Extracted from the American JournaI of the Medical Sciences, February, 1919, No. 2, vol. Clvii, p. 210.







From November 10, 1917 to June.1, 1918, we had 126 cases of epidemic cerebrospinal meningitis, with 65 recoveries and 61 deaths, a mortality of 48.26 per cent. A review of these cases disclosed certain facts as to the transmission, forms of the disease, symptomatology, treatment and complications which may be of interest.

TRANSMISSION: Our experience leads us to believe that the patient, ill of the disease, as a disseminator of the infection is not dangerous, especially after active treatment has been instituted. Of many throat cultures taken upon admission and during the course of the disease, only one culture in one patient proved suspicious. Not one of the officers, nurses or enlisted men constantly in the wards during this period contracted the disease, although during November and December no precautionary measures, such as the wearing of masks or the use of sprays, were taken. The enlisted men particularly were careless in their handling of and close personal contact to patients. We have still to look upon the carrier as the dangerous agent to others only, for we have no record of any carrier who developed the disease.

FORMS AND SYMPTOMATOLOGY: Three forms of the disease were noted: the ordinary (frank and masked), the fulminating and the chronic forms. The ordinary form presented itself either as a frank meningitis with premonitory symptoms, as headache, loss of appetite, malaise and later chill, fever, vomiting, intense headache, painful stiffness in the muscles of the neck, great sensitiveness to noise, hyperesthesia, photophobia and the usual signs of meningitis, or as a masked meningitis with the symptoms-complex of influenza or laryngitis, chilly sensations, fever, general malaise, headache, pains in bones, hoarseness, cough, sore-throat, etc. This last form during the prevalence of influenza presented at first a perplexing problem, more easily solved later when a careful inspection for the typical petechial eruption very often present in these cases gave us a clue. One case, correctly diagnosed only on the third day of the disease, presented at the onset a typical picture of acute articular rheumatism. One symptom, noticed in most of these masked cases, never proved misleading, a "slow mentality;" patients were slow to answer questions, showed an aversion to being disturbed and wanted to be let alone. This symptom always justifies a lumbar puncture. A leukocyte count is always helpful and will often suggest the diagnosis. One of our first cases showing indefinite symptoms was correctly diagnosed before puncture upon a leukocytosis of 66,000.

The eruption in our experience has been helpful as a diagnostic point, being present in almost 50 per cent. of our cases as a whole, and in the last series, when carefully looked for, in 80 per cent. It appears first on the shoulders', forearms, legs and chest as petechiae, erythema or rose-colored hyperemic spots in the ordinary form of the disease and as typical hemorrhagic spots of varying size in the fulminating forms or in very severe infections. We were so impressed with the value of this eruption as a diagnostic sign that it was our invariable rule to inspect carefully all patients presenting any suspicious symptoms. It was also noticed that these spots came on quickly, sometimes in a few hours, necessitating frequent inspections.

The fulminating form, of which we had 10 cases, proved how powerless we are in the face of this most dreadful disease. We include under this form only those cases which died within twenty-four hours of the onset. Five of these died within twelve hours. The onset was usually sudden, with violent chills, headache', great depression, fever, vomiting, slow, feeble pulse, hyperexcitability, followed by unconsciousness and delirium. Kernig's and later signs of the disease usually were not present. Two cases upon admission presented no definite symptoms and the disease was suspected only when unconsciousness supervened, a lumbar puncture in both yielding clear fluid under pressure with no organisms. Autopsy in both cases revealed only congestion of the meninges, a positive diagnosis being made on culture of the spinal fluid after death. One case lived six and a half and the other eight and a half hours after the appearance of the first symptoms. Another case was brought in, showing profound depression and overwhelming intoxication, a hemorrhagic eruption appearing within three hours of the first symptom, quickly spreading over the whole body, with death in ten hours. Spinal fluid, clear, showed meningococci. Fluid and blood culture were both positive. The other cases presented no unusual symptoms except profound depression and a general expression of being acutely and desperately ill, with no improvement whatever under treatment.

We had 2 cases of the chronic form, the typical long-drawn-out cases of preserum days. One case, actively treated three times during the space of seventy-five days by the intraspinal, intravenous and intraventricular routes, finally died of hydrocephalus, due to blocking. It is but fair to state that the injection of serum into the lateral ventricles was done as a last resort. The other case recovered after a three months' siege of the disease.

Two cases developed a postmeningitic septicemia, both after an actively treated meningitis by the intravenous and intraspinal routes, blood cultures in the first case giving a meningococcus growth on the thirty-sixth day and the second on the sixteenth day of the disease. The first case had seven lumbar punctures, with 280 c.c. serum and three intravenous doses, 180 c.c. serum, ran a typical course until the nineteenth day, when the temperature, normal for five days, assumed an intermittent type, normal in the morning to 103 to 104 degrees in the afternoon, after a daily chill, to return to normal in a few hours. The patient felt well between paroxysms and was up and about. Physical and blood examinations revealed nothing to account for the fever.

On the thirty-fifth day a petechial eruption was noticed. On the thirty-sixth day a blood culture gave a meningo-coccus growth. The intravenous treatment was again instituted, the patient showing very severe anaphylactic reaction. On the forty-third day he developed an acute endocarditis. On the forty- seventh day blood culture was negative. On the sixtieth day the patient was well.

The second, another typical case, rather severe, did well under intravenous and intraspinal treatment up to the sixth day, when the temperature went up to 104.6 degrees, developing physical signs of pneumonia, lobar. On the seventh day a blood culture gave a growth of pneumococci; a type differentiation, Avery's method, showed Type 1. Antipneumococcic serum 100 c.c. intravenously on the seventh and again on the eighth day brought the temperature to normal, with general improvement in pneumonia condition. On the tenth day the temperature again went up to 105.60, with cloudy spinal fluid. Blood cultures negative to pneumococci and meningococci. Active treatment, both routes, again instituted. On the twelfth day a blood culture again was negative. Temperature ran an up-and-down course, evening and morning, with the patient getting worse. On the sixteenth day a hemorrhagic eruption appeared, quickly spreading over the whole body, particularly thick and marked on the hands, forearms, shoulders, face and legs, some spots being 2 cm. in diameter with a periarticular inflammation of the wrist and ankle-joints. Blood culture gave a meningococcus growth. Up to this day he had received 15 intraspinal doses of serum, 600 c.c., and 5 intravenous 300 c.c. Active treatment was continued up to the day of death, the twenty-first day, when, realizing the futility of these methods, an injection of 20 c.c. of serum into the lateral ventricles and the subdural space was resorted to as a last measure. It is rather difficult to offer any explanation of the blood-stream condition in these two patients after active treatment unless we theorize in the first case upon the flaring up of a latent focus of infection, and in the second the breaking loose of a walled-off focus never reached by the serum, reinfecting cerebrospinal system and the blood stream.

TREATMENT. It is not necessary at this day to argue and present statistics as to the value of serum treatment in epidemic cerebro-spinal meningitis. It is conceded that a potent polyvalent serum, used in a systematic manner, is not only the accepted method of treatment but a specific. Major Flexner states that: "the serum acts locally upon the meningococcus and upon the exudate, and in this way arrests the infection and promotes subsidence of the inflammation and restoration of the damaged membranes. To effect this it must be brought in direct relation and kept in continuous contact with the seat of the infection and in high concentration. Now, since the serum does not reach the meninges, normal, and less so the inflamed, from the blood, it is useless to inject it subcutaneously or intravenously in the expectation that it will find its way into the subarachnoid space."

Our experience has led us to the conclusion that the disease is a blood-stream infection, with local manifestations in the cerebrospinal system. The great percentage of cases showing the eruption when carefully looked for, 80 per cent. in the last series, and the great percentage of positive blood cultures when our laboratory facilities were adequate, forced us to this conclusion, and as a practical consideration we are justified in formulating our treatment upon such a theory. Therefore, to bring the serum in contact with the meningococcus, we use it in the blood stream, i.e., intravenously, and in the subarachnoid space simultaneously. At the first puncture, unless there was positive evidence from the quantity, character and pressure of the cerebrospinal fluid that the disease was not epidemic cerebrospinal meningitis, 40 c.c. serum was administered after draining as much fluid as possible. If no untoward symptoms, such as intense headache, supervened the head of the bed was elevated to facilitate drainage. The serum was introduced by gravity only at an elevation of twelve to fifteen inches. Elevating the foot of the bed facilitated the introduction of the serum. The use of the syringe and pressure was discarded altogether; 1 c.c. serum was then given subcutaneously for desensitizing purposes. In one to one and a half hours 60 c.c. serum diluted in an equal quantity of 0.6 per cent. saline solution was given intravenously. This was repeated every twenty-four hours for three doses unless some indications existed for its continuation. In severe infections 100 cc. was given and repeated at closer intervals. In view of the fact that we had two cases of postmeningitic septicemia and several cases of blocking and reinfection from foci, and knowing that large doses of serum intravenously, repeated at frequent intervals, are well tolerated and practically harmless, we would recommend the larger dose at eighteen- or even twelve-hour intervals in all cases as a routine measure, in the hope of preventing these disastrous postmeningitic conditions and complications. The serum is not given with a view of reaching the subarachnoid space and acting locally upon the meningococcus in the cerebrospinal fluid, but to destroy the organisms in the blood and to prevent local complications in various organs, eyes, ears, heart, joints, etc. Lumbar puncture with a 40 c.c. dose of serum was repeated every twelve hours until the temperature reached normal. This was about the fifth or sixth puncture, at which time the fluid was generally clearing up. Lumbar puncture and the same dose of serum were repeated every twenty-four hours for a number of days, equal to one-half the number of punctures and serum injections it required to bring the temperature to normal, about three or four in the average case. The fluid was then found clear, with a predominance of lymphocytes in the cell count. Another spinal puncture was made in forty-eight hours and serum administered or not according to the appearance of the fluid and the general indications. On the fourth or fifth day after this last puncture another was made as a precautionary measure. In the average case the fluid was clear, with a slightly increased cell count, largely lymphocytes, and the patient convalescent. The temperature, after reaching normal about the fifth or sixth serum injection, often rose daily about four hours after each treatment. This rise is generally due to the serum, and in the management of our cases at this period we did not consider the temperature. Kernig's rigidity and retraction will in most cases be aggravated between the third and fifth day of treatment. As a rule this is due to the irritating action of the serum on the cerebrospinal system. Headache will also be more intense an hour or two after the serum injection. These signs and symptoms we generally neglected also, so that the management of our cases ultimately narrowed down to fluid findings.

From an analysis of fluid findings in many cases we have formulated the following, which represents the character of the fluid in the average case from day to day: At the first puncture the fluid may be clear, slightly cloudy, depending upon the duration or severity of the disease. Clear fluid in a positive case will show an increased globulin content and a greatly increased cell count, mostly polynuclears and no organisms. This fluid will be cloudy on the second or, at the latest, the third puncture, when organisms may be found. If fluid is cloudy it will show many pus cells or leukocytes and generally organisms. These, however, may not be found on first puncture.

On second day: Fluid is more cloudy, contains more pus cells; organisms are generally found.

On third day: Fluid clearing up slightly and color changing to pale yellow or straw color; many polynuclear leukocytes staining well; no organisms as a rule.

On fourth day: Fluid clearing up, straw color; leukocytes, polynuclear, less abundant, staining well.

On fifth day: Fluid light straw color; few healthy leukocytes, polynuclears, some degenerating, poorly staining ones, and a few lymphocytes

On sixth day: Fluid almost clear; few polynuclears and a preponderance of lymphocytes. In our experience, when the lymphocytes predominate in the cell count and the polynuclears show poorly staining qualities, the case is progressing satisfactorily and the twenty-four-hour puncture is discontinued.

To show the results of serum intravenously we have divided our cases into three series:

1. Those treated without serum intravenously, 83 cases, with 38 recoveries and 45 deaths; mortality, 54.2 per cent.

11. Those treated with serum intravenously late in the disease, 9 cases, with 4 recoveries and 5 deaths; mortality, 55.5 per cent.

111. Those treated intravenously on admission, 34 cases, with 23 recoveries and 11 deaths; mortality, 32.3 per cent.

Comparing figures in I and III shows the value of early intravenous treatment. However, comparison between I and 11 is not quite fair to the intravenous method for the reason that 8 of these 9 cases were very ill, almost hopeless, the method being used as a last resort. The fact that 4 of these cases recovered demonstrates the value of this procedure even late in the disease.

Other therapeutic measures: Hot baths, 1120 to 1150, used in 39 cases, were found of distinct value to allay restlessness, clear up delirium and induce sleep. The duration of the baths was from five to fifteen minutes. Morphine hypodermically was used freely, and, in our opinion, is indispensable. The bromides, aspirin, sulphonal, trional, etc., were found absolutely useless. Bright light and noise were distinctly harmful and tended to make patients restless and wakeful. It was often noticed that when one patient in the ward became noisy, the others also soon became restless, irritable and noisy. One patient in series 1, apparently in a dying condition, was tided over by a hot intravenous injection of 0.6 per cent. saline solution, 250 c.c., and ultimately recovered. The subsequent use of this measure in three other cases did not show such happy results.

Lumbar puncture in the first half of our cases was always done under chloroform anesthesia. Realizing, the possible bad effect of the drug used once or twice daily over an extended period; we abandoned it for local anesthesia, subsequently used altogether except in the case of delirious and unmanageable patients. A 2 per cent. cocain solution, 0.5 c.c. under the skin, anesthetized it sufficiently to make the skin puncture painless. The ligaments and deeper tissues did not prove very sensitive in most patients, for very few complained of pain unless unusual difficulty was encountered in getting into the canal. Morphine sulphate, gr. 1. hypodermically, was always given twenty minutes before a lumbar puncture under local anesthesia.

Four needles were broken, the accident occurring in delirious patients who became unmanageable, the needles already in the canal snapping off as the patients struggled to get away from the orderlies who held them.

COMPLICATIONS. All cases did not run a typical course. Some progressed satisfactorily up to the tenth, fifteenth or even twentieth day, when all symptoms reappeared, temperature, headache, vomiting, rigidity, retraction of the neck, irregularity or dilatation of pupils, slight occasional delirium, etc. Spinal fluid which had cleared up became cloudy again, with findings very similar to the first days of the disease and organisms. This occurred in cases having had active treatment and can be explained only by the breaking loose of a walled-off focus in some inaccessible place in the cerebral subarachnoid space, disseminating meningococci throughout the whole cerebrospinal system.

Blocking is another serious complication in the course of the disease. We understand by the term blocking the closing up by the exudate of the communication between the cerebral and spinal subarachnoid spaces at the base of the brain. This condition is generally due to one or more of three factors: insufficient treatment early in the disease; serum, in sufficient quantity, not reaching every portion of the subarachnoid space and ventricles, or treatment instituted late in the disease.

Blocking usually occurs late in the disease. It may, however, occur early, one of our cases blocking in forty-eight hours. This case presented an unusually severe infection. Symptoms may develop rapidly, as in this case, in six to eight hours, or may come on so gradually as to barely arouse suspicion until no fluid can be drained from the spinal canal. When the clinical picture of the disease does not improve under treatment it is well to be on guard. Headache, slow mentality, semicoma, delirium, vomiting, unequal pupils, nystagmus, early changes in retina and optic nerve suggestive of choked disk, a difference in note in auscultatory percussion of lateral ventricles, a gradually diminishing amount of cerebrospinal fluid changing from a pale yellow to a deep golden-yellow color, with few cells, generally lymphocytes, and later a dry puncture, should establish a reasonably certain diagnosis.

In the presence of these complications the intraspinal and intravenous routes of medication offer very little hope of getting the serum in contact with the seat of the disease. The direct introduction of serum into the lateral ventricles and under the dura at the base of the brain is our only hope. Intraventricular puncture through a trephine opening in the skull was done in 5 cases, 3 of blocking and 2 for recrudescence, with 1 recovery, a case of blocking. This patient presented a severe form of the disease and had a rather stormy time under intraspinal and intravenous treatment until the eighteenth day, when temperature went up with aggravation of all. symptoms, the spinal fluid diminishing in quantity and showing a deep yellow color. On the twenty-first day the patient had intense headache, was semidelirious, restless and generally worse; right eye showed marked internal strabismus; outlines of optic disk hazy; small bloodvessels of retina abnormally large and prominent; lumbar puncture dry. Up to this day the patient bad received three intravenous, 180 c.c., and 18 lumbar punctures, 730 c.c. serum. twenty-second day lumbar puncture again dry. No improvement wbatever. The left lateral ventricle was punctured through a trephine opening just below the left parietal eminence, some cloudy fluid drained and 10 c.c. serum was introduced in the ventricles and 10 c.c. under the dura. On the twenty-third day the general condition was the same: Left facial paralysis, right hemiplegia and aphonia. On the twenty-sixth day the patient was quiet and seemed to understand when spoken to. Intraventricular puncture through the same trephine opening, 45 c.c. clear fluid removed, 10 c.c. serum introduced. Fluid examination showed globulin double plus, considerable debris and some lymphocytes. On the thirtieth day the patient was able to move the right leg. On the tbirty-first day, lumbar puncture, 70 c.c. clear fluid drained. Fluid examination showed a thin transparent coagulum, some debris and a few lymphocytes. No serum given. On the thirty-fifth day paralysis and aphonia had disappeared. Recovery thence uninterrupted. Our results, while not brilliant, are encouraging when we consider the gravity of the condition for which this operative procedure was undertaken.

Most of our cases developing these complications had an ample quantity of serum early in the disease, so that we are more inclined to consider the serum not reaching every portion of the subarachnoid and the cerebral ventricles as the responsible factor. Just why this condition should obtain in some cases we are unable to state, and so far having no means of determining this point early, it is our opinion that in very severe infections and in cases not progressing satisfactorily after a week or ten days of active treatment early intraventricular injection of serum is justifiable.

Serum reaction: We had 3 cases of very severe anaphylaxis, 2 in cases who had had serum three and five weeks previously, and 1 upon the first intravenous injection where the desensitizing 1 c.c. of serum was inadvertently omitted. The first symptom noticed was flushing of the face and chest, quickly spreading over the whole body, with sensation of heat, followed by choking sensation, dyspnea, restlessness, severe chill, unconsciousness, cessation of respiration, a fast weak pulse and later high temperature followed by profuse sweating. The condition of these patients was alarming but improved under adrenalin hypodermically and artificial respiration. One case of late serum sickness was interesting in that it presented symptoms very similar to post-meningitic septicemia, differentiated only upon a negative blood culture The case ran a typical course until the ninth day, when temperature, normal for three days, went up to 1010 and a profuse general urticaria appeared over the whole body. Up to this day he had had seven lumbar punctures, 280 c.c., and three intravenous doses, 180 c.c. serum. On the seventh day spinal fluid was almost clear, with 60 per cent. lymphocytes. On the tenth day fluid was clear, showing nothing special. On the fourteenth day the eruption assumed a morbiliform appearance all over the body, less marked on the face, with intense itching and temperature of 102.40. Spinal fluid clear. On the nineteenth day the eruption was distinctly hemorrhagic, the spots being the size of a split pea, with pain and swelling of the joints. Blood culture was negative. On the twenty-sixth day the skin was clear and the patient convalescing.

END-RESULTS: The end-results of our 65 cases discharged from the hospital as cured have not been very encouraging. Two were discharged on a surgeon's certificate of disability, one for manic-depressive insanity, existing prior to meningitis, the other for complete deafness, a sequel of the disease. Twenty-two cases now in the hospital, suffering from various pains and aches, stiffness of back, legs, etc., all classified as "postmeningitic neuroses," are apparently unable to do duty, and as far as we are able to determine at present will never be of much service. Of the remaining forty-one who are apparently well it is impossible yet to judge how many will be able to stand up under hard work, for it has been our experience that most cases did fairly well until put to the test of hard drills and long hikes. The severity of the disease does not seem to have any bearing upon the ultimate condition. The case of post-meningitic septicemia apparently is in as good condition as any other, full of energy, active, doing duty. One of the mildest cases who recovered under three punctures and two intravenous doses of serum is suffering as much as the case of blocking and intraventricular punctures. We are tempted to believe that there may be an element of malingering in some. We have seen what we designate as the "post-lumbar puncture neurotic," in our opinion a malingerer. We have had in the hospital three such patients, punctured once or twice as meningitis suspects, who complained as much as the chronic case who had a three months' siege of the disease with twenty-five lumbar punctures. The true evaluation of the malingering element is the problem which confronts us now. However, we have no doubt that the majority really suffer and are disabled, although with our present means of diagnosis we are unable to detect any pathological lesions to account for their condition.

The work here reported was done in the service of Major James B. Guthrie, and we desire to thank him for allowing us to analyze it. Credit should be given to the following officers: Captains Ward, Dorsett and Steele and Lieutenants Zuercha, Ruka, Sharp and Bell, who were connected with the service and carried on the care and treatment with the compilers of this report.

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