Neurological diseases associated with viral and Mycoplasma pneumoniae infections

Bulletin of the World Health Organization, 58 (2): 297-311 (1980) Neurological diseases associated with viral and Mycoplasma pneumoniae infections F. ASSAAD, 1 R. GISPEN,2 M. KLEEMOLA,3 L. SYRUCftEK4 & K. ESTEVES 5 In 1963 the World Health Organization established a system for the collection and dissemination of information on viral infections and by 1976, laboratories in 49 countries were participating in this scheme. The present study is in two parts: part I is an analysis of almost 60 000 reports on neurological disease associated with viral and Mycoplasma pneumoniae infections reported during the 10-yearperiod 1967- 76. This analysis showed a steady increase in the yearly number of reports of viral neurological diseases, which closely followed thegeneral increase in the overallreporting of virusdiseases. Likewise, theseasonal pattern was similar to that seen in generalfor any given virus. Over 75%o ofthe cases were in children. Over halfofall viral neurological diseases were associated with enteroviruses, while the myxoviruses accountedfor almost 30%. Among the myxoviruses, mumps virus was byfar the mostfrequently reported. The polioviruses were the agents most commonly detected in cases ofparalytic disease. The other enteroviruses, mumps virus, and the herpesviruses were the most frequently reported viruses in cases of aseptic meningitis or encephalitis. On the other hand, one-third to over one-half of the reports on the myxoviruses (excluding mumps and measles) related to ill-defined clinical conditions. Part 2 of the study deals in particular with viruses whose role in neurological disease is less well documented. One laboratory reported an outbreak ofadenoviral aseptic meningitis in Czechoslovakia, while another described neurological disease associated with M. pneumoniae infection in Finland. Part 2 also includes a detailed appraisal of viral infec- tions diagnosed in the Netherlands during theperiod 1973- 76. The results are very similar to those routinely reported. In 1963, the World Health Organization established a system for the collection and dissemination of infor- mation on viral infections other than those due to arboviruses. By the end of 1976, virus laboratories in 49 countries were participating in the scheme. The first two studies dealt with circumscribed groups of viruses, namely, enteroviruses other than polioviruses (1) and respiratory viruses (2). The third study (3) concen- I Medical Officer, Virus Diseases, World Health Organization, Geneva, Switzerland. 2 Dean, Faculty of Medicine, University of Utrecht, Utrecht, Netherlands. I Virus Serological Department, Central Public Health Laboratory, Helsinki, Finland. 4Department of Epidemiology and Microbiology, Institute of Hygiene and Epidemiology, Prague, Czechoslovakia. 5 Technical Officer, Virus Diseases, World Health Organization, Geneva, Switzerland. trated on virus infections having a fatal outcome rather than on particular groups of viruses. By limiting the study of a specific outcome, it was hoped to reduce to a minimum the influence of differences in perform- ance and interest between laboratories when compar- ing groups of countries. The results of the study were encouraging enough to justify initiating the present study, which is limited to another possible outcome, namely, neurological diseases associated with viral and Mycoplasma pneumoniae infections. In this paper, the term "viral infections" will be used to include those due to M. pneumoniae. The study consists of two parts. Part 1 is an analysis of neurological diseases associated with viral infec- tions reported to the WHO Virus Reporting System during the period 1967-76. Part 2 (pages 304-310) is a more detailed investigation of viral association with neurological disease by three laboratories in Czecho- slovakia, Finland, and the Netherlands. 3948 -297- F. ASSAAD ET AL. PART 1. WORLDWIDE VIRAL NEUROLOGICAL INFECTIONS Countries participating in the WHO Virus Report- ing System were eligible for inclusion in the study provided that, during the period 1967-76, they had re- ported a minimum of 25 recorded instances of neuro- logical infections associated with any one specific virus. Viruses were included in the study only if an association with a neurological condition had been noted by at least one country in at least 25 reports in any one year during the same period. Once a country had been accepted into the study, all reports on neurological conditions associated with any of the viruses eligible for the study were included. The study is limited to the 10-year period 1967-76, i.e., the period during which the information is avail- able on magnetic tape and can be computer-processed and tabulated. The neurological clinical manifes- tations are presented under three headings: paralysis, meningitis/encephalitis, and other conditions, a limitation dictated by the coding scheme built into the WHO Virus Reporting System. The viruses are discussed here separately, and the different types of adenovirus, coxsackievirus A and B, echovirus, etc., are mentioned when of interest. No mention is made of the antigenic variation ofinfluenza virus A, but it is assumed that up to 1968, variants of A/Singapore/l/57(H2N2) were reported, and that after the summer of 1968, A/Hong Kong/1/68(H3N2) or its variants were reported. No distinction is made between the antigenic variants of influenza virus B. RESULTS Information from laboratories in 30 countries is included in the present study. These countries were divided into 6 groups according to geographical location and level of industrial development. By far the largest group, consisting of 15 countries, is in Europe, while the other groups consist of 2-4 countries each: Africa (excluding North Africa): Kenya, Mada- gascar, Senegal, South Africa. Middle and South America: Argentina, Mexico, Trinidad and Tobago. Asia (excluding the Pacific): Malaysia, Thailand. Eastern Mediterranean and North Africa: Egypt, Morocco. Europe: Austria, Belgium, Czechoslovakia, Den- mark, Finland, France, German Democratic Repub- lic, Federal Republic of Germany, Hungary, Ireland, Netherlands, Norway, Sweden, Switzerland, United Kingdom. North America and the Pacific: Australia, Canada, Japan, United States of America. The study comprises 59 281 reports of viral neuro- logical infections. Although only 19 out of the 30 countries (63%) are in the European or North American and Pacific regions, laboratories from these two groups provided about 907o of the reports. In other words only about 10% of the reports came from developing countries. The viruses that fulfilled the conditions for in- clusion in the study are shown in Table 1. Virusfrequencies From Table 1, it can be seen that enteroviruses were noted in over 55% and myxoviruses in almost 30% of the total number of reports analysed. The herpes- viruses and the adenoviruses followed in frequency: 8% and 6% respectively. Lymphocytic choriomenin- gitis virus (LCM) was recorded in less than 0.5% of the reports and M.pneumoniae in a little over 1I%o. In Europe and in the North American and Pacific regions, the relative frequencies with which the dif- ferent virus groups were found to be associated with neurological conditions were similar to the overall picture. In contrast, in the developing countries, i.e., in the African, Middle and South American, Asian, Eastern Mediterranean, and North African regions, the enteroviruses, mostly polioviruses, were associated with 97-100% of the total number of viral neurological conditions reported. Within the group of myxoviruses, mumps virus predominated by far, accounting for 78% of the total number of reports on myxoviruses in Europe and 68% in North America and the Pacific. Influenza virus A was next in order of frequency (between 8% and 1 I%), while the other myxoviruses accounted for between 20% and 8%. Within the herpesvirus group, herpes simplex virus accounted for 73% in Europe and 82% in North America and the Pacific. The other two viruses, i.e., varicella-zoster and cytomegalovirus, were noted in 6-14% of the reports on herpesviruses. Typing of viruses Where facilities for typing were available, the viruses were reported by type. Coxsackievirus A. Type 9 largely predominated in Europe and in North America and the Pacific, consti- tuting 80-81 o of all those typed. A small number were not typed: 5% in Europe and 7% in North America and the Pacific. No figures are available for Africa, the only other region where coxsackievirus A was reported. 298 VIRAL NEUROLOGICAL DISEASES Table 1. Reports of viral neurological infections by country group, 1967-76 Middle Asia E. Medi- N. America Africa & South excl. terranean Europe & Total Associated viruses America Pacific & N. Africa Pacific No. % No. % No. % No. % No. % No. % No. % Enteroviruses coxsackievirus A 315 16.0 0 0.0 1 1 0.7 0 0.0 1 646 3.9 378 3.5 2 350 4.0 coxsackievirus B 148 7.5 3 0.1 8 0.5 0 0.0 4921 11.5 1 395 13.0 6475 10.9 echovirus 59 3.0 40 1.9 15 1.0 0 0.0 13 147 30.8 4 934 46.1 18 195 30.7 poliovirus 1380 70.2 2051 96.8 1506 97.8 294 100.0 782 1.8 166 1.5 6 179 10.4 Herpesviruses herpes simplex virus 22 1.1 9 0.4 0 0.0 0 0.0 2 591 6.1 734 6.9 3 356 5.7 varicella-zoster virus 0 0.0 0 0.0 0 0.0 0 0.0 514 1.2 104 1.0 618 1.0 cytomegalovirus 2 0.1 0 0.0 0 0.0 0 0.0 465 1.1 52 0.5 519 0.9 Adenoviruses 10 0.5 6 0.3 0 0.0 0 0.0 2 784 6.5 583 5.4 3 383 5.7 Myxoviruses influenza virus A 6 0.3 4 0.2 0 0.0 0 0.0 1 144 2.7 262 2.4 1 416 2.4 influenza virus B 2 0.1 4 0.2 0 0.0 0 0.0 319 0.7 87 0.8 412 0.7 parainfluenza virus 1 0.1 2 0.1 0 0.0 0 0.0 525 1.2 134 1.3 662 1.1 respiratory syncytial virus 0 0.0 0 0.0 0 0.0 0 0.0 356 0.8 65 0.6 421 0.7 mumps virus 7 0.4 0 0.0 0 0.0 0 0.0 11 623 27.3 1 566 14.6 13 196 22.3 measles virus 15 0.8 0 0.0 0 0.0 0 0.0 898 2.1 190 1.8 1 103 1.9 Arenaviruses LCM virus 0 0.0 0 0.0 0 0.0 0 0.0 198 0.5 12 0.1 210 0.4 M. pneumoniae 0 0.0 0 0.0 0 0.0 0 0.0 738 1.7 48 0.4 786 1.3 Totals 1967 100.0 2119 100.0 1540 100.0 294 100.0 42651 100.0 10710 100.0 59281 100.0 Coxsackievirus B. Almost all were typed in Europe and in North America and the Pacific. The percent- ages of those typed represented by types 2, 3, 4, and 5 are shown below: Europe 22 22 18 31 93 N. America & Pacific 20 18 17 41 96 Echovirs. Almost all echoviruses were typed and all types were encountered. Types 4, 6, 9, 11, 19 and 30 were found most often but their relative frequencies (% of all echoviruses typed) in Europe differed markedly from those in North America and the Pacific: Echovirus type 4 6 9 11 19 30 Totals Europe 7 18 13 7 15 19 N. America & Pacific 6 12 32 12 3 14 79 79 Poliovirus. Poliovirus was reported in all regions. Type 1 predominated by far in Africa (75% of the total), Middle and South America (96%), and Asia (82%) and, to a lesser extent, in the Eastern Mediter- ranean and North Africa (58qo). In Europe, type 1 was still the predominant type but it accounted for only about 407o of all the polioviruses reported in the present study, followed by type 2 (31%o) and type 3 (28%). In North America and the Pacific, the relative frequencies of the 3 types in descending order were: type 3 (39%), type 2 (38%), and type 1 (23%). Coxsackievirus B type 2 3 4 5 Totals 299 F. ASSAAD ET AL. Herpessimplex virus. Only about 6-7% were typed virus in Europe and 74o in North America and the in Europe and in North America and the Pacific. Pacific. Type I predominated (87% in Europe; 82% in North America and the Pacific). Time trends Adenoviruses. Almost three-quarters of the adeno- The overall trend showed a gradual increase in the viruses reported by laboratories in North America and number of reports of viral neurological infections over the Pacific, and over two-thirds of those reported by the 10 years under study but the annual increment has European laboratories were typed. The types impli- been greatest during the last few years (Table 2). The cated in neurological diseases included types 1-17, 21, increase in the number of reports of neurological 26, 28-31. However, types 1, 2, 3, 5 and 7 predomi- infections more or less followed the pattern for the nated, the percentages being as shown below: total number of reports of virus infections received by WHO, i.e., irrespective of the clinical condition Adenovirus (unpublished data). type Europe N. America & Pacific The fluctuations in the annual number of reports on neurological disease associated with coxsackievirus A 1 21 23 and B, echovirus, and poliovirus followed more or less 2 28 28 the pattern for the total number of reports on these 3 10 17 viruses. However, neurological conditions associated 5 14 10 with coxsackievirus B infections showed-contrary to7 20 16 the total number of reports-a sustained increase Total 93 94 during 1975 and 1976. The fluctuations in coxsackievirus A reports re- Parainfluenza viruses. Only types 1 and 3 figure in flected changes in the number of reports on type 9. the study. Type 3 accounted for 6301o of the total Among coxsackievirus B, types 1 and 6 were reported neurological conditions associated with parainfluenza relatively infrequently in association with neuro- Table 2. Reports of viral neurological infections by year of collection or receipt of specimen, 1967-76 Associated viruses 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 Total Enteroviruses coxsackievirus A 209 167 278 262 160 212 246 196 235 385 2 350 coxsackievirus B 648 599 369 641 705 537 673 720 752 831 6 475 echovirus 2042 2085 1421 1580 1686 1023 1507 2144 3026 1681 18 195 poliovirus 710 907 494 807 794 817 365 496 511 278 6 179 Herpesviruses herpes simplex virus 157 183 192 228 302 327 391 506 524 546 3 356 varicella-zoster virus 20 26 26 36 53 44 88 105 98 122 618 cytomegalovirus 22 40 19 38 43 52 68 60 62 115 519 Adenoviruses 223 243 267 270 290 271 485 344 486 504 3 383 Myxoviruses influenza virus A 9 82 188 77 62 101 136 87 289 385 1 416 influenza virus B 5 29 31 20 46 12 21 70 25 153 412 parainfluenza virus 39 40 45 50 62 39 85 83 95 124 662 respiratory syncytial virus 14 23 19 24 22 27 53 47 99 93 421 mumps virus 1017 548 874 1618 1410 1350 1394 1233 2197 1555 13 196 measles virus 38 40 46 101 112 101 139 121 192 213 1 103 Arenaviruses LCM virus 28 11 13 24 22 5 30 45 28 4 210 M. pneumoniae 22 14 7 15 51 44 116 122 173 222 786 5203 5037 4289 5791 5820 4962 5797 6379 8792 7211 59 281 300 Totals VIRAL NEUROLOGICAL DISEASES logical diseases; in most years, type 5 predominated, particularly in 1970-74 and in 1976. Many cases of neurological disease were associated with coxsackie- virus type 2 in 1967 and 1971, with type 3 in 1967, 1968, 1970, and 1974, and with type 4 in 1975 and 1976. The high numbers of reports of echovirus-associ- ated neurological conditions referred mainly to types 6, 9, and 30 in 1967, types 6 and 30 in 1968, types 4 and 11 in 1971, and types 19 and 30 in 1974 and 1975. Echo- virus type 9 was also reported in comparatively large numbers in 1969, 1970, and 1973, but this had little impact on the total number of reports of echovirus- associated neurological disease. The fluctuations in the reported incidence of polio- virus-associated neurological disease were reflected in the incidence of poliomyelitis cases (mostly type 1) in a small number of countries (Table 3). Table 3. Number of reported cases of poliomyelitis in various countries, 1967-76 Country 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 Kenya - - - - - 14 74 135 44 70 Malaysia - - - - 255 476 - 1 2 0 Mexico 354 460 168 613 163 48 - - 97 - Morocco - - - - - - 25 19 101 - South Africa 144 208 34 45 86 114 36 130 70 3 Thailand 77 68 159 36 100 38 75 78 41 100 The marked rise in the number of reports of neuro- logical conditions in which an adenovirus was noted was not matched by a similar increase in the total number of repoqt$received byWHO on these viruses, which, on the. contrary, declined during 1975 and 1976. The hMrease in the number of neurological reports associated mainly with type 1, type 2 and, to a lesser extent, type 5. The number of reports on neuro- logical conditions associated with adenovirus type 7 rose rapidly to a peak in 1973 but quickly declined thereafter. The total number of adenovirus type 7 infections reported showed a similar sharp increase in 1973 followed by a marked decline. A very marked increase in the number of reports of neurological disease associated with influenza virus A was noted in 1975 and 1976. However, this was not matched by the increase in the total number of reports on influenza virus A. A/Port Chalmers/73 was the dominant virus in the winter of 1975 and A/Victoria/ 3/75 was dominant in the winter of 1976 (4). It should be noted that the first sharp increase in reports on influenza virus A, including those associated with a neurological condition, commenced in 1969 and was related to the advent of A/Hong Kong/68. Reports on neurological disease associated with influenza virus B showed three successive peaks, in 1971, 1974, and 1976. However, the relative increase in the number of infections associated with neuro- logical disease was not matched by a similar increase in the total number of reports on influenza virus B. The reports on neurological disease associated with parainfluenza virus and respiratory syncytial virus followed fairly closely the pattern depicted by the total number of reports on these viruses. With the exception of LCM virus, the reported incidence of other viruses followed the general pattern of a progressive yearly increase. Cases of LCM-associ- ated neurological disease were reported in very small numbers by a few countries. Of the total of 210 reports, 148 (70.5%) came from Hungary. Seasonal patterns Except for the adenoviruses, there is a close corre- lation between the seasonal variation of viral-associ- ated neurological infections and the seasonal variation in reports of virus infections in general. Thus, in the Northern Hemisphere (Table 4) neurological mani- festations were reported in association with influenza virusA and respiratory syncytial virus most frequently from December to March inclusive and with influenza virus B from January to April inclusive. Parainfluenza viruses associated with neurological disease were most frequently reported during the months October, November, and December, but were reported also in large numbers during the summers of 1973 and 1975. Reports of herpes simplex virus, varicella-zoster virus, cytomegalovirus, LCM, and M.pneumoniae associated with neurological disease, were more fre- quent during the winter, but did not show a pro- nounced seasonal pattern. In contrast, reports of mumps and measles viruses increased late in the winter and in the spring. Reports on adenovirus infections in which a neuro- logical condition was mentioned were fairly common during winter but were most frequent during the summer. Reports on neurological conditions associated with enteroviruses showed a pronounced seasonal vari- ation, particularly those associated with coxsackie- viruses A and B and echovirus, which were most frequent in summer and early autumn. Although reports of poliovirus-associated neurological disease increased during the same part of the year, there was an even more pronounced peak in January. This somewhat unexpected winter peak was related to the severe outbreak of poliomyelitis in Malaysia in the winter of 1972. 301 F. ASSAAD ET AL. Table 4. Reports of viral neurological infections by month of collection or receipt of specimen -Northern Hemisphere, 1967-76 Associated virus Jan. Feb. March April May June July Aug. Sept. Oct. Nov. Dec. Total Enteroviruses coxsackievirus A coxsackievirus B echovirus poliovirus Herpesviruses herpes simplex virus varicella-zoster cytomegalovirus Adenoviruses Myxoviruses influenza virus A influenza virus B parainfluenza virus respiratory syncytial virus mumps virus measles virus Arenaviruses LCM virus M. pneumoniae Totals 19 33 48 91 222 369 390 251 204 102 51 1843 59 61 116 234 515 1155 1392 885 613 291 112 5 529 186 230 283 683 1362 2667 3514 2852 1964 857 379 15 609 447 357 355 272 377 439 503 491 358 386 360 4 949 241 237 246 260 241 259 255 236 285 232 175 3 008 29 43 55 49 59 70 44 31 49 43 41 592 39 48 36 35 45 40 30 39 58 50 27 492 264 226 239 264 255 285 320 335 255 263 223 174 3 103 326 60 37 101 1140 88 375 243 81 22 11 11 5 12 10 31 202 1329 105 73 52 27 14 10 5 3 6 9 29 393 34 39 46 38 67 50 32 35 72 74 51 575 66 54 25 11 9 8 8 6 16 34 49 387 909 1231 1276 1184 1194 1096 815 569 767 944 939 12064 84 96 114 105 114 93 69 67 78 74 66 1 048 22 19 25 19 22 14 7 11 6 15 27 19 206 88 53 67 47 72 66 59 69 55 66 59 59 760 3986 2891 3076 3063 3360 4595 6653 7477 5793 484 3436 2733 51 887 A mirror-image of the above relationships holds for viruses reported in sufficiently large numbers in the Southern Hemisphere. Age distribution Except for herpes simplex virus, varicella-zoster, and LCM, viral neurological disease was reported mostly in children, but the relative frequency differed among the viruses (Table 5). Almost 90070 of reports on adenovirus, over 907o of reports on parainfluenza virus and RSV, and over 95% of reports on poliovirus concerned children, particularly those below 5 years Clinical neurological manifestations Three broad clinical groups were distinguished: paralysis, meningitis/encephalitis, and "others" (Table 6). No indication is available of the extent and site of the paralysis or even whether it was transient or persistent. The category "others" covers a very wide range of neurological conditions, including convul- sions, and may not necessarily indicate a viral infec- tion of the CNS. Considering that paralysis and meningitis/encephalitis may both be taken to indicate a direct infection of the nervous system, the associated viriu<ec tnpluuiIiaA in the ativiAw fall intro A actinet yratyri of age. - A- *-- 0--J, L -. E.. _. ,. Between 80% and 85% of the cases of mumps and according to frequency of association with neuro- measles with neurological manifestations concerned logical disease. children, mainly in the age group 5-14 years. Group 1, in which over 900/o of the virus infections A little over half of the herpes simplex virus, 66.6% reported were associated with a frank neurological of the varicella-zoster and 85.3% of the LCM neuro- condition: these included infections due to echo- logical infections were in adults, particularly in the age viruses, polioviruses, mumps, and LCM viruses. Very group 25-59 years, which accounted for about 30% of few of the reports on mumps virus, only 1% of those the total number of reports on both herpes simplex on echovirus, and 2% of those on LCM virus men- virus and varicella-zoster and over 50% of those on tioned paralysis among the clinical manifestations. In LCM. contrast, in 87% of the reports on polioviruses, 63 96 632 604 341 79 45 302 VIRAL NEUROLOGICAL DISEASES Table 5. Reports of viral neurological infections according to age," 1967-76 0-14years ; 15years Associated virus No. % No. % Total No. Enteroviruses coxsackievirus A 1 620 74.4 557 25.6 2 177 coxsackievirus B 4268 72.5 1 620 27.5 5888 echovirus 12 016 70.9 4 933 29.1 16 949 poliovirus 5 629 97.1 171 2.9 5 800 Herpesviruses herpes simplex virus 1 500 49.2 1 546 50.8 3046 varicella-zoster virus 195 33.4 389 66.6 584 cytomegalovirus 352 70.7 146 29.3 498 Adenoviruses 2 824 89.0 350 11.0 3174 Myxoviruses influenza virus A 880 65.2 469 34.8 1 349 influenza virus B 262 67.2 128 32.8 390 parainfluenza virus 571 92.5 46 7.5 617 respiratory syncytial virus 374 93.0 28 7.0 402 mumps virus 10 099 80.7 2 417 19.3 12 516 measles virus 876 84.0 167 16.0 1 043 Arenaviruses LCM virus 28 14.7 162 85.3 190 M. pneumoniae 443 59.0 308 41.0 751 Totals 41 937 75.7 13437 24.3 55374 8 In 3907 reports the age was unknown. paralysis was noted as the principal clinical feature. However, a marked difference was seen between developing and developed countries. In the developing regions, between 88% and 100% of the reported polioviruses were associated with paralysis, as against 32-40%/ in the developed world. Group 2, in which 80-907o of virus infections were associated with definite neurological disease. This group included coxsackieviruses A and B, herpes simplex virus, varicella-zoster virus, measles virus, and M.pneumoniae. Again the ratio between par- alysis and meningitis/encephalitis differed among the viruses. At one extreme, 22% of the total reported cases of varicella zoster showed paralysis. At the other extreme, only 2-4% of the reports on coxsackievirus B, herpes simplex virus, and measles virus mentioned paralysis. In between, 7-8% of coxsackievirus A and M.pneumoniae infections showed paralysis. Group 3, in which 50-80% of the virus infections were associated with well-defined neurological mani- festations; adenovirus, influenza virusesA and B, and cytomegalovirus belonged to this group. While only 4% of the adenoviral and influenza virus infections were reported to be associated with paralysis, such an association was reported in 17% of cytomegalovirus infections. Group 4, in which less than 50%7 of the virus infec- tions gave rise to definite neurological manifestations. This group comprised parainfluenza and repiratory syncytial viruses; less than 4% of the total number of reports on either virus mentioned paralysis. 303 F. ASSAAD ET AL. Table 6. Reports of viral neurological infections according to the main manifestation, 1967-76 Europe, North America, and Pacific Other country groups All country groups Menin- Menin- Menin- gitis Other gitis Other gitis Other Paralysis 8/or manifes- Total Paralysis W/or manifes- Total Paralysis W/or manifes- Total enceph- tations enceph- tations enceph- tations Associated virus alitis alitis alitis Enteroviruses coxsackievirus A 48 1700 276 2 024 134 118 74 326 182 1818 350 2 350 coxsackievirus B 124 5 258 934 6 316 34 114 11 159 158 5 372 945 6 475 echovirus 157 16 501 1 423 18 081 26 83 5 114 183 16 584 1 428 18 195 poliovirus 359 377 212 948 4 999 92 140 5 231 5 358 469 352 6 179 Herpesviruses herpes simplex virus 142 2 573 610 3 325 1 24 6 31 143 2 597 616 3 356 varicella-zoster virus 136 379 103 618 0 0 0 0 136 379 103 618 cytomegalovirus 90 211 216 517 0 1 1 2 90 212 217 519 Adenoviruses 138 2008 1 221 3 367 4 7 5 16 142 2 015 1 226 3383 Myxoviruses influenza virusA 50 728 628 1 406 3 6 1 10 53 734 629 1 416 influenza virus B 16 232 158 406 2 1 3 6 18 233 161 412 parainfluenza virus 12 300 347 659 1 2 0 3 13 302 347 662 respiratory syncytial virus 16 179 226 421 0 0 0 0 16 179 226 421 mumps virus 54 12 480 655 13 189 0 7 0 7 54 12 487 655 13 196 measles virus 32 826 230 1 088 4 7 4 15 36 833 234 1 103 Arenaviruses LCM virus 4 204 2 210 0 0 0 0 4 204 2 210 M. pneumoniae 57 619 110 786 0 0 0 0 57 619 110 786 Totals 1 435 44575 7 351 53361 5208 462 250 5920 6643 45037 7601 59281 PART 2. VIRAL NEUROLOGICAL INFECTIONS INVESTIGATED IN MORE DETAIL BY THREE SELECTED LABORATORIES The part played by enteroviruses and mumps virus in neurological disease is already well established. In 1972, a review of the information available in the WHO Virus Reporting System revealed, among other features, an unexpectedly high proportion of neuro- logical conditions were associated with infections with adenovirus, myxoviruses (other than mumps virus), and mycoplasma. Detailed investigations of the role of viruses other than enteroviruses and mumps virus in neurological disease were therefore undertaken at the following three laboratories: - Department of Virology, National Institute of Public Health, Bilthoven, Netherlands - Department of Epidemiology and Micro- biology, Institute of Hygiene and Epidemiology, Prague, Czechoslovakia - Virus Serological Department, Central Public Health Laboratory, Helsinki, Finland. In these laboratories, the viral or mycoplasmal agents were identified only after they had been sub- jected to thorough laboratory examinations. An attempt was also made to obtain data on the final clinical diagnosis at discharge to supplement the infor- mation on clinical signs noted initially. The clinical diagnosis was coded in much more detail than in the more general study reported in Part 1 (pages 298-304). RESULTS Bilthoven, Netherlands During the period 1973-76 inclusive, the regular contributions to the WHO Virus Reporting System comprised 826 reports on viral neurological infections from this laboratory. Virus infections other than enteroviruses and mumps amounted to 199 cases (or 304 VIRAL NEUROLOGICAL DISEASES 24.1 %). Of these, 138 (or 69.3%) are included in the detailed study: the others were excluded because of either an unsatisfactory clinical diagnosis or unsub- stantiated laboratory findings. The clinical grounds for exclusion included a revision of the diagnosis as well as rejection of ill-defined clinical manifestations, such as convulsions. Unsubstantiated laboratory diagnosis included the incrimination of possible etiological agents other than viruses or negative sero- logical findings in spite of virus isolation. The relative frequencies of the individual viruses in the original group of 199 cases and in the revised group of 138 cases are very similar (Table 7). The findings reported below concern only the revised group of 138 cases. Adenovirus headed the list of viruses and accounted for almost 38% of cases. Herpes simplex virus and varicella-zoster virus followed with relative frequencies of 18% and 17%, respectively. In other words these 3 viruses together accounted for almost three-quarters of the cases. The other viruses were the subject of between 2 and 10 reports each. Table 7. Relative frequency of viral neurological infections, other than enteroviral and mumps, reported by the Nether- lands during the period 1973-76 Reports included in the WHO Virus Reports Reporting included in the System detailed studies (Part 1) (Part 2) Associated virus No. % No. % Herpesviruses herpes simplex virus 34 17.1 25 18.1 varicella-zoster virus 29 14.6 24 17.4 cytomegalovirus 14 7.0 2 1.4 Adenoviruses 85 42.7 52 37.9 Myxoviruses influenza virus A 11 5.5 6 4.3 influenza virus B 7 3.5 7 5.1 parainfluenza virus 4 2.0 3 2.2 respiratory syncytial virus 3 1.5 2 1.4 measles virus 12 6.0 10 7.2 Arenaviruses LCM virus 0 0.0 0 0.0 M. pneumoniae 0 0.0 0 0.0 More than one virus 0 0.0 7 5.1 Totals 199 100.0 138 100.0 Adenovirus. Of the 52 adenovirus-associated cases, 19 were diagnosed solely on serological (complement- fixation) evidence. In these cases, the adenovirus type could not be determined. In 33 cases an adenovirus was isolated and typed. In 26 of these cases, a comple- ment-fixation test was carried out on paired sera and showed a four-fold rise in titre in 17 cases. In 9 cases, an initial high titre either remained the same or showed a two-fold rise. The predominant types were 1, 2, 3, and 7. Forty-eight cases were in children and the highest proportion was in the age group 1-4 years. The neurological manifestations most frequently seen were meningitis (28 cases) and encephalitis (19 cases). Two cases were diagnosed as meningoencephalitis, 2 cases were labelled "atonia", and in 1 case meningism was noted. The adenovirus type was apparently unrelated to the type of neurological manifestation. Herpes simplex virus. In 20 out of 25 cases, the diagnosis was made solely on serological evidence, i.e., a four-fold or greater rise in the complement- fixing titre in paired sera. In 5 cases herpes simplex virus was isolated and the infection was confirmed serologically in 3 of these cases. Typing of 3 of the 5 isolates indicated that they were type 1. Herpes simplex virus infection was encountered as frequently in the young as in adults: 12 cases in children below 10 years of age and 13 in adults aged 15 years and over. Encephalitis was the most frequent diagnosis (12 cases), followed by meningitis (7 cases), but in 5 cases a diagnosis of meningoencephalitis was made. One case of facial paresis was recorded. Varicella-zoster. In 23 cases, the diagnosis was made solely on the evidence of a four-fold or greater rise in the complement-fixing titre in paired sera. In one case, the virus was isolated and the diagnosis con- firmed serologically. Nine cases were in the age group 1-9 years, 1 case in the age group 10-14 years, and 14 cases in the age group 15 years and over. Two of the cases were diagnosed as meningism, 7 as meningitis, 3 as encephalitis, and 2 as meningoencephalitis. One notable feature was the frequency with which "paralysis" was recorded. In a total of 10 cases (i.e., over 40%), the following diagnoses were made: Age group (years) 1-4 10-14 15-24 25-58 .:60 No. cases 1 1 2 I2 Diagnosis Ascending paralysis Facial paralysis Facial paresis Hemiparesis Subacute paresis of right glosso- pharyngeal nerve Facial paralysis Facial paresis Facial paresis 305 F. ASSAAD ET AL. Thus, in 8 of the 10 cases, a cranial nerve was affected. Other viruses. In only 3 cases of influenza virus B and 2 cases of parainfluenza virus was the diagnosis based on both isolation and serology. Isolation only was the basis of diagnosis in 1 case of influenza virusA and 3 cases of influenza virus B. All the remaining cases were diagnosed on serological evidence only: influenza virus A (5), influenza virus B (1), para- influenza virus (1), respiratory syncytial virus (2), cytomegalovirus (1), and measles virus (10). Influenza virus A was diagnosed equally frequently in the young below 5 years of age and in adults aged 15-29 years: there were 3 cases in each age bracket. In contrast, influenza virus B, parainfluenza virus, and RSV were encountered only in children. Seven cases of measles were in the age group 1-4 years, one case in an infant below 1 year of age, one case in the age-group 5-9 years of age, and another in the age group 15-24 years. The two cytomegalovirus cases were over 25 years of age. The clinical picture was mainly that of meningitis or encephalitis. The 13 cases of meningitis were distri- buted as follows: influenza virusA (2), influenza virus B (4), parainfluenza virus (2), respiratory syncytial virus (2), and measles (3). There were 9 cases of encephalitis: influenza virus A (2), influenza virus B (2), parainfluenza virus (1), and measles virus (4). In addition, meningism was present in 1 case of measles, meningoencephalitis in 2 cases of influenzaA and 1 of measles, and paralysis in 1 case of influenza B, 1 case of measles, and 2 cases of cytomegalovirus infection. Of the cases with paralysis, no further information was given on the influenza B case, the measles case was diagnosed as myeloneuritis and the 2 cytomegalovirus cases as myelitis and radiculitis cum myelitis. In 7 cases more than one virus was diagnosed: Virus No. Meningism Meningitis Encephalitis Meningoencephalitis Paralysis I adenovirus 1, para- influenza virus 1 and coxsackievirus B4 I herpes simplex virus and mumps virus 2 adenovirus (not typed) and herpes simplex virus 1 varicella-zoster, measles and coxsackievirus B4 I herpes simplex virus and echovirus 6 I herpes simplex virus and varicella-zoster virus Prague, Czechoslovakia Between 1972 and 1975, a series of outbreaks of respiratory tract infection associated with neurologi- cal manifestations occurred in various parts of Czechoslovakia, most of them in Plzein and Ostrava. The details of these outbreaks are summarized in Table 8. In all cases, the disease was attributed to adenovirus infection. The accompanying neurological manifestations were aseptic meningitis in the majority of cases and meningism in a smaller number. There were 107 cases altogether, nearly all of them in chil- dren. The age group 5-9 years was most heavily af- fected. In all cases, the disease was benign and there was full recovery. Isolation of adenovirus, either from stools or from the nasopharynx, was possible in 52 cases, the pre- vailing types being 3 and 7, although types 1, 2, and 5 were also found in some outbreaks. Serological evi- dence (CF test) of infection was obtained in a total of 90 cases, and in 38 of these the virus had also been isolated. Helsinki, Finland From 1971, outbreaks of acute respiratory disease associated with Mycoplasma pneumoniae were reported from different parts of Finland. The out- breaks reached a peak in 1972, continued during 1974 and 1975, and began to abate in 1976. A number of these cases of M.pneumoniae acute respiratory disease showed neurological signs. However, during these prolonged outbreaks, cases of neurological disease occurred where there were no signs of acute respiratory infection but in which there was laboratory evidence of M. pneumoniae infection (a four-fold or more rise in CF titre in paired sera). Altogether, during the period 1973-76 inclusive, M. pneumoniae was diagnosed by the laboratory in 69 cases in which neurological involvement was a leading clinical manifestation. However, in 12 of these cases, viruses were also implicated, and in 2 cases the leading neurological sign was convulsions. M.pneumoniae was the only agent incriminated by the laboratory in 55 cases of definite neurological involvement. These 55 cases are the subject of the present study. The first case was reported in June 1973 and was diagnosed as aseptic meningitis. By the end of 1973, 12 cases had been noted. In 1974, there were 23 cases and in 1975 there were 16. In 1976, only 4 cases were diagnosed. In 33 cases the main clinical manifestation was aseptic meningitis, in 14 cases it was encephalitis, in 4 cases meningoencephalitis, in 3 Guillain-Barre syn- drome, and in 1 case hemiplegia. Fever was noted in 49 cases, respiratory involvement in 13 cases (signs of upper respiratory infection in 10 and of lower respir- atory infection in 3), enteritis in 7 cases, and skin rash in 3 cases. In 1 case of meningitis, endocarditis was also diagnosed. 306 VIRAL NEUROLOGICAL DISEASES Table 8. Reports of adenovirus infection associated with neurological disease in Czechoslovakia, 1972-75 No. cases Clinical Isolation of Serological Isolation + Adenovirus Date Place (age group) diagnosis adenovirus evidence serology types Nov. 1972 Plzen 27 URD,b 27 (from 23 23 2, 3 -Jan. 1973 (59)a conjunctivitis, faeces, 10 also aseptic from naso- meningitisc pharynx Late summer Ostrava 31 Aseptic 15 (from naso- 26 10 1, 3, 5, 7 & autumn, (5-14) d meningitise pharynx) 1973 Nov. 1973 Plzen 1 (5-9) URD, aseptic - 3 - - C. Budejovice 2 adults meningitis Late summer Ostrava 32 (1-24, half URD, aseptic 8 28 4 1, 3, 7 & autumn, in age group meningitis 1974 5-9)f (2 cases of meningism + 1 of encephalitis) Aug./Sept., Plzefi 5 (5-14) URD, meningism - 5 - - 1974 Usti 6 (1-14) URD, meningism 2 51 7 Brno 614)(1 meningitis) 1975 Plzen + 2 new 3 (6 mths, 1-4, Lower respir- 3 areas 15-24) atory infection, meningism, meningitisg a One child in age group 10-14. b URD = upper respiratory disease. c Lymphadenitis also in few cases. d Two cases in age group 1-4, one in age group 15-24. e Also enteritis in one case and tonsillitis in another. f One case in age group 25-59. 9 One case had enteritis and meningitis. Table 9. Reports of Mycoplasma pneumoniae-associated neurological infections according to age and the main clinical manifestation, Finland, 1973-76 All age groups were represented: 25 cases were in children and 30 cases in adults (Table 9). Meningo- Guillain- enceph- Barre Hemi- (years) gitis alitis alitis syndrome plegia Total <1 1 1 1 - - 3 1 -4 8 4 1 - - 13 5-9 2 1 - - - 3 10- 14 3 2 1 - - 6 Subtotal children 0-14 years 14 8 3 - - 25 15-24 1 4 - - - 5 25 - 59 16 2 1 3 1 23 )60 2 - - - - 2 Subtotal adults > 15 years 19 6 1 3 1 30 Totals 33 14 4 3 1 55 DISCUSSION Viral infections of the central nervous system are a fairly common occurrence, especially in children. Clinically they comprise a wide spectrum of con- ditions, usually designated according to the primary anatomical site involved, hence the descriptive terms aseptic meningitis, encephalitis, meningoencephalitis, encephalomyelitis, etc. For the purposes of the WHO Virus Reporting System, an attempt was made in 1967 to differentiate between: (a) definite neurological involvement without paralysis, e.g., aseptic meningitis, encephalitis, Age Menin- Enceph- 307 F. ASSAAD ET AL. (b) definite neurological involvement with par- alysis, including cranial nerve affection, and (c) other conditions that may not indicate a direct involvement of the central nervous system, e.g., men- ingism, convulsions. Many viruses can cause neurological disease and it is estimated that a viral (or mycoplasma) agent can be identified in 50-70%o of suspected viral neurological infections in laboratories with adequate facilities and trained personnel (5). The laboratory method used for identifying a viral neurological infection depends on the kind of speci- men the laboratory can obtain from the attending physician, the laboratory facilities, the available clinical data and epidemiological information and also the suspected viral agent (6). Thus, in the case of the enteroviruses a diagnosis is made in almost all cases on the evidence of isolation, since a diagnosis based on serology would require too large a battery of tests in view of the great number of known entero- viruses. For adenovirus infections, however, the complement-fixation test is a most useful single pro- cedure for serological diagnosis, but other methods are needed to determine the antigenic type. In the case of cytomegalovirus infections, the method of choice has "traditionally" been the direct isolation of the virus from urine, although the CF test is now used more frequently. On the other hand, in the case of M. pneumoniae, few virus laboratories have the facilities for culturing the organism, but they include the CF antigen among the antigens used for viral serology. Because of the time required and the tech- nical complexity of the procedure, the isolation of measles virus is rarely attempted, i.e., the diagnosis rests on serological findings. The need to use mice or guinea pigs for the isolation of LCM virus prevents routine isolation of this virus. In itself, the recovery of a virus from a patient does not necessarily mean that the illness can be attributed to that particular agent. However, if the virus is isolated from the brain or the cerebrospinal fluid, there is a very high probability that any neurological manifestations can be attributed to that agent. Similarly, a viral diagnosis is much more credible if the isolation is coupled with serological evidence of infec- tion. It appears that the laboratories participating in the WHO Virus Reporting System very rarely had access either to material from the CNS or the CSF, and in only a small proportion of cases did they carry out both isolation attempts and serological examinations on the same patient. On the other hand, in the Part 2 studies, the diagnosis is frequently based on both isolation and serological tests except for the M. pneumoniae outbreak in Finland, where the diagnosis was made solely on serological evidence. A comparison between the findings in Parts 1 and 2 is of special importance in the case of viruses whose poss- ible etiological role in neurological disease is doubtful or has not been well-documented. The most important among these are the adenoviruses, the influenza and parainfluenza viruses, and respiratory syncytial virus. Notwithstanding the shortcomings of Part 1, the study confirms that viral neurological disease is seen mostly in children (over 75%), that its incidence varies from year to year, and that it is seen throughout the year, although in the Northern Hemisphere the largest numbers are almost always encountered during late summer and early autumn (5, 7). The agents most commonly diagnosed in infections associated with neurological disease were enteroviruses. In Europe, the enteroviruses accounted for 480/ of all viral infec- tions accompanied by neurological involvement, in North America and the Pacific for 64%. In the devel- oping world they accounted for 97-1007o. There was a striking difference between the developing and the developed world in the number of instances in which polioviruses were diagnosed as causes of neurological disease and in the frequency of paralytic poliomyelitis. Out of a total of 6179 cases of laboratory-confirmed poliovirus infection reported in the Part 1 study, 5231 cases (85/o) were reported by the 11 laboratories from the developing world. Furthermore, of the total number of 5358 cases of paralytic poliomyelitis, the developing countries accounted for 4999 cases, or 93%. In the developed world, immunization pro- grammes against poliomyelitis have greatly reduced prevalence of the disease. In the developing world, low vaccination coverage is, as expected, accompanied by frequent outbreaks of the disease (8). In the developed world, most outbreaks of aseptic meningitis/encephalitis were associated with a limited number of enteroviruses, mainly the coxsackieviruses and echoviruses. Of the coxsackieviruses A, type 9 predominated, of the coxsackieviruses B, types 2, 3, 4 and 5 were common, and of the echoviruses, types 4, 6, 9, 11, 19 and 30 were frequently encountered. The outbreaks were irregular in pattern: a given type struck only one or a few countries at a time, recurred without any regular time interval and in general with- out an epidemiological progression from one country to another. In a few instances, one type caused epi- demics extending beyond one season, e.g., in the United Kingdom in 1974 only 5 cases of aseptic meningitis were associated with echovirus 30, while an outbreak starting in 1975 with 197 cases extended into 1976 with a total of 229 cases for that year. Enterovirus 71 was not included in the WHO Virus Reporting System until 1974, after recognition of the strain in an outbreak of aseptic meningitis/encepha- litis in Sweden in 1973 (9). Of the 20 isolations re- ported to WHO from this outbreak, 11 were from cases with neurological symptoms. Retrospectively, two outbreaks of viral neurological disease, one in Melbourne, Australia in 1972-73 (10), and one in 308 VIRAL NEUROLOGICAL DISEASES Bulgaria in 1975 associated with paralysis and several fatal cases (11), have been confirmed to be due to enterovirus 71. Only a very small proportion of enterovirus infec- tions cause apparent neurological disease but the ease with which enteroviruses spread in children of the developed world is striking. The neurological diseases caused by enteroviruses other than the polioviruses are, in general, self-limited benign conditions. But a poliovirus introduced in a community with a high vaccination coverage presents a real danger to the pockets of non-vaccinated, non-protected groups of the population. This was witnessed in 1970 in Texas, USA, where a cluster of 13 cases occurred in two communities among the non-vaccinated, all of them associated with poliovirus type 1 (12). Similarly, in 1972, 11 cases of poliomyelitis occurred in non-vacci- nated students belonging to a Christian sect in Connecticut, USA (13). In the Netherlands in 1971 an outbreak of 43 cases occurred in a group of the popu- lation that rejected vaccination on religious grounds (14). More recently, in 1978, an outbreak involving 108 cases was reported in the same religious group (15). It is of interest to note that in the USA a live trivalent vaccine is used, while in the Netherlands a killed vaccine is administered together with DTP vaccine. Mumps virus is recognized as one of the commonest viral causes of neurological disease. In the present study it accounted for 27% of all laboratory-diag- nosed cases in Europe and 15% in North America and the Pacific. It is doubtful whether immunization against mumps accounts for this difference. Again, aseptic meningitis was the most frequent clinical mani- festation. The enterovirus and mumps virus together were diagnosed in over three-quarters of the cases reported toWHO from these two groups of countries. In a little less than a quarter of the cases a wide spectrum of viral agents was identified. The possibility that a number of these agents, e.g., herpesviruses and measles virus, can infect the central nervous system has been well-documented and the findings in the present study confirm previously reported instances. On the other hand, the role of adenoviruses, influenza and parainfluenza viruses, and respiratory syncytial virus, in the causation of neurological disease has not been definitely established. In the Netherlands (Part 2 of the present study) the findings over the period 1973-76 tally very closely with the results obtained in the developed world as a whole. In 24%7o of the total number of reported cases, viruses other than enterovirus or mumps were ident- ified, and in almost 70% of these cases the laboratory findings established fairly conclusively the viral nature of the etiological agent. However, among these 138 cases, 51 cases were attributed to a herpesvirus infection, a finding that agrees with established views, but 52 cases were associated with an adenovirus whose role in neurological infection has been given little credence in the past. However, in Czechoslovakia, the adenovirus out- breaks in Plzefi in 1972 and in Ostrava in 1973 and 1974 lend support to the possible role of adenovirus in neurological infections. The outbreaks were primarily of upper respiratory infection among schoolchildren, aseptic meningitis was considered as a complication. No other viral agents could be detected. In a sizeable proportion of cases evidence of an adenovirus infec- tion was established by both isolation and serology. The virus was frequently recovered from the naso- pharynx, a site that would tend to confirm an infection by the adenovirus (it has been recognized that iso- lation from faeces does not in many instances relate to a concurrent infection). It may be of interest to note that two of these outbreaks occurred in winter, in con- trast to the findings in the Northern Hemisphere in the Part 1 study and in the Netherlands in the Part 2 study, where the peak incidence was in summer, i.e., when the enteroviruses are most commonly found. There were no reports of similar outbreaks from other parts of the world. Nevertheless, a close look at the role of adenoviruses in neurological disease is un- doubtedly warranted. The laboratory findings in the Netherlands impli- cating myxoviruses in neurological disease are less clear. For example, the number of influenza cases with neurological manifestations bears little relation to the actual toll from influenza. No cases of influenza CNS infections were diagnosed in the winter of 1973 but two were identified in the winter of 1974, two in the winter of 1975, and two in the winter of 1976. The winter of 1973 was marked by large outbreaks of influenza (and of excess mortality from respiratory diseases) caused by A/England/42/72.The 1973/74 season was rather calm, but the 1974/75 season was marked by outbreaks caused by A/Port Chalmers/72 and in the 1975/76 season A/Victoria/75 made its presence felt in the Netherlands (4). On the other hand, diagnosis of the seven cases of influenza B with neurological manifestations in January and February, 1974, tallies with the wide- spread outbreaks of influenza B during that season. Furthermore it was in 1974 that there were indications in the USA of an association between influenza B and Reye's syndrome (16). The 3 cases of parainfluenza and 2 cases of respirat- ory syncytial virus infection with signs of meningitis or encephalitis were all in children and all showed signs of respiratory infection. The numbers undoubtedly represent a very small fraction of the cases of croup or bronchiolitis and may well be evidence of genuine CNS complications. The outbreak of M. pneumoniae infection in Fin- land strongly suggests that this organism plays a role in 309 F. ASSAAD ET AL. the causation of various types of neurological dysfunction in children and young adults. Clinically, this picture of neurological involvement does not usually differ from that caused by viruses except for a high incidence of associated respiratory infection (6). In the present study, respiratory infection was present in one-quarter of cases, although it is most probable that the respiratory symptoms were overlooked when the more severe neurological disease was reported. Laboratory investigations in Finland showed that a significant rise in Mycoplasma antibodies could be detected concurrently with a rise in antibodies to meningococcus or Haemophilus influenzae in cases of bacterial meningitis. Therefore, in cases reported as aseptic meningitis associated with M. pneumoniae a non-specific rise in Mycoplasma antibodies cannot be entirely ruled out. The experience in Finland would warrant the inclusion of CF antigen against M. pneu- moniae in the battery of serological tests routinely carried out in virus laboratories. So far the laboratory methods used for the diagnosis of viral infections have rested on either isolation or serology. Isolation is time-consuming and, as men- tioned above, does not necessarily mean per se a con- current infection. Serological confirmation of the infection requires an even longer time in order to allow for the rise in antibody titres to be significant. The time lag between the clinical and laboratory diagnosis has disassociated the laboratory from the actual care of the patient. In other words, the laboratory investi- gations have become an epidemiological rather than a diagnostic tool. In turn, this has had its effects on the relationship between the clinician and the laboratory. The clinician finds the laboratory investigations irrel- evant to his patient's immediate needs. The laboratory cannot very well press for more precise information from the clinician, since little can be offered in return. In this context, an accurate assessment of the role of a given virus detected by the laboratory and the disease condition of the patient is, to say the least, not always an easy undertaking. Laboratory techniques for rapid diagnosis of viral infections are at present being developed (17). Tech- niques under consideration for the detection of viral antigens are immunofluorescence, the immunoper- oxidase reaction, and enzyme immunoassay. Similar techniques are being used for the detection of early, specific IgM antibodies under circumstances that warrant the diagnosis of the virus infection involved. The techniques promise to be both sensitive and specific for a very large number of etiological agents. These techniques would allow the laboratory to give a diagnosis within 3-4 hours of receiving the specimen. In this way, it will be possible for a dialogue to be established between the clinician and the virus lab- oratory. For the clinician, the laboratory would help in the choice of therapy, provide a sound basis for prognosis, and assist him in control of nosocomial infections. Conversely, once the laboratory findings are rel- evant to the diagnosis and care of the patient an accurate assessment of the etiological role of an agent detected by the laboratory becomes part of the diagnosis. With such developments in the future, perhaps a number of the questions raised in this paper will be answered.. RESUME TROUBLES NEUROLOGIQUES ASSOCIES A DES INFECTIONS VIRALES ET A MYCOPLASMA PNEUMONIAE La premiere partie de l'article a trait aux resultats de l'analyse des rapports provenant de laboratoires de 30 pays sur les troubles neurologiques associes A des infections A virus ou A Mycoplasma pneumoniae, qui sont parvenus au Virus Reporting System de l'OMS de 1967 A 1976. Ces troubles comprennent la paralysie, la meningite et l'ence- phalite, auxquelles s'ajoute un groupe de manifestations neurologiques cliniques mal definies. La deuxieme partie est consacree A des etudes plus approfondies du role joue par les divers virus responsables des atteintes neurologiques signalees, qui ont ete faites par trois laboratoires en Finlande, aux Pays-Bas et en Tchecoslovaquie. Plus de 55% des 59 281 rapports auxquels se refere la premiere partie mentionnent les enterovirus comme cause de maladie neurologique, et pres de 30% les myxovirus, alors que les herpesvirus et les adenovirus ne sont incrimines que dans 8% et 6/o des rapports respectivement. Le virus de la chorio-meningite lymphocytaire (CML) figure dans moins de 0,5%o des rapports et M. pneumoniae dans un peu plus de 1 %o. Les rapports provenaient A concurrence d'environ 90%o de laboratoires de pays developpes. Presque tous ceux qui emanaient de pays du tiers monde se rapportaient aux enterovirus, et principalement aux poliovirus. En fait, 85% de tous les cas de poliomyelite confirmes par un laboratoire et 93%7o de ceux ayant entrame une paralysie ont et enregis- tres dans les pays en developpement. Dans le groupe des myxovirus, le virus des oreillons a e le plus souvent cite (770/o des infections A myxovirus), suivi par le virus grippal de type A (87o), la part des autres types de myxovirus variant entre 2 et 6%. Dans le groupe des virus herpetiques, les virus de l'herpes simplex ont e les plus souvent mentionnes (dans 75% des rapports concernant ce groupe). La courbe ascendante, au cours de la periode considere (1967-1976), des rapports signalant des maladies neuro- logiques associees A des virus a e A peu pres parallele A celle traduisant l'augmentation du nombre des rapports 310 VIRAL NEUROLOGICAL DISEASES 311 concernant des infections virales requs A l'OMS; et l'une et l'autre ont subi les memes fluctuations annuelles et saison- nieres. Les cas enregistres affectaient des enfants A concurrence de plus de 757o; seuls les herpesvirus, le virus de la varicelle et du zona et le virus CML ont ete plus souvent signales chez les adultes. Sur le plan clinique, les entrovirus, le virus des oreillons et le virus CML ont e ceux les plus souvent associes A des atteintes du type meningite/encephalite, tandis que, parmi les ent&rovirus, les poliovirus etaient associes le plus souvent A une paralysie. En ce qui concerne les myxovirus, et si l'on exclut les virus des oreillons et de la rougeole, un tiers A plus de la moitie des rapports concernaient des manifestations cliniques neuro- logiques mal definies. Dans la deuxieme partie de l'article, consacree aux enquetes faites par trois laboratoires, les travaux du labora- toire des Pays-Bas sont commentes d'abord. Ils ont porte sur les troubles neurologiques associes A des virus autres que les enterovirus et le virus des oreillons pendant la periode 1973-1976. Sur 138 rapports plus particulierement etudies par ce laboratoire, 52 avaient trait aux adenovirus et con- cernaient surtout des enfants, 25 A des infections a herpes- virus ayant frappe dans une proportion A peu pres egale des enfants et des adultes, et 23 A des virus de la varicelle et du zona dont 10 ont et a l'origine de paralysie. Un nombre limit6 de cas mettaient en cause d'autres virus: virus grippal de type A et B, virus paragrippal, virus respiratoire syncytial, cytomegalovirus et virus de la rougeole. Les travaux du laboratoire tcheque ont porte sur les infec- tions a adenovirus qui ont provoque une maladie neuro- logique pendant la periode 1972-1975, au cours de laquelle ont e enregistrees, principalement chez les ecoliers, trois epidemies de maladie respiratoire avec complications neuro- logiques. Dans une forte proportion des cas, la responsa- bilite d'un adenovirus a e confirmee par une epreuve sero- logique aussi bien que par l'isolement de cet agent, aucun autre virus n'ayant pu etre identifie. Le laboratoire finlandais a fait rapport sur les troubles neurologiques provoques par une infection a M. pneu- moniae diagnostiquee durant la periode 1973-1976. Des poussees epidemiques dues a cet agent s'eaient manifestees des 1971 pour atteindre leur intensite maximale en 1972, se maintenir pendant les annees 1974-1975 et enfin d6croitre en 1976. Dans l'eude effectuee (1973-1976), M.pneu- moniae a e identifie comme seul agent etiologique dans 55 cas oui les manifestations cliniques principales etaient de type neurologique. Ces cas ont et enregistres dans tous les groupes d'age puisqu'ils concernaient 25 enfants et 30 adultes. REFERENCES 1. ASSAAD, F. & COCKBURN, C. Four-year study of WHO virus reports on enteroviruses other than poliovirus. 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