89 Meningitis

Meningitis is an acute inflammation of the menin­ges, the membranes covering the brain and spinal cord. The disease is usually the result of bacterial infection, but a number of viruses, fungi, and other microbial agents can also cause it.

Etiology and Epidemiology

Many species of bacteria can cause meningitis, but over 80 percent of all cases in developed countries in recent years have been due to only three: N. mening­itidis, Hemophilus influenzae, and Streptococcus (Diplococcus) pneumoniae. Other common members of the human bacterial flora such as Escherichia coli and various streptococci and staphylococci can also produce meningitis under special circumstances, as can members of the genera Listeria, Pseudomonas, and Proteus. Meningitis sometimes develops as a complication of tuberculosis.

Aseptic meningitis is usually the result of viral infection. Among the many types of viruses that can be involved are mumps, echovirus, poliovirus, cox­sackievirus, herpes simplex, herpes zoster, hepatitis, measles, rubella, and several mosquito-borne agents of encephalitis. Fungi, most commonly Cryptococcus, are other possible agents.

Laboratory study is necessary to determine the cause of any particular case of meningitis, so it is generally difficult to be certain of the exact etiology of past meningitis cases or epidemics.

N. meningitidis is a nonmotile, gram-negative coccus closely related to the organism that causes gonorrhea. Its protective capsule is composed of one of several possible large sugar polymers (polysaccha­rides), which provide the basis for assigning a given specimen into 1 of about 13 currently recognized serogroups. Serogroups B, C, W-135, and Y have been especially active in the Americas in recent years; group A organisms are the most likely to cause large-scale epidemics and have historically been very prevalent in Africa. Serogroups can be divided into serotypes; these finer distinctions are often crucial in tracing connected cases or determin­ing if a given outbreak has a common origin. Hu­mans are the only natural host.

N. meningitidis is a common inhabitant of the mucosal membranes of the nose and throat, where it normally causes no harm. As many as 5 to 50 per­cent of a population may be asymptomatic carriers without any cases of meningitis developing, but such carriers are crucial to the spread of the disease. The organism is transmitted by droplets sneezed or coughed from the noses and throats of carriers or, less commonly, meningitis patients. It is very suscep­tible to desiccation and to sunlight, so close and prolonged contact is favorable to propagation.

The majority of victims, especially in sporadic cases and small outbreaks, are children under age 5. Among adults, new military recruits crowded into barracks have traditionally been prime targets. Throughout the nineteenth and twentieth centuries, wartime mobilization in Europe and America was always accompanied by sharp increases in meningi­tis case rates.

Meningitis is a highly seasonal disease. In temper­ate regions, a large preponderance of cases develop in the winter and early spring.

Immunology

N. meningitidis stimulates the production of sero­type-specific antibodies in persons who have experi­enced infection. The antibodies in most serogroups develop against the polysaccharides of the bacterial capsule, but the basis for antigenicity in Serogroup B is unclear. Infants can acquire passive immunity from their mothers and be protected for a few months. Vaccines are available for protection against several serogroups, including A, C, Y, and W-135.

Clinical Manifestations and Pathology Infection with N. meningitidis can result in one of three conditions. In the large majority of cases, bacte­ria are carried in the nose and pharynx without any symptoms or with just a sore throat. Serious disease develops only if the bacteria reach the bloodstream. This can produce fulminating blood infection or meningococcemia, which is characterized by sudden prostration, high fever, skin blotches (.ecchymoses), and collapse. Most of these cases are fatal unless promptly treated, and death may ensue in a matter of hours, before the meninges become involved.

Meningitis, however, is the more common result, occurring when bacteria travel through the blood to infect the membranes of the brain and spinal cord. Fever, violent headache, stiff neck, and vomiting are typical symptoms, and, as in meningococcemia, many victims show a petechial rash due to blockage of small blood vessels. A thick, purulent exudate covers the brain, and arthritis, cardiac damage, and shock may develop. Coma, convulsions, and delirium are frequent, and death rates for untreated cases range from 50 to 90 percent. Even in epidemic condi­tions, however, only a small minority of persons har­boring the organism develop clinical disease.

Diagnosis is based on clinical signs and the recov­ery of pathogens from the cerebrospinal fluid or, in meningococcemia, from the blood. Culture of organ­isms from throat swabs is used to monitor carrier rates and circulating strains.

Therapy was revolutionized with the introduction of sulfa drugs in the late 1930s, and sulfonamides were widely used as a prophylaxis for exposed popu­lations. The appearance and spread of sulfonamide- resistant bacteria after 1963 has forced a shift in preventive tactics, but the pathogen is still very sensitive to treatment with penicillin. Military re­cruits are routinely vaccinated in most countries, and extensive inoculation campaigns have helped control epidemics in Africa. Better ventilation and reductions in crowding in living and sleeping areas are useful in barracks and other institutional set­tings. Prophylaxis with rifampin is helpful in reduc­ing carrier rates and preventing outbreaks after cases have occurred in specific populations, as, for example, children in day-care centers.

History and Geography

Meningococcal and other forms of meningitis occur throughout the world. Meningitis is endemic in tropi­cal and temperate regions and in both urban and rural settings, and sporadic cases and small epidem­ics can develop anywhere. In this century, epidemic cerebrospinal meningitis (CSM) has repeatedly cut a wide swath throughout African savanna country in a belt south of the Sahara; these unusual epidemics are caused by serotype A of N. meningitidis.

Antiquity Through the Nineteenth Century

Meningitis was not described in a form recognized as definitive until after 1800, so the antiquity of the disease is unknown. Mention of “epidemic convul­sion” in tenth-century China and a possible descrip­tion by T.

In the early months of 1805, a small epidemic of CSM was described in Geneva by Gaspard Vieus- seux. Most victims were infants and children. Clini­cal accounts, complemented by autopsy studies by A. Matthey, establish the identity of the disease. In March 1806, a cluster of 13 or 14 cases were de­scribed in Medfield, Massachusetts. As in Switzer­land, the victims were infants and children. Nine patients died, despite frantic application of an array of depletive and stimulating therapies. The case de­scriptions and five autopsies confirmed a diagnosis ' of CSM. An epidemic of apparent meningitis af­flicted British troops in Sicily in 1808, and French garrisons in Grenoble and Paris were struck in early 1814. In North America, meningitis epidemics were reported in Canada in 1807, in Virginia, Kentucky, and Ohio in 1808, in New York State and Pennsylva­nia in 1809, among American troops during the War of 1812, and were described as “sinking typhus” or “spotted fever” in New England from 1814 to 1816.

Relatively little more was heard about this deadly and apparently quite new disease until the years 1837 through 1842, when a series of outbreaks oc­curred in French garrisons, and civilians also came under attack in some nearby towns. Thus epidemics in Algeria from 1840 to 1847 began among French troops, but caused many deaths among the indige­nous Moslem population as well, especially in the Algiers and Constantine areas during 1846 and 1847.

The first recorded major epidemic of CSM began in Sweden in 1854, starting in Goteborg in the late winter and slowly spreading to the north and east during the next five winters. It died out in the sum­mers and resumed a slow, irregular progress during winters, reaching 61^o north in 1857 and 63^o north in 1858. The epidemic declined in 1859, with scattered cases reported in the next several years and a small flare-up in the years 1865 to 1867. Government re­turns showed a total of 4,158 meningitis deaths from 1854 to 1860 and 419 in 1865-7.

During the 1860s, numerous small but deadly epi­demics occurred in Germany, the Netherlands, En­gland, France, Italy, Portugal, Austria, Hungary, Greece, Turkey, Poland, and Russia. There were nu­merous outbreaks in the United States during the same decade, with both Union and Confederate troops suffering during the Civil War. In the United States and elsewhere, recruits and small children continued to be the most common victims. Scattered cases and sporadic outbreaks continued for the rest of the century, with flurries of activity in the mid- 1880s and at the end of the century.

Twentieth Century

There was a new burst of meningitis activity in the first decade of the twentieth century. The first cases from Australia were recorded in 1900-1. Portugal had more than 5,000 cases from 1901 to 1905; a series of North American epidemics from 1904 to 1907 involved much of the United States and Can­ada, with 2,755 patients in New York alone in 1905. A severe epidemic in Silesia caused almost 10,000 cases from 1905 to 1908.

For most of the twentieth century, meningitis in the developed countries has followed a pattern of small, local epidemics and scattered cases, mostly among children. The two world wars caused major spurts as military authorities crammed large num­bers of recruits into crowded barracks. In England and Wales, for example, cases rose from a few hun­dred a year prior to World War I to a peak of more than 3,500 by 1915. Similarly, annual cases and deaths rose more than fivefold in the early 1940s, with over 23,000 cases in 1940 and 1941. But except for a peak of almost 1,300 cases in 1974, there have been fewer than 1,000 cases a year reported since the early 1950s.

For the United States, there were 5,839 cases and 2,279 deaths among soldiers during World War I. In 1942 and 1943, however, although there were 13,922 military cases, thanks to new therapy there were only 559 deaths. Moreover, except for a spurt to about 14 cases per 100,000 people in 1942, civilian case rates in the United States have remained under 4 per 100,000 since the late 1930s. Total meningo­coccal infections have rarely exceeded 3,000 a year, but reported cases of aseptic meningitis have risen steadily and have totaled two to four times the meningococcal figure during the 1980s.

The situation in non-Western countries is quite different. Incidence rates tend to be much higher, and there are still major epidemics like those that afflicted Sweden and Silesia in the past. For exam­ple, China has experienced three major epidemics of Serogroup A meningococcal meningitis since 1949, with peak incidence rates of 50 to 400 per 100,000 in 1959, 1967, and 1977. During the 1963-9 epidemic, which coincided with the upheavals of the Cultural Revolution, there were more than 3 million cases and 166,000 deaths.

Africa has had two kinds of experience with the disease. In most of the continent, meningitis is a sporadic disease that behaves much as it does in the West, although often with higher incidence and fatal­ity rates. Much of north, central, east and southern Africa falls into this pattern. In South Africa, scat­tered cases were reported in the 1880s. Mining com­pounds have had favorable conditions for meningi­tis, with newly hired African workers forced to live in conditions similar to those of military recruits. CSM is endemic in east Africa, producing a few hundred cases in most countries in recent years.

On the other hand, there has been at least one terrible epidemic. In 1913 CSM swept Kenya and Tanganyika, killing over 20,000 people in Kenya alone and, partly as a result of military activity, lingering in Tanganyika until 1919. Both territo­ries, as well as neighboring Uganda, had dramatic surges during World War II. In North Africa, Algeria and Egypt experienced meningitis epidemics in the nineteenth century, and the disease has been re­ported throughout the region in recent decades. Mo­rocco had over 6,000 cases in 1967.

The classic area for epidemic CSM, however, has been the savanna zone south of the Sahara Desert from Sudan to Senegal. This “CSM belt” has been swept by a series of great epidemics during the twen­tieth century. Indeed, there the disease has behaved in a very different fashion, advancing on a regular front and killing tens of thousands of people in a season. Only the Swedish epidemic of the 1850s seems to have displayed a similar broad geographic pattern. In both places, macroscopic examination in­dicated that the disease advanced in a regular man­ner from season to season, but also that actual cases were scattered widely within the afflicted zone in a totally unpredictable manner. The epidemic hopped about, skipping many large communities and some­times striking hard at small, relatively isolated places. Areas struck in one CSM season were usu­ally spared in the next.

The reasons for the unusual behavior of CSM in the African “CSM belt” are unclear. Open grassland country facilitates mobility, and much of the region has a fairly dense population. A long, cool dry season creates dusty conditions and may dry out mucous membranes of the nose and throat while it also al­lows people to travel easily and encourages them to sleep indoors. Housing is often crowded and poorly ventilated. Perhaps the savanna dry season is analo­gous to the Swedish winter; people are forced to congregate indoors, and the seasonal low humidity in Africa was replicated in Sweden by home heating. The Swedish outbreaks ceased every year with the arrival of spring, whereas the sub-Saharan zone ex­periences relief with the first rains.

Although there has been a tendency, exemplified in the studies of the British colonial physician B. B. Waddy, to view the entire savanna belt as a single epidemiological unit, there have been distinct geo­graphic zones of CSM. Thus the disease did not spread in great waves from southern Sudan across the grasslands to West Africa. Epidemics in south­ern Sudan and northern Uganda, especially destruc­tive in the late 1920s, have been independent of developments in central and northern Sudan. And, with an exception in 1934 and 1935, central Suda­nese epidemics have not been linked to those in Chad and westward.

The antiquity of meningitis in the savanna zone is not known, but some evidence exists that the disease had occurred in central Sudan and the densely popu­lated Hausa country of northern Nigeria by the 1880s. Small outbreaks in troops in Senegal in the 1890s and in the Gold Coast (Ghana) in 1900 did not afflict wide regions. The first of the great West Afri­can epidemics began in northern Nigeria in early 1905. It spread westward as far as French Sudan (Mali) and northwest Ghana in 1906, lingering in these places until the rains of 1908. British authori­ties guessed the 3-year death toll in Ghana at some 34,000; case mortality was estimated at 80 percent. Total deaths in the 1905-8 epidemic are not known, but there clearly was a major disaster.

The second CSM cycle in the western savanna began in northwest Ghana in 1919, spread to Upper Volta (Burkina Faso) in 1920, and swept northern Nigeria and Niger from 1921 to 1924. Weak political and medical infrastructures precluded accurate esti­mates of cases or deaths, but the death toll in one northern Nigerian province, Sokoto, was put at over 45,000 in 1921 alone, and French officials assumed that at least 15,000 persons died in Niger over the 4­year period.

The third great cycle of CSM activity in West Africa began in 1935, when Chad was attacked by an epidemic that had raged during the previous year in the Kordofan and Darfur provinces of central Su­dan. This was the first and only time that a clear pattern of east-west spread from Sudan has been demonstrated. Carriers brought infection westward during the rainy seasons to Chad, to northern Nige­ria, and thence to Niger, with disastrous epidemics developing in early 1937. CSM hit Upper Volta in 1938 and Mali and northern Ghana in 1939, and local outbreaks continued through 1941. Mortality statistics are very unreliable, but even with the ad­vent of sulfa drugs, several tens of thousands died. CSM was again epidemic in the years 1943-7, with major outbreaks reported from Chad to Senegal. Up­per Volta, western Niger, and northwest Ghana were especially seriously afflicted.

Another cycle Ofepidemics developed in 1949 from foci in northern Ghana, northern Nigeria, and Up­per Volta, spreading eastward as far as Sudan by 1952. By this time, meningococcal meningitis had become well established throughout the region, and geographic patterns of spread were much less dis­tinct. At least 250,000 and perhaps a million or more people died of CSM in West Africa between 1905 and the end of the colonial period in 1960. The disease remains a very serious public health problem in the entire CSM belt, despite the advent of sulfa and penicillin therapy and vaccines against Serogroup A pathogens.

The puzzlingly late discovery of meningitis as a clinical entity did not retard development of knowl­edge of its etiology. The sporadic nature of outbreaks and the apparent lack of transmissibility of infection by victims led many nineteenth-century writers to believe that the disease was not contagious and was somehow linked to climate or environmental condi­tions such as crowding. By about 1860, however, it was widely assumed that there was some sort of specific poison or agent involved. In 1887 an Aus­trian pathologist, Anton Weichselbaum, described the meningococcus under the name Diplococcus in­tracellularis meningitidis. This organism was sus­pected of being the primary pathogen for many years, but its role was not proven until studies done in 1904 and 1905 in connection with the great Silesian epidemic. By 1910 it was recognized that the meningococcus was responsible for epidemics and that other bacteria could cause sporadic cases. Lumbar puncture, introduced in 1891 by Heinrich Quincke, provided an easy method to get cerebro­spinal fluid for study, and was sometimes used to provide relief from the terrible headaches caused by the disease. The crucial epidemiological role of asymptomatic carriers was appreciated by the turn of the century.

After 1905, inspired by success against diphthe­ria, there were many attempts to develop a therapeu­tic serum. Some early successes were reported, espe­cially in France, but by 1909 it was clear that there were important serologic differences among strains. Workers in Britain, the United States, and France had established four major serogroups by the end of World War I. Vaccine therapy remained of limited value, but in the absence of anything else, it was frequently tried. In the 1930s, French efforts to pro­tect Africans against serogroup A by vaccination had inconclusive results, and similar British trials in Sudan were unsuccessful.

The development of sulfa drugs in the 1930s revo­lutionized meningitis therapy. Gerhardt Domagk published on one such drug in 1935; French workers at the Institut Pasteur introduced a more effective active form, sulfanilamide, later in the same year. Clinical trials showed the almost miraculous impact of sulfanilamide on meningococcal infections in 1937. This drug, one of a group of chemicals called sulfonamides, reduced case-fatality rates from be­tween 50 and 80 percent to 20 percent and less, and saved many thousands of lives during the meningi­tis epidemics of World War II. Sulfa drugs were suc­cessfully used for prophylaxis and to reduce carrier rates by the U.S. Army beginning in 1943; the tech­nique was widely adopted for troops and during out­breaks.

The advent of this class of “wonder drugs” had an especially dramatic impact in the CSM belt of Af­rica, where they were introduced in early 1938 in the midst of major epidemics in Sudan and West Africa. Prior to this date, Africans had been well aware that European therapy was useless. Preven­tive measures seemed equally futile and were often arbitrary and very harsh. Victims were usually quar­antined, and cordons were sometimes thrown around whole villages and districts. Such efforts dis­rupted trade and care of the sick, but, given the key role of asymptomatic carriers and the use of bush paths to avoid police checkpoints, they did nothing to impede the spread of the disease. Annoying proce­dures like “nasopharyngeal disinfection” of travel­ers in Chad or destroying houses or removing their roofs in Sudan did not encourage African coopera­tion with colonial medical authorities. Indeed, Afri­cans very sensibly tried to hide cases, preferring not to add government public health measures to the burdens of an epidemic. Sulfa drugs were, however, extremely effective. Africans responded pragmati­cally to this new treatment and, seeing death rates plummet, eagerly began to report cases and seek treatment for themselves and their children. In many areas, a shortage of medical workers forced authorities to give supplies of drugs to chiefs to pass along to the sick. This and the introduction of drug prophylaxis meant that CSM, in sharp contrast to earlier decades, was overreported during the 1940s and 1950s.

In 1963 sulfa-resistant strains of N. meningitis were detected by U.S. military doctors and the spread of such strains has forced an end to sulfa prophylaxis. Penicillin therapy is still very effective, but this anti­biotic has no preventive value. Vaccines against Serogroup C and A organisms were introduced in 1971 and 1973, respectively. Improved vaccines for these and other serogroups have been developed in recent years, although there is still no protection against serogroup B bacteria. Meningitis will proba­bly remain a public health problem, especially in underdeveloped countries. Death occurs in about 5 percent of all cases, even with prompt treatment. Poverty, logistical problems, and financial difficulties make meningitis a continuing threat in the tradi­tional CSM belt of Africa.

K. David Patterson

Bibliography

Centers for Disease Control. 1986. Summary of notifiable diseases, United States, 1986. Atlanta.

Danielson, L., and E. Mann. 1983. The first American account of cerebrospinal meningitis. Reviews of Infec­tious Diseases 5: 967-72. [Reprint of 1806 article.]

Dowling, Harry F. 1977. Fighting infection: Conquests of the twentieth century. Cambridge, Mass.

Hirsch, August. 1886. Handbook Ofgeographical and his­torical pathology, Vol. III. London.

Lapeyssonie, L. 1963. La M6ningite c6r6bro-spinale en Afrique. Bulletin of The World Health Organization 28 (Supplement).

Netter, Arnold, and Robert Debr6. 1911. La Meningite cerebrospinale. Paris.

Patterson, K. David, and Gerald W. Hartwig. 1984. Cerebrospinal meningitis in West Africa and Sudan in the twentieth century. Los Angeles.

Solente, Lucy. 1938. Histoire de 1 Evolution des meningites c6r6bro-spinales aigues. RevuedeMedicine 55:18-29.

Vedros, Neylan A., ed. 1987. Evolution of meningococcal disease, 2 vols. Boca Raton, Fla.

Waddy, B. B. 1957. African epidemic cerebro-spinal menin­gitis. Journal of Tropical Medicine and Hygiene 60: 179-89, 218-23.