Boeck's sarcoidosis revealed at hemispherectomy in a case of infantile encephalopathy with epilepsy

76

JOURNAL OF THE NEUROLOGICAL SCIENCES

Boeck's Sarcoidosis Revealed at Hemispherectomy in a Case of Infantile Encephalopathy with Epilepsy C. A. PAGNI, P. H A Z E G H I A N D E. WILDI The Neurochirurgical Department, University of Milan, Milan (Italy); and The Institute of Pathology, University of Geneva, Geneva (Switzerland)

As far as we know evidence of sarcoidosis has not been mentioned by any of the authors who have studied histological preparations after hemispherectomies. We feel, therefore, that the following case should be of considerable interest, since we were able to demonstrate typical sarcoid lesions within a cerebral hemisphere removed on account of an epileptic syndrome which was resistant to drug therapy. Sarcoidosis rarely involves the central nervous system, but when it does the prognosis is usually bad. In the present instance however, there was a favourable postoperative course: seizures disappeared, and at a long term follow-up the patient was found to be in good condition.

CASE REPORT

The patient was a 13-year old boy. The family history was not contributory. There had been no birth injuries, and no anomalies of growth were noticed up to the age of 2 months, when the patient presented focal seizures affecting the left half of the body, lasting for 8 days. The infant was then referred to a hospital where pneumonia accompanied by a meningeal reaction was diagnosed. He recovered from this episode with no appreciable sequelae. The child's subsequent physical development seemed normal, but his parents, who were unusually observant, noticed slight mental retardation. However an electroencephalogram at the age of 7 years revealed no abnormal pattern. At I 1 years, the patient presented sudden psychomotor agitation with status epilepticus of 8 hours duration: the seizures again were localized to the left side and were followed by a left flaccid hemiplegia. In the following months there was only a limited recovery of motility on the left side: the patient had the dragging gait characteristic of hemiplegics and spasticity of the arm which was held in semi-flexion; the patient was unable to perform movements of the hand. From this time on he was subject to epileptic seizures lasting several seconds and characterized by turning of the head and trunk towards the left and elevation of the right arm. These attacks were resistant to anti-convulsant medication. At the age of 12 the following examinations were carried out: J. neurol. Sci. (1966) 3 : 7 6 - 8 9

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

77

Electroencephalogram: signs of right centro-parietal atrophy. X-rays skull: right cranial hemiatrophy, due probably to infantile atrophic encephalopathy, as indicated by thickening and elevation of the lesser wing of the sphenoid and of the ethmoidal surface, and by moderate reduction of the right cranial diameters. Chest: normal. Lumbar puncture: pressure not recorded; cerebrospinal fluid proteins, sugar, chlorides, cells: normal. No acid-fast bacilli were seen. Pneumoencephalography: slight dilatation of the anterior part of the right lateral ventricle, more evident in the sphenoidal horn; the third ventricle was also dilated and deviated to the right. When the boy was 12½ years of age, 6 months prior to the operation, the convulsive seizures changed, and were then characterized by a turning of the head to the right, tonic flexion of the trunk, tonic extension-abduction of the right leg and arm, and tonic-clonic convulsive movements of the left face and limbs without loss of consciousness. Some of the attacks lasted as long as 60 seconds. They occurred 5-10 times a day and were absolutely refractory to anti-convulsive therapy (dilantin 300 mg daily; mysoline 3 tablets daily; phenobarbital 300-400 mg daily). It was on account of this intractable epileptic syndrome that the patient was admitted to the Neurosurgical Clinic of Milan on May 15, 1961, for observation and possible surgical treatment. Physical examination on admission The general physical examination was normal. There was a slight mental retardation. The patient was apathetic and had but little facial expression. There were no behaviour disturbances or irritability. Very slight left-sided facial paralysis; the other cranial nerves appeared normal. Left spastic hemiplegia, more noticeable in arm and hand. The only possible movements were those of the proximal joints, the skilled movements of the extremities being impossible. Gait could not be observed owing to the exhaustion from repeated epileptic fits. Moderate muscular hypotrophy on the left side but without any shortening of the limbs. Deep reflexes very brisk on the left side. Sustained clonus of the left patella and ankle. Left Babinski response. The patient's torpor made it difficult to assess his sensory functions, but pain was obviously perceived on both sides. Blood sugar, blood urea and a blood count were normal. Chest X-ray: normal. Electroencephalograms (May 16-17, 1961). Signs of atrophy of the right hemisphere, more pronounced in the frontocentral region. Almost continuous paroxysmal activity: symmetrical bilateral very high voltage spikes were recorded, sometimes a little higher on the midline and left hemisphere. No further encephalography or lumbar puncture were done. During the week prior to operation, the patient continued to have 5-8 seizures a day in spite of anti-convulsive therapy in very high doses (dilantin 300 mg, mysoline 2 tablets, phenobarbital 300 mg daily). Operation (May 22, 1961). An extra-thalamo-caudate right hemispherectomy was carried out in association with hypothermia and general anaesthesia, the plane of section passing between the insula and putamen. The temporal ventricular horn was opened and the adjacent hippocampal structures were removed. J. neuroL Sci. (1966) 3:76-89

78

c.A.

PAGNI, P. HAZEGI-II, E. W1LDI

Post-operative course. A few hours after the operation the patient was awake and conscious; there was a complete left-sided flaccid hemiplegia with an extensor response and brisk tendon reflexes and clonus. Pain stimuli were perceived equally on both sides. From the 2nd to the 4th day after operation, despite anti-epileptic medication, the patient had several tonic epileptic seizures with turning of the head to the left, elevation and abduction of the right arm, and occasionally of the left arm, but without loss of consciousness. On the 5th day the seizures ceased altogether. The post-operative course was otherwise uneventful. The patient was discharged from hospital seizurefree. Laboratory tests 18 months after the operation yielded the following results: Katz's index, 15; serum calcium, 8.5 mg/100 ml; blood proteins, 6.8 g/100 ml; albumin/globulin ratio, 0.88; albumin, 46.93 %, ; 0~rglobulin, 2.04%; o~2-globulin, 2.04°/~, ; fl-globulin, 20.42%; ~-globulin, 28.57°/,, Forty months after operation, there was some recovery of locomotor control equal to the pre-operative level (dragging gait, inability to carry out fine movements of the extremities). A marked reduction of spasticity and an improvement in mental functions were noted. The patient had had no further seizures during the 40 months since the operation (anti-convulsive medication had been continued viz. : phenobarbital 250 mg daily).

Fig. 1. External surface of the right hemisphere. Pronounced cicatricial atrophy of the orbital convolutions, as well as F1, F2, F3. Widening of their sulci. In the posterior two-thirds of the hemisphere, the cortical lesions are barely distinguishable through the meninges. J. neurol. Sci. (1966) 3:76-89

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

79

PATHOLOGICAL FINDINGS

The excised right hemisphere measured 13 by 9 cm and weighed only 200 g (but it should be remembered that the plane of surgical section passed lateral to the basal ganglia which were left in situ). It showed very pronounced uniform atrophy. The convolutions of the external cerebral surface (F1, F2, F3) in the frontal region were marked by considerable atrophy and cicatricial sclerosis, greatly increased consistency, pallor and widening of the sulci (Fig. 1). The leptomeninges were opaque and thickened but were thinner in the region where they covered the frontal lobe just anterior to the frontal ascending convolution which, like the central region, showed relatively little abnormality. In these central areas the thickness of the cortical gray matter was within normal limits, except in the territory supplied by the middle cerebral artery, where it showed extensive cicatrization. In several other places (T1, lower part of FA, pericallosal convolution) there were small linear scars 2-5 mm in length. The leptomeninges covering the posterior 2/3 of the hemisphere showed greater hyperaemia than those covering the zone of cortical atrophy; certain of the veins were markedly turgescent. Areas of cicatricial cortical retraction were found in T3 and in the lower and supero-external part of the parietal cortex, as well as in the anterior portion of Oa. Similar lesions were found here and there on the internal surface of the hemisphere (pericallosal convolution, superior portion of the calcarine area). Under the prefrontal cortical lesions the anterior horn of the ventricle was extremely dilated, presenting a sort of diverticulttm running in a supero-posterior direction and terminating adjacent to the upper portion of the ascending frontal convolution; the distance separating the cpendyma from the meninges barely exceeded 3 to 4 mm. This ventricular enlargement was much less pronounced in the parietal and occipital lobes, although it was still obvious. X-rays of the anatomical specimen revealed the enormous enlargement of the frontal horn of the lateral ventricle (Fig. 2C). The cortex of the parietal and occipital lobes showed scarring at the depth of the majority of sulci, especially on the external surface of the hemisphere. There was a direct correlation between the severity of cortical lesions and the degree of the underlying demyelination. Thus practically nothing was left of the centrum ovale in the anterior part of the frontal lobe. Below the parietal and occipital cortex, which showed fewer changes, large cavities had developed through the confluence of alveolar spongiosis (Fig. 3). The myelin underlying the central region, which was the best preserved portion of the entire pallium, remained abundant and compact. Histological examination revealed 3 distinct kinds of lesions: operative, cicatricial and inflammatory. The operative lesions consisted of several recent small and discrete non-confluent extravasations near the plane of the surgical section. The most pronounced of these were found in the corpus callosum and its adjacent convolution, in the inferior temporal and insular cortex. There were no subarachnoidal haematomata. As already noted in the macroscopical description of the specimen, the cicatricial lesions were much more extensive than the surgical ones, and varied considerably in degree in the different parts of the hemisphere. In the frontal lobe the cortex had been reduced to a thin ribbon of tissue, regular and uninterrupted, composed of clusters and islands of neuroglial tissue, inside which there was not a single intact neuron. J. neurol. Sci. 0966) 3:76-89

80

C . A . PAGNI, P. HAZEGHI, E. WILDI

Fig. 2 A.

Fig. 2. A and B. Pneumoencephalography 1 year before operation: moderate dilatation of the right ventricle; note the relatively slight enlargement of the frontal horn. C. X-rays of the surgical specimen: huge dilatation of the frontal horn with a diverticulum running anterior to the ascending frontal convolution. neurol. Sci. (1966) 3 : 7 6 - 8 9

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

81

Fig. 2 B.

Fig. 2 C. J. neuroL Sci. (1966) 3 : 7 6 - 8 9

82

C.A. PAGNI, P. HAZEGHI, E. WILDI

Fig. 3. Parietal lobe. Ventricular dilatation. The tapetum and optic radiations are relatively well preserved except above the ventricular roof. External to the optic radiations is an extreme diffuse non-spongioid demyelination. Marked cavitation of the white substance of the superior parietal lobe. The arrow shows cortical scarring at the level of the zone of granular atrophy. The cortex at the depth of the sulci reveals the greatest degree of cicatrization throughout the external surface of the parietal lobe, particularly towards its base (this aspect is even more evident in Fig. 4). Celloidin. Luxol-van Gieson's stain; × 1.5.

This p a r t o f the cortex c o n t a i n e d a n e t w o r k o f fibrosed capillaries a n d fine calcifications o c c a s i o n a l l y fused, in the vicinity o f which m a n y calcified n e u r o n s were found. A little further b a c k there was still c o n s i d e r a b l e gliosis o f the F 2 c o n v o l u t i o n as well as o f the entire t e r r i t o r y o f g r a n u l a r atrophy*. T h e t e m p o r a l cortex presented far fewer lesions t h o u g h at the level o f T3, its d e e p e r layers c o n t a i n e d b a n d s o f discont i n u o u s spongiosis. T h e cortex o f the d e p t h o f the p a r i e t a l a n d occipital sulci was a l m o s t entirely r e p l a c e d b y gliofibrous a n d s p o n g y l a m i n a r scarring (Fig. 4). T h e white m a t t e r o f the a n t e r i o r p a r t o f the f r o n t a l loboDwas r e d u c e d to little m o r e * The reader will find a considerable number of data and references in WILDI'Spaper (1959). J. neurol. Sci. (1966) 3:76-89

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

83

Fig. 4. Occipital lobe. Spongioid linear scarring of the cortex at the depth of the sulci, with exception of the calcarine area (on the left). Note the comparatively better preservation of the cortex of the convolutional convexities. Hyperaemia of the meningeal veins. Extreme diffuse demyelination. Celloidin. Luxol-van Gieson's stain; × 2.8.

than a fissure separating the deepest layer of the cortex from the ventricular wall, which was thickened by gliosis with no trace of ependyma. However in the occipital horn of the ventricle the ependyma was still present in several places, resting on a glial substratum. The accentuation of scarring in the depth of the sulci (particularly in the parietooccipital region) along with relatively better preservation of the dome of the convolutions,-indicates beyond doubt that these cicatricial lesions were the result of an anoxic injury. The large number of calcified neurons constitute further evidence of this (Fig. 5). The fact that there were no vascular, meningeal or parenchymatous lesions seems to preclude the possibility of a local anoxic injury, and the fact that the lesions involved the territories supplied by the 3 branches of the cerebral circulation, constitutes a further argument in favour of an extracerebral origin of anoxia. The absence of meningeal fibrosis seems to exclude a meningo-encephalitic affection during early childhood. In this connection it must be remembered that the contralateral hemisphere seems, at least from a clinical point of view, to be normal. The cicatricial lesions are old, having become stationary many years previously, as J. neurol. ScL

(1966) 3:76-89

84

c.A.

PAGNI, P. HAZEGHI~ E. WILDI

shown by their histological characteristics which suggest that they probably originated at the age of 2 months. Also the X-rays of the cranium, taken when the subject was 12 years old, showing a certain degree of cranial asymmetry, speak well for a remote origin of these lesions. The inflammatory lesions, which were sarcoid granulomas, were invisible to the naked eye. However it is well-known that they are macroscopically visible in only a little over half of the cases (HAZEGm 1964). The description which follows will therefore be strictly histological. Many of the cortical spongioid cicatricial lesions were infiltrated by inflammatory granulomatous tissue, characteristic of Boeck's sarcoidosis. The most striking sarcoid lesions were small, round nodules of epithelioid cells, either isolated or in clusters, showing no signs of necrosis and sometimes showing central fibrosis. These nodules contained a large number of Langhans cells (Fig. 6) which were also found at a considerable distance from the nodules and were devoid of asteroid bodies and of Schaumann's spherical corpuscles. Unexpectedly, some of them contained phagocytozed calcified neurons (Fig. 7). However it is important to note that they probably were not originally foreign body giant cells, since they were in much closer relationship with the granulomas than with the calcified neurons: their neuronophagic

Fig. 5. External parietal cortex. Celloidin. Gomori-iron stain. A: × 93. Calcified neurons in the cortical cicatrices. J. neurol. Sci.

(1966) 3:76-89

BOECK'S SARCOIDOSIS REVEALV~DAT I~ISPHER~CTOMY

85

activity may be an incidental phenomenon of secondary importance. Peripherally these nodules were bound by a very dense lymphoplasmocytic infiltration, which was often continuous with perivascular cuffs containing the same inflammatory cells (Fig. 8). The glial tissue surrounding the granulomatous nodules showed a very marked concentration of tumefied astrocytes. These granulomas were only rarely encountered in the white matter and not at all in the meninges.

Fig. 6. Supero-external parietal cortex. Diffuse glial scarring invaded by an inflammatory granulomatous tissue consisting of small epithelioidnodules surrounded by a lymphoplasmocyticinfiltration, containing numerous giant cells. Celloidin. Luxol-van Gieson's stain; × 55.7.

DISCUSSION In this case the exceptional feature is that the sarcoid lesions are localized almost exclusively in the regions of the cortical scarring. The very slight meningeal lymphocytosis of this case (most frequently localized in the depth of the sulci and more pronounced where the meninges cover the cortex occupied by the granulomas) is another unusual feature in cerebral sarcoidosis. However in this case the meningeal lymphocytosis was more pronounced on the ventral aspect of the hemisphere: the accentuation of the exudate at the base of the hemisphere is, on the other hand, more typical of Boeck's meningitis. 3. neuroL Sci.

(I 966) 3:76-89

86

c.A. PAGNI, P. HAZEGHI,E. WILDI

Fig. 7. Sarcoid nodules containing a number of giant cells containing phagocytozedcalcifiedneurons. Celloidin. Gomori-iron Stain. × 142. It should be stressed that the cortical scars invaded by the granulomatous process were on the external surface of the hemisphere, especially in the zone of granular atrophy. This topographical peculiarity was originally noted by HAZE6m (1964) in the report on the first case of his series of cerebral sarcoidosis. Although some of the clinical and histopathological evidence tells against the diagnosis of sarcoidosis the general aspect of the lesions argues strongly in its favour. The nature and topography of the inflammation are highly characteristic of Boeck's disease, as are the presence of a large number of giant cells, the absence of caseification, the presence of epithelioid cell nodules, the same distribution of granulomatous lesions on the zone of granular atrophy as that reported by HAZEGHI(1964), and the meningitic exudate more evident at the base of the hemisphere. Although the absence of granulomatous ependymitis is not in itself a decisive factor since, as HAZEGm (1964) remarked, it is present only in 3 2 ~ of the cases, the absence of angiopathy is another particular feature of our case of sarcoidosis : in fact the giant cell proliferative angiopathy was almost constant in the 52 cases which were studied by HAZEGHI (1964). The aetiology of our case of granulomatous encephalopathy was certainly not tuberculous. Even if there exist some doubts after histological examination (in spite of the absence of caseification and the abundance of giant cells) it seems to us highly J. neurol. Sci.

(1966) 3:76-89

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

87

Fig. 8. Supero-external parietal cortex. Epithelioid nodules, giant cells and perinodular lymphoplasmocytosis, continuous with a similar perivascular infiltration. Celloidin. Nissl's stain; X 67.2.

improbable, on clinical grounds, that the patient should have remained in good health 40 months after the operation, if his brain or the meninges had been the site of tuberculous lesions, for he did not receive any specific therapy. The topography of the sarcoid lesions was remarkable, i.e. their very elective disposition inside the spongioid cortical scars especially in the zone of the granular atrophy. How can we account for this tropism? One possible explanation of the extension of the lesions into the zone of granular atrophy might be a local slowing of the circulation, as suggested by HAZEGHI(1964). Even a minute reduction in bloodflow might suffice to favour the penetration of pathogenic agents (antigens?) through the vascular walls and their fixation in the surrounding tissues. Moreover, the disposition of granulomatous lesions within the cortical scars could be explained in the same way. It is also very probable, that in addition to vascular disturbances of dyshoric nature* the tissue defence mechanisms are undermined by hypoergy or anergy inside the scars. The fact that our patient was a child does not exclude the possibility of encephalic * Some information as to disorders of vascular permeability is to be found in SURBEK'Swork (1961) on the dyshoric angiopathy of the cerebral vessels. J. neurol. Sci. (1966) 3:76-89

88

C . A . PAGNI, P. HAZEGHI, E. WILDI

sarcoidosis, for the cerebral form of this disease has been found in 2 boys, one 3 months and the other 6 years (HAZEGHI 1964). The serological analyses, carried out 18 months after operation showed slight hyperglobulinaemia but no hypercalcaemia. However the latter has been noted in too few cases to be assigned a diagnostic value comparable to that of dysproteinaemia. The absence of lymphadenopathy, pulmonary calcification, or other clinical manifestations during the postoperative months does not exclude sarcoidosis. As a matter of fact, in his review of the literature HAZEGHI(1964) found 13 out of 52 anatomically verified cases (by autopsy or cerebral biopsy) in which encephalic sarcoidosis was probably primary, i.e. confined to the central nervous system. Our case probably, belongs to this variety. As a rule it is extremely difficult to determine the age of the particular lesions under study on the basis of anatomopathological findings. In this particular case, however, the presence of relatively mild fibrosis in the centre of a small number of sarcoid nodules leads us to believe that they are probably not very old. This interpretation is supported by the clinical report, which states that a lumbar puncture carried out 1 year bofore operation, when the patient was 12 years old, demonstrated that the cerebro-spinal fluid was normal. In view of the statistical findings of HAZEGHI'S study (1964), which showed the presence of an increased albumin in 94°,/o of the cases, and an increased CSF globulin in all the examined cases of cerebral sarcoidosis, it appears probable that our patient was not yet suffering from sarcoidosis at the age of 12, a conclusion which tallies with the histopathological findings. The epileptic seizures which had not occurred since the episode at the age of 2 months, reappeared when the patient was 11 years old. Should this recurrence be attributed to a cicatricial retraction of the hemisphere, or to incipient sarcoidosis? We cannot answer this question. However we may mention that convulsive seizures have been observed in 57% of infantile encephalopathies (GraBs AND GIBBS 1963), and in 30°/~, of cases of cerebral sarcoidosis (HAZE~HfS series). At the time of the pneumoencephalography, performed when the patient was 12 years old, the left hemiplegia had already become stable and was not subsequently exacerbated or complicated by further psychical symptoms. It should nevertheless be mentioned that approximatively 6 months after pneumoencephalography the convulsive seizures changed somewhat in character: perhaps this is caused by late evolution and tissue changes of the anoxic cicatricial lesions. In fact the ventricular dilatation increased enormously over the course of the 12 months preceding the operation, as shown by a comparison of the air-studies carried out one year previously and the X-ray of the operative specimen (Fig. 2). This increase in ventricular volume is to be put down to further reorganization of the post-anoxic cicatricial lesion, and thus represents the terminal phase of the lytic process involving the white matter. As long as the continuity of the ventricular ependyma covering spongious areas was preserved the ventricular dilatation remained limited in extent. Only after lacerations of the ependyma is the communication between the ventricle and the spongioid cavities of the white matter established. In our opinion the initial stages of this process are well illustrated in Fig. 3. The principal question, namely whether at the time of the hemispherectomy (and J. neurol. Sci. (1966) 3:76-89

BOECK'S SARCOIDOSIS REVEALED AT HEMISPHERECTOMY

89

perhaps even now) both hemispheres contained sarcoid granulomas, cannot be conclusively answered. It is well known that sarcoidosis frequently originates bilaterally in the meninges of the basal region of the brain. However, the post-operative evolution of this case, which after 40 months is still astonishingly satisfactory, leads us to reject the suggestion of an active granulomatosis in the hemisphere left in situ. Nevertheless, it must be realised that although the prognosis in cases of sarcoidosis of the central nervous system is relatively poor, the clinical course is sometimes interrupted by spontaneous remissions of considerable duration (HAZE~HI 1964). In view of the excellent post-operative course of this particular case, no antituberculous or cortisone therapy was undertaken, despite the dysproteinaemia noted 18 months after the operation; this treatment, although effective against the visceral manifestations of sarcoidosis, seems to be inactive in the encephalic forms (CARES et al. 1957; GARClN et al. 1957). SUMMARY A 13-year old boy suffering from a spastic hemiplegia and an intractable epileptic syndrome was subjected to hemispherectomy. Histological examination of the excised hemisphere disclosed three types of lesion: (a) operative; (b) cicatricial with glial cortical spongioid scarring rich in calcified neurons; and (c) inflammatory with granulomatous lesions typical of Boeck's sarcoidosis. The cicatricial lesions were probably of long standing, dating back to an anoxic accident in early infancy, whilst the sarcoid lesions were almost certainly of more recent date, embedded secondarily within the old cortical scars. REFERENCES CARES,R. M., B. S. GORDONANDE. KREUGER(1957) Boeck's sarcoid in chronic meningo--encephalitis. Organic psychosis with massive softening due to Boeck's disease, J. Neuropath. exp. NeuroL, 16: 544-554. GARCIN,R., R. A. MARQUEZY,J. LAPRESLE,CH. BACHANDJ. C. DAYRAS(1957) Sur un cas de sarcoidose du syst~me nerveux central, l~tude anatomo-clinique, Presse mdd., 86: 1926-1930. GIBBS,F. A. ANDE. L. GIBBS(1963) Encephalographic prediction of epilepsy as a complication of cerebral palsy, Neurology, 13 : 143-145. HAZEGHI,P. (1964) Les formes nerveuses de la sarcoidose (maladie de Besnier-Boeck-Schaumann). l~tude anatomo-clinique de 2 cas, Schweiz. Arch. Neurol. Neurochir. Psychiat., 94" 21-62. SURBEK,E.B. (1961) L'angiopathie dyshorique (Morel) de l'6corce c6r6brale, l~tudeanatomo--clinique et statistique; aspect g6n6tique, Acta neuropath., I : 168-197. WILDI,E. (1959) l~tat granulaire syst&natis6 cardiopathique de l'6corce c6r6brale (atrophic granulaire), t~tude anatomo--clinique,Bull. Schweiz. Akad. med. Wiss., 15: 18-83. J. neuroL ScL (1966) 3:76-89