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THE SUBACUTE FORM OF MULTIPLE SCLEROSIS *

WILLIAM G. SPILLER, M.D.

Professor of Neurology, University of Pennsylvania

PHILADELPHIA

In order to obtain a more correct understanding of the histology of multiple sclerosis it is necessary to examine the lesions when the course of the disease has been rapid. Cases of multiple sclerosis with necropsy are exceedingly rare in America, and therefore one in which death occurred within the second year after the onset, as it did in the case presented in this paper, should be of interest. This study permits me to conclude that, at least in some cases, multiple sclerosis may be regarded as multiple glioma. There is also a possibility that at times syphilis may play a rôle, and opportunity is taken to consider the findings justifying this point of view.

The patient who afforded the opportunity for the present study was a male, aged 25. The symptoms began in February, 1915, with headache. In June, 1915, vision began to fail. In July, 1915, optic neuritis was observed. Weakness of the limbs developed gradually, with nystagmus, incoordination, vertigo, scanning speech, intention tremor and progressive impairment of gait until walking finally became impossible and mentality very feeble. Death occurred Dec. 21, 1916 The notes of this case are as follows:

History.-E. B., white man, aged 25, was admitted to the University Hospital of the University of Pennsylvania, July 21, 1916, and died Dec. 21, 1916. He had been well until February, 1915, when he began to have severe frontal headache. At this time he had no motor symptoms. In June, 1915, his vision began to fail. In the middle of July, 1915, he was admitted to the University Hospital on Dr. de Schweinitz's service. The diagnosis of optic neuritis was made. As vision failed the headache subsided. The sensation of twitching of the arms and legs grew worse and he became weak. He was greatly improved by one month's stay at the seashore. Since January, 1916, his condition has become steadily worse. In February, 1916, he developed ataxia of the lower limbs and vertigo, and the weakness of the lower limbs increased. His speech has become somewhat slurring, nasal, and monotonous since March, 1916. Since May he has had an intention tremor of the forearms. Since June 20, 1916, he has not been able to walk.

He has had chickenpox, whooping cough, influenza in infancy and early childhood. He denies venereal disease. His family history is negative. He does not use alcohol. He is a student in the Wharton School of the University of Pennsylvania.

* Read by title at the Annual Meeting of the American Neurological Association, May, 1917.

Examination. The pupils are equal; irides react promptly and equally to light and in convergence. Horizontal nystagmus of large amplitude occurs when he looks to either side, and vertical nystagmus when he looks upward. Extraocular rotations are unimpaired. Facial musculature is unimpaired. Hearing of the watch tick is fair in each ear. The tongue is protruded slightly to the right of the midline without tremor and is freely movable to either side.

Extremities: Grip fair with the right hand, poor with the left. Marked ataxia and, at times, course intention tremor developed in both arms by finger to nose and finger to finger tests. Diadochokinesis is impaired in both forearms. Sense of position and stereognostic sense are normal in the hands. Biceps reflex is normal and equal on both sides. Triceps reflex is questionably present on both sides. Cremasteric reflex is prompt on the left side, sluggish on the right. Patellar reflex is slightly exaggerated on the right side, normal on the left. Achilles reflex is moderate on both sides and equal. Plantar stimulation induces plantar flexion on the left side, dorsal flexion on the right side. Ankle clonus was obtained on the right side at the first examination, but could not be elicited on either side at the second examination. Heel to knee test shows marked ataxia on both sides. Both legs show slight spasticity. Legs and trunk are weak and probably ataxic. The man cannot stand or even sit up unsupported. Sensations of touch and pain are normal throughout. Slight coolness is mistaken for warmth in the right calf. Otherwise objective sensation is unimpaired.

The voice is slow, monotonous, thick and somewhat slurring. The laugh is deep, expressionless, almost spastic, not unlike the laugh of Wilson's disease. The lower limbs are very weak. There is more power in extension than in flexion. There are frequent brief rapid changes in the amount of power in all the movements of the extremities. He passpoints outward with both hands spontaneously.

July 25, 1916: (Ocular report by Dr. Langdon.) O. D., vision 6/15; O. S., 6/45. Both disks show decided loss of capillarity, well defined central cups and sharply defined margins. There are no other fundus changes.

July 22, 1916: Blood: Red blood cells, 5,160,000; white blood cells, 8,400; hemoglobin, 80; polymorphonuclears, 78; lymphocytes, 19; large mononuclears, 1; transitionals, 1; eosinophils, 1; basophils, 1. Urine analysis: Cloudy, ambercolored; flocculent sediment; specific gravity, 1.025; acid reaction; albumen, none; sugar, none; casts, no cylindroids; mucus, plus; no red blood cells; white blood cells, occasionally present; epithelium was present, also calcium oxid crystals.

July 28, 1916: Lungs are negative except for slightly increased vocal fremitus over the right upper lobe. Heart is negative except for slightly accentuated pulmonic second sound.

Sept. 18, 1916 (ocular report dictated by Dr. Shumway): There is a marked pallor of the temporal half of the optic nerve on each side and paralysis of the right internal rectus.

Oct. 10, 1916: Patient is somewhat delirious. Wassermann test of the blood has been taken several times in the hospital and was always negative. The patient's father states that the blood taken outside the hospital for the Wassermann test he thinks was positive. Owing to certain circumstances a lumbar puncture was not done.

Oct. 13, 1916: The patient is not able to take care of himself and lies in bed except when moved in a wheeling chair. He has marked ataxia, scanning

speech, nystagmus and intention tremor. His mentality has gradually failed and is now greatly impaired.

Dec. 21, 1916: This morning the patient's temperature, pulse and respiration suddenly went up above normal and he could not be aroused. He had been without change in his condition on retiring the night before. His heart was fast and irregular. At 8 a. m. on this date he was still unconscious and his breathing was difficult and irregular, and, while still fast, there was no increased area of cardiac dulness.

Postmortem Examination (Dec. 21, 1916).—The postmortem examination revealed practically nothing abnormal with the viscera. The areas of sclerosis are very numerous and are found in every section taken from the spinal cord, but they are more pronounced in the cervical and lumbar regions than in the thoracic. These areas are in some places fairly sharply defined from the normal tissue, but in many places the shading off into normal tissue is observed. Lacelike structure is found in some of the patches. The areas are infiltrated with numerous mononuclear cells, and these are especially numerous about the blood vessels within the cord and in some of the septa running into the cord. These cells are very numerous in both the pia of the cord and brain, and in some places form dense masses. The large spider cells (Deiters' cells), so numerous in the foci within the cerebrum, are not found in the cord.

The alteration in the medulla oblongata is as intense as in the cord. The Marchi sections of the cord and brain show intense recent degeneration except in areas of long standing in the cord. The nerve cells of the anterior horns of the cervical and lumbar regions are well preserved even in sclerotic foci, as shown in the thionin stain, and do not show pigmentary degeneration, although occasionally a cell showing chromatolysis and swelling may be found.

The optic chiasm, tracts and nerves are greatly degenerated and show much infiltration with cells of mononuclear type. Some foci of degeneration are found in the cerebellum, as in the right dentate nucleus.

Sections from many parts of the cerebrum show disappearance of medullary substance in the altered areas. The sharpness of definition of the degenerated from the normal tissue is possibly even more pronounced here than in the spinal cord. The nerve cells in the altered cortex are well preserved. The cerebral foci contain many large glia cells (Deiters' cells), mononuclear cells and fatty granular cells, and these foci differ greatly from the foci of the spinal cord in that the former are almost entirely cellular. These areas look like so many distinct gliomas, and while they appear under low power to be sharply defined, under high power scattered glia cells may be seen penetrating into the adjacent tissue like scouts of an invading army.

There have been few cases of multiple sclerosis with necropsy reported in this country a statement also made by Taylor and the study of this disease must be made chiefly from the foreign literature. There we find cases in which the brain has been seriously affected by the lesions, but in most cases the description has been based on the study of the spinal cord. In this case of subacute multiple sclerosis recently under my care every section taken from any part of the cerebrum shows foci with lesions peculiar to this disease. The alteration in the cerebrum is very different from that in the spinal cord, and my findings confirm the statement of Marburg, namely, that cellular

proliferation of glia is greater in the brain than in the spinal cord, and that the large glia cells are found more in the brain than in the spinal cord.

The glia proliferation of the spinal cord is in large measure of the character of the overgrowth of glia seen in the replacement of nerve fibers from secondary degeneration caused by some lesion at a higher level; it is therefore chiefly fibrillar. In the cerebrum the glia proliferation is of a different character, it is chiefly cellular and is more. recent than that of the cord. Mental failure usually does not precede the other symptoms of multiple sclerosis, it occurs later in the disease.

[graphic]

Fig. 1.-Vessel in the left paracentral lobule surrounded by many cells of mononuclear type.*

and the lesions producing it must be of late development. In this case the mental failure became pronounced and it is to be explained by the extensive alteration of the cerebrum. If one, therefore, desires to find the earlier changes of multiple sclerosis he should look for them in the cerebrum. The lesions are usually less numerous in the cerebellum.

The changes in the cerebrum in the case recorded in this paper were in overgrowth of the glia causing a microscopic picture resembling that of a glioma. Indeed, my studies of these sections lead me

*I am indebted to Dr. A. J. Smith for the photomicrographs.

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