THE AMERICAN JOURNAL OF CANCER A Continuation of The Journal of Cancer Research

VOLUME XXXII FEBRUARY, 1938 NUMBER 2

GLIONEUROMA AND SPONGIONEUROBLASTOMA, FORMS OF PRIMARY NEUROECTODERMAL TUMORS OF THE BRAIN

JOSEPH H. GLOBUS, M.D. (From the Neurological Service of Dr. Israel Strauss and the Laboratories of The Mowlt Sinai Hospital, New York)

It is the general impression that primary cerebral neoplasms of neuro­ ectodermal derivation, such as are composed of both neural and glial ele­ ments, are rare. Indeed, since 1901, when Worcester (1) reported the first instance of cerebral neuroglioma, only a few such tumors have been described. In spite of their small number, but because of minor differences, they were recorded under a relatively large assortment of names. The latter include the neuroglioma ganglion are of Dumas (2); the ganglioglioneuroma amyeli­ cum of Schmincke (3 and 6), Robertson (7) and Olivecrona (10); the ganglio­ neuroma amyelicum of Bielschowsky and Pick (4); the ganglioneuroma of Achucarro (5), Berblinger (8), Greenfield (9), Lhermitte and Duclos (11), Marinesco (16), Horrax and Bailey (17), Bielschowsky and Simons (21), Doyle and Kernohan (22), Alpers and Grant (23), Cox (24), Hoffmann and Matulay (25), and Vercelli and Ferrero (26); the ganglioneuroma myelicum of Olivecrona (10); the ganglioglioneuroma of Ostertag (12), Bielschowsky and Henneberg (18) and Watjen (20); the multiple ganglioneuroma of Bielschowsky (13); the ganglioblastoma of Paul (14); the ganglioglioma of Perkins (15) and Courville (19). In all, 29 cases have thus far been re­ ported, of which only 21 are actually supratentorial in location. When one considers the vast number of recorded supratentorial gliogenous tumors, it becomes obvious that the reported instances of ganglioneuroma or ganglioma, and other closely related and similarly named tumor forms, repre­ sent but an exceedingly small fraction of the neuroectodermal tumors. This becomes still more striking when the more reliable statistics are reviewed. Cushing's series, for example, is found to contain but three cases of ganglio­ neuroma, of which only one was supratentorial. He says (27): "These tu­ mors are pathological curiosities and scarcely deserve consideration from a 163 164 JOSEPH H. GLOBUS surgical point of view." Further on, referring to the only instance of supra­ tentorial ganglioneuroma in his collection, he continues: " ... the history of the patient with six years of convulsions, the fact that the tumor which filled the frontal fossa showed calcification on the X-ray, and the general appear­ ance of the sections, in spite of the presence of a few possible ganglion cells, so closely resembles an oligodendroglioma that it might well enough be put in that category." Thus, among 862 verified gliogenous tumors in his collec­ tion, there is only one supratentorial ganglioneuroma, and that one doubtful. In marked contrast to Cushing's observations is the fact that in a group of 178 verified supratentorial gliogenous neoplasms in the Mount Sinai Hospital collection of brain tumors, there are 12 cases of ganglioglioma and 10 instances of spongioneuroblastoma. In other words, the supratentorial glioneuroma and spongioneuroblastoma constitute a little more than 12 per cent of the total number of supratentorial tumors of neuroectodermal derivation. It must be said, however, that prior to this present study the true histological character of many of these tumors was not recognized, and that only on critical re­ examination were these neoplasms, previously placed in some other category, found to belong to one or the other of the two tumor groups under discussion. The infrequency with which these tumor types have hitherto been re­ corded cannot be due to their rarity, as is evident from our present experience. It may be attributed to the probable failure to recognize their true character in some instances, with the result that they have been labeled incorrectly. This failure to identify these tumors is due, in part, to the abandonment of the rather simple but classical staining method of Nissl-a procedure too frequently neglected in the study of brain tumors. It is the employment of this stain, so well adapted to the recognition of neurons in various stages of differentiation, that has helped to identify the character of the tumors herein described. With this method it has become possible to salvage many tumors of this type which would otherwise be regarded as unclassifiable or as other forms of glioma (transitional, oligodendroglial). In a way, the 22 cases to be described constitute essentially one common tumor form and are certainly of a common lineage, but, because of differences in the degree of maturation of their component cells and of some other related features, they are here grouped in two categories, the glioneuroma and the spongioneuroblastoma.

THE GLlONEUROMA Under the heading glioneuroma are assembled 12 cases, in which the cere­ bral neoplasm consists of neurons and glial cells in varying ratios, with both of these elements presenting a relatively high degree of differentiation. Be­ cause of the greater maturity of its cellular components, this tumor form may be regarded as non-malignant or as benign, if the latter term is permissible. It will be found that the fairly uniform and characteristic histological char­ acter of the tumor is paralleled by similarly uniform gross anatomical fea­ tures, which may be used as an aid in its identification by the unaided eye and the palpating finger. The glioneuroma, as will be seen, is distinguished by its rubbery consistency, by the gradual, often imperceptible, merging with GLIONEUROMA AND SPONGIONEUROBLASTOMA 165

the normal brain tissue, and by the glistening, slimy, myxomatous appear­ ance of its free or cut surface. In its location it is not restricted to any divi­ sion of the cerebral hemisphere, but is most commonly found in the white matter subjacent to, and invading for various distances, the overlying gray matter; not uncommonly it spreads inward toward the ependymal lining. A survey of the clinical manifestations of the glioneuroma reveals that a large number of them hold out promise of providing diagnostic leads not only for accurate localization, but also for clinical recognition of their anatomical character. Thus a precipitate onset, ushered in by a convulsive seizure of the Jacksonian variety, or by recurrent petit mal attacks in the nature of brief periods of unconsciousness, or by a short episode of transient aphasia, is a rather common and characteristic clinical feature. The subsequent events are no less typical: with but few exceptions, convulsive seizures occur with increasing frequency and are followed by intellectual depreciation and devel­ opment of more discrete focal signs. The final course is characterized by abrupt accentuation of signs and symptoms and rapidly advancing fatal termination.

Case Records

CASE 1. Sudden onset and rapid development of mental deterioration; meager localizing signs; lumbar puncture followed by a succession of convulsive seizures; subtemporal de­ compression; rapid decline; death; necropsy. History (Adm. 347335; P. M. 8580): P. B., a man aged twenty-eight years, was ap­ parently well until two weeks prior to admission to the hospital when he began to display some mental changes: lapses of memory and slowness of thinking, particularly when called upon to calculate or recall prices. This condition continued for a week, at the end of which time, following excessive drinking and repeated vomiting lasting for half a day, he lapsed into a state of marked confusion. He was then seen by a physician, who considered him to be bordering on a psychosis. On that day he was found taking a shower while dressed in his pajamas and a bathrobe. The next few days were marked by further mental disinte­ gration. He would break up a conversation abruptly and remain mute for two to three minutes, though apparently making an effort to say something. He would then suddenly regain his speech but would talk of irrelevant matters. It was also noticed that he would speak to his wife in English and to his business associates in French, while the reverse was his usual custom. Examination: The neurological findings were exceedingly meager.. There 'was a left central facial weakness, but there were no significant changes in reflexes and no sensory disturbances. The patient displayed repeated mental lapses during which his mind appeared to be blank and he seemed to struggle to speak, but without success. In the intervals he was apparently clear and made no errors. When asked to write his name, however, he wrote something totally irrelevant in French. His blood pressure was 120 systolic and 90 diastolic and the pulse rate was 86 per minute. The Wassermann and other tests of the blood and cerebrospinal fluid were negative. Course: The patient was considered to have a brain tumor, probably in the right frontal lobe. His speech impairment was not out of harmony with this localization, since he was said to be ambidextrous and there was a likelihood that he was left-handed. A lumbar puncture was done the day after admission. The cerebrospinal fluid was found to be under pressure of 120 mm. water. Within two and one-half hours after the lumbar puncture the patient passed through a series of about twenty epileptiform convulsions, remaining stuporous and cyanosed during the free intervals. Each convulsion was characterized by a tonic stage, lasting ten to fifteen seconds, which was followed by clonic movements, more marked on the left side. At the same time there was deviation of the eyes to the right and the patient bit his tongue. During the convulsive seizures the deep reflexes were more active on the 166 JOSEPH H. GLOBUS

FIG. 1. CASE 1 A. Gross appearance of a coronal section of the brain showing the hypertrophy of the left hemisphere and the small cyst-like defect in the left superior frontal convolution. B. Histologic appearance of the neoplasm showing the presence of many quite mature nerve cells amid the faintly stained glial elements. X 200. Nissl stain. left. Immediately after the last convulsion. in spite of the fact that it was apparent that the patient was in a moribund condition, surgical intervention was attempted. A right sub­ temporal trephine opening was made. Bloody cerebrospinal fluid was aspirated from the ventricle. Death occurred shortly thereafter. Gross Necropsy Findings: The brain was swollen. The right frontal area appeared somewhat pale, while the left frontal area was congested. In the region of the left superior FIG. 2. CASE 1 A. Astrocytes in the center of the tumor displaying very delicate processes. X 375. Globus modification of the Hortega silver carbonate method. B. Area of dense gliosis in the tumor. X 150. Globus modification of the Cajal gold sub­ limate method. C. Island of undifferentiated spongioblasts and neuroblasts in the tumor. X 180. Biel­ schowsky silver stain.

167 168 JOSEPH H. GLOBUS

FIG. 3. CASE 1 A. Large (monstrous) nerve cell in the tumor tissue. X 375. Bielschowsky silver stain. B. Cyst-like defect surrounded by zone of dense gliosis in the tumor tissue. X 98. Globus modification of the Hortega silver carbonate method. C. Myelinated fibers running through the tumor tissue. X 150. Spielmeyer's myelin stain.

frontal convolution an area of greater resistance was encountered which later proved to be a firm infiltrating tumor. On sectioning of the brain, a definite disproportion in the size of the two cerebral hemispheres was observed. It was most striking in the prefrontal region, the left hemisphere being the larger. The enlargement appeared to be due to a decided increase of the white matter (Fig. lA). The demarcation between white and gray matter was in­ distinct, as the latter had lost some of its characteristic color. In the region of the left superior frontal convolution, at the level of the genu of the corpus callosum, was a circular, GLIONEUROMA AND SPONGIONEUROBLASTOMA 169 somewhat excavated area measuring about 3 mm. in diameter. Mesially and inferior to this area, about 1 em, above the wing of the corpus callosum, was a small area of softening, and still more mesial in the gray matter directly above the fissure of the gyrus cingulae was another area of softening. These three areas of softening marked, in a fashion, the boundaries of an irregularly nodular area of increased consistency; it appeared to correspond to the outlines of the tumor, which had its posterior extremity at the level of the genu of the corpus callosum. Microscopic Findings: Sections taken from various parts of the tumor varied somewhat in the dominance of cellular elements. In some parts neurons (ganglion cells) were more numerous (Fig. 1B). They displayed a fairly well advanced differentiation and were dis­ tributed quite regularly on a background of faintly stained, but quite numerous, glial ele­ ments. In other areas glial cells occupied the field to the exclusion of neurons. The glial elements (Fig. 2A) attained full differentiation but, in the delicacy of their processes and the smallness of their cell bodies, had the appearance of the (lilliputian) glial structures seen in the infant's brain. In some areas these glial islands assumed the character of a very dense network (Fig. 2B). Had such an area been obtained by means of the aspirating needle and submitted to the pathologist for an opinion, the diagnosis of astrocytoma would invariably have been made and justifiably so, though incorrectly. In other parts of the tumor were groups of cells forming little nests about the blood vessels. These cells bore a strong resemblance to undifferentiated spongioblasts and may be regarded as feeding centers of the tumor (Fig. 2C). Then again, areas of dense glial scars were found about little cyst-like defects (Fig. 3B). The latter were often large enough to be detected with the naked eye. Not infrequently such defects were filled with" mucinous" material. In isolated areas myelinated fibers were seen forming small irregular streams (Fig. 3C). At the periphery of the tumor, at the point of transition into the apparently normal cortex, there were recognized anomalous cell forms (Fig. 3A) which, by the size of their cell bodies and the length of their processes and irregular nuclear formations, resembled cell forms seen in tuberous sclerosis.

Comment: This case was selected as typifying the anatomical features of a glioneuroma. It shows the poor gross anatomical demarcation of the neo­ plastic mass and the presence of mature glial and neuronic elements. Not without significance is the fact that among the riper elements are here and there less differentiated glial and, perhaps, similarly poorly ripened neuronic elements. Even the mature glia cells show certain peculiarities. Though fully differentiated, they bear a close resemblance to astrocytes seen in the infant's brain; they are well formed, but infantile in the size of the cell body and delicacy of their processes. Clinically, the case exhibited several of the features characteristic of this type of tumor, such as an abrupt onset, meager localizing findings, intellectual disintegration, and Jacksonian seizures.

CASE 2. Abrupt onset of headache, vertigo, and pain in eyes, followed by impaired vision and projectile vomiting; unsteady gait; bilateral papilledema,. vague localizing signs; uentriculography; exploratory craniotomy ; rapid decline; death. History (Adm. 339208; P. M. 8334): M. E., a married woman aged thirty-three years, was in good health until five weeks prior to her admission to the hospital, when she began to experience right frontal and parietal headaches, vertigo, and pain in both eyes. The pain, which sometimes made it difficult for her to see, occurred in attacks of an hour's dura­ tion. For a week before admission she had been unable to read, due to blurring of vision. Occasionally headache was accompanied by projectile vomiting. Her gait became unsteady. She became alarmed over her condition and expressed fears of going insane. Examination: Examination showed advanced bilateral papilledema with retinal hemor­ rhages. The visual fields were intact. There was slight weakness of the right side of the 170 JOSEPH H. GLOBUS

FIG. 4. CASE 2 A. Coronal section of the brain showing the tumor. B. Histologic appearance of the tumor j fairly mature nerve cells with faintly stained glia cells in the background. X 150. Nissl slain. face. The deep reflexes were hyperactive with some increase in the reflexes of the left upper extremity. The abdominal reflexes were depressed and exhaustible. There was moderate intellectual disintegration, with a certain amount of euphoria and jocosity. There was percussion tenderness over the skull, more pronounced on the right. There was some impairment of the associated movements of the right upper extremity. Course: The diagnosis of a cerebral neoplasm was made and, in spite of the right facial weakness, it was believed to be in the right frontal lobe. This localization was suggested by the mental changes and the presence of more pronounced pyramidal tract signs on the left side. The absence of speech disturbance also favored this site. Encephalography was carried out, but unfortunately insufficient air entered the ventricles and little information could be obtained from this procedure. Ventricular puncture was then done. The left lateral ventricle was entered and found to be displaced to the right. The right ventricle was punctured and found to be normal in position. Both ventricles were dilated. Again little air entered the ventricles and the procedure gave no assistance in diagnosis. Because of the displacement of the left lateral ventricle, however, the left frontal region was explored. An area of softening was disclosed, but no tumor was found. There was a rapid decline terminating in death. Gross Necropsy Findings: On sectioning of the brain, a tumor was found (Fig. 4A) ex­ tending from about the frontal pole back as far as the anterior pillars of the fornix. At the frontal pole it occupied the entire subcortex. Further back it was found to occupy the sub­ cortex below the corpus callosum, infiltrating the septum pellucidum and displacing it. The tumor, when traced posteriorly on the left side, was found to infiltrate the white substance surrounding the corpus striatum and the white substance underlying the insula. The neo­ plasm was of a' pearly white appearance, homogeneous in structure, of an elast ic consistency, having the appearance of a myxomatous growth. GLIONEUROMA AND SPONGIONEUROBLASTOMA 171

FIG. 5. CASE 2 A. Histologic appearance of tumor stained by the Bielschowsky silver method. X 315. B. Partially matured neuroblasts. X 2.10. Bielschowsky silver stain. C. Routine preparation showing the presence of mature nerve cells in the tumor. X 140. Hematoxylin and eosin stain.

Microscopic Findings: Sections obtained from the central portion of the tumor and stained by the Nissl method disclosed the characteristic appearance of a glioneuroma (Fig. 4B). There were visible many mature neurons alongside small" undersized" but well dif­ ferentiated nerve cells. In the background there were recognized the faintly stained glial elements. In this case even a routine preparation stained with hematoxylin and eosin re­ vealed well ripened nerve (ganglion) cells (Fig. 5C). When silver stains were employed, 172 JOSEPH H. GLOBUS

FIG. 6. CASE 3 A. Longitudinal section of the brain showing enlargement of the left hemisphere, particularly of the frontal lobe, lodging the poorly demarcated tumor. B. Histologic appearance of the tumor i fairly ripe nerve cells with many faintly stained glial elements. X ISO. Nissl stain. however, infantile (lilliputian) glial structures were found swarming about nerve cells. The latter, being in a stage of full differentiation, displayed exceedingly long processes (Fig. 5A). In other fields by similar staining methods unripe neuroblasts could be readily detected (Fig. 5B).

Comment: This tumor agrees in almost all of its anatomical features with the one in the previous case. Here again the transition of tumor tissue into adjacent normal brain tissue is gradual and hardly recognizable. The cellu­ lar architecture is the same, except that neuroblasts (unripe neurons) are more readily demonstrated. The sudden onset and the vague localizing signs are in accord with the clinical histories obtained in other instances of glio­ neuroma.

CASE 3: A brief episode of loss of consciousness, followed by good health, interrupted by a convulsive seizure, followed by recurrent petit mal attacks; headaches of growing in­ tensity, stupor, and vague localizing signs; death; necropsy. History (Adm. 354261; P. M. 8835): N. E., a woman aged thirty-five years, in April 1932 passed through what was described as a momentary loss of consciousness. She re­ mained well for the subsequent eight months, until December 1932, when her husband, attracted by her scream, found her in a convulsive state with her knees drawn up, arms flexed, head turned to the left, and eyeballs rolled upwards and to the left. Her arms were trembling and she was frothing at the mouth. There was no incontinence or vomiting. The attack lasted about ten minutes and was followed by a feeling of weakness and by severe frontal headache. From that time on she was subject to momentary lapses of con­ sciousness and experienced six major convulsive attacks. None was preceded by an aura. There developed, also, some impairment of vision in the right eye, which was more marked shortly after an attack. For the week preceding admission to the hospital the patient was GLIONEUROMA AND SPONGIONEUROBLASTOMA 173

FIG. 7. CASE 3 A. Island of fairly ripe nerve cells surrounded by neuroblasts in various stages of transition. X 275. Nissl stain. B. Giant multinuclear cell surrounded by a crown of undifferentiated capsule cells. C. Enormous, well differentiated astrocyte surrounded by many atypical elements. X 485. Globus modification of the Hortega silver carbonate method. kept in bed by severe frontal headache. On the night of July 6, 1933, she was given mor­ phine by a physician to relieve her headache which was very intense. She soon became stuporous and was brought to the hospital. Examination: The pupils were dilated and fixed. There seemed to be a left facial asymmetry. The fundi showed only moderate blurring of the margins of the left disc. Course: In the course of the next twelve hours the patient declined progressively; she became markedly cyanosed and her respirations were very shallow. Supportive therapy was without avail, and death occurred shortly thereafter. Gross Necropsy Findings: The brain was swollen; the convolutions were flattened. The 174 JOSEPH H. GLOBUS left cerebral hemisphere was distinctly larger than the right. There, was a tumor involving the whole of the temporal lobe on the left side, extending forward into the posterior part of the frontal lobe, obliterating the Sylvian fissure, and extending upward into the inferior part of the parietal lobe. The tumor appeared, also, to extend across the midline anterior to the optic chiasm. It was firmer in consistency than the rest of the brain tissue. On section, it was pale in color and smooth. It was found in the left hemisphere, mainly in the frontal lobe, involving the anterior two-thirds of that lobe throughout its entire depth (Fig. 6A). The entire left hemisphere was large. The ventricles were enlarged, distorted, and displaced to the right. Microscopic Findings: The histologic character of this tumor is readily recognized in the photomicrograph of a Ni~~l preparation (Fig. 68). Though the cells display the form and structure of well differentiated neurons, they are nevertheless of rather small propor­ tions. A search through the tumor revealed several other typical features, as well as some departures. Thus, groups of larger (ganglion) nerve cells were often found to form small islands (Fig. 7A) amidst poorly differentiated undersized neuronic elements. On the other hand, there were found giant multinucleated cells surrounded by an array of small cells not unlike the capsule cells, enclosing ganglion cells. It seemed quite likely that the giant ceIls were neuroblasts in a dividing phase (Fig. 7B). Enormous but fully differentiated astro­ cytes (Fig. 7C) could also be found alongside atypical nerve cells occasionaIly containing more than one nucleus.

Comment: Aside from the presence of giant cell forms, the cellular con­ tent of this tumor differs little from that in Cases 1 and 2. There is also a close resemblance in the clinical features to the two preceding cases.

CASE 4. Sudden onset wit" a Jacksonian fragment followed by periodically recurrent convulsive seizures; mental deterioration; tremor GI/d forced grasping of left hand; euceph­ alograp"y,. craniotomy; removal of tumor; subdural bleeding; death, History (Adm. 392865; P. M. 9930): W. A., a white man aged forty-five years, had a lapse of consciousness two years and two months before entering the hospital. While driving his car he first experienced twitchings of his toes, a " peculiar feeling inside of him," and mild dizziness. He apparently lost consciousness for a while, for he had slumped over the wheel and his car had veered. This was noted by a cab driver, who brought the car to a stop. On regaining consciousness the patient returned home. feeling weak and dizzy. During that night he passed through six convulsive seizures, each lasting about twenty min­ utes. They were described as generalized twitchings, accompanied by complete loss of consciousness and biting of the tongue. During the following months the convulsions re­ curred periodically, but grew less frequent in occurrence and steadily milder in character, so that more recently they had not been accompanied by loss of consciousness and were limited mainly to the left side. At the same time, the patient's memory showed progressive impairment, particularly for recent events. and he became irritable and quarrelsome. There developed unsteadiness and twitching of the left hand with inability to release an object in its grasp without effort. Examination: The positive neurologic findings included unequal pupils, the left being larger than the right (both reacted well to light and in accommodation); left-sided hemi­ paresis with left foot drop; left forced grasping; increased deep reflexes on the left side; absence of abdominal reflexes on the left side; a Babinski sign on the left side; left-sided hemihypalgesia. Course: In the absence of fundus changes or other manifestations of increased intra­ cranial tension, encephalographic studies were found necessary to establish the existence of an expanding intracranial lesion. They disclosed marked depression of both lateral ven­ tricles and obliteration of the subarachnoid channels on the right side. suggesting the presence of a large mass in the right side of the brain. There was a concavity in the superior surface of the lateral ventricle which was probably also due to impingement by the mass. The lesion was thought to be in the right parietal or frontoparietal region. A right frontal craniotomy was performed and the major portion of the tumor was GLIONEUROMA AND SPONGIONEUROBLASTOMA 175 removed. The patient at first reacted well, but somewhat later became drowsy and re­ mained in that state for four days. He died on the fourth day after operation. Gross Necropsy Findings: A large accumulation of clotted blood was found between the dura and skull. At one point it was large enough to have indented the brain. There was a small amount of blood in the region of the operation. In the brain substance in the right parietal lobe, adjacent to the falx, was a large defect filled with clotted blood and partly macerated tissue. It was thought that tumor tissue still remained for some distance about the defect. This area of the brain was of increased consistency and in certain portions felt nodular; it showed a violaceous discoloration and was intensely hyperemic. The left hemisphere was normal to palpation and in appearance. The corpus callosum appeared to be slightly thinned out.

FIG. 8. CASE 4 Histological appearance of the tumor i many nerve cells of various sizes in various stages of maturation. X 200. Nissl stain.

Microscopic Findings: Material removed at operation was reported as spongioblastoma of the type usually associated wit!l tuberous sclerosis. It was described as follows: "The tumor is of a very cellular pattern. The cells lie in a background of densely woven glia fibers. It is a highly vascular tumor and there is marked endothelial proliferation. There are many small areas of pericapillary and peri-arteriolar hemorrhage. The cytoplasm in many cells is abundant and the nuclei are both centrally and eccentrically placed. The cytoplasm of some is densely stained. in others pale. It is usually irregular in outline, but no processes are made out in the hematoxylin and eosin stained preparation. The nuclei are of all sizes and shapes, some extremely large and pale with little chromatin. Many are elongated and have the cytoplasm at both poles. Many of the nuclei, especially the larger ones, have nucleoli, and some have two nucleoli. One cell was seen undergoing mitotic cell division. Multinuclear giant cells are numerous. Most of the cellular elements are fairly well differentiated, some approaching mature astroglia. Silver stains reveal fairly mature glial cells." On a restudy of the structure of the tumor with the aid of the Nissl staining method, 176 JOSEPH H. GLOBUS applied to the surgical material as well as to fragments of tumor tissue discovered in the brain about the postoperative excavation, the tumor was found to be a typical glioneuroma (Fig. 8).

Comment: It is significant that the routine examination of this tumor re­ vealed some features which indicated its close relationship to gliogenous tu­ mors often associated with lesions of tuberous sclerosis. The significance will be more obvious when the histological features of the spongioneuro­ blastoma, discussed elsewhere in this paper, are considered.

CASE 5. Recurrent Jacksonian attacks; impaired memory; emotional instabilit».. mani­ festations of increased intracranial tension.. signs pointing to neoplasm in left hemisphere; encephalography .. craniotomy.. rapid decline; death. History (Adm. 320101; P. M. 7472): A. H., a white man aged fifty-one years, was well until six months prior to admission to the hospital, when he experienced severe headache and pain in the lumbar region, lasting for a few hours. Shortly after this he began to have repeated convulsive seizures characterized by clonic contractions affecting the right arm and leg. These seizures lasted about two minutes and were occasionally accompanied by a fall, but never by loss of consciousness. There was no aura and the patient could never predict an attack. During the seizures, which occurred from one to four times a day, he would feel dizzy and would occasionally lose control of feces and urine. In the course of time his memory had become somewhat impaired and he displayed a certain amount of emo­ tional instability. In the course of two months he lost twenty pounds in weight. Examination: There was a right facial weakness, central in type, more marked on mimetic innervation. The tongue deviated to the right. The deep reflexes were more active on the right. All abdominal reflexes were diminished. Olfactory acuity was dimin­ ished on both sides. There was a mild tremor on the finger-to-nose test on the right side and a tendency to grasp reflex on the same side. Bilateral papilledema was present. OD: 2D and OS: 3D. The pulse was slow; the blood pressure was recorded as 146 systolic and 88 diastolic. Course: The diagnosis of a neoplasm of the left hemisphere was made. In order to verify this diagnosis, 150 c.c, of air were injected by the endolumbar route. The enceph­ alogram was reported as follows; "The left lateral ventricle appears somewhat dilated but normal in position, and apparently compressed from below. The anterior horn of the right ventricle is well visualized and is distinctly dilated. There is a further collection of air above the right lateral ventricle with what appears to be a fluid level. A calcified shadow, probably the pineal, is distinctly displaced to the right, and the third ventricle, although normal in size, is also displaced in the same direction. The fourth ventricle is normal in size, shape and position. The subtentorial air is well shown and is normal in distribution. No air is noted in the subarachnoid space. The findings suggest the presence of a mass in the left parietal region, superior to the cerebellum." Of interest in this report is the fact that the ventricle on the side of the tumor was dilated. Following encephalography the patient passed into deep stupor. His pupils became dilated and sluggish to light; the corneal reflexes were diminished. There were periodic clonic movements of the right arm and, to a lesser degree, of the right leg, which was in a state of tonic extension. There was a bilateral Babinski sign, and bilateral ankle clonus. A spinal puncture yielded turbid fluid under increased pressure containing 2,000 cells. The patient gradually came out of the stupor and, when examined, was found to be greatly con­ fused. There was a suggestion of temporal anomia and perseveration. There was a tremor of the right upper extremity. The reflexes were more active on the right side and the plantar response on the right side was poor. There was bilateral astereognosis but, because of the patient's mental condition, this was not regarded as significant. A craniotomy disclosed an infiltrating mass in the left prefrontal area. The surgeon was uncertain whether or not he was dealing with some infiltrating sclerotic process. A portion of the mass was then removed and was later reported to be a fragment of spongio- GLIONEUROMA AND SPONGIONEUROBLASTOMA 177

FIG. 9. CASE 5 A. Coronal section of the brain showing enlargement of the left hemisphere and the poorly demarcated tumor. B. Histological appearance of the tumor, showing the infiltration of a blood vessel with numerous nerve cells in various stages of differentiation. X 140. Nissl stain. Compare with 9C. C. Section of a fetal brain showing an accumulation of developing nerve cells along a vas­ cular channel. X 255. Nissl stain. neuroblastic tissue. Two days later the patient passed into deep stupor, the blood pressure dropped to 60 systolic and 40 diastolic, and the temperature rose. He died on the following day without regaining consciousness. Gross Necropsy Findings: The brain was voluminous. The left hemisphere was much larger than the right and displayed a crater-like defect. Directly above this defect and in front of it were a few gyri which bore a close resemblance to convolutions seen in tuberous sclerosis. On incision, a large area of increased rubbery consistency was found in the left hemisphere (Fig. 9A). It cut with difficulty. Its margins were not discrete and were recognized mainly on palpation, where the consistency differed from the adjacent, less in­ volved tissue. It extended from the frontal pole as far back as the anterior margin of the parietal lobe, occupying almost the entire width of the hemsiphere, involving for a dis­ tance the outer part of the corpus striatum. A similar area was found in the left parietal region at the point of its transition to the occipital lobe. The ventricular system was distorted and displaced to the right. The right lateral ventricle was distended, the left was compressed. Microscopic Findings: The histology of the tumor varied little from that in the pre­ ceding case. Of significance here was the finding of nerve cells in various stages of matura­ tion assembled about blood vessels and in the interspaces of the adventitia (Fig. 9B). This is not unlike the condition prevalent in the brain of the infant, when nerve cells are seen gathered about vessels (Fig. 9C).

Comment: It is significant that the diagnosis from the surgical specimen was diffuse spongioneuroblastosis, a form of tuberous sclerosis, and that at autopsy the gross inspection of the brain led to the impression that the case was one of tuberous sclerosis. 178 JOSEPH H. GLOBUS

FIG. 10. CASE 6 A. Coronal section of the brain showing enlargement of the right frontal lobe, the somewhat better demarcated tumor and a cyst within the tumor. B. Blood vessel showing the adventitia infiltrated with maturing nerve cells. C. Large vessel and smaller vessel, the walls of which are infiltrated with numerous neuroblasts,

The relationship of nerve cells to the blood vessels is also of significance, in so far as it serves to emphasize the fact that in the gangliogliomas there is a tendency to reproduce the pattern of the developing brain tissue.

CASE 6. Sudden onset of headache, followed by impaired vision and sensory disturb­ ll1ICeS in the right hand ; bilateral papilledema,. vague localizing signs; subtemporal decom­ pression; fatal bronchial pneumonia. History (Adm. 318436; P. M. 7388): L. B., a white woman aged thirty-six years, was well until three weeks before admission to the hospital. Then, following the evening meal, she suddenly became ill and vomited voluminously and repeatedly. Severe occipital head­ ache developed and in the course of the next two weeks vision became slightly impaired and the patient occasionally experienced sensations of pins and needles in the right hand. Examination .. There was moderate hypertension. All the deep reflexes were depressed; the superficial reflexes were diminished. There was bilateral papilledema with retinal hem­ orrhages, more pronounced on the right side. The cerebrospinal fluid was under increased pressure (220 mm. of water). There was tenderness over the left mastoid, with evidence of a chronic purulent otitis media of the left ear. Course: In view of an old history of otitis media and a discharging ear, the proba­ bility of a simple uncomplicated mastoiditis was suggested by the otologist, and the possi­ bility of a suppurative intracerebral process was considered. Accordingly, a mastoidectomy was performed, but no evidence of a suppurative process was uncovered. This operation was followed by the development of a left peripheral facial palsy, which was thought to be traumatic. However, as there also developed hyperactive right knee and ankle jerks. a brain abscess in the left temporal lobe was suspected and an exploratory craniotomy was advised. The left ventricle was punctured and found to be of normal size, and hence a subtemporal lesion was excluded. A subtemporal decompression on the right side was then carried out, and an aspiration needle was introduced, recovering xanthochromic fluid. Soon after the operation the patient passed into deep coma, developed a flaccid hemiplegia on the left side, and a bronchopneumonia, terminating fatally on the day following the operation. Gross Necropsy Findings: The surface of the brain showed evidence of a marked in­ crease in intracranial pressure. There was some disorganization of tissue in the tempore- GLJONEUROMA AND SPONGIONEUROBLASTOMA 179

parietal region on the right side and, to a lesser extent, on the left side. On palpation there was noted an increased resistance of the right frontal lobe, which also appeared to be hyper­ trophied. The tumor was found in the right frontal lobe, extending from the tip of that lobe as far back as a point in line with the genu of the corpus callosum (Fig. lOA). In the most anterior part of the tumor was a cyst occupying an area about 3 em. in diameter. It was irregularly circular in outline. Microscopic Findings: The cellular structure of the tumor in this case (Fig. lOB and C) parallels closely that of Case 5.

Comment: It is not unlikely that the cyst was responsible for the stormy clinical course. Here again nerve cells were found in large numbers in the rather thick walls of the larger vessels.

CASE 7. Recurrent Jacksonian seizures [ollounng alleged trauma to the head; met/tal deterioration; localizing signs uncertain; encephalography ; craniotomy; fatal issue. History (Adm. 384393; P. M. 9691): T. M., a white male aged thirty-two years, was said to have had some gastro-intestinal complaints, described as " sour stomach," for several years before the onset of the fatal illness. Ten months before admission to the hospital he received a blow on the head. (He was said, also, to have received a blow to the head at the age of fifteen years.) He did not become unconscious, but on arriving home he felt ill, did not care to eat, and retired to bed. The following morning he awoke suddenly with both arms and the right leg in a convulsive seizure. It was of short duration and without loss of consciousness, but was followed by a feeling of general weakness. The patient nevertheless went to work. Soon, however, he began to display irritability and a moody disposition. He ignored what was said to him as though he did not hear it, making no attempt to reply. At one time, while at work, he suddenly seized a vacuum cleaner and smashed it to the ground. Soon afterward he was seized by a convulsion accompanied by apparent loss of consciousness. The attack lasted twenty minutes. In the course of the next few weeks he had several more convulsive seizures which appeared to affect mainly the right side of the body. A physician for some reason advised appendectomy, which was carried out. During the early postoperative days the patient had several convulsive seizures, after which he was free from attacks for three months. One week prior to admis­ sion to the hospital he suddenly fell and a generalized convulsion ensued. This time froth appeared at the mouth and he bit his tongue. Several seizures of a similar character fol­ lowed. As on other occasions, the right side was more affected than the left. Examination: The pupils were unequal, the right being larger than the left and sluggish to light; both reacted well in accommodation. The discs showed slight fullness of veins. There was a right lower facial weakness. The visual fields were negative. The gait was slow and unsteady, with some reeling to the right. The right arm did not swing but swayed and drifted on extension. There was a Romberg sign, and ataxia of the right upper and lower extremities. Speech was dysarthric and often incoherent, due to omission of words. There was generalized hyperreflexia, the right deep reflexes being more active than the left. There was transient ankle clonus bilaterally, greater on the right than on the left. The abdominal reflexes were diminished on the right side. An equivocal Babinski sign was pres­ ent on the right side and poor plantar flexion on the left. There were no sensory changes. A lumbar puncture yielded clear cerebrospinal fluid under normal pressure. Course: In view of the history of trauma, a diffuse degenerative process of the brain affecting the left hemisphere more than the right was considered. A considerable intel­ lectual defect was present, indicating an early organic psychosis. While under observation, the patient passed through a convulsion in which the forearm and hand on the right side were held up with the fingers in abduction and slight flexion. The hand displayed a tendency to tremor and some large involuntary excursions from right to left. During the episode the patient was fully conscious and repeated the words, ,; Power, power." The episode lasted but one minute. Encephalography was carried out and the report was as follows, "There is a distinct displacement of the ventricular system to the right, more marked anteriorly than posteriorly. 180 JOSEPH H. GLOBUS

FIG. 11. CASE 7 A. Coronal section of the brain showing enlargement of the left hemisphere and an area of discoloration pointing to the more vascular part of the tumor. B. Histologic appearance of the tumor; many well formed nerve cells. X 240. Nissl stain.

The left lateral ventricle is normal in size but is displaced downward and the relationship of its anterior to its posterior horns is broadened. The right lateral ventricle is normal in size but is somewhat compressed in its lateral diameter. The third ventricle is also slightly displaced to the right. There are no subarachnoid markings on the left; those on the right appear normal, Air is seen in both subtentorial regions. The space on the left side is distinctly narrower than on the right. The basilar cisterns are normal in size and con- GLIONEUROMA AND SPONGIONEUROBLASTOMA 181

FIG. 12. CASE 7 A. Section of the tumor showing a number of germinal centers represented by the spherical areas of dense collections of cells. ,x 210. Hematoxylin and eosin stain. B. Section of the tumor showing examples of atypical vacuolated giant cells and bipolar spongioblasts. X 200. Globus modification of the Hortega silver carbonate method. figuration. The appearance is very suggestive of a left-sided mass, probably in the para­ sagittal region anteriorly." An exploratory craniotomy disclosed no tumor. Following the operation aphasia increased and complete right-sided hemiplegia developed. The pa­ tient passed into coma and died without regaining consciousness. Gross Necropsy Findings: The left hemisphere was larger than the right. In the medial longitudinal sulcus was seen a tongue of cortex projecting from the medial surface of the frontal lobe lodged in a defect in a corresponding portion of the frontal lobe. It marked the location of the tumor, which was found in the depth of the dorsal longitudinal fissure, 182 JOSEPH H. GLOBUS occupying the mesial surface of the left frontoparietal lobe (Fig. 11A). The left hemisphere seemed to project over the right, with some displacement of the falx with the opposite lobe. Anteriorly the tumor extended to within almost 1.5 em. of the frontal pole. Microscopic Findings: The general architecture of the tumor was in the main similar to that in the preceding cases; neurons in various stages of differentiation were found scat­ tered among more numerous glial elements (Fig. 11B). In addition, there was observed an aggregation of cells in little nodules, recalling the similar aggregation in the infant's brain, where they serve as germinal centers (Fig. 12A). In other parts of the tumor degenerating vacuolized giant cells, basket-like cell arrangement, and bipolar spongioblasts were common (Fig. 12B).

Comment: In this case the presence of germinal centers adds further weight to the probability that in the gangliogliomas one deals mainly with a blastomatous malformation. In practically every case of this group there were encountered various remnants of the embryonal stages in brain forma­ tion. The tumor, thus being in the nature of a blastomatous malformation, could under no circumstances be caused by the alleged head trauma, whether recent or old, nor was there any evidence of influence of the trauma on an already existing tumor.

CASE 8. Recurrent convulsive seizures ; gradual mental deterioration ; status epilep­ ticus ; fatal termination. History (Adm. 258602; P. M. 5151): V. M., a white married woman, aged twenty-two years, had experienced suddenly and for the first time, at the age of sixteen years, a series of generalized convulsions. Since then convulsive attacks had occurred daily in milder or more severe forms, with occasional periods of relief for several days. In a mild attack the body would stiffen, the eyes would become glazed, and the patient would rub her hands, re­ peating the phrase, "what you say." More severe attacks were accompanied by loss of consciousness and stiffening of the body; the extremities became flexed and rotated in­ ternally; clonic twitchings of the body, biting of the tongue and frothing at the mouth followed; the eyes rolled up and there appeared to be difficulty in breathing. During one of these episodes a mental disturbance developed for which the patient had to be sent to a state hospital. During the past year she appeared to have improved, but three days prior to admission to the hospital she passed through a severe attack and became dull and apathetic. Examination: The pupils were unequal, the right being larger than the left. They reacted promptly to light and in accommodation. The fundi were normal. The deep re­ flexes were increased on the left side and there was a bilateral Chaddock sign. Course: Shortly after admission to the hospital a convulsive attack occurred. This began with tonic spasm of the entire body; the fists became clenched, the legs flexed, and the lips were cyanotic. The eyes deviated to the right. The attack, lasting several minutes, recurred almost hourly for the next two days. The patient finally sank into stupor. A lumbar puncture yielded cerebrospinal fluid under increased pressure. On the fourth day in the hospital status epilepticus supervened and death ensued within a few hours without return of consciousness. Gross Necropsy Findings: The brain was voluminous; the gyri were flattened and the leptomeninges showed an area of discoloration over the occipital lobe. On incision, a large neoplastic mass was found replacing almost the entire right temporal lobe and a large part of the right occipital lobe (Fig. 13A). Dorsally it displaced upward the inferior frontal convolution; anteriorly it extended as far as the temporal pole, and posteriorly as far as the middle of the occipital lobe. It invaded the island of Reil and the corpus striatum. The tumor was somewhat soft but tenacious, smooth, and yellowish in color. A few cysts were seen in its depth. It had a myxomatous appearance. It was poorly demarcated from the surrounding normal tissue. The right ventricle was compressed, the left dilated. GLIONEUROMA AND SPONGIONEUROBLASTOMA 183

FIG. 13. CASE 8 A. Coronal section of the brain showing enlargement of the right temporal lobe which con­ tains a poorly demarcated tumor. B. Section of the tumor showing the embryonal pattern of the vascular channels. X 160. Globus modification of the Hortega silver carbonate method.

Microscopic Findings: The gradual transition of the tumor into the apparently normal cortex made it difficult at first to recognize the fact that the neurons were tumor cells (Fig. 14A). In the beginning it was thought that the cells were either extensions from the normal cortex, or normal cortex caught in the midst of an invasion by neoplastic glial cle­ ments, but the small size of the neural elements, their incomplete maturation, and their close resemblance to similar cells in other glioneuromata, as well as their distinct difference from the neurons in the normal cortex, made certain their neoplastic origin. Moerover, the background of neoplastic glia added further proof of their blastomatous character. By special staining method these glial elements could be recognized as distinct and fairly well differentiated astrocytic structures (Fig. 14B). An embryonal pattern of the vascular channels (Fig. 13B) was observed, as well as many cyst-like defects. FIG. 14. CASE 8 A. Histologic appearance of the tumor; numerous nerve cells in various stages of ripening with a background of poorly stained glial elements. X 200. Nissl stain. B. Section of the tumor showing the character of the glial cells. X 240. Globus modification of the Hortega silver carbonate method.

184 GLIONEUROMA AND SPONGIONEUROBLASTOMA 185

Comment: Attention is drawn to the presence in the tumor of a vascular pattern which is seen in the infant's brain. It is another feature which, in common with others already noted, points to the probability that here also the neoplastic lesion is but a part of a blastomatous malformation.

CASE 9: Recurrent headaches; alexia; aphasia; agraphia; paresis of the right arm; transient loss of consciousness ; tremor of right leg; semistupor; exploratory craniotomy; biopsy; decline; death. History (Adm. 403997; P. M. 10220): L. Z., a white woman aged fifty-five, who was subject to recurrent headaches for many years, four months prior to her admission to the hospital began to have difficulty in recognizing letters, although vision seemed to be un­ impaired. This trouble increased so that there occurred periods during which she found it

FIG. 1$. CASE 9 Longitudinal section of the brain showing enlargement of the left hemisphere and the ex­ tensive tumor. impossible to read. She soon began to experience difficulty in writing, also, although there was no apparent weakness of the arm. This was followed by the development of difficulty in finding the proper word to express herself, so that she would break off in the middle of a sentence and start a new idea. She became irritable and suspicious. She remained in this condition until two weeks before admission, and at that time began to complain of paroxysms of severe frontal headache accompanied by nausea. Progressive loss of power in the right arm developed, and the patient was seen occasionally to elevate the right elbow at right angles to the body and hold it in that position until it was gently put back to the side. More recently she could no longer recognize letters and was unable to construct a sentence correctly. She displayed marked general weakness and took to bed. Two days before admission she suddenly lost consciousness for about ten minutes. On regaining consciousness she vomited. Twitching of the right leg and sagging of the right side of the 186 JOSEPH H. GLOBUS

FIG. 16. CASE 9 Histologic appearance of the tumor showing many unripe nerve cells, X 500. Nissl stain. face became noticeable and she seemed to be unable to move the left arm. She became incoherent. Examination: The patient was somnolent, unresponsive, and apparently aphasic. There were tenderness over the left parietal region, weakness of the right arm and leg, and a tremor of the right arm. The deep reflexes were active, more so on the right side. The right abdominal reflexes were absent. There was plantar flexion on the right side. The cerebrospinal fluid was under increased pressure (210 mm. of water). The blood pressure was 130 systolic and 90 diastolic. Course: The diagnosis was neoplasm of the left cerebral hemisphere, and exploratory craniotomy was performed. An area of increased resistance was noted in the region of the angular gyrus. An incision was made into the cortex and a small amount of hard, somewhat fibrotic tissue was removed. The patient declined rapidly and died two days after the operation. Gross Necropsy Findings: The left hemisphere was larger than the right and all the gyri were flattened. On the inferior surface of the brain, at about the junction of the inferior temporal and occipital lobes, was a hard mass with indefinite boundaries which, on section, showed a gelatinous consistency. On sectioning, a large tumor was found oc­ cupying the entire subcortical region of the left parietal occipital region and extending anteriorly into the posterior half of the temporal lobe (Fig. 15) ventrally and mesially so as to leave but a very narrow rim of cortex, while dorsally it ended at a point on a level with the lateral fissure and slightly above it in the parietal region. The tumor felt some­ what rubbery and had the gross appearance frequently seen in ganglioglioma or neuro­ spongioblastoma. The ventricles were distorted, the left lateral ventricle being displaced dorsally; this was true particularly of the posterior horn and to some extent also of the anterior horn. All ventricles were somewhat larger than normal, the right perhaps more so than the left, with the outlines somewhat rounded. Microscopic Findings: Histologically this tumor was characterized by the large number of unripe cells. Thus, in a Nissl preparation (Fig. 16) the neurons were recognized as deli­ cate in outline, still poor in tigroid substance, but displaying the clear nucleus and nucleolus. In silver preparation (Figs. 17A and B) their neuroblastic character was well demonstrated. GLIONEUROMA AND SPONGIONEUROBLASTOMA 187

FIG. 17. CASE 9 A. Neuroblasts in various stages of differentiation shown by the Bielschowsky silver stain. X 665. B. Neuroblasts and more mature nerve cells in another part of the tumor. X 890. Biel­ schowsky silver stain.

Comment: In spite of the less differentiated character of the neuronic and glial elements, the case is grouped with the glioneuromas because there were no tuberous nodules elsewhere in the brain. It cannot be classified with the spongioneuroblastomas; at best, it may be regarded as a transitional form be­ tween the two types of the tumor under discussion. 188 JOSEPH H. GLOBUS

CASE 10: Recurrent petit mal attacks (diencephalic fits?); uncinate fits; meager local­ izing signs; sudden loss of consciousness; decerebrate rigidity; exploratory craniotomy; death. History (Adm. 396992; P. M. 10021): H. v. D., a white male, aged fifty years, was well until four years prior to admission to the hospital, when he began to experience episodes characterized by sudden collapse and loss of consciousness for ten to fifteen minutes. He would recover from these "spells" without any ill effects. There were no convulsions, frothing, biting of the tongue, or cyanosis. One year later the attacks were preceded by a "chill running over the body" and by the appearance of goose flesh. The attacks had now become daily events and at times recurred several times during the day. For the past year the patient was frequently annoyed by a bad odor resembling that of rotten eggs, which marked the onset of a seizure consisting of chills, alternating with a feeling of heat in the extremities, terminating in bouts of prolonged deep sleep. During the seven months preceding his entering the hospital he began to experience recurrent intense headache and a noise in the head. His vision became blurred and there developed weakness in both legs. More recently he became aware of clumsiness of the thumb of his left hand, so that he found it difficult to carry out skilled movements, as in buttoning. He became disinterested in his work and irritable. Examination: There was impairment of the sense of smell on the right side. The pupils were irregular, the left larger than the right; both, however, reacted well to light and in accommodation. There was bilateral papilledema, more pronounced on the right side. The visual fields showed slight peripheral contraction. There was a left facial (cen­ tral) paralysis. There was also a questionable weakness of the extremities on the left side. The biceps reflex on the left side was more active than on the right, but the right ankle jerk was more active than the left. The cerebrospinal fluid was under normal pressure and showed four lymphocytes per cubic millimeter. Course: During his stay in the hospital the patient passed through a brief attack of disturbance of consciousness and a generalized "cutis anserina," more pronounced on the left side of the body. It was regarded as a fragment of a diencephalic fit. The diagnosis of a cerebral neoplasm located in the right temporal lobe was considered. On Aug. 17, 1936, the patient suddenly went into coma and presented the picture of decerebrate rigidity. Hypertonic glucose was given without definite improvement. Ventricular puncture was performed, followed by an exploratory craniotomy. The neoplasm was found in the right temporal lobe. Part of it was removed, but the patient failed rapidly and died shortly after the operation. Gross Necropsy Findings: The right half of the brain was larger than the left and caused the sagittal fissure to be pushed toward the left side of the midline. The gyri were flattened and the sulci were narrowed. The temporal lobe on the right side was the seat of a large (postoperative) necrotic hemorrhagic excavation. The antero-inferior part of the middle fossa of the skull on the right side was crepitant to touch, showing that the bone of that portion was thinned out. The olfactory tract on the right was also thinner than that on the left. On sectioning, a large defect was found in the right tempore-frontal region. Part of it was due to the surgical procedure, part to the removal of blocks for histological study. Adjacent to this defect in the region of the island of Reil, involving the putamen, was an area of discoloration, lenticular in outline, of a dark brownish red hue, consisting apparently of congealed blood. Section through the pons at its anterior extremity showed a very extensive hemorrhagic area extending throughout the entire tegmentum and down into the basis pedunculi. The ventricular system was enlarged and deformed. Microscopic Findings: Sections of the surgical specimen, as well as from small parts of the tumor left in the surgical defect, revealed a typical picture of glioneuroma.

Comment: Here again the localizing signs were meager, but of great sig­ nificance were the Jacksonian" equivalents," under which may be grouped the diencephalic and the uncinate fits. GLIONEUROMA AND SPONGIONEUROBLASTOMA 189

CASE 11: Recurrent convulsive seizures; signs of increased intracranial tension; vague localization; ventriculography; death. History (Adm. 270290; P. M. 5468): M. P., a married woman aged forty-one years, was well until about nine months before entering the hospital. She then began to complain of frequent attacks of dizziness, nausea, and hot flushes. A radical hysterectomy was done for a fibroid uterus. For one month following the operation the patient felt well, and then on the day when menstruation would have occurred she passed through a con­ vulsive seizure with loss of consciousness lasting about five minutes. These attacks recurred every month, lasting longer each time. When an attack occurred the patient would fall,

FIG. 18. CASE 11 Longitudinal section of the brain showing enlargement of the right hemisphere and the vas­ cular part of the poorly demarcated tumor. no matter in what position she happened to be. The second month she complained of dizziness, severe headache, and falling to the left. Finally the frequency of the convulsive attacks forced her to bed, and led to hospital admission. Examination: Nystagmus was present, more marked to the right. There was bilateral papilledema with retinal hemorrhages. Dysdiadokokinesia was noted on the left side; also a tendency to fall backwards and to the left. There was a right Babinski sign. Course: The diagnosis of neoplasm was made, but its site was uncertain and, because of a probable posterior fossa localization, ventriculography was resorted to. But little air entered the ventricles and their outlines could not be made out. Following this procedure the patient developed transient visual hallucination. On the third day following the opera­ tion she passed into stupor and died soon thereafter. Gross Necropsy Findings: The brain was under increased pressure. The meninges were free of changes with the exception of a wide area in the region of the lower part of the 190 JOSEPH H. GLOBUS

frontal lobe, where it was somewhat opaque. On incision, a large infiltrating mass was found involving the frontoparietal and the temporal lobes of the right hemisphere (Fig. 18). The tumor presented a markedly hemorrhagic center with a more or less gelatinous periphery. The corresponding hemisphere was swollen and edematous. The lateral ven­ tricle on the left side was compressed in its anterior horn and body, normal in the descending horn but markedly distended in all the branches on the left side. The third ventricle, par­ ticularly in the anterior portion, was also almost completely obstructed. Microscopic Findings: The histologic structure of the tumor corresponded in its main features to that of the previous cases.

Comment: Sections of the tumor when studied routinely showed it to be invasive in character and a densely cellular glial cell neoplasm. Numerous giant cells were observed. It was regarded as a transitional form of glioma. The gross appearance, however, resembled so closely that of the glioneuroma, that it was decided to have it restudied with the aid of the Nissl method. It was then found to be another instance of glioneuroma. The gelatinous aspect of the surface of the tumor was noted when the gross appearance was de­ scribed some twelve years ago.

CASE 12: Recurrent attacks of loss of consciousness accompanied by convulsions ; head­ aches; mental changes; signs pointing to expanding lesion ill the left hemisphere. History (Adm. 352710; Surg. 47942): T. B., a housewife aged forty-two years, three years before admission to the hospital became subject to convulsive seizures. The latter, ushered in by sudden loss of consciousness. became generalized and were accompanied by incontinence and biting of the tongue. During the three months preceding her hospital admission the patient began to experience head pains localized to the left side of the occiput and neck. There also developed a buzzing sensation in both cars, but mostly in the left. For the last month there had also been speech difficulty; the patient was unable to find words with which to express herself. Mental and personality changes had developed. Examination: The patient was somewhat somnolent, not fully oriented and, though apparently willing, was not able to give full cooperation. There was bilateral papilledema; a right central facial weakness was most pronounced on mimetic innervation. The right upper extremity was somewhat paretic. The right biceps reflex was more active than the left; the left ankle jerk was more active than the right; all other deep reflexes were hyper­ active and equal. The gait was somewhat guarded, with a tendency to veer to the right. Speech was defective, particularly when the patient was called upon to give names and numbers. The skin over the right leg displayed numerous nevi; there was a fibroma in the pubic region. The face was covered by an eruption. Course: With the above findings in mind, the following note was dictated by me: "The history of convulsive seizures occurring in adult life. the changes in intellect, the numerous pigmented nevi and the skin eruption of the face would suggest the diagnosis of tuberous sclerosis with a neoplasm in the thalamo-striatal area on the left side." Ventriculography was performed and the report was as follows: "Both lateral ven­ tricles are fairly well outlined. There is definite displacement of the interventricular septum to the right. The left lateral ventricle appears to be somewhat smaller and distorted. The third ventricle is fairly well seen. It appears normal in size. The fourth ventricle is not clearly seen. The appearance is that of a left-sided mass." Craniotomy was performed by Doctor Ira Cohen, who made the following report: "In the pre-Rolandic area cystic fluid was encountered and the dura was then opened bv an L-shaped incision extending along the base of the flap and upward along its anterior margin, The tumor, or rather its outcropping, was then seen on the surface and could he palpated as distinct from the rest of the brain. Although it was infiltrating, its limits were well de­ fined. It measured approximately, when finally exposed, 8 em. in diameter, and extended into the depths for a distance of 4 cm. It had two cavities containing yellow fluid. Its surface outcropping was a little bit purplish. Surface vessels were coagulated, cortex in- GLIONEUROMA AND SPONGIONEUROBLASTOMA 191 cised with a cutting current, and the rest carried out by finger and scissors, so that a disc­ shaped piece of tumor with the above-mentioned dimensions was lifted out. The little tumor left at the margin below was then excised. The operator firmly believes that he went well beyond the tumor in all directions." The postoperative course was satisfactory. Improvement was noted immediately in mentality, speech, and vision. There were no more convulsive seizures. The histologic report on the tumor was as follows: "Section of the tumor tissue shows a cellular structure made up of large cells with round vesicular nuclei. The cytoplasmic structure is irregular with numerous processes which intermingle densely to form a glial network; the latter is demonstrated mainly by special silver stains. The nuclei are mainly round with a definite nuclear membrane and sparse chromatin. However, many variant forms are also noted: more mature deeply staining nuclei, larger irregular nuclei suggesting giant formation, and occasional bizarre forms. Mitotic figures are present though not

FIG. 19. CASE 12 Histologic appearance of the tumor; many nerve cells in various stages of ripening. X 200. Nissl stain. frequent. In many areas there are large spaces contammg serous hyaline staining ma­ terial. The tumor is well vascularized and shows scattered focal areas of hemorrhage. There is no evidence of capsule formation and for the most part the tumor invades the adjacent brain tissue diffusely; however, in one area it is separated by a distinct hemor­ rhagic line of demarcation. Diagnosis: Transitional glioma, potentially malignant." The patient remained well for several months and then experienced a generalized con­ vulsion. She was readmitted to the hospital and was found to be somewhat dull. She displayed a right mimetic facial weakness, absence of the right ankle jerk, a right Babinski sign, and diminished right abdominal reflex. She remained in the hospital one week, during which time there was no recurrence of convulsions, and was allowed to return home with the instruction to take small doses of phenobarbital. In the four years following craniotomy the patient was seen and examined periodically (twelve times) in the Follow-Up Clinic. During these four years she had four convulsive seizures (all during the first two years). More recently, aside from minor complaints, such 192 JOSEPH H. GLOBUS as a rare headache or fatigue, she has remained in good health, ful1y able to carryon her house duties.

Comment: The fact that this patient made such a good and so well sus­ tained a recovery led me to restudy the surgical specimens, with the result that the following report was submitted to Doctor Ira Cohen: II The fact that the patient remained well, without any recurrence of ill­ ness over a period of four years, raised a suspicion as to the correctness of the original diagnosis of transitional glioma. II The material was then reexamined, grossly as well as microscopically, and the first striking observation was that the tumor, although fixed in forma­ lin for a long period of time, still had retained the peculiar slimy feeling and the peculiar rubbery consistence that I have noted in tumors which we now recognize as glioneuroma, previously known as ganglioglioma. Histological studies, particularly by means of the Nissl stains, reveal now that our original diagnosis was, in some way, incorrect because it did not take cognizance of the presence of neural elements (Fig. 19) which were not recognized by silver, gold and other stains. The failure to employ Nissl stains at that time was responsible for the failure to recognize these elements. II The reason for naming it transitional glioma was mainly the fact that the tumor did not fit into the spongioblastoma group, nor into the benign glioma group. Cell forms have been recognized as atypical and difficult for classification and this has led to the use of the term transitional glioma. Now that ganglion cells have been found in various stages of differentiation, it can be said with certainty that we are dealing with a glioneuroma pretty well defined, as far as the larger number of cells are concerned, with a fairly large quota of cells in stages of various differentiation. The tumor now is to be known as glioneuroma. Its malignant properties, while not entirely negli­ gible, are not as great as in the so-called transitional glioma."

Anatomical Observations Summarized The neoplasms which have been described above, under the heading Glio­ neuroma, have several gross anatomical features in common. The tumors are usually poorly delineated, merging almost imperceptibly with the surround­ ing, relatively normal brain tissue. The zone of mergence is represented by interdigitations of normal and neoplastic tissue. Frequently the tumor is recognized mainly by the enlargement of the hemisphere lodging it, by the increased firmness and by the smooth, slimy, mucinous-appearing surface. At times this increased firmness is recognized by the exploring finger of the neuro­ surgeon. Not infrequently the tumor contains one or more large cysts filled with mucinous material, or cyst-like defects of varying sizes and in varying numbers may be scattered throughout the tumor. The ventricular system responds to the presence of the tumor by deformities and displacements in a way and to a degree varying from those seen in supratentorial neoplasms of other varieties. Thus, not uncommonly the ventricle on the side of the lesion is unusually large and shows very little displacement. The tumor shows no predilection for either of the two sides of the brain. GLIONEUROMA AND SPONGIONEUROBLASTOMA 193

TABLE I: Clinical Observations in Twelve Cases of Glioneuroma

Case Mode of Onset Prominent Findings on Admission Outcome 1. Abrupt; mental confusion Mental deterioration; convul­ Subcortical decompres­ sions; meager localizing signs sion; death 2. Abrupt; headache; vertigo; Amblyopia; alexia; papille­ Craniotomy; death pain in the eyes dema; vague localizing signs 3. Abrupt; transient loss of con­ Stupor; uncertain localizing Coma; death sciousness; petit mal attack; signs headache 4. Abrupt; Jacksonian equivalent Recurrent convulsions; sug­ Craniotomy; death gestive localizing signs 5. Abrupt; severe headache Recurrent convulsions; mental Craniotomy; death deterioration; signs of in­ creased intracranial tension; localizing signs 6. Abrupt; headache Impaired vision; papilledema; Craniotomy; death sensory Jacksonian features; vague localizing signs 7. Abrupt (?); convulsion Recurrent convulsions; vague Craniotomy; death localizing signs 8. Abrupt (?); convulsive seizures Recurrent convulsions Status epilepticus; death 9. Insidious; transient loss of con­ Localizing signs Craniotomy; death sciousness; aphasia; agraphia; alexia 10. Abrupt (?); petit mal attacks Vague localizing signs Craniotomy; death 11. Subacute; headache; dizziness; Recurrent convulsions; signs of Ventriculography; death nausea increased intracranial tension; vague localizing signs 12. Abrupt; transient loss of con­ Recurrent convulsions; mental Craniotomy; tumor (gli­ sciousness changes; localizing signs oneuroma) removed; re­ covery; four years post­ operative observation

Of the 12 cases herein reported, 6 occurred in the left hemisphere and an equal number in the right hemisphere. In 8 of the 12 cases, however, the frontal lobe was, either alone or in conjunction with the adjacent lobes, the seat of the tumor. In one instance the tumor was limited to the temporal lobe, in another to the parietal, in two others to the temporo-occipital region. Histologically, these tumors display a remarkable uniformity in cellular contents and arrangement. There are large numbers of fairly well differen­ tiated nerve cells distributed among fairly dense masses of equally well dif­ ferentiated neuroglial elements. The nerve cells have as their characterizing features the relatively small size of the cell body, the paucity of cell processes for the majority of cells, and the rather restricted amount of Nissl substance. The glial elements also have small cell bodies and short and delicate processes. They bear a strong resemblance to glial elements in the young brain. Undif­ ferentiated elements, such as neuroblasts and spongioblasts, are found in small numbers; equally inconspicuous are the giant and other anomalous cells in the majority of instances.

Clinical Observations Summarized An analysis of the clinical manifestations of the 12 cases of glioneuroma described would seem to yield diagnostic leads for the identification and 10- 194 JOSEPH H. GLOBUS calization of the tumor. Such leads may be obtained from a careful study of the mode of onset of symptoms (Table I), the signs and symptoms presented at the height of the clinical course, and a closer study of the incidence and character of convulsive and equivalent seizures (Table II). It is obvious from Table I that convulsive seizures of one form or another mark some phase of the clinical course. The incidence and character of these convulsions are summarized in Table II.

TARLE II: Convulsive Seizures in Glioneuroma Series

Type of Seizure At Onset Jacksonian In 2 cases (5 and 7) Generalized In 3 cases (8,11 and 12) Petit mal attack or equivalents In 6 cases (1, 3,4,6,9 and 10)

It must be borne in mind that in several instances the convulsions were not seen by competent observers and hence their character still remains some­ what obscure. Of great significance is the frequent occurrence of transient loss of consciousness without convulsions and the frequent and abrupt deteri­ oration of intellect and behavior, unrelated to distorted cortical function of a type which may be grouped with seizures allied to Jacksonian attacks. At this point may be recorded the observation that in 9 of the 12 cases no evidence was disclosed to indicate the existence of a disease of the nervous system antedating the onset of the fatal illness. In only one case were epi­ leptiform attacks present for six years preceding the terminal illness; in one, headache was a symptom of long standing, and in one other the preoperative course extended over a period of three years. Another clinical observation of significance is the probability that early in the clinical history evidence of increased intracranial tension is lacking and that encephalography may fail to disclose ventricular distortion.

THE SPONGIONEUROBLASTOMA The spongioneuroblastoma, as already indicated, consists of cell types of a lineage similar to those of the glioneuromas, except that in the spongioneuro­ blastoma they are of a more primitive character. The glial derivatives here are spongioblasts, encountered in the related tumor form known as spongioblas­ toma multiforme, and similarly assume the character of pyriform elements and the multinuclear giant type cells not to the exclusion of more differ­ entiated glial cells. Added to these cell forms, the spongioneuroblastornas contain varying quotas of neuronic elements in early stages of maturation and also present, in various parts of the brain at various distances from the tumor, disseminated hyperplastic lesions, similar to those found in tuberous sclerosis. The coexistence of spongioneuroblastomas with lesions typifying tuberous sclerosis has been designated as spongioneuroblastoma disseminatum. In its gross features the spongioneuroblastoma differs from the glioneu­ roma in that its location is almost invariably deep in the substance of the hemisphere, close to the striothalamic angle. It is friable, has a granular GLIONEUROMA AND SPONGIONEUROBLASTOMA 195

surface, and is more readily distinguishable from the adjacent normal brain tissue. As already pointed out, it is associated with tuberous nodules present in other parts of the brain. Clinically, in some respects the spongioneuroblastomas bear a close re­ semblance to the glioneuromas, This is true particularly of the rather abrupt onset and the frequency with which convulsive seizures mark the clinical course; but the uninterrupted and rapid progression of clinical signs and symptoms in the spongioneuroblastoma is in sharp contrast to the majority of cases in the glioneuroma group. In certain instances which represent transitional forms, this separation cannot, of course, be very sharp.

CASE 13: Recurrent convulsions over a period of one year; sudden development of stupor; no localizing signs; no objective signs of increased intracranial tension; death; necropsy, History (Adm. 279243; P. M. 6457): L. D., a male aged thirty-seven, had been subject during the past year to repeated attacks of generalized convulsions which were favorably

FIG. 20.-\. CASE 13 Coronal section of the brain showing enlargement of the left hemisphere which contains a poorly demarcated brain tumor.

influenced by the administration of luminal. On the morning of admission he suddenly passed into stupor. Examination: The patient was in stupor and restless. The pupils were equal and regular and reacted to light. The fundi were negative. All deep reflexes were intact. There were no pathologic reflexes. A catheter specimen of urine was negative. The cerebrospinal fluid was clear and under normal pressure. Course: The stupor deepened and the patient died without regaining consciousness about five hours after admission to the hospital. Gross Necropsy Findings: The left hemisphere was distinctly larger than the right (Fig. 20A). The convolutions on the left side were flattened. The consistency of the brain was distinctly increased and of rubbery hardness. On section, the hemispheres were distinctly asymmetrical, the left being larger than the right. The left hemisphere showed marked reduction in the gray matter and corresponding increase in the white matter. There 196 JOSEPH H. GLOBUS

FIG. 20B. CASE 13

Histologic appearance of the tumor j poorly differentiated and extremely large nerve cells. X 500. Nissl stain. were no circumscribed areas of softening nor were there circumscribed areas of tumor formation. The lateral ventricle was somewhat distended on the right side and narrow on the left. The ventricular axis was shifted somewhat to the right. The ependyma was normal. Microscopic Findings: There was diffuse gliosis throughout the white matter of the involved hemisphere. The cells were predominantly of the large " giant" type with single or multiple nuclei displaced to the periphery (Fig. 20B). When stained by the Herxheimer method, these cells displayed large quantities of fat. Special silver impregnation stains re­ vealed the glial character of some, while a Nissl stain proved some to be neurons. The search for atypical zones in the right hemisphere was rewarded by the disclosure of minute tuberous nodules and atypical, monstrous giant glial elements.

Comment: The most significant clinical features in this case are the oc­ currence of repeated generalized convulsions for a period of one year, the sudden development of terminal stupor, and the absence of localizing signs and of objective findings of diagnostic significance. Anatomically this case reveals all the cellular alterations seen in tuberous sclerosis, but presents an unusually massive diffuse spongioneuroblastosis in one hemisphere without the existence of a well circumscribed brain tumor.

CASE 14: Jacksonian attacks for fifteetl years; change in personality for one year; signs of increased intracranial tension with recent manifestations of a focal expanding lesiou; craniotomy; death; necropsy. History (Adm. 280865; P. M. 5828): J. N., female aged thirty-five, had been subject to epileptiform attacks since the age of twenty. The convulsions were Jacksonian in char­ acter, limited to the left side of the body, and without loss of consciousness. They oc­ curred about once in two months. During the last year there had been observed a change in personality. The patient was irritable at times, talked irrationally, and expressed ideas of persecution. . GLIONEUROMA AND SPONGIONEUROBLASTOMA 197

FIG. 21. CASE 14 A. Coronal section of the brain showing the enlargement of the right hemisphere and part of the tumor. B. Histologic appearance of the tumor; nerve cells in various stages of ripening. X 445. Bielschowsky silver stain.

Examination: The patient was restless and agitated, delusional, and resisted examina­ tion. Her memory and orientation were greatly impaired. The pupils were unequal, the left being larger than the right, and both reacted well to light and in accommodation. There were bilateral papilledema. left spastic hemiparesis involving the tongue, and diminu­ tion of all forms of sensation on the same side. All deep reflexes were hyperactive, whereas all abdominal reflexes were absent and a bilateral Babinski sign was elicited. Course: The diagnosis of a tumor in the right cerebral hemisphere was made. A craniotomy was performed and a tumor in the cortex of the right cerebral hemisphere was revealed. The surgeon, having noted several hard areas in the neighborhood of the tumor, believed it to be a type associated with tuberous sclerosis. The patient failed rapidly and died the following day. Gross N ecropsy Findings: The convolutions of the cerebral hemispheres, particularly of the right one, were much flattened. Some of the convolutions, particularly those in 198 JOSEPH H. GLOBUS

FIG. 22. CASE 14 A. Section of the tumor showing blood vessels enveloped by many unripe cell clements re­ calling the structure in a fetal brain. X 140. Nissl stain. B. Glial elements. X 140. Globus modification of the Hortega silver carbonate method.

the region of the temporal pole, showed unusual prominence and hardness. In the frontal gyrus, in its middle third, a granular area marked the site of a large, deep-seated tumor (Fig. 21A). Further posteriorly the tumor was in the midline. It almost completely re­ placed the corpus callosum, leaving a narrow band of commissural fibers in the anterior end of that structure. The tumor extended from the knee of the corpus callosum as far back as the splenium. Spreading laterally, it invaded mainly the right hemisphere, oblit­ erating almost all of the landmarks of the thalamus and the mesial part of the lenticular nucleus. GLIONEUROMA AND SPONGIONEUROBLASTOMA 199

FIG. 23. CASE 14 A vessel showing its wall infiltrated by many neuroblastic elements. X 540. Nissl stain

Microscopic Findings: The tumor presented a strikingly uniform histological picture. It was made up of cells which were large in size and frequently multinuclear. On staining with various methods, many were found to be neurons (Fig. 21B). With the Nissl method a frequent finding in the glioneuroma was also observed here: vessels surrounded by many non-inflammatory cellular elements (Fig. 22A), a reminder of an embryonal condition. The character of the cells is better seen under higher magnification (Fig. 23).

Comment: The focal epileptiform attacks of Jacksonian type over a period of fifteen years and the more recent intellectual disturbances are, of course, significant when considered in the light of the generalized disease of the brain. The later appearance of signs of increased intracranial pressure indicates the development of a focal process superimposed upon the generalized lesions in the brain. It is of interest that the surgeon recognized the existence of tuberous nodules while performing the craniotomy.

CASE 15: Abrupt onset of manifestations of increased intracranial pressure with vague signs; sudden death; necropsy. History (Adm. 189170; P. M. 3250): 1. V., male aged fifteen years, six months before admission began to suffer with severe frontal headache of progressively increasing intensity. It was occasionally followed by vomiting and attacks of dizziness and fainting. Vision in the left eye became impaired and failed progressively. Examination: The patient was alert and not acutely ill. There was papilledema of 1.5 to 2.0 diopters in the right eye. In the left fundus the papilledema was less marked, but there was incipient pallor of the nerve. There was a right hemiparesis. Course: While in the hospital, the patient suddenly and without any apparent cause lost consciousness, the pulse becoming rapid and feeble and the respiration slow (4 to 6 per minute). The corneal reflexes disappeared and the limbs became completely relaxed. Death occurred without return of consciousness. 200 JOSEPH H. GLOBUS

Gross Necropsy Findings: The floor of the third ventricle was replaced by a large mass which had the appearance of a cyst pressing on the optic chiasm. On sectioning. of the brain, however, this structure was found to be only a part of a large neoplasm which was embedded in the brain substance in the region of the left basal ganglia, protruding into the third ventricle, completely filling it and closing both foramina of Monro. Both lateral ventricles were greatly distended throughout their extent. Microscopic Findings: Sections taken from various parts of the tumor showed features not unlike those recorded in the preceding case. The tumor cells were arranged about blood vessels or cyst-like openings in a radiating fashion, with their fine filamentous processes directed to the walls of the enclosed structures. In some instances these cellular groupings

FrG. 24. CASE 15 A. The dominant cell type of the tumor. X 100. Bielschowsky silver stain. B. Large atypical ganglion cell. X 700. Bielschowsky silver stain.

assumed the form of rosettes. The dominant cell type was the giant spongioblast (Fig. 24A). A thorough search of the cerebral cortex revealed a number of monster ganglion and glia cells (Fig. 24B).

Comment: This case is of interest mainly because of the similarity of the anatomic findings to those of the preceding case. Because of the meager clinical observations, no instructive conclusions can be drawn.

CASE 16: Awte onset and rapid evolution of Sig11S and symptoms of an expanding intracranial lesion located in the hypothalamic zone; headache; amaurosis, uncinate fits, intellectual deterioration; fatal issue i11 three months; necropsy. History (Adm. 281204; P. M. 5842): A. C., a male aged forty-two, three months prior to admission developed headache, vomiting, and a moderate rise in temperature for a period of three days. It was diagnosed as " grippe" and was followed by a short period of apparent well-being. Soon afterward the patient complained of being annoyed hy a " bad odor" and began to vomit repeatedly. One week later the frontal headache returned and he complained of dizziness, blurred vision, of " seeing black before the eyes" and of continual pain in the right leg. About this time his relatives noticed transient episodes of confusion, especially when he attempted to name members of the family. He was GLIONEUROMA AND SPONGIONEUROBLASTOMA 201 anxious to stay in bed. During the last week he had shown generalized weakness; he had been unable to get out of bed and dropped objects from his hands. His vomiting con­ tinued and became very distressing. He became apathetic, indifferent, dull, disoriented, and incontinent. Examination: The patient seemed dazed, moving about restlessly and aimlessly, resisting examination. The pupils were equal but did not react to light. There was complete amaurosis. The fundi showed bilateral papilledema with hemorrhages and exudates. There were bilateral pyramidal tract signs, more marked on the right side, and complete motor and sensory aphasia. The blood pressure was 130 systolic and 80 diastolic. The blood Wassermann and urine tests were negative.

FIG. 25. CASE 16 Longitudinal section of the brain showing the tumor in the left occipital lobe.

Course: A diagnosis was made of a lesion, most probably neoplastic, in the left hemi­ sphere and invading the corpus callosum. The patient declined steadily, occasionally mani­ festing conjugate deviation of the eyes to the left. Death occurred with terminal pyrexia on the sixth day of his residence in the hospital. His condition on admission was such as not to encourage surgical interference. Gross Necropsy Findings: The brain was voluminous, the left hemisphere being some­ what larger than the right. Their surfaces showed evidence of increased intracranial tension. On section, a large tumor was found in the left occipital lobe (Fig. 25), mesial to the pos­ terior hom and spreading into the pulvinar. It was cystic in places and of rubbery hard­ ness. It contained a hemorrhagic and more meaty nodule in the region of the pulvinar. Microscopic Findings: Sections through the neoplasm showed it to be of gliogenous character not unlike the nodules associated with tuberous sclerosis. The cells were arranged radially, containing large amounts of fat. They were of the large giant-cell type and were frequently multinuclear, differing somewhat from those found in spongioblastoma multiforme by their long processes (Fig. 26). In the cerebral cortex in areas distant from the tumor abnormal nerve cells and glia cells of the type seen in tuberous sclerosis were found quite frequently. 202 JOSEPH H. GLOBUS

FIG. 26. CASE 16 A. Dominant cell type of the tumor. X 445. Bielschowsky silver stain. B. Dominant cell forms. X 445. Globus modification of Hortega silver carbonate method.

Comment: Of significance in this case is the rapid unfolding of the clin­ ical picture with the development of amaurosis, bilateral papilledema, bilateral pyramidal tract signs, aphasia, and terminal pyrexia. The anatomical find­ ings were, as described, typical of disseminated neurospongioblastosis with local intensification of the disease process so as to give rise to tumor formation.

CASE 17: Recurrent weakness of right leg of five years' duration, suggesting progressive extension of a disseminated lesion; recurrent, transient cramp-like pain in right arm and leg.. mental deterioration; aphasia .. encephalograpliy .. death; necropsy. History (Adm. 284769; P. M. 5983): F. R., a female aged forty-two, had been troubled for the past five years with weakness of the right lower extremity. Four months before GLIONEUROMA AND SPONGIONEUROBLASTOMA 203

FIG. 27. CASE 17 A. Longitudinal section of the brain showing enlargement of the left hemisphere and the enclosed tumor. B. Histologic appearance of the tumor under lower magnification. X 130. Globus modifica­ tion of the Hortega silver carbonate method. C. Atypical monster cells, probably nerve cells. X 360. Bielschowsky silver stain. admission to the hospital she had undergone a hysterectomy, following which the weakness in her right leg became more pronounced. Two and one-half months later her right arm became similarly involved. At the same time she experienced repeated attacks of severe cramp-like pains in the right arm and leg, lasting for about ten minutes. Shortly before entering the hospital her memory became poor, her speech became impaired, and the right hemiparesis became complete. Examination: The patient was emotionally unstable. There was a mixed type of aphasia, right temporal hemianopsia, complete right hemiparesis, and impairment of all forms of sensation on the same side. There was also a hyperaffectivity on stimulation of the right half of the body. Pyramidal tract findings, including a Babinski sign and absence of abdominal reflexes, were observed on the right side. 204 JOSEPH H. GLOBUS

Course: The diagnosis of a tumor in the left cerebral hemisphere was made. For more accurate localization encephalography was performed. The patient reacted poorly to this, with development of bulbar signs, and died forty-eight hours later in spite of a ventricular puncture done to release the air which was thought to be responsible for the poor condition. Gross Necropsy Findings: The brain presented evidence of increased intracranial pres­ sure. A large tumor was found in the left cerebral hemisphere on a level with the island of Reil, and directly beneath it (Fig. 27A). The growth invaded the posterior part of the lenticular nucleus and reduced the optic thalamus to a narrow strip on its mesial plane, completely wiping out the posterior limb of the internal capsule. Microscopic Findings: Sections of the tumor revealed a densely cellular, highly vas­ cular neoplasm with extensive areas of degeneration. Here again the nest-like arrangement of the cellular elements was quite characteristic (Fig. 27B). Multinucleated cells, which were numerous and of enormous size, irregular in outline and variable in shape, dominated the histologic picture (Fig. 27C).

Comment: Of note here were the progressive development of a hemiparesis, the cramp-like pains in the right upper and lower extremities, the intellectual disturbances, and speech impairment. All clinical findings pointed to a lesion in the left parietal lobe with extension into adjacent parts of the brain. There was nothing in the clinical picture to suggest the coexistence of tuber­ ous sclerosis.

CASE 18: Abrupt onset of paresthesias; visual impairment; Jacksonian convulsions; progressive development of increased intracranial tension, uncertain localizing sigus ; '?II­ cephalography; exploratory craniotomy; death; necropsy. History (Adm. 277640; P. M. 5709); 1. B., a male aged fifty-six, began to complain of a "burning" sensation in both ears and of dimness of vision three months before ad­ mission to the hospital. Two months later he was suddenly seized with intense pain over the right frontal region and shortly afterwards developed a transient Jacksonian attack which began with twitchings of the right face and rapidly spread to the right arm and leg. It lasted several minutes and was followed later in the day by a similar attack. The patient took to bed and every attempt to get up precipitated a similar attack, preceded by a tingling sensation in the tips of the fingers of the right hand. Examination: The pupils were equal, regular, and reacted well to light and in accom­ modation. The fundi showed moderate sclerosis of the vessels. There was a questionable bilateral ptosis of the eyelids. The area over the right frontal region of the skull was tender to percussion. The deep reflexes were hyperactive but equal on both sides. The abdominal reflexes were intact. There was a bilateral equivocal Babinski sign. The blood pressure was 112 systolic and 70 diastolic. Urine and blood Wassermann tests were negative. Course: The diagnosis of an irritative lesion in the cortex of the left hemisphere of either a vascular or a neoplastic character was made, and the patient was discharged in care of his family physician. He was readmitted one month later because of greater fre­ quency of the Jacksonian attacks. Examination now revealed the following: the right pal­ pebral fissure was wider than the left; there was weakness of the right hand and foot; the deep reflexes on the right side were hyperactive; the right abdominal reflexes were absent. All other findings were as on previous examination. Ventriculography was suggested but the patient preferred to return home. He was readmitted six months later complaining of more severe headaches and more frequent convulsive seizures. He now presented, in addition to previous findings, marked intellectual changes, advanced bilateral papilledema, slight flattening on the left side of the face, and a suggestive Babinski sign on the left. An encephalography was performed and the roentgenogram showed displacement of the body and anterior horn of the left ventricle to the right and upward. Two days later an exploratory craniotomy was performed in search for a tumor in the left hemisphere, but this disclosed only an area of altered cerebral cortex. This was thought to be caused either GLIONEUROMA AND SPONGIONEUROBLASTOMA 205

FIG. 28. CASE 18 A. Section of the left hemisphere showing part of the tumor. Band C. Monster glia and nerve cells. by the deep-seated tumor rising to the surface or by some other disease process. The pa­ tient's condition declined rapidly and he died the following day. Gross Necropsy Findings: In the region of the gyrus marginalis of the left hemisphere was a crater-like defect. The gyrus angularis was flattened and hard. In coronal sections of the brain a tumor was found in the subcortical substance in the region of the middle third of the inferior frontal convolution of the left hemisphere (Fig. 28A). It measured about 2 em. in diameter. A similar mass, somewhat larger in size, was present on the mesial aspect of the same hemisphere, extending from about 2 ern. posterior to the frontal pole backward as far as the anterior horn of the lateral ventricle. In some other sections the cortex was definitely narrowed in areas corresponding to zones of increased consistency noted on palpation of the surface of the brain. Microscopic Anatomy: The histologic study of the main tumor revealed a fairly uni­ form picture. The dominating cell types were giant spongioblasts and neuroblasts. In areas remote from the seats of the tumor were nodules presenting features of local spongio­ blastosis. Monster neuroblasts and spongioblasts were frequently seen in the cerebral cortex free among other cells (Fig. 28B and C).

Comment: The most prominent clinical features in the case are the pre­ cipitate onset of paresthesias, visual disturbances, Jacksonian attacks, the lack of localizing signs with later development of cardinal signs of increased tension, and manifestations pointing to a focal lesion in the left hemisphere. Here again the anatomical findings show features of disseminated spongio­ neuroblastosis (tuberous sclerosis).

CASE 19: Acute onset of cerebral manifestations with disturbances of intellect; pro­ gressive development of severe headache; somnolence; asthenia; an unusual febrile course; death; necropsy. History (Adm. 292310; P. M. 6293): J. S., a female aged fifty-two, became jaundiced FIG. 29. CASE 19 A. Coronal section of the brain showing asymmetry of the cerebral hemispheres and part of the tumor. B. Large undifferentiated cell form containing many nuclei and about to be broken up into independent neuroblasts. C. Histologic appearance of the tumor. X 300. Globus modification of the Hortega silver carbonate method.

206 GLIONEUROMA AND SPONGIONEUROBLASTOMA 207 about two months prior to admission to the hospital, without apparent abdominal signs or symptoms. At the same time her memory began to fail and she appeared confused and disoriented. Progressive asthenia and constant inclination to somnolence developed, and there were severe headaches and incontinence of urine. Examination: The patient was confused, disoriented, and forgetful. There was tender­ ness on pressure over both frontal and maxillary sinuses. Pain was elicited on pressure over the gaJlbladder region. The pupils were smaJl but reacted normaJly to light and in ac­ commodation. The fundi oculi were normal. The tongue was tremulous. The abdominal reflexes were present. The deep reflexes were hyperactive and equal. There were no pathologic reflexes. Course: The patient's mental condition declined rapidly and she became irrational, dull, and confused. She ran a mild febrile course, the temperature varying between 100 0 and 102° F. Incontinence continued. The tenderness over the gaJlbladder region dimin­ ished. Roentgen examinations of the gaJlbladder and chest were negative. Blood cultures and the Widal test were negative. Several intravenous injections of typhoid vaccine were without any effect upon the clinical course except for a rise in temperature. Cystoscopy revealed moderate cystitis. The ureteral specimens of urine were turbid, due to the pres­ sure of clumps of leukocytes and bacilli. The white blood ceJl count rose from 11,250 to 19,500 with 90 per cent polymorphonuclear leukocytes. A lumbar puncture yielded clear fluid under normal pressure containing 2 ceJls per cubic millimeter. The temperature gradu­ ally mounted to 1040 F. The patient became more stuporous. An exploratory laparotomy was performed with negative findings. Death occurred on the following day. Gross Necropsy Findings: The meninges were normal. The brain was rather small with the gyri somewhat atrophic. On section, an ependymal nodule about the size of a kidney bean was found in the anterior horn of the left lateral ventricle. In was continuous with a mass infiltrating the septum pellucidum and was of firm consistency. Another coronal section on the level of the optic chiasm showed a tumor in the body of the corpus callosum, measuring about 1.5 cm. in its long axis (Fig. 29A). Below this tumor was an­ other mass in the right hypothalamic region directly above the right optic tract. This tumor mass was grayish in color, firm in consistency, and extended backwards for about 1 em. where the optic tract penetrated the hypothalamus. There was a slight degree of dilatation of the anterior hom of the right lateral ventricle with narrowing and shifting of the left anterior hom to the left. Microscopic Anatomy: Sections showed a vascular, infiltrating tumor which was densely cellular, with large areas of degeneration. There were vast numbers of large multinucleated giant cells (Fig. 29B and C), many of which were undergoing mitosis. The tumor had the typical appearance of a spongioblastoma. In areas remote from tumor, histologic zones of neurospongioblastoma were found.

Comment: Among the unusual features in this case is the febrile course throughout the illness. This is very likely explained by the location of one of the tumor masses in the tuber einereum, which was not recognized during life. Strauss and Globus (28) have demonstrated in a series of cases that neoplastic lesions in the hypothalamus may provoke a disturbance in tem­ perature regulation. In this way they have furnished additional proof for the probable existence of a temperature-regulating center in the tuber cine­ reum. The dissemination of the lesion is another significant feature, although it is not uncommon in spongioblastoma, as pointed out by Globus and Strauss (29).

CASE 20: Headaches; focal Jacksonian attacks; gradual intensification of symptoms; development of transient speech disturbances; signs and symptoms pointing to a lesion in the left parietal lobe; cnmiotomy ; remoual of tumor; death; necropsy. History (Adm. 287212; P. M. X360): H. B., a female aged forty-three, had suffered 208 JOSEPH H. GLOBUS for a number of years from frequent frontal headache. During periods of excitement, which were frequent and easily provoked, she manifested severe tremors of the head and hands. For about two to three months prior to admission to the hospital she complained of numbness in the right upper extremity, and for one month was annoyed by "pins and needles" sensations in the right hand. During the last few days she had begun to drool. On the day of admission she was seized with a transient attack of convulsive twitchings of the right side of the face and right upper extremity lasting for about half an hour. During the attack she lost the power of speech, though retaining consciousness. Speech soon re­ turned but remained defective. The twitchings reappeared from time to time and the headache became continuous. Examination: There were constant convulsive twitchings of the right upper extremity and the head was drawn to the left. The pupils were somewhat irregular, unequal, the right being larger than the left, and reacted sluggishly to light. The jaw deviated to the left and there was weakness of the right masseter muscle. There was hyperesthesia of the right side of the face. The fundi were negative. There was a right hemiparesis. The deep reflexes were more active on the right side. The abdominal reflexes were active. There was a bilateral Babinski sign. Astereognosis and diminution of all forms of sensation in the right hand, except vibration, were noted. There was retention of urine, necessitating catheterization. Course: A lumbar puncture yielded clear fluid under normal pressure, containing 2 cells per cubic millimeter. The blood and spinal fluid Wassermann tests were negative. The blood pressure was 120 systolic and 90 diastolic. The diagnosis was a lesion, probably neoplastic, in the parietotemporal region of the left hemisphere, though the possibility of a vascular or inflammatory process could not be excluded. The Jacksonian twitchings con­ tinued in spite of the administration of large doses of luminal. The sensory changes of the right hand gradually disappeared but the astereognosis persisted. One month later a crani­ otomy was performed under local anesthesia, with removal of tumor tissue from the left parietal lobe. A complete paralysis of the right side of the face and the right arm followed the operation. Three days later the patient was found in a stupor, from which she failed to rouse, death occurring on the sixth day after operation. Gross Necropsy Fit/dings: The left cerebral hemisphere presented a large defect in the depths of the brain substance, extending forward into the frontal lobe and backward into the occipital lobe. There were several scattered areas in the cerebral cortex which pre­ sented an unusual rubbery hardness to the touch. Such an area, on section, showed an indistinct demarcation between the gray and white substance. Microscopic Findings: Circumscribed fields of gliosis were revealed in the areas of sclerosis amid the cellular elements of which typical giant cells of the spongioblastic type were found. A similar picture was obtained in the material removed at operation.

Comment: The outstanding clinical features in this case are severe head­ ache of long standing, the frequent occurrence of severe tremors provoked by moderate excitement, the paresthesias, the drooling, the focal convulsions of Jacksonian character, and the speech disturbances, at first transient and later gradually progressive. The dominant signs pointed to the existence of the main lesion in the left parietal lobe. The anatomical findings were of the character best described as disseminated spongioblastosis.

CASE 21. Repeated attacks of transient amblyopia with manifestations of increased intracranial tension; signs pointing to dissemination of lesion; ventriculography; tumor localized; cmniotomy ; tumor removed in part; death. History (Adm. 230307; P. M. 4326): H. G., a male aged twenty-two years, fell at the age of one and struck his head, causing a severe laceration over the left eye. Five years before admission a trap-door had fallen on his head without causing loss of consciousness. The present illness began two years before he entered the hospital, with a transient attack of blurred vision. About two months later, he began to experience sharp pain in the left eye. The pain was recurrent over a period of six weeks, lasting several hours at a time. GLIONEUROMA AND SPONGIONEUROBLASTOMA 209

A hemorrhage in the left eye was then detected by an ophthalmologist. A period of six months followed without symptoms. Then for a period of four weeks frontal headaches and blurred vision reappeared. At this time the left eye turned in and double vision re­ sulted. There was no rise in temperature and no evidence of any other constitutional dis­ order. Again these symptoms disappeared spontaneously and the patient appeared to be well for a year, at the end of which time he once more began to suffer with frontal head­ aches and double vision. During the two months prior to admission he complained of paresthesias on both sides of the face, but more often on the left side. There was also numbness of the left side of the tongue and of the left side of the nose. At the end of one month practically all of these symptoms had again disappeared. For two weeks the patient had noticed flattening of the left side of the face, had experienced pain in the right lumbar region, and more recently had experienced short periods of difficulty in speech. He would use the wrong words, though he knew the word he wanted to employ and was aware of his mistakes. He vomited only once. Examination: There were fine nystagmus in all directions, slight bilateral exophthalmos, bilateral choked discs, and atrophy of the masseter and temporal muscles on the left side. The deep reflexes were active and equal, except that the right biceps was more active than the left. Course: Ventriculography was performed, showing the anterior and posterior horns of the ventricles to be greatly distended. There was a defect in the body of the right lateral ventricle which had such an appearance as would be produced by pressure of a deep tumor in the right centrum semiovale or by a tumor arising somewhere in the brain stem and exerting pressure forward. A study of the plates suggested that the neoplasm lay near the posterior portion of the third ventricle, probably more to the left side or outer side of the third ventricle. In the next few weeks the papilledema became more marked. There developed an inequality of the pupils, slight left ptosis, and distinct weakness of the left internal rectus. The exophthalmos became more pronounced and there appeared bilateral corneal hypes­ thesia, bilateral diminution in hearing, and slight right facial weakness (central). The left knee reflex became more marked than the right. The patient left the hospital at his own request, but returned for further study. At home his vision continued to decline, headache became more intense, and pain developed in the left suprascapular region, radiating to the left breast and causing a sensation of muscular fibrillation. The papilledema became less severe but post-neuritic atrophy set in. Ventriculography was again performed and the entire ventricular system was found to be dilated. There was a defect in the outline of the body of the right ventricle due to a tumor of considerable size bulging into the ven­ tricle and seemingly attached above and to the right. The right ventricle was more dilated here than the left and was dislocated. Craniotomy was performed and a tumor was found in the body of the right ventricle. Fragments were removed for diagnosis. As there was extensive bleeding, it was deemed advisable to close the wound. A second operation was performed and a great part of the tumor was removed. The general condition after the second operation was good for a time, but on the fourth day the patient suddenly passed into stupor and died. Gross N ecropsy Findings: The body of the right lateral ventricle in its posterior two­ thirds was almost completely obliterated by a growth projecting from its lateral wall (Fig. 30A). This growth was rather hard in consistency, rounded, and presented an irregular surface. In front of it was an excavation lined with rough, somewhat necrotic tissue, probably the seat of that part of the neoplasm which was removed at operation. The floor of the third ventricle was thinned out and bulging. In several regions of the cerebral hemi­ spheres there were marked retractions of the gyri and these, on palpation, showed a great increase in consistency. When such areas were incised they showed a uniform pearly white substance with lack of normal demarcation between the gray and white matter. Such areas were found in both occipital lobes in their anterior portions, in the supramarginal gyri, and in the posterior portion of the superior temporal gyrus on the right side. A horizontal incision at the level of the roof of the lateral ventricles brought the dilated ventricles into view, the right posterior and descending horns being more distended than the corresponding parts of the opposite side. The ependymal lining of the ventricles was much thickened 210 JOSEPH H. GLOBUS

FIG. 30. CASE 21 A. Gross appearance of the hemisphere containing the tumor, showing also the granulations in its ependymal lining. B. Ependymal granulations. X 610. Globus modification of the Hortega silver carbonate method. C. Cellular character of the tumor.

and presented a highly irregular surface with numerous granules and irregularly scattered small papillomatous elevations (Fig. 30B). A similar condition was seen in the lining of the fourth ventricle. Microscopic Findings: Sections of the cerebral hemispheres presented typical areas of tuberous sclerosis, showing a loss of the normal arrangement of the cortical layers and the presence of primordial elements, such as monster glia ganglion cells and bipolar ganglion cells; the underlying white matter showed a greatly increased number of glia cells, at times approaching a degree of sclerosis. Sections through the tumor presented a uniform appear­ ance, with nest-like aggregations of tumor cells with glia cells as the predominating element, of giant size and spindle shape (Fig. 30e). The cells were arranged in interlacing bundles. The spindle-shaped, fusiform, or occasionally conical cells often contained more than one nucleus. Rosette formations and radiations about cyst-like structures were common cell arrangements. GLIONEUROMA AND SPONGIONEUROBLASTOMA 211

FIG. 31. CASE 22 Longitudinal section of the brain showing the marked internal hydrocephalus and the loca­ tion of the tumor.

Comment: The location of the main lesion in this case was probably re­ sponsible for the outstanding clinical features, such as the transient episodes of increased intracranial pressure and the paucity of signs of localizing value. The antecedent history was of slight diagnostic aid since there was very little to indicate the presence of lesions characteristic of tuberous sclerosis.

CASE 22: A history of convulsive seizures in infancy; retarded intellectual development; skin lesions (sebaceous adenoma); abrupt onset of manifestations of increased intracranial tension; headache; impaired uision; papilledema; meager localizing signs; ventriculography; coma; death; necropsy. History (Adm. 269948; P. M. 5469): L. H., a female aged sixteen years, had one brother who died in infancy of " convulsions" and a sister who succumbed to " brain fever" at two and a half years of age. In addition to the common diseases of infancy, the patient was subject to convulsions during the period of dentition. For the past two years she had suffered from occasional cramp-like pains in the calves. About seven months previous to admission she developed persistent frontal headache, and shortly thereafter she noticed blurring of vision. With but a short period of improvement, the headache grew in intensity and she was forced to give up work because of gradually increasing weakness. For the last two months it had been observed that she tilted the head backward and veered to the right when walking. Examination: The pupils reacted normally to light and in accommodation. There were bilateral exophthalmos and bilateral papilledema, more marked in the left eye. The corneal reflexes were diminished. There was a left central facial weakness. The deep and superficial reflexes were active and equal. There was hypotonia ofboth upper extremities. In walking, the head was tilted with the chin carried to the right. There was a diffuse sebaceous eruption on the face (adenoma sebaceum). The visual fields were normal. 212 JOSEPH H. GLOBUS

FIG. 32. CASE 22 General histologic structure of the tumor showing the nest-like arrangement of the undiffer­ entiated cell elements. X 165. Globus modification of the Hortega silver carbonate method.

Blood, urine, and serologic examinations were negative. Roentgenograms of the skull showed evidence of increased intracranial pressure. Intellectually the patient was somewhat retarded. Course: An expanding lesion in the posterior fossa was postulated and, in view of the convulsive seizures, the skin lesions, and the retarded mentality, tuberous sclerosis was considered. A patch near a blood vessel in the left fundus was observed on ophthalmologic examination and was regarded as a nodule not unlike that found in tuberous sclerosis. The patient returned home and for nine months her condition remained unchanged. In the next three months she complained of progressive dimness of vision, vertigo, periodic vomiting. and some vaguely described twitchings of the right upper extremity. She was readmitted to the hospital where, in addition to the previous findings, she manifested a fixed facial expression and dilated pupils, the left practically fixed and the right sluggish to light. Her vision was greatly reduced. There was an equivocal right Babinski sign. The gait was uncertain with a tendency to veer to the right. There was tenderness over the left temporo­ parietal region of the skull on percussion. Ventriculography was performed. Several hours after this procedure the patient was found in a comatose condition and deeply cyanotic. She died on the following day. Gross Necropsy Findings: The brain showed evidence of increased intracranial pres­ sure. 'Palpation revealed numerous areas of the cortex which were hard and nodular. A tumor was found in the region of the right thalamus, almost completely replacing the anterior two-thirds of that structure on the right side (Fig. 31). The tumor was brownish red in color, measured 2.5 ern, in the antero-posterior diameter and extended downward as far as the massa intermedia, compressing the third ventricle from above downward. A similar and much smaller mass was found in the mesial portion of the left thalamus. A smaller rounded mass about 7 mm. in diameter was found in the region of the left pulvinar, projecting into the body of the left lateral ventricle. The cerebral cortex was very ir­ regular in its width; in some areas, as under the flattened and hardened tuberous areas, it was almost completely obliterated, only an exceedingly narrow zone of gray matter rc­ maining. The ventricular cavities, including all the compartments of the lateral ventricles, FIG. 33. CASE 22 A. A nest of undifferentiated over-sized nerve cells surrounded by glial elements. X 260. Globus modification of the Hortega silver carbonate method. B. Nerve cells of a more mature type. Nissl stain. C. Well formed nerve cell of enormous size. Bielschowsky silver stain.

213 214 JOSEPH H. GLOBUS

FIG. 34. CASE 22 A. A monstrous, exceedingly long form of nerve cell. Globus modification of the Hortega silver carbonate method. B. Monstrous giant multinucleated nerve cell.

were distended and filled with bloody fluid. The third ventricle in its upper part was re­ duced to a narrow slit by the two opposing tumors. Below the subthalamic groove the third ventricle retained its normal dimensions. The same was true of the aqueduct and the fourth ventricle. The ependymal lining was thickened and was studded with numerous granulations. Microscopic Findings: Sections throughout the tumor presented a characteristic his­ tologic appearance. The tumor cells were arranged in nest-like aggregations separated by strands of myelinated fibers (Fig. 32). Among the tumor cells were many giant cells, some of which when stained with Nissl stains displayed their neuronic character (Fig. 33B and C). The alterations in the cerebral hemispheres were typical of tuberous sclerosis. The thick­ ening and gliosis of the tangential layer and the tuberous nodules with collections of atypical spongioblasts and neuroblasts were numerous and conspicuous (Fig. 34A and B).

Comment: The family history, the convulsive seizures in the early life of the patient, and the skin eruption on the face, as well as the small retinal nodule, were, of course, of great diagnostic value, but were somewhat obscured by the fact that the symptoms and signs of increased intracranial tension, such as impaired vision, papilledema, and the roentgenographic findings, pointed to the existence of a circumscribed intracranial tumor. The anatomical find­ ings in this case include abundant evidence that the generalized lesion was in the nature of tuberous sclerosis, in which a local intensification of the process resulted in a large tumor formation and provoked the symptoms of increased intracranial tension. GLIONEUROMA AND SPONGIONEUROBLASTOMA 215

Anatomical Observations Summarized The 10 cases of spongioneuroblastoma described contain several gross fea­ tures common to this subgroup. They are commonly associated with lesions of either fully developed or somewhat abortive forms of tuberous sclerosis. They have a fairly constant location in the striothalamic region. Histologic­ ally the tumor cells in the main mass are arranged in nest-like aggregations of neuroblasts and spongioblasts. Both ceil types occur in varying numbers and in various stages of differentiation. The presence of these two cell types of tuberous sclerosis suggests the term spongioneuroblastoma for this tumor. The fact that it is associated with the typical lesions of tuberous sclerosis, a related blastomatous process, suggests the probability that the tumor is but a local accentuation of the neoplastic potencies inherent in the cell elements in tuberous sclerosis. Since the original contributions of Bourneville (30) and Hartdegen (31) several important observations have been made on the pathogenesis of tuber­ ous sclerosis, resulting in the present day consideration of this disease as an expression of disturbed development. While a number of investigators, in­ cluding Perusini (32), Vogt (33), and Geitlin (34), are inclined to look upon the disturbance as a form of architectural maldevelopment, others, led by Bielschowsky (35), regard this developmental anomaly as a blastomatous (neoplastic) tendency on the part of the gliogenous elements of the brain. The first interpretation of the lesion, which is in accord with some features of this disease, assumes that some of the embryonal glia and nerve cells were, so to speak, derailed from their normal course of the histogenesis, and on the way to full differentiation acquired unusual morphologic features. It does not, however, indicate the existence of some force responsible for progression in the pathogenesis of the disease. In this regard the conception of Biel­ schowsky and his followers holds out better promise by offering the hypothesis that we are dealing with an ontogenetic disturbance which acquires the char­ acter of a blastomatous disease, in which some of the gliogenic elements of the brain retain their embryonal character beyond the normal and critical develop­ mental time limits. Under such circumstances the glial and other elements maintain their proliferative potencies and give rise to widely disseminated circumscribed tumor formations. These may vary in size from a microscopic structure to the dimensions of a full size tumor. There is need for some slight modifications of the concept of Bielschowsky, mainly concerning the cell types which are incriminated. While Bielschowsky stressed the participation of the gial elements in this dysontogenetic process, there is ample proof now for the inclusion, also, of the 'nerve cells. Atypical forms of glia and nerve cells, which are, of course, none other than undevel­ oped or malformed spongioblasts and neuroblasts, are found side by side in this disease, a form of diffuse spongioneuroblastosis which is here, in this tumor type, designated as spongioneuroblastoma.

Clinical Manifestations Summarized The presence of disseminated lesions throughout the brain, in addition to larger neoplastic masses, makes for the overlapping and confusing clinical 216 JOSEPH H. GLOBUS manifestations. An analysis of some of the clinical features, however, may disclose some suggestive diagnostic leads. Thus in 5 patients (Cases 13, 14, 17,20 and 22) there were manifestations indicating the existence of a disease of the nervous system antedating the final illness, and 4 of these were subject to convulsive seizures of both the focal and general character. Some other clinical considerations are recorded in Tables III and IV.

TABLE III: Spongioneuroblastoma: Length of Clinical COline of Terminal Illness tjrom Initial Symptoms to Fatal Termination i ; Mode of Onset and Terminal Events

Length of Clinical Case Course Signs at On set Terminal Euents 1.3 1 day Stupor Death spontaneous, precipitate 14 I year Personality changes (psychoses) Death following craniotomy 15 6 months Headache, vomiting, fainting speIls, impaired Death spontaneous, precipitate vision 16 3 months Headache, vomiting, uncinate fits, blurred vi­ Death spontaneous, precipitate sion, mentality changes, elevation of temper­ ature 17 4 months Paresis of right leg, cramps and pain in right Death following encephalog­ arm raphy 18 3 months Headache, Jacksonian convulsions, impaired Death foIlowing craniotomy vision 19 2 months Mental changes, general weakness, somno­ Death following surgical inter­ lence vention 20 3 months Paresis, paresthesias, Jacksonian convulsive Death foIlowing craniotomy attacks 21 2 years Pain in left eye, blurred vision, diplopia, Death following craniotomy paresthesia, transient aphasia 22 7 months Headache, blurred vision, general weakness Death following ventriculog­ raphy

DISCUSSION The classification of cerebral neoplasms of neuroectodermal derivation, as formulated by Globus and Strauss (29) and modified by Bailey and Cush­ ing (36), Penfield (37) and others, although subject to future revision, offers a valuable working plan for the morphologic identification of tumors primary in, and peculiar to, the nervous system. In accordance with this plan several well defined tumor forms, such as spongioblastoma multiforme, ependymoma, astrocytoma, and oligodendroglioma, have come to be clearly recognized and better understood. But the wide divergence of the histologic character of the primary neuroectodermal tumors has left many which are as yet without proper designation and whose significance is not fully stressed. These in­ clude the glioneuroma and spongioneuroblastoma herein described. The importance of these two closely related tumor forms becomes apparent when the several histogenetic phases through which the glia cell and the neuron pass, before they reach full maturation, are reviewed. Fig. 35 illus­ trates roughly the several critical stages in the histogenesis of the two main cell elements of the nervous system. This chart also makes it clear how, at certain points of departure, the primordial glial and neuronic cell forms, GLIONEUROMA AND SPONGIONEUROBLASTOMA 217

TABLE IV: Spongioneuroblastoma: Some of the More Prominent Cl-inical Features

Case 13 Sudden stupor; no evidence of increased intracranial pressure; no localizing signs. 14 Left hemiparesis; left hemihypesthesia; mental changes. 15 Abrupt onset; exceedingly brief course; sudden spontaneous death; no localizing signs. 16 Uncinate fits, transient confusion, mental changes and clonic twitchings on right side of body. 17 Transient attacks of monoplegia and aphasia; mental changes; no evidence of increased intracranial pressure; right hemianopsia; right-sided hyperaffectivity: right hemiparesis. 18 Sensory explosions; Jacksonian seizures; encephalogram showed process in left hemisphere. 19 Mental changes, asthenia, somnolence, elevation of temperature; no evidence of increased intracranial pressure; no localizing signs. 20 Transient aphasia; Jacksonian attacks; sensory disturbances; clonic twitching's of right side of body; deviation of jaw. 21 Repeated transient attacks of monoplegia; aphasia and paresthesia; dissemination of organic signs; ventriculography an aid in localization. 22 Abrupt onset of signs of increased intracranial pressure, left facial weakness, cerebellar tilt of head. when retarded in the process of their differentiation and migration, may form tumor types which contain a combination of the histological constituents com­ mon to both the frankly gliogenous and purely neuroblastic neoplasms. This occurrence provides an important link in the chain of morphologic circum­ stances favoring the acceptance of the Cohnheim embryonal rest theory as Neuro-ectoderm (Neuroepithelium) -----1 I I Glio-Neuro-Epithelium Germinal Cells Neural Crest (Primitive Spongioblasts) I I I Neuroblasts 1-----1 I I (Apolar of H,ld) cr Neuroblasts Schwann Mern- Ependyma Cells Spongioblasts brane Cells and I I Capsule Cells Glia Neuroblasts Sympathoblasts (Asrrocytes, etc.) (Unipolar Cells of His) I I Neurons I I Ganglion Paraganglion Cells Cells

FIG. 35. STAGES IN THE DIFFERENTIATION OF THE NEURO-ECTODERMAL DERIVATIVES the probable explanation for the genesis of true cerebral tumors. This theory assumes that groups of embryonic cells which retain their undifferentiated character and fail to reach their normal destination remain dormant as em­ bryonal remnants in foreign locations for some time and may suddenly be aroused by some unknown force to renewed activity, vigorous growth, and cell division, so as to form the germinal center for new growth formation. It is obvious that the cells in such embryonal remnants are capable of giving rise to several divergent cell types, each one corresponding to some stage in the 218 JOSEPH H. GLOBUS normal process of cell differentiation. By virtue of this capacity they are instrumental in the production of a large variety of tumors according to the dominance of one cell type or another, which, though differing in form, are still of common lineage. This theory is particularly favored by the associa­ tion of the less differentiated form of tumor herein described with the blas­ tomatous lesions peculiar to a congenital brain malformation characterized by heterotopic and histiotopic lesions, such as tuberous sclerosis. The occurrence of intracranial tumors which have the character of teratoid growths, such as the craniopharyngioma, the pinealoma and the autochthonous growths, such as the meningioma (Globus, 39), now makes it possible to re­ gard the glioneuroma and spongioneuroblastoma, in which practically all the components of the nervous tissue and its supporting elements are jointly rep­ resented, as forms of autochthonous neoplasms. It not only does this, but it also points to the correctness of the concept that a departure in the histo­ genesis and migratory habits of nervous tissue elements may be at the basis of brain tumor formation. Little need be added to the description of the tumor which was designated as glioneuroma. There we find the neoplastic cells rapidly acquiring their mature form and retaining but a few earmarks of the embryonal pattern, such as neuroblasts assembled in large numbers in and about vessel walls, circum­ scribed cellular nests (germinal centers) and primitive vascular patterns, such as are seen in the infant's brain (Globus, 38). Much more instructive is a discussion of the features and the histogenetic position of the so-called spongin­ neuroblastoma. This tumor is closely related to spongioblastoma multi forme and, as already mentioned, is further typified by its association with the dis­ seminated hyperplastic lesions in the brain, commonly found in tuberous sclerosis. It contains cellular elements which may be regarded as derivatives from the primitive spongioblasts and neuroblasts and hence the term spongio­ neuroblastoma disseminatum was once suggested (3) for its designation. This tumor has in many respects strong similarities to the spongioblastoma multiforme, which consists of spongioblasts and other incompletely differ­ entiated glial elements. Both tumors have in common several cell forms, such as the giant and pyriform cells and the somewhat more differentiated glia. Their differences are many, among them the presence of neuroblasts and, at times, of quite mature neurons in the spongioneuroblastoma and particularly the association of the latter tumor with the lesions of tuberous sclerosis. In the literature there are recorded but a few cases which were clinically diagnosed as brain tumors and which, on anatomical study, disclosed charac­ teristic lesions of tuberous sclerosis (Berliner 40). This association of clin­ ically identified gliogenous tumors with tuberous sclerosis, which was discov­ ered only anatomically, is of particular significance when scrutinized in the light of the conception of Bielschowsky (35), which maintains that in tuberous sclerosis we are very likely dealing with a widespread and disseminated form of blastomatous disease of the central nervous system. In this condition, co­ existent with the small multiple islands of nodule formation, there may be found well developed and fairly well circumscribed tumors which may be con­ sidered as local exaggerations of the basic disturbance typical of cases of GLIONEUROMA AND SPONGIONEUROBLASTOMA 219 tuberous sclerosis. No less significant are the findings in the material herein recorded, which show that tumors associated with tuberous sclerosis bear in their histologic features a strong morphologic resemblance to spongioblastoma multiforme, but in addition contain another cell form, the neuroblast, which places them in another and quite distinct category of cerebral neoplasms, designated here as spongioneuroblastoma. As to the clinical pictures presented by the two tumor types, the reader is referred to individual case studies and the summarized clinical observations. At this point, however, three striking clinical manifestations may be stressed: (1) the occurrence in a great majority of the cases of convulsive seizures, most commonly of the Jacksonian variety, occasionally of the generalized form, at some point in the clinical course; (2) the not infrequent onset with transient loss of consciousness without convulsive seizures; (3) the rather rapid dis­ integration of the intellect, occurring in a large quota of cases. The question arises whether all these manifestations are not peculiar to these types of tumor because of the presence of a large number of nerve cells of either unripe or over-ripe variety. It invites speculation as to whether these cells, derailed as they are from the normal path of orderly development, have acquired not only a certain independence of morphologic behavior, but also a poorly integrated physiologic conduct. Under such conditions it may be further hypothecated that these cells, interwoven as they are with the normal cellular elements of the brain, may either initiate and precipitate widespread purposeless activity, as seen in convulsive state, or may block the normal flow of nervous energy, as in the instances of transient loss of consciousness, conditions which char­ acterized the clinical course of many of the cases described.

CONCLUSIONS 1. A relatively large group of primary brain tumors, neuroectodermal in origin and supratentorial in location, which have hitherto been regarded as rare, are described under the designations of glioneuroma and spongioneuro­ blastoma. 2. The glioneuromas are anatomically relatively benign and may lend themselves to successful surgical intervention; while the spongioneuroblas­ tomas are of a more malignant form and their timely recognition may spare the patient and surgeon alike unnecessary and hazardous surgical intervention. 3. A survey of the clinical histories in both tumor forms yields some diag­ nostic leads for the recognition of their anatomical character and their precise localization. 4. The proper evaluation of the histological character of these tumors gives promise of clarifying the understanding of the genesis of primary brain tumors. The presence of both spongioblastic and neuroblastic derivatives in these tumors lends support to the Cohnheim embryonal rest theory of tumor formation. The frequent finding of the heterotopic and histiotopic lesions of tuberous sclerosis in association with the more malignant form, the so-called spongioneuroblastoma, and the equally frequent finding of other cellular pat­ terns similar to those occurring in the infant's brain, are other important fea­ tures favoring this theory. 220 JOSEPH H. GLOBUS

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