Aseptic Meningitis

ASEPTI~

MENINGITIS

CRAWFORD S. ANGLIN, M.D.

The purpose of this paper is to review the current status of aseptic meningitis and present a discussion of the problem chiefly from the standpoint of the physician who may encounter the condition in practice. Aseptic meningitis, in reality, is not a specific entity, but rather a syndrome which, from an (Etiological standpoint, may be caused by a great variety of agents both infectious and non-infectious. HISTORICAL NOTE

The condition was first described by Wallgren in 1924 as a result of his observations of a number of outbreaks of this disease in various parts of Europe. It was implied in Wallgren's paper that the disease was a new and specific entity. Certainly the outbreaks described may well have been of a common (Etiology because of the geographical localization. It is now apparent, however, as a result of information obtained by more recent laboratory diagnostic techniques, especially in the field of virus culture and isolation methods, that the syndrome may be induced by many agents, but is principally of viral origin. The criteria for the diagnosis of aseptic meningitis as outlined by Wallgren in 1924 were as follows: (a) acute onset with meningeal symptoms; (b) cerebrospinal fluid, pleocytosis, predominantly mononuclear; (c) sterile cerebrospinal fluid; (d) comparatively short duration without secondary complications and with complete recovery; (e) absence of any indications of a para-meningeal retiology such as otitis, sinusitis, trauma, and so on, or of such meningitogenic infections as mumps, poliomyelitis, epidemic encephalitis, leptospirosis, and so forth; From the Department of Pcediatrics, University of Toronto, and The Hospital fOT Sick Children, Toronto, Ontario, Canada.

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(f) absence of epidemiological connections with the above-mentioned infectious diseases. At the time Wallgren outlined the criteria for the diagnosis of aseptic meningitis, virus research was in its infancy, and the diagnosis was based on clinical and epidemiological grounds and a process of exclusion of the then known infections. Now it is possible, in many cases, to determine the specific retiological agent, and, as Wallgren stated in 1951, he accepts the general opinion that aseptic meningitis represents a syndrome likely to be encountered in a number of different diseases. In the broad sense of the term and for practical purposes, any condition producing meningeal irritation and a cellular response in the cerebrospinal fluid, but bacteriologically sterile, might be considered under the broad classification of aseptic meningitis. CLINICAL PICTURE

The clinical picture in aseptic meningitis may be as varied as the number of different causes. The more typical case, however, presents with a history of several days' indisposition characterized by drowsiness, headache which is usually frontal and may be severe, fever of 100° to 103° F., nausea, vomiting, and a variable degree of neck and back pain and stiffness. In addition, a significant number of cases are accompanied by abdominal pain, diarrh~a, generalized muscular aches and pains, and sore throat. Some cases have a definite prodromal phase followed by a two- or three-day period of relative well-being, this in turn followed by the major phase of the illness, a so-called dromedary type of illness, not infrequently observed in acute poliomyelitis. For the past few years we have been seeing aseptic meningitis in the Toronto area accompanied by a maculo-papular cutaneous eruption during the acute phase. In the majority of cases of aseptic meningitis after the first few days of acute illness there is a steady general improvement in the patient's condition toward complete recovery over the following four to 10 days with no complications or sequelae. On physical examination these patients show surprisingly little, aside from the stiffness of the neck and spinal muscles. There may be some pharyngeal injection with petechire or even ulceration. In some the maculo-papular cutaneous rash mentioned above is seen; however, no localizing neurological signs are present. The peripheral white blood cell count is normal or only slightly elevated with a relatively normal differential. The cerebrospinal fluid is under some increased pressure, and a pleocytosis of 30 to 3000 cells may be found, usually 50 to 300. These cells are mostly mononuclears, but early in the disease they may be predominantly polymorphonuclear, leading to the erroneous diag-

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315

nosis of a purulent meningitis. The cerebrospinal fluid protein may be moderately elevated; however, the sugar and chloride are normal. As the name of the disease implies, blood and cerebrospinal fluid cultures are bacteriologically sterile. )ETIOLOGY

In 1955 Dr. Alex Steigman 10 prepared an excellent paper on this subject in Pediatric Clinics of North America and summarized the causes of aseptic meningitis in a comprehensive table. With his permission, this table is reproduced with a few additions made in the light of further virus research material published during the two years subsequent to the appearance of his paper (Table 9). From this table it is apparent that the syndrome of aseptic meningitis may be produced by a wide variety of agents. It is predominantly the infectious causes, however, with which we propose to deal in this outline. This is undoubtedly the most frequently encountered form of the disease and the one for which it is of some importance to have a rational concept and plan of management. The chief infectious causes for the aseptic meningitis syndrome and simulating conditions have been summarized in Table 10 with clinical and laboratory aids to differentiation. DISCUSSION OF DIFFERENTIAL DIAGNOSIS

It has been our experience at The Hospital for Sick Children that the most confusing problem, especially for the house physicians, is the differentiation of cases of aseptic meningitis from conditions which simulate this syndrome, namely, early tuberculous meningitis and early acute purulent bacterial meningitis. In both these conditions the cerebrospinal fluid, history and physical examination may closely simulate the aseptic meningitis syndrome. In most cases, however, the patient with aseptic meningitis does not appear as ill as the one suffering from an early acute purulent meningitis. The cerebrospinal fluid cell counts may be identical in the two conditions, but in the bacte~ial meningitis the sugar will be decreased in most cases, and within 24 hours the culture will reveal the causative organism. The peripheral white blood cell count will be elevated with a polymorphonuclear increase in most cases of purulent meningitis. If there is any reasonable doubt about the differential diagnosis, it has been our policy to treat the patient as having purulent meningitis for at least 24 hours until the results of the cerebrospinal fluid cultures are available and may contribute to a more definite diagnosis. In tuberculous meningitis the history, intracutaneous tuberculin test,

316 TABLE

ASEPTIC MENINGITIS

9. Clinical Conditions Which May Induce the Aseptic Meningitis Syndrome (After A.

J.

Steigman lO ) AGENT

I. Infectious: A. Viral: 1. Established viral origin: a. Transmitted (1) Man to man: Poliomyelitis, mumps, herpes simplex, herpes zoster, Coxsackie Band A9, atypical pneumonia, infectious hepatitis, ECHO virus 4, 6, 9 (2) Rodent to man: Lymphocytic choriomeningitis (3) Arthropod to man: Arthropod-borne encephalitides, including Eastern, Western and St. Louis 2. Presumed viral origin: B. Spirochretal: Leptospira icterohremorrhagire, canicola, pomona, Treponema pallidum C. Yeast D. Protozoal E. Helminthic F. Bacterial: 1. M. tuberculosis 2. Bacteria causing purulent meningitis 3. Bacteria leading indirectly to mechanical encephalopathy II. Post-infectious

III. Non-infectious: A. Meningeal irritation or reaction from neighbouring lesions B. Toxins and irritants: 1. Systemic poisons 2. Intrathecal injections C. Allergy: 1. Medications 2. Prophylactic injections 3. Other allergens (?)

DISEASE

Infectious mononucleosis, infectious lymphocytosis, cat scratch disease Leptospirosis, syphilis

E.g., torulosis Toxoplasmosis Trichinosis 1. Very early meningitis 2. Meningitis modified by partial suppression of organism by suboptimal antibiotic therapy 3. Pertussis Measles, rubella, varicella, mumps, vaccinia, variola

Sinus, mastoid, abscess, thrombosis, haematomas, infiltrates E.g., lead, arsenic, bacterial Sera, antibiotics, air, Lipiodol Serum sickness, including due to antibiotics Rabies, pertussis vaccine Seen rarely in association with urticaria and arthralgias

chest x-ray and reduced sugar and chloride in the cerebrospinal fluid plus the cerebrospinal fluid cultures later will clarify this differential diagnostic problem. Suboptimally treated purulent meningitis may also simulate the

CRAWFORD S. ANGLIN TABLE

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10. Diagnostic Aids in Common Types of Aseptic Meningitis and Simulating Infections

TYPE OF MENINGITIS

CLINICAL DATA

LABORATORY AND CEREBROSPINAL FLUID DATA

A. Viral 1. Non-paralytic poliomyelitis 2. Mumps (non-glandular) 3. Coxsackie B

4. Echo virus 4, 6, 9

1. Concurrent epidemic 2. Seasonal distribution 3. Development lower motor neuron paresis 4. Reflex changes 1. Known exposure to case 2. Development of parotitis, pancreatitis, orchitis 1. Accompanying or following pleurodynia occasionally 1. Concurrent epidemic 2. Maculo-papular rash

1. Virus isolation from stool or pharyngeal secretions 2. Acute and convalescent sera for neutralization tests and antibody titre 1. Elevated serum amylase 2. Positive mumps complement fixation test on serum 1. Virus isolation from stool 2. Acute and convalescent sera for virus neutralization tests 1. Virus isolation from cerebrospinal fluid and stool 2. Acute and convalescent sera for virus neutralization tests 1. Neutralization and complement fixation tests on sera

5. Specific viral en- 1. Geographic distribution cephalitis (Eastern, 2. Reflex abnormalities, sensory disturbances Western, Equine, St. Louis, etc.) 6. Post-infectious en- 1. History of measles, rubella, cephalitis varicella, vaccinia, variola or recent exposure 2. Typical rash at time of illness or developing shortly after onset B. Non-viral (bacterial simulating aseptic meningitis) Cerebrospinal fluid pellicle 1. Tuberculous 1. History of exposure meningitis 2. Positive intracutaneous formation tuberculin test Reduced chloride and sugar 3. Chest x-ray Tubercle bacillus on smear and culture 2. Acute purulent 1. Early in course of disease Cerebrospinal fluid bacterial meningitis 2. Modified by suboptimal identification on smear anti-microbial therapy and culture Reduced sugar 3. Leptospirosis History of exposure to pos- Sera for agglutination and sible source; icterus, complem!:nt fixation tests. nephritis

aseptic meningitis syndrome, but in this condition the history, course and cerebrospinal fluid cultures will help clarify the diagnosis. Leptospirosis is an extremely uncommon condition in this area; however, if evidence of icterus or nephritis develops during the course of an illness typical of aseptic meningitis, this diagnosis should be considered and the blood, urine and cerebrospinal fluid examined for leptospirosis in addition to agglutination tests on the patient's blood. As lepto-

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spirosis may be anicteric, in some areas this condition may prove a difficult differential problem early in the course of the illness. In most instances the aseptic meningitis syndrome appears to be of obvious viral origin, and in probably over 80 per cent of cases the chief viruses incriminated in North America are mumps, lymphocytic choriomeningitis, herpes simplex, poliomyelitis, Coxsackie B and ECHO virus 6, 9 and 4. I do not know of any published figures on the incidence of all these various types of viral aseptic meningitis. It is obvious that this figure must vary considerably, geographically and seasonally. TABLE

II. Virus Isolations from Cases of Aseptic Meningitis (After Robert Ward)

YEAR

INVESTIGATOR

NUMBER

ECHO

COXSACKIE

OF CASES

1951

1952 1956

Enders Enders Smadel Dalldorf

8 43 17 ?

Wenner Habel

105

Rhodes Karzon Davis and Melnick Rhodes

33 24 24

POLIOMYELITIS

8 37 (all type 6) * 13 (11 type 6)* Outbreaks of type 6 in Troy and Buffalo" 55" Outbreak of type 4 "Type 6 predom."

8 Type 6 Type 6

3 (B's) 4 (B's)

B's (24%) Occas. A9 (5%) 13 (B 4s)

3

Type 1, 2 Rare 3 (33%) 3

Type 9 with rash Also 4 and 6

* All patients showed type 6 antibody rise.

Non-glandular mumps constitutes one large group of the aseptic meningitis syndrome, and this specific diagnosis must be considered in practically every case. History of exposure, concurrent epidemic, elevated blood serum amylase, abdominal pain, and orchitis in the older patient may be helpful diagnostic clues; however, in the absence of typical salivary gland involvement the most reliable specific diagnostic test is a positive mumps complement fixation test on the patient's serum. Lymphocytic choriomeningitis is a relatively rare disease in most parts of North America, occurring usually in localized outbreaks among people exposed to or handling infected mice. It is therefore a hazard of laboratory personnel. The cerebrospinal fluid usually shows a decided pleocytosis, and the virus may be cultured from this source. Herpes simplex is also a rare form of aseptic meningitis and can be diagnosed only in the absence of mucocutaneous lesions by isolation

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of the virus from the cerebrospinal fluid or demonstrating a rise in titre of antibodies during convalescence. Of all the viral causes of the aseptic meningitis syndrome, the most frequently encountered agents in this area appear to be similar to those reported in many parts of the United States. This group includes nonparalytic poliomyelitis, Coxsackie B and the various ECHO virus infections. On a clinical basis we have found it impossible to differentiate these viral aseptic meningitides in most cases, and we are dependent on the virus laboratory to provide the definitive or specific diagnosis. I believe that this must be universally true, judging from the virus isolations from aseptic meningitis cases shown in Table 11, in which the patients all had similar histories and physical findings. ASEPTIC MENINGITIS WITH RASH (A RECENTLY RECOGNIZED ENTITY)

An interesting illness has been appearing in the Toronto area during the past few years, occurring predominantly in the summer and fall months. It is characterized by a typical aseptic meningitis picture in children from infancy to 10 years of age; however, it is accompanied by a characteristic maculo-papular cutaneous eruption. This disease has been a relatively common condition in practice, and a number of cases have been admitted to The Hospital for Sick Children with various diagnoses and have received careful investigation, including virus studies. The rash has been present at some time during the course of the illness in as high as 60 per cent of some series of aseptic meningitis patients admitted to the Hospital. It has been observed to involve all parts of the body, but appears to have a predilection for the face and trunk. In some cases involvement of the palms of the hands and soles of the feet has been a notable feature. A few cases have had a petechial type of rash and were admitted as possible meningococcal infection; however, on further investigation and observation they were proved to be aseptic meningitis. The rash subsides over a period of five to 10 days with no scaling or desquamation. The rash is similar in most cases to that of rubella; however, occipital glandular enlargement has not been a prominent feature in these eases. ECHO 9 virus has been isolated from the stool and cerebrospinal fluid in a number of these cases by the virus laboratory under the direction of Dr. A. J. Rhodes. It is interesting to note a report by Hennessen, Odenthal and Wunder of the Academy of Medicine, Diisseldorf, Germany, describing an epidemic of aseptic meningitis which occurred in northwest Europe in 1956. A virus was isolated from the sputa and freces of patients with this disease; however, it was not classified further than

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to report that it was not a strain of poliomyelitis. A number of these patients were reported to have transient rashes, a fact which fits closely the picture presented by the cases observed in the Toronto area. Before a newly recognized agent can be said to be the retiological agent of a disease, it must be shown to have a high correlation with the occurrence of the illness. Although some of the viruses isolated from stools of patients with aseptic meningitis have also been found in apparently normal members of the population, there have been sufficient isolations from the cases of aseptic meningitis to establish a firm retiological relationship. The fact that the virus is recoverable from the cerebrospinal fluid in some of these cases is most convincing evidence to incriminate specific viruses in the aseptic meningitis syndrome. The differential diagnosis of aseptic meningitis has been a confusing problem in many centres for a number of years. With the encouraging progress in virus isolation techniques and serological studies in conjunction with a more general awareness among physicians of the syndrome, many of these cases are now falling into their correct specific group entities and are being more accurately diagnosed. It is apparent from these remarks that the problem of aseptic meningitis is a complex one and requires careful clinical and laboratory study to arrive at an accurate diagnosis. In this part of North America it appears that at present about 20 per cent of all cases of aseptic meningitis are due to poliomyelitis virus, 20 per cent to Coxsackie B, and a variable number of the remainder to ECHO and other viruses; however, it is obvious that these figures may vary considerably from year to year. MANAGEMENT OF CASES OF ASEPTIC MENINGITIS

As viral aseptic meningitis is a relatively benign condition and responds to no specific drug therapy, as far as is known at present, the management is symptomatic. Isolation, bed rest, fluids, light diet and aspirin and codeine for the fever and malaise are usually all that are indicated. In some instances when vomiting is a prominent feature, intravenous fluids may be necessary to correct or prevent dehydration and maintain acid-base balance. Under ideal conditions the patient with aseptic meningitis should remain isolated until the diagnosis has been confirmed and such specific entities as non-glandular mumps, non-paralytic poliomyelitis and tuberculous meningitis have been reasonably well excluded by the history, physical examination, course of the illness, cerebrospinal fluid studies and virus cultures. We have not found hot packs, physiotherapy or other adjuncts

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necessary in these cases, since patients have all made satisfactory recovery on symptomatic therapy as outlined. Antibiotics are unnecessary if the diagnosis is definite; and when a number of cases have been seen, the syndrome is rarely confused with the conditions requiring specific antimicrobial therapy. As the temperature subsides, usually in five to 10 days, and the patient commences feeling well, a gradual return to full activity is indicated. Isolation of the patient until clinical recovery is probably advisable. Follow-up lumbar punctures are unnecessary; however, in some of the patients in whom this procedure has been repeated we have been somewhat surprised to find a cerebrospinal fluid pleocytosis persisting for two to three weeks. In the patients exhibiting the rash in conjunction with aseptic meningitis, this has gradually subsided, and the skin has returned to normal by the time clinical recovery has been attained in other respects, usually five to 10 days from the onset. LABORATORY INVESTIGATION OF ASEPTIC MENINGITIS CASES

In order to compile significant statistical evidence on the aseptic meningitis problem, it would be advisable to obtain virus studies on each case of this syndrome diagnosed. Most large centres have virus laboratory facilities available which are at the disposal of private physicians as well as hospitals. In Ontario, specimens from cases of aseptic meningitis should be forwarded to The Division of Laboratories, Ontario Department of Health, 360 Christie Street, Toronto, Attention: Virology Department. A short history, a sample of the patient's stool, cerebrospinal fluid, and acute and convalescent sera (i.e., 10 ml. of clotted blood taken during acute phase, and 10 to 14 days later) should be forwarded to the Laboratory. These specimens should be packed in ice, or, if possible, carbon dioxide snow and delivered as soon as possible. Animal inoculation, tissue cultures and virus neutralization tests are then performed and in many cases make a positive identification of the specific retiological agent. Similar virus research centres throughout Canada and the United States, of course, are available for this service. * In the Toronto area Dr. A. J. Rhodes, the Director of The School of Hygiene, University of Toronto, has organized a virus research unit. When notified by a practicing physician of an outbreak of a virus-like illness, a field worker from the group will be sent into the area to study the cases, collect specimens and give advice, if requested, on the management of the illness. By this method much valuable information on these viral diseases is being obtained. As this project is being supported mainly with funds from the National Health Grants programme of the Ontario and Federal Governments, this investigation is conducted at no expense to the patient or the physician in charge of the case.

* In the United States serum specimens, together with a concise clinical summary, may be sent to Virus and Rickettsia Section, Communicable Disease Center, Public Health Service, U.S. Department of Health, Education, and Welfare, P.O. Box 61, Montgomery 1, Alabama.

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SUMMARY AND CONCLUSIONS

As one physician has aptly remarked, at this stage of the study of aseptic meningitis it would appear that there are many viruses looking for diseases, and many diseases looking for viruses! It is questionable whether aseptic meningitis is a new disease syndrome. I believe the consensus is that it has been with us for many years, and has been passed over with the mistaken diagnosis of nonparalytic poliomyelitis, lymphocytic choriomeningitis or other conditions which, in reality, are probably much less common causes of the aseptic meningitis syndrome than recently isolated virus strains which appear to be more prevalent and widespread than formerly realized. The multiplicity of viruses responsible for the clinical syndrome of aseptic meningitis which have already been isolated indicate that the search for the causative agents in this condition has only begun and that in epidemics or outbreaks of the future many more isolations of different specific viral strains undoubtedly will be made. REFERENCES 1. Adair, C. V., and others: Aseptic Meningitis; A Disease of Diverse Etiology.

Ann. Int. Med., 36:675, 1953. 2. Beale, A. J., and others: Further Observation on the Laboratory Diagnosis of Aseptic Meningitis Caused by Group B Coxsackie Virus. Canad. J. Pub. Health, 47: 179, 1946. 3. Davis, D. C., and Melnick, J. L.: Association of Echo Virus, Type 6, with Aseptic Meningitis. Proc. Soc. Exper. Biol. 6 Med., 92:839, 1956. 4. Gard, S.: The Etiology of Acute Aseptic Meningitis (Wallgren). Acta pcediat. (supp. 100),43:54,1954. 5. Hennessen and others: German Medical Monthly, 2:39,1957. 6. Hummiker, K., and others: Aseptic Meningitis Caused by Coxsackie Virus with Isolation of Virus from the Cerebrospinal Fluid. l.A.M.A., 156:676, 1954. 7. Karzon, D. T., and others: Isolation of Echo Virus, Type 6, during Outbreak of Seasonal Aseptic Meningitis. l.A.M.A., 162:1298, 1956. 8. LaForest, R.: Aseptic Meningitis. Bull. Hosp. Sick Children, Toronto, 6: Jau 1957. 9. McLeod, D. L., and others: Clinical Features of Aseptic Meningitis Caused by Coxsackie B Virus. Lancet, 2: 701, 1946. 10. Steigman, A. J.: The Acute Aseptic Meningitis Syndrome. PEDIAT. CLiN. NORTH AMERICA, 1955, pp. 47-'53. 555 University Avenue Toronto 2, Ontario Canada