ol. 64, No. 26. Whole No. 1729.

Original Articles.

UMORS OF THE PONTO-MEDULLO-CEREBELLAR SPACE. ACOUSTIC NEUROMATA. (CENTRAL NEUROFIBROMATOSIS.)*

BY JOSEPH FRAENKEL, M.D.,

AND

J. RAMSAY HUNT, M.D.,

NEW YORK.

INDER the above title will be considered a group of ases characterized by a local or regional manifestaion of neurofibromatosis. This consists in the ormation of tumors (single or multiple) on one or more cranial nerves. The acoustic nerve is most requently thus affected and next in order the rigeminus. How often and to what extent the ther cranial nerves become implicated in the eurofibromatous process is not definitely settled. The pathological occurrences on the cranial erves are identical with those of generalized eurofibromatosis of the cerebrospinal and sympahetic nerves. The two types are not infrequently jund associated.

One of the first cases belonging to the group nder discussion was reported by Foerster1 in 862. In 1900 Von Monakow' reported three ases in which the anatomical and clinical peculiaries were accurately stated. He called especial ttention to the surgical possibilities of the conition. Since then Henneberg and Koch, Hartlan' and Sternberg3 have made valuable contribuons to the subject.

The

The condition is by no means a rare one. ajority of the recorded cases are found classified nder the various headings of intracranial tumors umors of the posterior fossa, tumors of the erebellum, pontine tumors, etc.). Our contribuon consists of the report of five cases with autopes. Three were cases of tumors of the acoustic; ne a case of bilateral tumor of the acoustic, and ne a case of tumor of the trigeminus. Four of the ases were observed by ourselves and for permission > publish the fifth we thank Dr. B. Onuf. Etiology. The underlying causative factor in all ases is a teratological one. The rôle played by raumatism, frequently mentioned in the histories f these cases, is apparently of no greater importance nd is as uncertain as in cases of brain tumor in eneral.

Pathology.-Regarding the frequency of neuroibromatous involvement of the cranial nerves, it $ necessary to emphasize that we consider here articularly the involvement of the intracranial egment of the respective nerves. The acoustic hows a marked predisposition and is most frequently involved, rather rarely on both sides. The trigeminus is next in order, but rarer. The acial is believed by some to be occasionally the seat of these tumors; its proximity to the acoustic nerve renders pathological decision difficult.

The neurofibromatous involvement of the other ranial nerves, which has been reported, was *From the Montefiore Home and the Pathological Laboratory of the Cornell University Medical College. Read before the American Neurological Association,

May 13, 1903.

nerves

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mostly extradural. It is also to be noted that the neurofibromata found on the other cranial were usually associated with generalized neurofibromatosis, and rarely of clinical significance. The fibromatous growths of the acoustic are of rounded form, varying in size from a cherry to a hen's egg, of fibrous consistency and distinctly encapsulated. The surface is nodular and irregular. Care in the examination will usually demonstrate their attachment to the atrophic nerve trunk. A small remnant of the nerve trunk, a few blood vessels and loose meningeal adhesions form the only connections of the tumor with its surroundings; hence it may be lifted with ease from its attachments, leaving a corresponding excavation in the structures composing the ponto-medullo-cerebellar space.

Sometimes the growth diffuses itself along the acoustic nerve, penetrating the meatus auditorius. internus. Histologically these tumors are neurofibromata. Medullated nerve fibers may be demonstrated by the Weigert method in the peripheral and central portions of the tumor. Very commonly, in the more advanced stages, the growth assumes a sarcomatous nature. The cells become enlarged, proliferate and show mitotic changes; increased vascularization with hemorrhages are also observed.

In a limited number of cases glia tissue has been demonstrated in these tumors, and gliosarcomatous degeneration has taken place. Myxomatous and cystic degeneration is also noted.

One of our cases was accompanied by curious changes in the cerebral cortex, consisting of protrusions and minute hernia, attached to and sometimes perforating the dura. These appeared

as minute tufts and excrescences, which, when the dura was stripped off, left depressions with sharply demarcated boundaries. Histologically these herniæ were formed of brain substances, composed largely of ganglion cells of the spindle type and of glia cells. The outer portion is fungoid and structureless. There were no evident vascular or inflammatory changes observed.

Interesting cortical findings in cases of fibromata of the acoustic were reported by Henneberg and Koch. They reported hyperplasia and hypertrophy of the glia cells of the cortex, especially in the deeper layers. In some areas these changes could be observed with low power. Another associated pathological change was found in one case reported by Henneberg and Koch and in one of our cases; namely, endotheliomata and psammomata of the dura mater. Cases are recorded which were complicated by the presence of sarcomatous tumors within the substance of the brain. These changes may all be cited as further evidence of a congenital tendency to teratological conditions.

The point of origin of the tumors under discussion is still an undecided question. The subject is somewhat complicated by the occasional heterogeneous structure of the tumors (fibrosarcomata, gliosarcomata.)

For a short but variable distance, prolongations of the glia accompany the nerve trunks after they pierce the fibrous sheath. This would afford an

explanation for the occurrence of glia elements in the growth.

Another attempt to explain the origin and nature of these tumors is made by Sternberg on the basis of developmental peculiarities. Sternberg believes that these tumors arise from embryonal rests of the so-called dorsal cranial nerves. Of these the trigeminus, acoustic, facial, glossopharyngeal and vagus arise from the so-called neural ridge, while the other cranial nerves are outgrowths of the original cerebral vesicles.

The neural ridge appears at an early embryonal date, when structural differentiation has not yet taken place. This affords an explanation of the presence of groups of atypical cells, which subsequently take on fibromatous, sarcomatous, or gliomatous proliferation.

Symptomatology. This group of tumors courses under the clinical picture of tumors of the posterior fossa of the skull. The essential feature distinguishing these tumors from those originating within the substance of the brain-stem or cerebellum, is the early appearance of symptoms referable to a single

Fig. 1.

cranial nerve. These, because of the benign character and slow growth of the tumors may precede for a considerable time, any other focal or general symptom. As stated above, the nerves most frequently thus affected are the eighth and the fifth; hence tinnitus aurium with progressive diminution of hearing; attacks of Ménière's syndrome (aural vertigo) in the one case-obstinate and atypical attacks of facial neuralgia in the other case, will prove points of diagnostic importance.

With the further progress of the disease, structural changes of the fibers occur with objective clinical evidences. Because of histological peculiarities which these tumors possess in common with the neurofibromata of the spinal peripheral nerves, the conductivity of the fibers is not always completely abolished. Thus it happens that even in advanced

stages, the affected nerves still preserve some of their functions.

With the increase in the size of the tumor, the neighboring parts, pons, cerebellum, medulla and basal nerves, show evidences of pressure: Peduncular ataxia, tendency to deviate or fall to the same or opposite side, cerebellar ataxia, nystagmus, irregularities in size and reaction of pupils, paralysis of associated movements of the eyeballs, dysarthria, dysphagia, homo- and contra-lateral and crossed paralyses of the extremities, paralysis of the facial or abducens of the peripheral type, motor disturbances of the palate or tongue, circulatory, respiratory, vasomotor phenomena and attacks of AdamStokes' syndrome.

Diagnosis.-The diagnosis of the condition rests upon the symptom complex of tumor of the posterior fossa of the skull, preceded by well-marked and long-continued symptoms, referable to disease of the fifth or eighth nerves. Naturally, many other pathological conditions in the posterior fossa may produce symptoms simulating quite closely those of the primary neurofibromata of the fifth or eighth nerve. (Aneurysm of vertebral artery, primary disease of the structures of base of skull or meninges.)

From the standpoint of differential diagnosis, the chronological relation of the neural symptoms to the general symptoms, the relative intensity of the neural and the other central symptoms, are determining factors.

Prognosis. Owing to the proximity of vital centers these tumors share the fatal prognosis with other severe lesions of this locality. The favorable features are the extreme chronicity of the condition, which, however, may at any time be interrupted by a more rapid proliferation of the growth, owing to sarcomatous or other malignant change.

Therapy-Removal of the growth by operative procedure offers the only hope. Because of the loose attachment of these tumors to their surroundings, we may hope, that in spite of the unfavorable location, a perfected surgical technique will improve the prognosis.

CASE I.-Female, fifty-one years old. Disease began six years ago with headache, vomiting, vertigo, progressive left-sided hemiplegia. Static ataxia, falls toward left, paralysis of left seventh with changes of the electrical reactions, left-sided hemiparesis and hemiataxia, choked disk. left-sided deafness, nystagmus, left-sided abducens palsy, increased salivation, stupor, somnolence.

Autopsy. Solitary neurofibroma in left pontomedullo-cerebellar space. Left fifth adherent to surface of growth. Left eighth is not demonstrable. C. M., a married Russian Jewess, entered the Montefiore Home July 6, 1894. The mental condition of the patient at the time of admission was such as to yield only meagre and unreliable data of her previous history. Dr. R. Abrahams of this city. who directed patient to the hospital and who had observed her for some time previously, kindly furnished the following notes: About one and one-half years ago, patient began to suffer from paralysis of the left side of the body, beginning in the leg, gradually ascending to the arm and finally invading the face of the same side. Speech was difficult; vision

and hearing of left side were impaired; memory was imperfect and vomiting was an occasional symptom. During the patient's stay in the institution the following notes were taken: Family history: No definite information obtainable. Previous personal history: No definite information obtainable. Cause of present illness: Not definitely known; no history of traumatism or previous infectious disease. It is said to have begun about five years ago. The initial symptoms were occasional attacks of severe generalized headache, rarely accompanied by vomting. The intervals between the attacks grew shorter, the attacks became more severe, and were more frequently associated with projectile vomiting. Since about one and one-half years left sided hemiplegia with slight speech disturbances. At time of admission, the patient complained of severe continuous headache, not particularly localized, vertigo, vomiting, impairment of sight and hearing, and annoying increase of salivation.

Examination showed: Static ataxia; swaying with closed and open eyes; inclines and falls toward left side; hemiplegico-atactic gait; pupils unequal, right smaller, all reactions present; when eyes turn toward left, the left eyeball stops at middle line;

when turned toward right and upward, marked nystagmus (abducens palsy); paralysis of left facial with quantitative changes of electrical reactions; hearing impaired on both sides, particularly on left; moderate paralysis of left sided extremities with increased tendon reflexes; left sided hemiataxia; choked disk.

Up to time of death in May, 1895, these symptoms grew worse. Patient suffered particularly from headache and incessant drooling. Frequently serious attacks of somnolence were noted.

Autopsy. Brain only was removed. A tumor the size of a bantam's egg was found in the left ponto-medullo-cerebellar space (Fig. 1). The growth was of firm, fibrous consistency, having a nodular surface. The attachments to the base consist of a few meningeal adhesions and blood-vessels. The left fifth is adherent to the surface of the growth. The tumor is readily removed, leaving a deep excavation on the pons, medulla, and cerebellum. The root of the eighth nerve could not be demonstrated, and was evidently torn away. Microscopically the growth presented the characteristics of a neurofibroma. The other cranial nerves were normal.

CASE II (Dr. Onuf's case).-Male, forty-one

years old. Onset: Headache, aural vertigo, tinnitus, later choked disk, facial neuralgia. Ataxia, deviation to right side, left-sided facial tic, leftsided deafness, choked disk, nystagmus, exaggeration of reflexes.

Autopsy. Neurofibroma in the left ponto-medullo-cerebellar space, probably originating from the left acoustic. Curious cortical depressions.

S.I., Forty-six years old, janitor, born in the United States, was admitted to St. Catherine Hospital May 2, 1902. No specific history. Family history: No data of importance. Previous personal history: No venereal infection; no history of traumatism. Present disease: Began in the winter of 1902.

The first symptoms were headache in left occipital and left temporal regions, shooting pain with tinnitus and curious noises "like a steam pipe" in the left ear. The latter was particularly noticeable in recumbent position. In March, 1902, attacks of severe vertigo, with disturbances of equilibrium and vomiting, lasting from three to five minutes and recurring two to three times weekly. In April, sharp pain in both upper jaws, which persisted after removal of some defective teeth. At same time vision began to fail, and within two weeks only quantitative light perception was left. No diplopia.

Status præsens: Static and locomotor ataxia. Deviates to right side. Mentally excited and irritable. Dulness of olfactory sense on both sides. Choked disk, more marked on right side. Pupils widely dilated. No reactions. Rotatory nystagmus, also during ophthalmoscopic examination. No ocular palsies. Motor and sensory portion of fifth undisturbed. Occasional clonic twitchings in left facial musculature. No facial paralysis. Deafness on left side. No motor or sensory paralysis. No defects of coördination. Fine tremor of hands. Tendon reflexes not elicitable on upper extremities. Knee-jerks variable. In the early stages left knee-jerk weaker than right; later both kneejerks exaggerated, especially right. Bilateral ankle clonus. Abdominal, epigastric, cremasteric reflexes absent. Plantar reflex exaggerated, flexion type. Death occurred from typhoid fever.

Autopsy. Brain only removed. In the left pontomedullo-cerebellar space a firm tumor was found, enclosed in a smooth, glistening capsule, approximately the size of a hen's egg (Fig. 2). The surface is broken by irregular nodulations. On removal from its attachments a deep excavation is exposed, corresponding to the junction of pons, medulla, and cerebellum. This depression is 1 inches long and inches wide. No nerve trunks can be demonstrated microscopically, passing into the capsule of the tumor. The left fifth nerve has been compressed by, but not incorporated in the tumor. The left sixth, seventh, and eighth nerves could not be demonstrated, having been torn off in removal. All other cranial nerves were normal. The tumor. presented quite extensive areas of cystic degeneration with hemorrhages and necroses. Histologicallythe tumor is a neurofibroma; no evidences of sarcoma were noted.

By the Weigert method a nerve trunk is demonstrated entering the capsule of the tumor. At this point a network of nerve fibers courses around the periphery. A few scattered medullated nerve fibers are also situated centrally. The pyramids, lemniscus, fasciculus longitunalis posterior, posterior columns, showed no evidences of degeneration. The ascending root of the left fifth nerve showed slight evidences of atrophy.

The cerebral cortex was the seat of curious microscopical changes (Fig. 3). One similar spot was

observed in the upper part of the vermis-cerebelli. These consist of small depressions with a very sharply demarcated boundary. The larger number have the size of a pin's head; some are smaller,

F. C., a Russian widow, forty years old, entered the Montefiore Home, October 11, 1898. Family history: No reliable data obtainable. Previous personal history: Negative. Onset and first symptoms of the disease were uncertain. Began about five years ago with attacks of severe headache apparently frontal. Some time afterward vomiting accompanied the headache. About one and a half years ago vision began to fail. Since December, 1897, inability to walk. The patient complains of loss of vision, attacks of headache and vomiting, almost constant and annoying pain in left half of body, particularly in left upper extremity.

The patient is of medium height, somewhat pale, poorly nourished. Skin flabby, markedly inelastic; a skin fold is slow in disappearing. The entire attitude of patient is strikingly immobile. Patient answers questions correctly in a very slow and monotonous fashion. All motor functions are executed in the same slow way. Patient is unable to stand or walk without assistance. Inclines and falls toward the right side (Fig. 4). Attitude hemiplegic. Gait hemiplegico-attactic.

Head.-Skull is not tender to percussion. Percussion note is dull on left side. Patient is unable to keep head balanced, it falls to right side like a dead weight. Face is covered with beads of perspiration on both sides; pallor and flush alternate; mechanical irritation of face evokes a long lasting vasomotor reaction. Lateral excursions of head are fairly normal; movements in antero-postero direction are limited and apparently painful. Mentally the patient is dull and apathetic, frequently going into a semi-stuporous state. Speech is slow and monotonous. No other decided mental defects.

Fig. 3.

some larger. Many of them have projecting from the interior, a small fungoid tuft, which is adherent at the base, but unattached to the rim.

Many of the depressions contain no such tufts, they having apparently been torn away in the removal of the dura, as these projections were not only attached to the dura, but often perforated it. They were noted at the base of the brain, but more particularly over the temporal and parietal lobes.

No special abnormality was noted in the region of the Pachionian bodies; from which the tufts were easily distinguishable.

Histological examination by the Nissl and Van Gieson methods: In general these depressions correspond to the tip of a cortical medullary column, from which wave-like groups of spindle cells pass through the various layers of the cortex to the external surface. Here the cells protrude as structureless tufts seen macroscopically. The general cell type is fusiform with large oval nuclei and nucleoli of the ganglionic type. The cortical cells immediately enclosing and surrounding these plugs of spindle. cells are normal in character and distribution. There are no evidences of inflammatory reaction.

CASE III.-Russian, female, forty years old. Disease began about five years ago with attacks of headache. Static and locomotor ataxia, deviation to right side, paralysis of right seventh with changes of the electrical reactions, right-sided facial tic, hypæsthesia of right side of face tonus and reflexes variable, choked disk.

Autopsy-Gliosarcoma in right ponto-medullocerebellar space, apparently originating from right fifth. Small tumor on left fifth nerve.

Fig. 4.

Cranial Nerves.-Sense of smell is apparently dulled on both sides. The olfactory nasal reflex present, though very sluggish. The right optic nerve seen with difficulty. Contour cannot be traced. Corneal opacity. General optic reflex whitish. The left optic nerve much more easily seen. Contour indistinct. Central artery divides quickly above and below into small and very tortuous branches. Spots of hemorrhage are found

here and there. Both retinæ very red; vision entirely gone.

Ocular axes are not parallel; no stable position of eyeballs; palpebral fissures are frequently varying in width, changing from position of semi-ptosis to one of normal width or even stare. The right palpebral fissure usually narrower than left. Pupils somewhat dilated, left somewhat wider. Direct pupillary reactions perverted; illumination dilates the pupils still further. Pain reaction present; other reactions cannot be tested. When patient is asked to move eyes in different directions, it is noticed that she moves eyeballs upward and downward normally, but less so to right and left-in fact, hardly any to left. Now and then the eyeballs. twitch when turned in lateral direction. The conjunctival sacs are filled with purulent secretion, particularly on right side. The opticopalpebral reflexes are absent. The conjunctival reflexes are present, diminished, particularly on right side. Patient permits flies to promenade in right conjunctival sac.

Motor portion of fifth nerve is apparently normal. Sensibility on right half of face apparently dulled. Total paralysis of right seventh nerve, including the upper branch. The face drawn to left side. Fibrillary and tonic contractions of musculature of right half of face frequently observed. Mechanical irritability of right-sided facial musculature is increased, but the response is very slow and vermicular. Faradic response of right facial musculature absent; with the galvanic current a partial degeneration reaction is obtained.

Sense of hearing is diminished on both sides, particularly on right.

Innervation of soft palate apparently normal and equal on both sides. No dysphagia. Pharyngeal reflexes absent. Tongue shows heavy coating, limited to right half; on protusion it deviates markedly to right side. The right half is flabbier, the electrical response of this half is markedly vermicular. Sense of taste is considerably impaired in anterior two-thirds of right half of tongue; in the posterior third and in the pharynx gustatory paræsthesias exist.

Upper Extremities.-The musculature is flabby, interdigital spaces sunken, particularly on right side. Marked hypotonia, particularly on right side. General motor weakness of both upper extremities. No incoördination. Tendon reflexes not elicitable. The muscles respond to stimuli, voluntary, mechanical and electrical, in a curious slow, almost vermicular, fashion. Sensibilities, as far as could be ascertained, unaltered.

Lower Extremities.-The position, attitude, and volume were without noteworthy features. General motor weakness. Marked hypotonia, particularly on right side. Patellar tendons soft. Knee and Achilles jerk cannot be elicited. Plantar reflex present; slow, flexion type. Slight ataxia; no evident disturbances of sensibility. Muscular responses the same as in the upper extremities.

Trunk and Abdomen.-No motor paralysis. Respiration superficial; intercostal functions fairly normal; diaphragmatic, weaker. Abdominal reflexes absent on left side. Neck is well formed. Thyroid

gland not palpable. No demonstrable abnormalities of visceral organs. Sphincters occasionally derelict. Marked constipation. Urine negative. Pulse 96, temperature 97, respiration 6. Course. October 16, 2.40 P.M.: Patient is perspiring profusely, drools, passes urine involuntary.

October 18: Complains of severe pain throughout left half of body, particularly left half of face and left upper extremity; the latter is uncomfortable in any position.

October 20: Attack of profuse perspiration, increased salivation.

October 25: Ocular excursions normal. Kneejerks present on both sides, exhaustible and intermittent on right, always demonstrable on left. Achilles reflex ditto.

October 30: Lateral ocular excursions limited; normal in other directions. Achilles and kneejerks obtainable.

November 6: Ocular excursions to right side limited and accompanied by nystagmus. Kneeand Achilles jerks not obtainable.

November 12: Complains of pain in left eye and left upper extremity, severe occipital headache. Knee and Achilles jerks not obtainable. Ocular excursions normal. Considerable ataxia in both upper and lower extremities of left side. Marked diminution of motor power of left lower extremity. Now and then a knee-jerk is obtained, vermicular without locomotor effect. On right, Achilles jerk is present, intermittent; also on left.

Tem

November 21: Patient is semi-conscious; does not recognize any one; profuse perspiration. perature 97°, pulse 100, respiration 8. Patient is restless, throws arms and legs about; this condition lasted half an hour.

November 28: Patient complains of pain in left upper extremity. Knee-jerks elicitable, varying in intensity; so also muscular tone. Achilles jerk not elicitable.

From now until the middle of January the state of the tendon reflexes and muscle tonus of the lower extremities were examined daily. This examination revealed the following facts: (1) The inconstancy of these phenomena, varying daily even in a short time during the same examination. (2) The constant diminution of the right-sided tendon jerks and muscle tonus. (3) The occasional exaggeration of both tendon jerks and muscle tonus on left side; on this side a spurious ankle clonus was frequently observed.

January 14: Patient complains of general weakness and pain in eyes, particularly in right. Neuroparalytic keratitis of right side. Right palpebral fissure smaller. Right-sided extremities show hypotonia; left sided, hypertonia. Left knee-jerk strong; right, diminished and exhaustible. Rightsided Achilles jerk present; on left side, ankle clonus.

February 15: Right eye considerably congested, cornea hazy, showing a number of abrasions; conjunctival reflexes present, diminished on right side. Deep sensibility of upper lids preserved. Ocular excursions show irregular deficiencies, are jerky. The excursions of each eye, separately and in conjunction, show weakness of the superior oblique; all ocular movements are slow, hesitating, interrupted, and jerky. Pain sense considerably diminished on right half of face. Left knee-jerk present; slight left-sided ankle clonus; right-sided tendon reflexes weaker.

March 7: Tendon reflexes of lower extremities not elicitable. A few minutes later left knee-jerk present and left-sided ankle clonus. Reflexes on right side absent.