the infero-medial parts of the temporal lobes in several psychotic patients as an extended form of leucotomy. Unexpectedly, he found that those patients in whom the surgical removal included the hippocampi and the parahippocampal cortex on both sides developed a severe defect of recent memory whereas those with a more limited anterior resection did not. PetitDutaillis and his colleagues in 1954 reported a transient disorder of recent memory after a bilateral temporal lobectomy for the treatment of epilepsy. Even though the hippocampi were largely spared in this patient, he was left with a permanent retrograde amnesia of several months. This report was followed by Terzian & Ore (1955) who resected enough of both temporal lobes from an epileptic patient to include the amygdaloid and hippocampal regions. They too found'a serious deficiency in memory' and much the same may be said of the many other reports which have been concerned with the clinicopathological features of the relatively selective removal or destruction of the medial temporal

The late effects oflimbic encephalitis in man grey matter. Severe disorders of recent memory, for example, may follow infarction within the territory of the posterior cerebral arteries (Victor et al. 1961; De Jong et al. 1969; Brindley & Janota, 1975), while Rose & Symonds (1960) and Drachman & Adams (1962) have emphasized the severity of the recent memory defects that tend to occur in patients who survive what is considered clinically to have been a herpes simplex encephalitis or at least an encephalitis involving the temporal lobes. Indeed, one of the 4 cases studied clinically by Rose & Symonds is included in the present report (Case 4). Corsellis et al. (1968) also drew attention to a similar memory disorder in patients with a form of ' limbic encephalitis' associated with carcinoma. It is not therefore surprising that severe defects, particularly in recent memory but sometimes going back for many years, together with the inability to store new facts were obvious in all those of the present patients in whom close enough clinical contact could be made to assess any defect (Table 2). Kliiver-Bucy syndrome The disturbance of recent memory was perhaps the best defined clinical feature in the present cases for, as just explained, it was found to a marked degree in all those who were not too confused, too retarded or too deteriorated to be tested. There was nevertheless, in all but the one permanently unconscious patient, a much wider variety of bizarre behavioural and emotional aberrations many of which were more than a little reminiscent of one or other feature of the Kliiver-Bucy syndrome. They may, therefore, be considered within this framework although it would be foolish to compare too readily observations made on man with those made on experimental animals. This is partly because of the obviously vast intellectual and behavioural differences but also because lesions in man produced by disease are rarely, if ever, circumscribed to the extent that an experimental one may be. Thus, in the present cases, the lesions tended to be appreciably more extensive on one side than the other while damage to relatively clearcut structures like the amygdaloid nucleus still formed only part of a larger poorly defined area of destruction. Finally, it may be misleading to compare animal experiments in which there

39

was a relatively short length of survival with human illnesses that have lasted for years. In outline, the essential features of the KliiverBucy syndrome were listed as oral tendencies, altered eating habits, hypersexual behaviour, and visual agnosia, or psychic blindness as Kliiver and Bucy called it. Of the present patients, 4 showed 'oral tendencies' which were striking enough to be emphasized in the records and in one instance to be filmed. The activity was described variously a s ' sucking fingers and blankets', and 'chewing clothes'; one patient would investigate objects like a patella hammer or the doctor's hand with his mouth. Eating habits were not in general strikingly altered but it is interesting that in one case a vegetarian changed, like Kliiver and Bucy's monkeys, into a more indiscriminate carnivore. Several other patients were considered to have developed exceptional to excessive appetites. Hypersexual behaviour of a modest degree was observed in only 1 of the 10 cases and this consisted merely of trying to kiss the staff and patients effusively. Impotence was never mentioned. 'Visual agnosia' could scarcely be assessed in retrospect in the patients and little can be said beyond the fact that several found it difficult or impossible to recognize their families or friends. The emotional state of all the patients was seriously disturbed at least intermittently. The most commonly noted feature was aggression with bouts of ill-temper and destructiveness. Periods of apathy, sometimes enduring, and depression were also notable and the one blind patient tried several times to kill himself. Several patients were inclined to be restless and overactive. As might have been expected, therefore, no constant pattern of disturbed behaviour or of affect emerged, even though all but one of the patients had been sufficiently handicapped by their chronic disability to require the long-term shelter of a psychiatric hospital or an institution. The general conclusion would seem to be that nothing approaching the full-blown picture of the Kliiver-Bucy syndrome of monkeys has been encountered so far in people in whom the major part of both limbic areas has been destroyed, and it does not seem possible, as yet, to relate in man any particular element of the syndrome to a more refined localization of the damage. In other words, the clinical picture can range from

Memory

(8) RH.9/72

(7) RH. 191/68

Comatose. Inaccessible Occasionally — dressed herself. Mute; incontinent; grossly retarded .— Knew name of hospital. Confused and disorientated. Developed akinetic mutism Infantile; dysphasic; Loss of memory incontinent. Confused

(5) RH.37/66 (6) RH.234/70

Could repeat 6 digits forwards and 4 backwards but unable to retain simple facts. Amnesia for 20-30 years. Could give dates for 1st World War —

Felt lost. Could dress herself

Jargon dysphasia. Severe loss Did not understand. Incontinent Answered questions Unable to store simplest facts. clearly; did simple Amnesia for 15 sums. Could dress years and feed himself. Unable to find his way about Aware of being in Unable to retain hospital. Tended to simple facts lose his way; high level of verbal comprehension and arithmetic (IQ 114)

General state

(4) RH.213/73

(3) RH.28/64

(2) MH.5857

(1) MH.2505

Case no.

Emotional state

—

—

—

Occasionally noisy and restless

Put objects in her Restless, destructive mouth. Chewed her at times aggressive clothes liable to temper tantrums — Cheerful and friendly

Solitary, withdrawn. No spontaneous conversation

•—

Flat mood; bewildered. Mildly depressed (aggressive early on)

Sucked his fingers Ill-tempered when and blankets; put shaved, otherwise objects in his mouth placid Profound depression. Repeated suicide attempts

Oral tendencies

Table 2 'Visual agnosia'

Probably unable to recognize familiar faces

Excessive appetite

Seemed unable to recognize' common objects

Mistook ward orderly for his father (could recognize friends ? by voice)

Extremely good appetite

Good appetite. Field defect Vegetarian, turned meat eater Enjoyed food Blind in both eyes

Feeding habits

Occasionally able to feed herself

Increased tone in all limbs

Dense L. hemiplegia

L. hemiparesis

Played cards, draughts, table tennis; complained of cold; hypersensitive to touch; collected objects; meddled with things Knitted, played piano, washed dishes, cooked a meal. Hoarded rubbish. Constantly going to bed

Complained of cold; preferred to stay in bed

Walked well. Mild R. hemiparesis

Other features

s

I

Loss of recent memory. Amnesia for several years

Memory Put objects in her mouth. Kissed strangers, patients and staff Ate rubbish, chewed clothes and bed linen

Oral tendencies

Noisy, aggressive, destructive, overactive

Swearing, aggressive

Emotional state Very good appetite

Feeding habits

—

'Visual agnosia'

Evidence of hypersexuality was found only in Case 9. 'Five patients (Cases 1, 3, 6, 7 and 9) had epileptic fits.

Infantile, no dysphasia dyslexia or dysgraphia Noisy, could not speak. Severely retarded

(9) BH.N4/76

(10) MH.81/77

General state

Case no.

Table 2 (cont.)

Could dress himself

Played cards, helped with washing up

Other features

The late effecti • oflimbic encephilitis in m

42

R. Hierons, I. Janota and J. A. N. Corsellis

an amnesic but otherwise relatively intact person to a severely demented patient with whom all human contact appears to have been lost. Within this broad spectrum a considerable range of affective and behavioural anomalies is seen, some of which, such as the unusual oral tendencies and the aggression or the apathy, point to the possibility of an illness that is more localized in the brain than are the common diffuse processes which occur in the better known forms of organic dementia. This localization strikes predominantly, if unequally, at the limbic grey matter of both hemispheres. We greatly appreciate the generous help and advice of many colleagues in psychiatry, neurology and neuropathology as well as the collaboration of those in the laboratories in which much of the work was carried out. It is impossible to name them all individually. The work was assisted by grants from the Medical Research Council and from the Bethlem Royal and Maudsley Hospitals. REFERENCES Angevine, J. B. & Yakovlev, P. I. (1964). Limbic nuclei of thalamus and connections of limbic cortex. Archives of Neurology 10, 165-180. Bechterew, W. V. von (1900). Demonstration eines Gehirns mit Zerstdrung der vorderen und inneren Theile der Hirnrinde beider Schlafenlappen. Neurologisches Zentralblatt 19, 990-991. Bogaert, L. van, Radermecker, J. & Devos, J. (1955). Sur une observation mortelle d'encephalite aigue necrosante. Revue neurologique 92, 329-356. Brindley, G. S. & Janota, I. (1975). Observations on cortical blindness and on vascular lesions that cause loss of recent memory. Journal of Neurology, Neurosurgery and Psychiatry 38, 459-464.

Broca, P. (1878). Anatomie comparee des circonvolutions cerebrales. Revue D'Anthropologie series 3, 1, 385-455. Corsellis, J. A. N., Goldberg, G. J. & Norton, A. R. (1968). Limbic encephalitis and its association with carcinoma. Brain 91, 481-496. DeJong, R. N., Itabashi, H. H. & Olson, J. R. (1969). Memory loss due to hippocampal lesions. Report of a case. Archives of Neurology 20, 339-348. Drachman, D. A. & Adams, R. D. (1962). Herpes simplex and acute inclusion-body encephalitis. Archives of Neurology 7, 45-63. Friedman, H. M. & Allen, N. (1969). Chronic effects of complete limbic lobe destruction in man. Neurology 19, 678-690. Gascon, G. G. & Gilles, F. (1973). Limbic dementia. Journal of Neurology, Neurosurgery and Psychiatry 36, 421-430. Haymaker, W. (1949). Herpes simplex encephalitis in m a n with a report of three cases. Journal of Neuropathology and Experimental Neurology 8, 132-154. Heathfield, K. W. G., Pilsworth, R., Wall, B. J. & Corsellis, J. A. N. (1967). Coxsackie B5 infections in Essex, 1965, with particular reference to the nervous system. Quarterly Journal of Medicine 36, 579-595. Klilver, H. & Bucy, P. C. (1938). An analysis of certain effects of bilateral temporal lobectomy on rhesus monkey with special reference to psychic blindness. Journal of Psychology 5, 33-54. Malamud, N. & Hirano, A. (1974). In Atlas of Neuropathology (2nd edn). University of California Press. Papez, J. W. (1937). A proposed mechanism of emotion. Archives of Neurology and Psychiatry 38, 725-743. Petit-Dutaillis, D., Christophe, J., Pertuisset, B., DreyfusBrisac, C. & Blane, C. (1954). Lobectomie temporale bilaterale pour epilepsie. Evolution des perturbations fonctionelles post-operatives. Revue neurologique 91, 129-133. Rose, F. C. & Symonds, C. P. (1960). Persistent memory defect following encephalitis. Brain 83, 195-212. Scoville, W. B. (1954). The limbic lobe in man. Journal of Neurosurgery 11, 64-66. Terzian, H. & Ore, G. D. (1955). Syndrome of Kliiver and Bucy reproduced in man by bilateral removal of the temporal lobes. Neurology 5, 373-380. Treviranus, G. R. (1820). Vermischte Schriften. Bremen. Victor, M., Angevine, J. B. Jr, Mancall, E. L. & Fisher, C. M. (1961). Memory loss with lesions of hippocampal formation. Archives of Neurology 5, 244-263.