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Early acute anterior poliomyelitis without an increase of cells in the spinal fluid
EARLY ACUTE ANTERIOR POLIOMYELITIS
WITHOUT
AN
INCREASE OF CELLS IN THE SPINAL FLUID s SIDNEY O. LEVINSON,
CHICAGO,
M.D.
ILL.
stage of acute T HEwell prepara]yt~e established clinical entity.
anterior poliomyelitis has become a The history, physical examination, and neurological findings are usually sufficiently significant to make a tenta*ive diagaaosis. There is one test,~however, which is usually relied upon to confirm the diagnosis. This is the examination of the spinal fluid secured by lumbar puncture. In order t~ make a positive diagnosis o~ preparalytic poliomyelitis, even when other simulating conditions are ruled out, it has been considered essential to find changes in the spinal fluid ir~dicative of mild meningeal inflammation. Although it is commonly accepted t h a t the spinal fluid in this condition should show an i n c r e a s e d n ~ m b e r of cells and an increased globulin, it is notable that the}'e is a great variation in these spinM fluid findings. D r a p e r 1 states that in the p r e p a r a l y t i c stage, following meningeal invasion, the pressure is lowered, and there is an increase in the cell content, ranging between 10 and 2,500 p e r c.mm. At the earliest period the cells are chiefly ' " p o l y n u e l e a r s , " but within twenty-four to thirty-six hours, l y m p h o e y t e s comprise over 90 per cent of the cells. The globulin also becomes definitely increased. There was one group to which he called p a r t i c u l a r attenfion, a group in which the cell count was quite low, usually u n d e r 100 p e r e.mm. ; and in which the course of the disease was quite mild. I n the New York epidemic of 19162 the cell content o$ the spix~al fluid ranged between fifteen and twenty a n d 1000 per c.mm. Ayeock and L u t h e r a report the spinal fl~uid to be u n d e r moderately increased pressure, the cell count 50 to 250 p e r c.mm. and the globulin increased. W a r d n e r D. A y e r 4 finds the average cell count to be 350 cells per c.mm. ; slightly increased pressure of the f u i d and an increased 9gl~ content. Various reports indicate that the spinal fluid returns to no~nal at a valgying interval (four to fourteen days) a f t e r paralysis has developed. I n our series of 130 cases of acute anterior poliomyelitis (reported elsewhere.) t including 65 t h a t were obs.erved in the preparMytic stage, our fiItdings co~formed to those just reviewed in almost all the cases, ~he cell count us,~ally being between 50 and 250 per e.mm. However, * F r o m t h e S a m u e l D e u t s e h Convs S e r u m Center, M i c h a e l R e e s e H o s p i t a l , Chicago. R e c e i v e d for p u b l i c a t i o n , A u g u s t 4, 1932. t L e v i n s o n ; S i d n e y O., 3/feDougall, C l a r i e e , a n d T h a l h i m e r , W i l l i a m : A c u t e A n t e r i o r :Poliomyelitis i n t h e C~hieago A r e a in 1981. T h i s a r t i c l e h a s been a c c e p t e d for p u b l i c a tion in tlae J. A. IV[. A. 337
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of particular interest and significance were five eases, in which, although the clinical findings pointed to acute anterior poliemyelitis, the: spinal fluid showed only an increase in globulin but not an increase in cells. All of these patients disclosed muscle weakness at the: initial examination, or subsequently developed a t e m p o r a r y or p e r m a n e n t paralysis of the t y p e seen iI~ poliomyelitis. I n Case 1, the clinical picture was so strongly suggestive of poliomyelitis because of the muscular weakness and absent reflexes, that despite the failure to find an increased cell count in the spinal fluid, we were tempted to administer serum. However, and to o~ar later regret, the absence of cells caused us to delay t h e r a p y for t w e n t y - f o u r hours, until a second l u m b a r p u n c t u r e did show an increased cell count (of which 45 p e r cent were mononuelear cells). By this time actual paralysis had developed. A f t e r this experience we became more alert for those cases seen so early in the p r e p a r a l y t i e stage that sufficient meningeal involvement had not occurred t o cause a cellular response in the spinM fluid. We also were forced to realize that even i~ the ]ate p r e p a r a l y t i c stage, the meningitis m a y at times be so slight that no cellular increase is produced, although practically always an increased globulin is found. A brief r@um6 of the five cases fo.]]ows. Normal findings are omitted. CASE 1.--S. R , femal% aged three was admitted to the hospital with a history of pain in the legs for four days ~md inability to walk. There was no history of contact or of recent ~llness. For twenty-four hours the patient had diarrhea and complained of pain in the back of the neck. Examination revealed a normal temperatnr% slight neck rigidity, limited motion ia the lower extremities with muscular pain on movement, absent knee jerks and absent ankle jerks. The spinal fluid was clear, containing 4 lymphocytes per c.mm. and increased globulin (Ross-Jones test). The following day the spinal puncture was repeated because of a marked increase in the weakness of the lower extremities and at this time there were 186 cells, 55 per cent polynuclears and 45 per cent mononuclears. Convalescent serum was then administered both intraspinally (20 c.c.) and intravenously (60 c.c.), This case progressed to a complete paralysis of both lower extremities~ and partial paralysis of the muscles of the back. CASE 2. K. D., female, aged twenty-two months, was admitted with a history of onset twenty hours previously with vomiting, weakness of the legs for eight hours when walking, and pain in the right thigh. There was no history of recent illness or of contact. One brother, thirteen years old~ was well. The temperature was 100 ~ pulse 120, and respirations 22. Examination revealed only a slight tremor of the extremities~ hyperactive knee jerks, some weakness of the right thigh against resistance, and to a less exten L some weakness of the. left thigh. Spinal puncture revealed a clear fluid, with a cell count of 6 per c.mm. and a positive globulill (Ross-Jones test). Convalescent serum was administered both intraspinally (20 c.c.) and intravenously (60 c.c.). The tremor and brisk knee jerks persisted for several days. Within five days there seemed to be complete recovery with disappearance of fever and muscular
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weakness. The spinal fluid at the end of 1%re days c o n t a i n e d only 4 l y m p h o e y t e s per cu. turn. ; the globulin was still pesitive. CaSE 3 . - - T . M., f e m a l e , a g e d twelve, h a d been ill for two d a y s before a d m i s s i o n with a sore t h r o a t , followed b y h e a d a c h e a n d stiff a n d a c h i n g legs. Thel'e was no h i s t o r y o f r e c e n t ilhmss or contact, a n d one other child in the f a m i l y h a d been well. On t h e d a y following t h e onset of t h e illness a p h y s i c i a n observed ea~ i n j e c t e d throat a n d fever, The h e a d a c h e a n d . p a i n s in t h e legs h a d i n c r e a s e d a n d there also developed dull p a i n in the back a n d in the back of t h e neck. The a d m i s s i o n t e m p e r a t u r e w a s 100.6 ~ (mouth)~ pulse 104, r e s p i r a t i o n s 24. The p a t i e n t , t h o u g h not toxie~ h a d a flushed f a c e with a perioral pallor and the t h r o a t was injected. A l t h o u g h t h e r e w a s no" cervical or back r i g i d i t y , t h e r e was a head drop, t e n d e r n e s s in t h e back, back of neck~ b o t h thighsj a n d left leg. There was l i m i t a t i o n of m o v e m e n t due to pain, b u t no obvious weakness. The knee jerks were e x a g g e r a t e d , a n d a e o n t r a l a t e r a l O p p e n h e i m a n d left Chaddock were present. B o t h u p p e r a n d t h e r i g h t lower a b d o m i n a l reflexes were absent, the l e f t lower weak. The spinal fluid was clear, u n d e r i n c r e a s e d pressure, showed a cell count of 6 per e.mm. (5 l y m p h o c y t e s , I po]ynuclear) a n d a f a i n t l y positive R o s s - J o n e s test. S e r u m w a s a d m i n i s t e r e d b o t h i n t r a s p i n a l l y (20 c.e.) a n d i n t r a v e n o u s l y (60 c.e.). I n the n e x t few days~ w e a k n e s s of t h e dorsiflexors of t h e feet a n d a b d u c t o r s of the left lower t h i g h developed,' b u t t h e t e m p e r a t u r e r a p i d l y d r o p p e d to n o r m a l a n d a t d i s c h a r g e two weeks later, t h e w e a k n e s s h a d disappeared. CASE 4 . - - A . P., femal% a g e d n i n e t e e n years. The p a t i e n t was well u n t i l the d e v e l o p m e n t of a sore t h r o a t w i t h p a i n in the back ~nd g e n e r a l i z e d a c h i n g muscles. There was also some t e m p e r a t u r e . The following a f t e r n o o n the neck became stiff a n d this lasted for t h r e e days. The p a i n a n d t e n d e r n e s s of the m u s c l e s had become p r o g r e s s i v e l y worse u n t i l t h e t i m e of e x a m i n a t i o n , five days a f t e r onset. A t this tim% t h e t e m p e r a t u r e was ]00 ~ i% b y mouth~ pulse 110, a n d r e s p i r a t i o n s 20. T h e r e w a s no cervical r i g i d i t y , b u t t h e back w a s r e s i s t a n t . T h e r e was m a r k e d t e n d e r n e s s a n d pain of all t h e extremities, p a r t i c u l a r l y the fore.~rms. There was no f r a n k paralysis; b u t t h e r e was some weakness o f the flexors a n d extensors of both f o r e a r m s , the flexors a n d a b d u c t o r s of the left h a n d , e x t e n s o r s of the t h i g h s a n d of t h e l e f t foot. T h e degree of w e a k n e s s could not he a c c u r a t e l y determh~ed because of the muscle p a i n p r o d u c e d b y m o t i o n a g a i n s t resistance. The triceps jerks were absent, the w r i s t jerk very weak on the left, b r i s k on t h e right, ~md the a b d o m i n a l reflexes very weak to absent. The spinal ~ u i d was u n d e r in'creased pressure, eyes L c o n t a i n i n g 4 cells per e.mm. (lympho,~'ytes)' a u d showed a definitely increased globulin ( R o s s - g o u e s test). S e r u m w a s a d m i n i s t e r e d both ] n t r a s p i n a l l y (20 e.e.) a n d i n t r a v e n o u s l y (60 c.c.). The t e m p e r a t u r e d r o p p e d to n o r m a l in t w e n t y - f o u r hours. A f o o t drop on {he left side, a n d paresis of the r i g h t h a n d developed. One m o n t h later, there was still r e s i d u a l weakness of the r i g h t f o r e a r m a n d h~tnd to flexion a n d extension, a n d of t h e l e f t f o o t to dors iflexion. The p a t i e n t w~s i n c a p a b l e of p e r f o r m i n g these m 6 v e m e n t s a g a i n s t a n y resistance. C~SE 5.'--J. G., male, aged fiv,e a~ld one-half years, gave a h i s t o r y of exposure to a, ease of a n t e r i o r poliomyelitis in t h e school. The child became ill with p a i n h~ the back of t h e head, v o m i t i n g , a n d fever. He was a d m i t t e d t w e n t y - e i g h t h o u r s a f t e r onset of t h e illness~ a n d at this t i m e h a d a t e m p e r a t u r e of 100 ~ F. ( r e c t a l ) , a pulse of 156, a n d r e s p i r a t o r y r a t e of 28. The p a t i e n t was p r o s t r a t e d a n d irritable. T}lere was a s l i g h t pcrioral pallor. T h e r e was a m a r k e d head drop, slight r e s i s t a n c e of. the neck, a n d definite stiffness of the back. T h e r e was mus~de t e n d e r n e s s in b o t h f o r e a r m s a n d t h i g h s , a tremor of t h e lower extremities, b u t no
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a p p a r e n t w e a k n e s s w a s discernible. All the reflexes were brisk~ except t h e knee j e r k s , w h i c h were elicited with diff• a n d t h e a b d o m i n a l s w h i c h were absent. Ths:-e w a s a b i l a t e r a l O p p e n h e i m . The s p i n a l fluid w a s clear, c o n t a i n e d 6 cells ( l y m p h o e y t e s ) per c.mm. a n d showed a t r a c e of globulin. S e r u m w a s a d m i n i s t e r e d b o t h i n t r a s p i n a l l y (20 c.c.) a n d i n t r a v e n o u s l y (60 s.c.). The following day~ t h e t e m p e r a t u r e w a s no~'mal, t h e child m u c h b r i g h t e r . The knee j e r k s could not be obtMned. Ttiere was still a positive O p p e n h e i m and a positive Chaddoek on t h e r i g h t side. No f r a n k p a r a l y s i s developed. A c a r e f u l a n d t h o r o u g h muscle e x a m i n a t i b n p e r f o r m e d two m o n t h s later disclosed definite evidence of m u s c l e involvement. T h e r e w a s d i m i n i s h e d power in t h e a b d o m i n a l s , t h e r i g h t g l u t e n s maximus~ a n d the flexors of t h e toes, more m a r k e d on t h e r i g h t . T h e m e a s u r e m e n t s of t h e r i g h t leg were s l i g h t l y less t h a n the corr e s p o n d i n g m e a s u r e m e n t s of t h e left leg.
A n u m b e r of other patients were seen, who seemed most likely to be ifl the p r e p a r a l y t i c stage of anterior poliomyelitis, but whose spinal fluid showed 11o increase in cells, although some h a d an increased globulin. Most of these were given serum and went on to an uneventful recovery, without the development of any paresis. A brief :~ccount of two such cases follows : CASE 6 . - - R . O., male~ a g e d nine years, became sick with a sore t h r o a t , a chill a n 4 fever, v o m i t i n g , a n d some consUpation. The child h a 4 n o t b e e n ill recently a n d h a d two brothers, a g e d t e n a n d twelve, who were well. There was no h i s t o r y of contact. T h e child i n two days developed a m o d e r a t e headache, p a i n in t h e back a n d back of t h e neck, a n d slight stiffness of t h e neck. E x a m i n a t i o n revealed a m o d e r a t e l y sick flushed child w i t h a t e m p e r a t u r e of 102 ~ :~'., a n i n j e c t e d t h r o a t , slightly r i g i d neck a n d back, w i t h t e n d e r n e s s in t h e s e areas. T h e r e w a s a taehe cerebra]e. T h e r e was no i m p a i r m e n t in muscle s t r e n g t h a n d the reflexes were all n o r m a l l y p r e s e n t except t h e l e f t knee jerk which w a s diminished. T h e s p i n a l fluid w a s clear, u n d e r m a r k e d l y i n c r e a s e d pressure, e o n t s i n e d 5 cells per e.mm. a n d definitely i n c r e a s e d globulin ( R o s s - J o n e s t e s t ) . S e r u m was a d m i n i s t e r e d b o t h i n t r a s p i n a l l y a n d i n t r a m u s c u l a r l y w i t h i n twentyf o u r h o u r s of t h e onset of m e n i n g e a l s y m p t o m s . T h e following d a y b o t h knee j e r k s d i s a p p e a r e d , b u t t h e t e m p e r a t u r e d r o p p e d r a p i d l y to n o r m a l a n d t h e child m a d e a n u n e v e n t f u l recovery w i t h o u t development of muscle weakness. CASE 7 . - - J . H., female, a g e d seven years, b e c a m e sick with a sore throat, m o d e r a t e f e v e r a n d some constipation. The child trod b e e n well a n d two other children i n t h e f a m i l y were in good health. This child h a d been cxposed~ t h o u g h n o t i n t i m a t e l y , to a n o t h e r child in school who h a d developed a c u t e poliomyelitis. W i t h i n t h e n e x t two days, t h e p a t i e n t developed headache, pahn in t h e legs, neck, a n d side of t h e chest. E x a m i n a t i o n revealed a m o d e r a t e l y sick child w i t h a t e m p e r a t u r e of 102 ~ F. T h e t h r o a t was injected a n d t h e r e was some exudat, e present. T h e r e was slight r i g i d i t y of t h e neck, m o r e obvious r i g i d i t y of t h e spine, a n d tendm'ness of t h e back a n d back of t h e neck. A t a c h e eerebrale was present. T h e r e was no muscle weakness a n d the reflexes were n o r m a l except for the r i g h t knee jerk w h i c h w a s obtained with difficulty. The s p i n a l fluid was u n d e r i n c r e a s e d pressure, clear, showed uo i n c r e a s e in globulin a n d c o n t a i n e d 7 cells p e r e.mm. S e r u m was a d m i n i s t e r e d both intraspinaUy and intramuscularly. The child m a d e a r a p i d a n d u n e v e n t f u l recovery w i t h o u t developing a n y other findings or a n y paresis.
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3 4 l.
Although we had a number of such cases, wishing to be conservative, we did not include them in our group of preparalytic poliomyelitis in tile absence of the confirmatory spinat fluid changes and the failure to develop muscle weakness. Because we felt that this condition was probably present, these patients were treated with convalescent poliomyelitis serum. There might be a tendency to place such cases in the " a b o r t i v e " group, but with the presenee of meningismus, and the clinical evidence o.f cord disturbance, these eases cannot be classed under what is commonly accepted as abortive poliomyelitis, but really should be considered as early instances of preparalytic poliomyelitis without cellular i11crease in. the spinal fluid. Cases of acute anterior poliomyelitis have been reported in which the cell count of the spinal fluid has been normal. Clarke and Dow 5 repo.rt a ease in which the spinal fluid obtained within twenty-four hours of development of flaccid paralysis of the right arm, contained 2 cells per e.mm. with a faint trace of globulin. Collier s reports 2 eases of nonparalytic poliomyelitis, in which he specifies that there were normal spinal fluids during the period of the a.cute illness, although one subsequently developed the findings that are characteristic of the fluid bt poliomyelitis (similar to our Case 1). Collis ~ in discussing some unusual cases of poliomyelo-encepha]itis, records 2 eases in which palsies had developed, but the spinal fluids, aside from increased pressure, were quite normal. Maenamara and Morgan s in reporting 133 cases of proparalytic poliomyelitis treated with convalescent serum, have records of the spinal fluids in 115 eases. Of these, 3 had a cell count under 10; 2, in which the fluid examination was delayed, had a count of 8 and subsequently developed paralysis. The third ease, a four-year-old girl, whose brother had developed paralysis the day before onset of her illness, had a temperature of 1.01~ headache, a ++ spine sign, Amoss's sign, and was irritable and delirious. The fluid in this ease showed a cell count of 5 per e.mm. (lymphoeytes) and an increased globulin. The child was treated with serum both intraspinally and intravenously and reeovered without subsequent paralysis. A normal number of cells in the spinal fluid in obvious eases of poliomyelitis has been recorded by other observers, but no particular emphasis had been placed upon this occurrence. MeMs and Bower 9 have recently reported a series of poliomyelitis eases in which they point out that contrary to current medical opinion, 12.8 per cent of their eases which showed characteristic neurologie findings had spinal fluids that cytologically were n o r m a l They assert that "oeeasionalty the spinal fluid was entirely unchanged, especially in the mild infections, and a diagnosis then had to. be made on clinieal findings alone. Also i n t h e early systemic preparalytic phase of the disease, the spinal fluid findings were frequently negative and misleading, and we learned in questionable cases to defer puncture (but no{ treatment)
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until some clinical evidence of neurologic involvement, principally changing or asymmetrical reflexes or painful anteflexion of the spine was p r e s e n t . " To our knowledge, this is the first time that this finding is emphasized, and its relatively frequent occurrence is stressed. In the effort to report only indisputable cases, we excluded from eonsideration all those eases in which the spinM fluid cell count was normal and in which no evidence of paralysis appeared. There were still 5 eases in our series of 130, which we were obliged to include, despite the normal spinal fluid cell count, because the development of muscular weakness assured us we were dealing with poliomyelitis. Considering only these 5 eases, they comprise 3.9 per eent of our total group. I f we were to add those eases that have been eliminated because of failure to develop paralysis the figure would approximate that given by Meals and Bower. It is of some interest, in this connection to eonsider the study on the preparalytic stage of experimental poliomyelitis produced in monkeys. There is a definite period, from five to eight days after intraeerebral inoeulation of tile virus, that is recognized as the prodromal stage TM 1, and is analogous to the preparalytie stage that is seen in man. This is characterized by restlessness and excitement, occasionally by marked apathy, ruffled fur and tremor. IIarmon, Shanghnessy, and Gordon ~'~ made a study of the temperature, blood, and spinal fluid during this prodromal period and an analysis of the latter reveals some interesting facts. In normal monkeys they found that in 83 per cent the cell count was between 33 and 77 per c.mm., although there was a range from 16 to 132, and the Ross-Joss test was negative. Consequently, they eonsidered a fluid pathologic when it had 150 cells per c.mm. and over, or 100 to 150 per e.mm. in the presence of a positive Ross-Jones reaction. On this basis, they found the following changes in the eerebrospinal fluid in 18 monkeys during the course of the experimental disease. All the spinal fluids examined were normal until the third day before onset Of paralysis. Three days before paralysis, 50 per cent of the fluids eomlted were positive. Two days and one day before paralysis, 16 of 18 monkeys examined on each day had fluids that could be considered pathologic, 2 of each group apparently having a normal fluid. This gives a figure of 11 per cent that had no pathologic spinal fluid even 24 hours before paralysis. On the day of development of paralysis, all the fluids were positive, but of those examined one day adter paralysis, there was 1 out of 11, even at this late stage, in which the fluid was not pathologic. If the prodromal period in monkeys can be considered analogous to the preparalytie stage in man and the experimental disease to the human disease, then these experimental findings may be considered as evidence that a pathologic spinal fluid is not a constant accompaniment of the disease, particularly in the preparalytic stage.
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A brief consideration of the pathology of early poliomyelitis is necessa.ry in order to arrive at an explanation of the marked variance of spinal fluid cell count, and satisfactorily to reconcile a normal spinal fluid with the disease in the preparalytie stage. A conception of the mechanism of the meningeal reaction with its eo.rresponding spinal fluid change is clarifying. In the physiology of the central nervous system and drainage of tissue fluids, the normal direction of flow is centrifugal along the perivaseular spaces from the center of the cord to. the meninges, and any marked accumulation of ceils in these spaces is discharged into the pial meshes. Harbitz and Scheel is noted piat inflammatory changes in areas corresponding to involved regions of the cord, but since they found areas of meningitis without subjaee~t cord changes, they coneluded the meningitis to be primary. This consideration was also expressed by Wiekman, 1~ Schr'ciber, 1~ etc., Amoss, 1~ relatively reeently, asserted that the meningeal reaction was probably the first lesion of the disease. The postulate that meningitis is the p r i m a r y lesion in poliomyelitis is based upon pathologic examination of fatal eases in man. Even where such eases were early, they were rapidly progressive and relatively advanced, certainly beyond the period that can be designated as proparalytic. Walter ~7 maintained that pial changes and cord changes were independent, and contrary to the former opinions, if there was any correlation it was reversed, for the degree of inflammatory change in the cord diminished as the surface was approached, and certain areas showing severe cord involvement disclosed no pial inflammation. Sehrgder, ~8 taking into consideration the physiology of fluid drainage, expressed the feeling that pia] infiltration may be merely a diseharge of cells from overdistended perivascular spaces. In a study of the histology of experimental poliomyelitis, P. Weston H u r s t ~9 found that in the stage of advancing paralysis, in many eases pial infiltration was insignificant until a fairly late stage, and that it was not always observed at all levels where definite changes were present in the cord. He concluded that meningitis was not a necessary feature of the disease, and, in his study, i t was only occasionally definite in the early stages. In a f u r t h e r study upon the pathogenesis of, and propagation of the virus in, experimental poliomyelitis, ]~airbrother and H u r s t 2o stated that poliomyelitis begins as a p r i m a r y degeneratio~ of nerve cells accompanied b y inflammation in the interstitial tissues, and, as Sehr5der emphasized, meningeal infiltration occurs only where an infiltrated vessel reaches the surface and evidently is due, ~ot to a. p r i m a r y mening'itis, but to an overflow of inflammatory cells from the distended and engorged perivaseular spaces of the deeper vessels. This conception of the production of meningitis in poliomyelitis may explain the marked variability of the cell connt of the spinal fluid, a n d also of the slight or negative findings in the spinal fluid of certain
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eases in the preparalytic stage. This redliz~tion, we believe, does not narrow the usefulness of a spinal fluid exalnination when poliomyelitis is suspected, but broadens "the field for early diagnosis in the preparalytic stage. It is readily conceivable that during the first advance of the disease process to the central nervous system, there are changes which are manifested by those clinical findings that we are accustomed to interpret as poliomyelitis; i.e., muscle pain and tenderrtess, altered reflexes, and changes in muscle strength. However, until the inflammatory reaction in the cord becomes sufficiently severe to pour ceils from the perivascular spaces into the pial meshes, an increase of cells in the spinal fluid is not to be expected. It was noticed in most of our eases that an increased globulin existed, and this change presumably preceded the increased cell count, but a completely normal spinal fluid is still compatible with early preparalytie poliomyelitis at a period when nerve cell disturbance can be recognized by the clinical manifestations. F r o m our experience, and from a consideration of the experimental disease from clinical, physiologic, a~d pathologic aspects, we feel th.at the increased cell count of the cerebrospinal fluid, although reliable because o.f its frequency is not infallible, for i~ is not a constant accompaniment of preparalytic poliomyelitis. Therefore, those eases that give clinical and neurologie evidence of this disease, but in which the spinal fluid does not reveal confirmation, should, nevertheless, be treated . as eases of prepara]ytie poliomyelitis. Most of our eases were treated by serum, both intratheeally and intravenously (as we treated all cases of preparalytic poliomyelitis) and we did not observe any marked advance of the process sueh as might be eaused by, and attributed to, harmful, effect of the serum given intratheeally. I f there is any fear of administering intratheeal convalescent serum, because of the theo.retieal danger of disrupting a meningoehoroidal barrier that may still be intact, the serum, in large doses., 80-100 c.e., should be given intravenously. It is hazardous to wait until the spinal fluid becomes positive, for delay defeats the purpose of serum therapy, which seems to be of greatest value in the very early st@*es of the disease. CONCLUSIONS
1. In poliomyelitis, cord- involvement precedes meningeal inflammation mud the accompanying increase of cells in the spinal fluid. 2. Cases of preparalytie poliomyelitis may occur in which there is clinical manifestations of cord disturbance without the production of increase of cells in the' spinal fluid. 3. Five such cases developing confirmatory paresis, are reported. 4. TheSe patients should be given the treatment f o r typical preparalytic poliomyelitis.
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POLIOMYELITIS
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I wish to t h a n k all of the physicians who cooperated with me in the case reports, especially Dr. Julius Hess, Dr. Philip Lewin~ Dr. I. Harrison Tumpeer, Dr. N. T. We]ford, Dr. Bert Beverly, and Dr. George Weaver. I particularly wish to express my sincere appreciation to Dr. Wrn. Thalhimer, Director of Laboratories, for his kind advice and constant help in this study. REFERENCES L Draper, George: Monograph, Acute Poliomyelitis, 1917. 2. Report of N. Y. C. Department of Health, 1917. 3. Aycozk, W. L., and Luther, E. H.: Preparalytic Poliomyelitis, J. A. M. A. 91: 387, 1928. 4. Ayer, W. D.: Poliomyelitis, Am. J. Iv[. Sc. 177: 540, 1929. 5. Clarke, F., and I)ow, A. G.: Roscnow's Serum in Prevention of Paralysis in Poliomyelitis, J. A. M. A. 83: 421, 1924. 6. Collier, J . : Clinical Features of Poliomyelitis, Lancet 1: 321~ 1927. 7. Collis, W. A. F.: Unusual Cases of Poliomyelo-encephalitis, Lancet 1: 927, 1927. 8. Nfaenamara, J., and Morgan, F. G.: Poliomyelo-encephalitis in Victoria, Lancet 1; 469, 1932. 9. Meals, R. W., and Bower, A. G.: Poliomyelitis, J. Lab. & Clin. Med. 17: 409, 1932. !0. Flexner, S., and Lewis, P. A.: Experimental Epidemic Poliomyelitis in Monkeys, J. Exper. Med. 12: 227, 1910. 11. RSmer, P. H.: Naehlese aus der experimentellen erfoschung der poliomyelitis acuta, Med. Kiln. 7: 1069, 1911. 12. Harmon, P. H., Shaughnessy, H. J., and Gordon, F. B~: Preparalytie Polio~ myelitis in Monkeys, J. Prevent. Med. 5: 115~ 1931. 13. I-Iarbitz, F., and SeheeI, O. : Epidemic Acute Poliomyelitis in Norway in the Years 1903-1906, J. A. M. A. 49': 1420~ 1907. 11. Wickman, I.: Monograph, 1911~ Die Akute Poliomyelitis bzw. Heine Medinsehe Krankheit. 15. Schrieber, G.: La Poliomy~lite @id@mique, 1911. 16. Amoss, H . L . : Filterable Viruses, Baltimore, p. 159, 1928. 17. Walter, R.: Zur Histopathologle der Akuten Poliomyelitis, Deutsche Ztsehr. f. Nervenh. 45: 79~ 1912. 18. SchrSder, P.: Myelitis and Poliomyelitis, Deutsche reed. Wchnsehr. 51: 973, 1925. 19. Hurst, E. W.: Histology of Experimental Poliomye]itis~ J. Path. & Baet. 32: 457, 1929. 20. Fairbrother, R. W., and Hurst, E. W.; Pathogenesis of, and Propagation of Virus in, Experimental Poliomyelitis, J. Path. & Bact. 33: 17~ 1930. MICttAEL REESE HOSPITAL.
WITHOUT
AN
INCREASE OF CELLS IN THE SPINAL FLUID s SIDNEY O. LEVINSON,
CHICAGO,
M.D.
ILL.
stage of acute T HEwell prepara]yt~e established clinical entity.
anterior poliomyelitis has become a The history, physical examination, and neurological findings are usually sufficiently significant to make a tenta*ive diagaaosis. There is one test,~however, which is usually relied upon to confirm the diagnosis. This is the examination of the spinal fluid secured by lumbar puncture. In order t~ make a positive diagnosis o~ preparalytic poliomyelitis, even when other simulating conditions are ruled out, it has been considered essential to find changes in the spinal fluid ir~dicative of mild meningeal inflammation. Although it is commonly accepted t h a t the spinal fluid in this condition should show an i n c r e a s e d n ~ m b e r of cells and an increased globulin, it is notable that the}'e is a great variation in these spinM fluid findings. D r a p e r 1 states that in the p r e p a r a l y t i c stage, following meningeal invasion, the pressure is lowered, and there is an increase in the cell content, ranging between 10 and 2,500 p e r c.mm. At the earliest period the cells are chiefly ' " p o l y n u e l e a r s , " but within twenty-four to thirty-six hours, l y m p h o e y t e s comprise over 90 per cent of the cells. The globulin also becomes definitely increased. There was one group to which he called p a r t i c u l a r attenfion, a group in which the cell count was quite low, usually u n d e r 100 p e r e.mm. ; and in which the course of the disease was quite mild. I n the New York epidemic of 19162 the cell content o$ the spix~al fluid ranged between fifteen and twenty a n d 1000 per c.mm. Ayeock and L u t h e r a report the spinal fl~uid to be u n d e r moderately increased pressure, the cell count 50 to 250 p e r c.mm. and the globulin increased. W a r d n e r D. A y e r 4 finds the average cell count to be 350 cells per c.mm. ; slightly increased pressure of the f u i d and an increased 9gl~ content. Various reports indicate that the spinal fluid returns to no~nal at a valgying interval (four to fourteen days) a f t e r paralysis has developed. I n our series of 130 cases of acute anterior poliomyelitis (reported elsewhere.) t including 65 t h a t were obs.erved in the preparMytic stage, our fiItdings co~formed to those just reviewed in almost all the cases, ~he cell count us,~ally being between 50 and 250 per e.mm. However, * F r o m t h e S a m u e l D e u t s e h Convs S e r u m Center, M i c h a e l R e e s e H o s p i t a l , Chicago. R e c e i v e d for p u b l i c a t i o n , A u g u s t 4, 1932. t L e v i n s o n ; S i d n e y O., 3/feDougall, C l a r i e e , a n d T h a l h i m e r , W i l l i a m : A c u t e A n t e r i o r :Poliomyelitis i n t h e C~hieago A r e a in 1981. T h i s a r t i c l e h a s been a c c e p t e d for p u b l i c a tion in tlae J. A. IV[. A. 337
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of particular interest and significance were five eases, in which, although the clinical findings pointed to acute anterior poliemyelitis, the: spinal fluid showed only an increase in globulin but not an increase in cells. All of these patients disclosed muscle weakness at the: initial examination, or subsequently developed a t e m p o r a r y or p e r m a n e n t paralysis of the t y p e seen iI~ poliomyelitis. I n Case 1, the clinical picture was so strongly suggestive of poliomyelitis because of the muscular weakness and absent reflexes, that despite the failure to find an increased cell count in the spinal fluid, we were tempted to administer serum. However, and to o~ar later regret, the absence of cells caused us to delay t h e r a p y for t w e n t y - f o u r hours, until a second l u m b a r p u n c t u r e did show an increased cell count (of which 45 p e r cent were mononuelear cells). By this time actual paralysis had developed. A f t e r this experience we became more alert for those cases seen so early in the p r e p a r a l y t i e stage that sufficient meningeal involvement had not occurred t o cause a cellular response in the spinM fluid. We also were forced to realize that even i~ the ]ate p r e p a r a l y t i c stage, the meningitis m a y at times be so slight that no cellular increase is produced, although practically always an increased globulin is found. A brief r@um6 of the five cases fo.]]ows. Normal findings are omitted. CASE 1.--S. R , femal% aged three was admitted to the hospital with a history of pain in the legs for four days ~md inability to walk. There was no history of contact or of recent ~llness. For twenty-four hours the patient had diarrhea and complained of pain in the back of the neck. Examination revealed a normal temperatnr% slight neck rigidity, limited motion ia the lower extremities with muscular pain on movement, absent knee jerks and absent ankle jerks. The spinal fluid was clear, containing 4 lymphocytes per c.mm. and increased globulin (Ross-Jones test). The following day the spinal puncture was repeated because of a marked increase in the weakness of the lower extremities and at this time there were 186 cells, 55 per cent polynuclears and 45 per cent mononuclears. Convalescent serum was then administered both intraspinally (20 c.c.) and intravenously (60 c.c.), This case progressed to a complete paralysis of both lower extremities~ and partial paralysis of the muscles of the back. CASE 2. K. D., female, aged twenty-two months, was admitted with a history of onset twenty hours previously with vomiting, weakness of the legs for eight hours when walking, and pain in the right thigh. There was no history of recent illness or of contact. One brother, thirteen years old~ was well. The temperature was 100 ~ pulse 120, and respirations 22. Examination revealed only a slight tremor of the extremities~ hyperactive knee jerks, some weakness of the right thigh against resistance, and to a less exten L some weakness of the. left thigh. Spinal puncture revealed a clear fluid, with a cell count of 6 per c.mm. and a positive globulill (Ross-Jones test). Convalescent serum was administered both intraspinally (20 c.c.) and intravenously (60 c.c.). The tremor and brisk knee jerks persisted for several days. Within five days there seemed to be complete recovery with disappearance of fever and muscular
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weakness. The spinal fluid at the end of 1%re days c o n t a i n e d only 4 l y m p h o e y t e s per cu. turn. ; the globulin was still pesitive. CaSE 3 . - - T . M., f e m a l e , a g e d twelve, h a d been ill for two d a y s before a d m i s s i o n with a sore t h r o a t , followed b y h e a d a c h e a n d stiff a n d a c h i n g legs. Thel'e was no h i s t o r y o f r e c e n t ilhmss or contact, a n d one other child in the f a m i l y h a d been well. On t h e d a y following t h e onset of t h e illness a p h y s i c i a n observed ea~ i n j e c t e d throat a n d fever, The h e a d a c h e a n d . p a i n s in t h e legs h a d i n c r e a s e d a n d there also developed dull p a i n in the back a n d in the back of t h e neck. The a d m i s s i o n t e m p e r a t u r e w a s 100.6 ~ (mouth)~ pulse 104, r e s p i r a t i o n s 24. The p a t i e n t , t h o u g h not toxie~ h a d a flushed f a c e with a perioral pallor and the t h r o a t was injected. A l t h o u g h t h e r e w a s no" cervical or back r i g i d i t y , t h e r e was a head drop, t e n d e r n e s s in t h e back, back of neck~ b o t h thighsj a n d left leg. There was l i m i t a t i o n of m o v e m e n t due to pain, b u t no obvious weakness. The knee jerks were e x a g g e r a t e d , a n d a e o n t r a l a t e r a l O p p e n h e i m a n d left Chaddock were present. B o t h u p p e r a n d t h e r i g h t lower a b d o m i n a l reflexes were absent, the l e f t lower weak. The spinal fluid was clear, u n d e r i n c r e a s e d pressure, showed a cell count of 6 per e.mm. (5 l y m p h o c y t e s , I po]ynuclear) a n d a f a i n t l y positive R o s s - J o n e s test. S e r u m w a s a d m i n i s t e r e d b o t h i n t r a s p i n a l l y (20 c.e.) a n d i n t r a v e n o u s l y (60 c.e.). I n the n e x t few days~ w e a k n e s s of t h e dorsiflexors of t h e feet a n d a b d u c t o r s of the left lower t h i g h developed,' b u t t h e t e m p e r a t u r e r a p i d l y d r o p p e d to n o r m a l a n d a t d i s c h a r g e two weeks later, t h e w e a k n e s s h a d disappeared. CASE 4 . - - A . P., femal% a g e d n i n e t e e n years. The p a t i e n t was well u n t i l the d e v e l o p m e n t of a sore t h r o a t w i t h p a i n in the back ~nd g e n e r a l i z e d a c h i n g muscles. There was also some t e m p e r a t u r e . The following a f t e r n o o n the neck became stiff a n d this lasted for t h r e e days. The p a i n a n d t e n d e r n e s s of the m u s c l e s had become p r o g r e s s i v e l y worse u n t i l t h e t i m e of e x a m i n a t i o n , five days a f t e r onset. A t this tim% t h e t e m p e r a t u r e was ]00 ~ i% b y mouth~ pulse 110, a n d r e s p i r a t i o n s 20. T h e r e w a s no cervical r i g i d i t y , b u t t h e back w a s r e s i s t a n t . T h e r e was m a r k e d t e n d e r n e s s a n d pain of all t h e extremities, p a r t i c u l a r l y the fore.~rms. There was no f r a n k paralysis; b u t t h e r e was some weakness o f the flexors a n d extensors of both f o r e a r m s , the flexors a n d a b d u c t o r s of the left h a n d , e x t e n s o r s of the t h i g h s a n d of t h e l e f t foot. T h e degree of w e a k n e s s could not he a c c u r a t e l y determh~ed because of the muscle p a i n p r o d u c e d b y m o t i o n a g a i n s t resistance. The triceps jerks were absent, the w r i s t jerk very weak on the left, b r i s k on t h e right, ~md the a b d o m i n a l reflexes very weak to absent. The spinal ~ u i d was u n d e r in'creased pressure, eyes L c o n t a i n i n g 4 cells per e.mm. (lympho,~'ytes)' a u d showed a definitely increased globulin ( R o s s - g o u e s test). S e r u m w a s a d m i n i s t e r e d both ] n t r a s p i n a l l y (20 e.e.) a n d i n t r a v e n o u s l y (60 c.c.). The t e m p e r a t u r e d r o p p e d to n o r m a l in t w e n t y - f o u r hours. A f o o t drop on {he left side, a n d paresis of the r i g h t h a n d developed. One m o n t h later, there was still r e s i d u a l weakness of the r i g h t f o r e a r m a n d h~tnd to flexion a n d extension, a n d of t h e l e f t f o o t to dors iflexion. The p a t i e n t w~s i n c a p a b l e of p e r f o r m i n g these m 6 v e m e n t s a g a i n s t a n y resistance. C~SE 5.'--J. G., male, aged fiv,e a~ld one-half years, gave a h i s t o r y of exposure to a, ease of a n t e r i o r poliomyelitis in t h e school. The child became ill with p a i n h~ the back of t h e head, v o m i t i n g , a n d fever. He was a d m i t t e d t w e n t y - e i g h t h o u r s a f t e r onset of t h e illness~ a n d at this t i m e h a d a t e m p e r a t u r e of 100 ~ F. ( r e c t a l ) , a pulse of 156, a n d r e s p i r a t o r y r a t e of 28. The p a t i e n t was p r o s t r a t e d a n d irritable. T}lere was a s l i g h t pcrioral pallor. T h e r e was a m a r k e d head drop, slight r e s i s t a n c e of. the neck, a n d definite stiffness of the back. T h e r e was mus~de t e n d e r n e s s in b o t h f o r e a r m s a n d t h i g h s , a tremor of t h e lower extremities, b u t no
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a p p a r e n t w e a k n e s s w a s discernible. All the reflexes were brisk~ except t h e knee j e r k s , w h i c h were elicited with diff• a n d t h e a b d o m i n a l s w h i c h were absent. Ths:-e w a s a b i l a t e r a l O p p e n h e i m . The s p i n a l fluid w a s clear, c o n t a i n e d 6 cells ( l y m p h o e y t e s ) per c.mm. a n d showed a t r a c e of globulin. S e r u m w a s a d m i n i s t e r e d b o t h i n t r a s p i n a l l y (20 c.c.) a n d i n t r a v e n o u s l y (60 s.c.). The following day~ t h e t e m p e r a t u r e w a s no~'mal, t h e child m u c h b r i g h t e r . The knee j e r k s could not be obtMned. Ttiere was still a positive O p p e n h e i m and a positive Chaddoek on t h e r i g h t side. No f r a n k p a r a l y s i s developed. A c a r e f u l a n d t h o r o u g h muscle e x a m i n a t i b n p e r f o r m e d two m o n t h s later disclosed definite evidence of m u s c l e involvement. T h e r e w a s d i m i n i s h e d power in t h e a b d o m i n a l s , t h e r i g h t g l u t e n s maximus~ a n d the flexors of t h e toes, more m a r k e d on t h e r i g h t . T h e m e a s u r e m e n t s of t h e r i g h t leg were s l i g h t l y less t h a n the corr e s p o n d i n g m e a s u r e m e n t s of t h e left leg.
A n u m b e r of other patients were seen, who seemed most likely to be ifl the p r e p a r a l y t i c stage of anterior poliomyelitis, but whose spinal fluid showed 11o increase in cells, although some h a d an increased globulin. Most of these were given serum and went on to an uneventful recovery, without the development of any paresis. A brief :~ccount of two such cases follows : CASE 6 . - - R . O., male~ a g e d nine years, became sick with a sore t h r o a t , a chill a n 4 fever, v o m i t i n g , a n d some consUpation. The child h a 4 n o t b e e n ill recently a n d h a d two brothers, a g e d t e n a n d twelve, who were well. There was no h i s t o r y of contact. T h e child i n two days developed a m o d e r a t e headache, p a i n in t h e back a n d back of t h e neck, a n d slight stiffness of t h e neck. E x a m i n a t i o n revealed a m o d e r a t e l y sick flushed child w i t h a t e m p e r a t u r e of 102 ~ :~'., a n i n j e c t e d t h r o a t , slightly r i g i d neck a n d back, w i t h t e n d e r n e s s in t h e s e areas. T h e r e w a s a taehe cerebra]e. T h e r e was no i m p a i r m e n t in muscle s t r e n g t h a n d the reflexes were all n o r m a l l y p r e s e n t except t h e l e f t knee jerk which w a s diminished. T h e s p i n a l fluid w a s clear, u n d e r m a r k e d l y i n c r e a s e d pressure, e o n t s i n e d 5 cells per e.mm. a n d definitely i n c r e a s e d globulin ( R o s s - J o n e s t e s t ) . S e r u m was a d m i n i s t e r e d b o t h i n t r a s p i n a l l y a n d i n t r a m u s c u l a r l y w i t h i n twentyf o u r h o u r s of t h e onset of m e n i n g e a l s y m p t o m s . T h e following d a y b o t h knee j e r k s d i s a p p e a r e d , b u t t h e t e m p e r a t u r e d r o p p e d r a p i d l y to n o r m a l a n d t h e child m a d e a n u n e v e n t f u l recovery w i t h o u t development of muscle weakness. CASE 7 . - - J . H., female, a g e d seven years, b e c a m e sick with a sore throat, m o d e r a t e f e v e r a n d some constipation. The child trod b e e n well a n d two other children i n t h e f a m i l y were in good health. This child h a d been cxposed~ t h o u g h n o t i n t i m a t e l y , to a n o t h e r child in school who h a d developed a c u t e poliomyelitis. W i t h i n t h e n e x t two days, t h e p a t i e n t developed headache, pahn in t h e legs, neck, a n d side of t h e chest. E x a m i n a t i o n revealed a m o d e r a t e l y sick child w i t h a t e m p e r a t u r e of 102 ~ F. T h e t h r o a t was injected a n d t h e r e was some exudat, e present. T h e r e was slight r i g i d i t y of t h e neck, m o r e obvious r i g i d i t y of t h e spine, a n d tendm'ness of t h e back a n d back of t h e neck. A t a c h e eerebrale was present. T h e r e was no muscle weakness a n d the reflexes were n o r m a l except for the r i g h t knee jerk w h i c h w a s obtained with difficulty. The s p i n a l fluid was u n d e r i n c r e a s e d pressure, clear, showed uo i n c r e a s e in globulin a n d c o n t a i n e d 7 cells p e r e.mm. S e r u m was a d m i n i s t e r e d both intraspinaUy and intramuscularly. The child m a d e a r a p i d a n d u n e v e n t f u l recovery w i t h o u t developing a n y other findings or a n y paresis.
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3 4 l.
Although we had a number of such cases, wishing to be conservative, we did not include them in our group of preparalytic poliomyelitis in tile absence of the confirmatory spinat fluid changes and the failure to develop muscle weakness. Because we felt that this condition was probably present, these patients were treated with convalescent poliomyelitis serum. There might be a tendency to place such cases in the " a b o r t i v e " group, but with the presenee of meningismus, and the clinical evidence o.f cord disturbance, these eases cannot be classed under what is commonly accepted as abortive poliomyelitis, but really should be considered as early instances of preparalytic poliomyelitis without cellular i11crease in. the spinal fluid. Cases of acute anterior poliomyelitis have been reported in which the cell count of the spinal fluid has been normal. Clarke and Dow 5 repo.rt a ease in which the spinal fluid obtained within twenty-four hours of development of flaccid paralysis of the right arm, contained 2 cells per e.mm. with a faint trace of globulin. Collier s reports 2 eases of nonparalytic poliomyelitis, in which he specifies that there were normal spinal fluids during the period of the a.cute illness, although one subsequently developed the findings that are characteristic of the fluid bt poliomyelitis (similar to our Case 1). Collis ~ in discussing some unusual cases of poliomyelo-encepha]itis, records 2 eases in which palsies had developed, but the spinal fluids, aside from increased pressure, were quite normal. Maenamara and Morgan s in reporting 133 cases of proparalytic poliomyelitis treated with convalescent serum, have records of the spinal fluids in 115 eases. Of these, 3 had a cell count under 10; 2, in which the fluid examination was delayed, had a count of 8 and subsequently developed paralysis. The third ease, a four-year-old girl, whose brother had developed paralysis the day before onset of her illness, had a temperature of 1.01~ headache, a ++ spine sign, Amoss's sign, and was irritable and delirious. The fluid in this ease showed a cell count of 5 per e.mm. (lymphoeytes) and an increased globulin. The child was treated with serum both intraspinally and intravenously and reeovered without subsequent paralysis. A normal number of cells in the spinal fluid in obvious eases of poliomyelitis has been recorded by other observers, but no particular emphasis had been placed upon this occurrence. MeMs and Bower 9 have recently reported a series of poliomyelitis eases in which they point out that contrary to current medical opinion, 12.8 per cent of their eases which showed characteristic neurologie findings had spinal fluids that cytologically were n o r m a l They assert that "oeeasionalty the spinal fluid was entirely unchanged, especially in the mild infections, and a diagnosis then had to. be made on clinieal findings alone. Also i n t h e early systemic preparalytic phase of the disease, the spinal fluid findings were frequently negative and misleading, and we learned in questionable cases to defer puncture (but no{ treatment)
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until some clinical evidence of neurologic involvement, principally changing or asymmetrical reflexes or painful anteflexion of the spine was p r e s e n t . " To our knowledge, this is the first time that this finding is emphasized, and its relatively frequent occurrence is stressed. In the effort to report only indisputable cases, we excluded from eonsideration all those eases in which the spinM fluid cell count was normal and in which no evidence of paralysis appeared. There were still 5 eases in our series of 130, which we were obliged to include, despite the normal spinal fluid cell count, because the development of muscular weakness assured us we were dealing with poliomyelitis. Considering only these 5 eases, they comprise 3.9 per eent of our total group. I f we were to add those eases that have been eliminated because of failure to develop paralysis the figure would approximate that given by Meals and Bower. It is of some interest, in this connection to eonsider the study on the preparalytic stage of experimental poliomyelitis produced in monkeys. There is a definite period, from five to eight days after intraeerebral inoeulation of tile virus, that is recognized as the prodromal stage TM 1, and is analogous to the preparalytie stage that is seen in man. This is characterized by restlessness and excitement, occasionally by marked apathy, ruffled fur and tremor. IIarmon, Shanghnessy, and Gordon ~'~ made a study of the temperature, blood, and spinal fluid during this prodromal period and an analysis of the latter reveals some interesting facts. In normal monkeys they found that in 83 per cent the cell count was between 33 and 77 per c.mm., although there was a range from 16 to 132, and the Ross-Joss test was negative. Consequently, they eonsidered a fluid pathologic when it had 150 cells per c.mm. and over, or 100 to 150 per e.mm. in the presence of a positive Ross-Jones reaction. On this basis, they found the following changes in the eerebrospinal fluid in 18 monkeys during the course of the experimental disease. All the spinal fluids examined were normal until the third day before onset Of paralysis. Three days before paralysis, 50 per cent of the fluids eomlted were positive. Two days and one day before paralysis, 16 of 18 monkeys examined on each day had fluids that could be considered pathologic, 2 of each group apparently having a normal fluid. This gives a figure of 11 per cent that had no pathologic spinal fluid even 24 hours before paralysis. On the day of development of paralysis, all the fluids were positive, but of those examined one day adter paralysis, there was 1 out of 11, even at this late stage, in which the fluid was not pathologic. If the prodromal period in monkeys can be considered analogous to the preparalytie stage in man and the experimental disease to the human disease, then these experimental findings may be considered as evidence that a pathologic spinal fluid is not a constant accompaniment of the disease, particularly in the preparalytic stage.
LEVINSON
:
POLIOMYELITIS
343
A brief consideration of the pathology of early poliomyelitis is necessa.ry in order to arrive at an explanation of the marked variance of spinal fluid cell count, and satisfactorily to reconcile a normal spinal fluid with the disease in the preparalytie stage. A conception of the mechanism of the meningeal reaction with its eo.rresponding spinal fluid change is clarifying. In the physiology of the central nervous system and drainage of tissue fluids, the normal direction of flow is centrifugal along the perivaseular spaces from the center of the cord to. the meninges, and any marked accumulation of ceils in these spaces is discharged into the pial meshes. Harbitz and Scheel is noted piat inflammatory changes in areas corresponding to involved regions of the cord, but since they found areas of meningitis without subjaee~t cord changes, they coneluded the meningitis to be primary. This consideration was also expressed by Wiekman, 1~ Schr'ciber, 1~ etc., Amoss, 1~ relatively reeently, asserted that the meningeal reaction was probably the first lesion of the disease. The postulate that meningitis is the p r i m a r y lesion in poliomyelitis is based upon pathologic examination of fatal eases in man. Even where such eases were early, they were rapidly progressive and relatively advanced, certainly beyond the period that can be designated as proparalytic. Walter ~7 maintained that pial changes and cord changes were independent, and contrary to the former opinions, if there was any correlation it was reversed, for the degree of inflammatory change in the cord diminished as the surface was approached, and certain areas showing severe cord involvement disclosed no pial inflammation. Sehrgder, ~8 taking into consideration the physiology of fluid drainage, expressed the feeling that pia] infiltration may be merely a diseharge of cells from overdistended perivascular spaces. In a study of the histology of experimental poliomyelitis, P. Weston H u r s t ~9 found that in the stage of advancing paralysis, in many eases pial infiltration was insignificant until a fairly late stage, and that it was not always observed at all levels where definite changes were present in the cord. He concluded that meningitis was not a necessary feature of the disease, and, in his study, i t was only occasionally definite in the early stages. In a f u r t h e r study upon the pathogenesis of, and propagation of the virus in, experimental poliomyelitis, ]~airbrother and H u r s t 2o stated that poliomyelitis begins as a p r i m a r y degeneratio~ of nerve cells accompanied b y inflammation in the interstitial tissues, and, as Sehr5der emphasized, meningeal infiltration occurs only where an infiltrated vessel reaches the surface and evidently is due, ~ot to a. p r i m a r y mening'itis, but to an overflow of inflammatory cells from the distended and engorged perivaseular spaces of the deeper vessels. This conception of the production of meningitis in poliomyelitis may explain the marked variability of the cell connt of the spinal fluid, a n d also of the slight or negative findings in the spinal fluid of certain
344
TI-IE J O U R N A L OF P E D I A T R I C S
eases in the preparalytic stage. This redliz~tion, we believe, does not narrow the usefulness of a spinal fluid exalnination when poliomyelitis is suspected, but broadens "the field for early diagnosis in the preparalytic stage. It is readily conceivable that during the first advance of the disease process to the central nervous system, there are changes which are manifested by those clinical findings that we are accustomed to interpret as poliomyelitis; i.e., muscle pain and tenderrtess, altered reflexes, and changes in muscle strength. However, until the inflammatory reaction in the cord becomes sufficiently severe to pour ceils from the perivascular spaces into the pial meshes, an increase of cells in the spinal fluid is not to be expected. It was noticed in most of our eases that an increased globulin existed, and this change presumably preceded the increased cell count, but a completely normal spinal fluid is still compatible with early preparalytie poliomyelitis at a period when nerve cell disturbance can be recognized by the clinical manifestations. F r o m our experience, and from a consideration of the experimental disease from clinical, physiologic, a~d pathologic aspects, we feel th.at the increased cell count of the cerebrospinal fluid, although reliable because o.f its frequency is not infallible, for i~ is not a constant accompaniment of preparalytic poliomyelitis. Therefore, those eases that give clinical and neurologie evidence of this disease, but in which the spinal fluid does not reveal confirmation, should, nevertheless, be treated . as eases of prepara]ytie poliomyelitis. Most of our eases were treated by serum, both intratheeally and intravenously (as we treated all cases of preparalytic poliomyelitis) and we did not observe any marked advance of the process sueh as might be eaused by, and attributed to, harmful, effect of the serum given intratheeally. I f there is any fear of administering intratheeal convalescent serum, because of the theo.retieal danger of disrupting a meningoehoroidal barrier that may still be intact, the serum, in large doses., 80-100 c.e., should be given intravenously. It is hazardous to wait until the spinal fluid becomes positive, for delay defeats the purpose of serum therapy, which seems to be of greatest value in the very early st@*es of the disease. CONCLUSIONS
1. In poliomyelitis, cord- involvement precedes meningeal inflammation mud the accompanying increase of cells in the spinal fluid. 2. Cases of preparalytie poliomyelitis may occur in which there is clinical manifestations of cord disturbance without the production of increase of cells in the' spinal fluid. 3. Five such cases developing confirmatory paresis, are reported. 4. TheSe patients should be given the treatment f o r typical preparalytic poliomyelitis.
LEVINSON :
POLIOMYELITIS
3~5
I wish to t h a n k all of the physicians who cooperated with me in the case reports, especially Dr. Julius Hess, Dr. Philip Lewin~ Dr. I. Harrison Tumpeer, Dr. N. T. We]ford, Dr. Bert Beverly, and Dr. George Weaver. I particularly wish to express my sincere appreciation to Dr. Wrn. Thalhimer, Director of Laboratories, for his kind advice and constant help in this study. REFERENCES L Draper, George: Monograph, Acute Poliomyelitis, 1917. 2. Report of N. Y. C. Department of Health, 1917. 3. Aycozk, W. L., and Luther, E. H.: Preparalytic Poliomyelitis, J. A. M. A. 91: 387, 1928. 4. Ayer, W. D.: Poliomyelitis, Am. J. Iv[. Sc. 177: 540, 1929. 5. Clarke, F., and I)ow, A. G.: Roscnow's Serum in Prevention of Paralysis in Poliomyelitis, J. A. M. A. 83: 421, 1924. 6. Collier, J . : Clinical Features of Poliomyelitis, Lancet 1: 321~ 1927. 7. Collis, W. A. F.: Unusual Cases of Poliomyelo-encephalitis, Lancet 1: 927, 1927. 8. Nfaenamara, J., and Morgan, F. G.: Poliomyelo-encephalitis in Victoria, Lancet 1; 469, 1932. 9. Meals, R. W., and Bower, A. G.: Poliomyelitis, J. Lab. & Clin. Med. 17: 409, 1932. !0. Flexner, S., and Lewis, P. A.: Experimental Epidemic Poliomyelitis in Monkeys, J. Exper. Med. 12: 227, 1910. 11. RSmer, P. H.: Naehlese aus der experimentellen erfoschung der poliomyelitis acuta, Med. Kiln. 7: 1069, 1911. 12. Harmon, P. H., Shaughnessy, H. J., and Gordon, F. B~: Preparalytie Polio~ myelitis in Monkeys, J. Prevent. Med. 5: 115~ 1931. 13. I-Iarbitz, F., and SeheeI, O. : Epidemic Acute Poliomyelitis in Norway in the Years 1903-1906, J. A. M. A. 49': 1420~ 1907. 11. Wickman, I.: Monograph, 1911~ Die Akute Poliomyelitis bzw. Heine Medinsehe Krankheit. 15. Schrieber, G.: La Poliomy~lite @id@mique, 1911. 16. Amoss, H . L . : Filterable Viruses, Baltimore, p. 159, 1928. 17. Walter, R.: Zur Histopathologle der Akuten Poliomyelitis, Deutsche Ztsehr. f. Nervenh. 45: 79~ 1912. 18. SchrSder, P.: Myelitis and Poliomyelitis, Deutsche reed. Wchnsehr. 51: 973, 1925. 19. Hurst, E. W.: Histology of Experimental Poliomye]itis~ J. Path. & Baet. 32: 457, 1929. 20. Fairbrother, R. W., and Hurst, E. W.; Pathogenesis of, and Propagation of Virus in, Experimental Poliomyelitis, J. Path. & Bact. 33: 17~ 1930. MICttAEL REESE HOSPITAL.