Other Neurological Infections in Japanese Inpatients

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1 å ORIGINAL ARTICLE D Nationwide Survey of the Annual Prevalence of Viral and Other Neurological Infections in Japanese Inpatients Satoshi Kamei and Toshiaki Takasu Abstract Objective To estimate the annual prevalence of viral and other neurological infections at large hospitals in Japan during the period from 1989 to Methods A nationwide questionnaire survey on the numbersof inpatients with viral and other neurological infections wassent for completion to the chiefs of Departments of Internal Medicine, Neurology and Pediatrics at all hospitals with more than 200 beds. Results The average annual number of inpatients (and the number per 106 population) with encephalitis in large hospitals was estimated to be 2, (17.7±3.2), while it was 32,000±16,000 (258±129) for meningitis, and 650±50 (5.2±0.4) for myelitis. Among the inpatients with encephalitis, meningitis, and myelitis, an unknownetiology was the most common (51.2% in encephalitis, 73.2% in meningitis, and 36.3% in myelitis), followed by a viral etiology for all three diseases. Conclusion The first estimate was madeof the annual prevalence of viral and other neurological infections and their etiology in Japan. (Internal Medicine 39: , 2000) Key words: encephalitis, meningitis, myelitis Introduction Estimation of the annual prevalence of viral and other neurological infections is difficult, because the diagnosis of neurological infections requires serial and extensive examination of the pathogens involved. The annual number of inpatients with such infections at large hospitals is thought likely to represent the minimumannual prevalence of these diseases in Japan. Therefore, a nationwide questionnaire survey of the number of inpatients with neurological infections was undertaken in an attempt to estimate the annual prevalence of such infections in Japan. Materials and Methods A nationwide questionnaire survey on the annual number of inpatients with encephalitis, meningitis, or myelitis from 1989 to 1991 was undertaken between 1993 and The chiefs of departments of internal medicine, neurology, and pediatrics at all hospitals with more than 200 beds were asked to complete the questionnaire. In the first questionnaire, "encephalitis" included meningoencephalitis and meningoencephalomyelitis, and "myelitis" included meningomyelitis. The categories of encephalitis were classified as viral (viral pathogen identified) encephalitis, bacterial encephalitis, acute disseminated encephalomyelitis, Creutzfeldt-Jakob disease, subacute sclerosing panencephalitis, fungal encephalitis, others (another pathogen identified), and unknown etiology. Meningitis was classified as viral (viral pathogen identified) meningitis, bacterial meningitis, tuberculous meningitis, fungal meningitis, others (another pathogen identified), and unknownetiology. Myelitis was also classified as viral, including viral-associated, (viral pathogen identified) myelitis, others (another pathogen identified), and unknown etiology. The pathogenic virus in each patient with viral encephalitis, meningitis, and myelitis was researched in the second questionnaire, but the detailed diagnostic criteria for each category of neurological infection was not included in that questionnaire. The pathogenic bacteria in each patient with bacterial meningitis and encephalitis was not investigated in the questionnaire. Moreover, brain abscess and neurosyphilis were not included in the questionnaire. The recovery rate of the first questionnaire was 1,250/4,477 departments (27.9%). Wesent a second questionnaire concerning the etiological diagnosis of these diseases to those departments. The recovery rates of the second questionnaire was 377/1,250 departments (30.2%) and 13,374/34,416 patients (38.9%). The annual prevalence of each disease was estimated by extrapolating the actual numberfrom the returned questionnaires to cover the unreturned cases. Weused the %2test to examine the differences in the recovery rate of the questionnaires depending on the kind of hospital and department, bed-numbers, and hospital location (Table 1 ). Significant differences in the recovery rate were noted between university hospitals and general hospitals, among de- From the Department of Neurology, Nihon University School of Medicine, Tokyo Received for publication September 30, 1999; Accepted for publication May 13, 2000 Reprint requests should be addressed to Dr. Satoshi Kamei, the Department of Neurology, Nihon University School of Medicine, 30-1 Oyaguchi kami-machi, Itabashi-ku, Tokyo

2 , Inpatients with Neurological Infections Table 1. Differences in the Questionnaire Recovery Rate Recovery rate TT..,., Differenceinrecoveryrate Hospitaldetails, 0. J First survey Second survey A (y test) Universityhospital 49.6%(241/486) 16.7%(81/486) TT...., ^,L à" i., f,.. Universityhospital>Generalhospital Generalhospital 25.3% (1,009/3,991) 7.4% (296/3,991) (p<0.01) Internal Medicine 23.8% (584/2,454) 5.0% (122/2,454) Department Neurology 29.5% ( 1 54/522) 1 1.3% (59/522) Neurology, Pediatrics>Internal Medicine ^p^u.ui) Pediatrics 34.1% (512/1,501) 13.1% (196/1,501).,, >3 23.9%(401/1,678) 16.3%(27^^" above300> Numberofbeds ( ^^^ % (854/2,799) 3.7% (103/2,799) (p<u.u i ; Hokkaido % (72/276) 8.3% (23/276) Tohoku 25.4% (98/386) 9.3% (36/386) Kanto 30.7% (347/1,131) 8.5% (96/1,131) Region Chubu-Hokuriku 28.3% (220/778) 9.3% (72/778) no significant regional differences Kinki-Chugoku 26.5% (296/1,1 16) 8.3% (93/1,1 16) Shikoku 30.1% (58/193) 9.8% (19/193) Kyushu 27.3% (163/596) 6.4% (38/596) _. partments, and between hospitals with over 300 beds and those with beds. Regional differences were not evident. The nationwide prevalence of these diseases was thus estimated by extrapolation according to the kind of hospital and department, and hospital bed numbers, based on the assumption of a randomresponse. The annual number of inpatients per 106 population was calculated from the total population in Moreover, each neurological infection with a different etiology was further analyzed from the results of the second questionnaire. Statistical differences in the estimated values per 106 population or the total population between different regions and years of the survey were evaluated by tests for proportion with a Poisson distribution. Results Estimated annual number of inpatients with encephalitis, meningitis, or myelitis in Japan. The estimated annual numberof inpatients with encephalitis, meningitis, or myelitis in Japan is listed in Table 2. The rate of patient transfer from one hospital to another (transfer rate) was 5.9% for encephalitis, 0.68% for meningitis, and 2.8% for myelitis based on the data from the second survey. Following revision of the annual prevalence of inpatients with these diseases according to these transfer rates, the annual number of inpatients (annual numbers of inpatients per 106 population) was estimated to be 2,200±400 ( ) for encephalitis, 32,000±1 6,000 (258±1 29) for meningitis, and 650±50 (5.2±0.4) for myelitis. The estimated annual number of inpatients for each etiological diagnosis is listed in Table 3. An unknown etiology was the most commoncause of these diseases, accounting for 51.2% of encephalitis, 73.2% of meningitis, and 36.3% of myelitis, followed by viral infection in all three diseases. The estimated annual number of inpatients with each etiological diagnosis among the viral neurological infections is listed in Table 4. The estimated annual number of inpatients with each etiological diagnosis among other pathogen-identified neurological infections is listed in Table 5. Analysis of encephalitis, meningitis, and myelitis of different e tio logies. Herpes simplex virus encephalitis (HSVE) The estimated annual number of inpatients with HSVEwas 290 in 1989, 484 in 1990, and 525 in There were no 895

3 Kamei and Takasu Table 2. Estimated Annual Numberof Inpatients with Neurological Infections in Japan (meantstandard deviation) significant regional differences in the estimated numberper 106 population for the three years. Amonga total of 157 patients with HSVE,registered in the second questionnaire, 29 patients (18.5%) were in departments of internal medicine, 102 patients (65.0%) were in departments of neurology, and 26 patients (16.5%) were in departments of pediatrics. Thus, the estimated annual number of pediatric patients with HSVEin Japan was 76±20 in 1989 to Japanese B encephalitis The estimated annual number of inpatients with Japanese B encephalitis was 20±15 and that per 106 population was 0.16 ± 0.12 in the study period. This represented 0.9% of all encephalitis and 3.0% of encephalitis with a pathogen identified. All patients with this formof encephalitis were registered in regions to the west and south of the central area of Japan (Kanto district). In fact, 57%of the patients were registered in the most southerly districts (Kyushu and Okinawa). Other types of identified viral encephalitis (other than HSV and Japanese B encephalitis) The estimated numberof inpatients with other types of identified viral encephalitis during the three-year period was for varicella-zoster virus, 49±26 for rubella virus, 46±26 for measles virus, 28±21 for influenza virus, and 20±21 for mumps. The total estimated annual number of inpatients with identified viral encephalitis did not vary significantly over the three years. The estimated annual number of inpatients with encephalitis caused by each of the viruses in the total population showed no significant differences over the three years. However, there was a significant difference in the annual numbers of inpatients with each type of viral encephalitis among all patients with viral encephalitis (Fig. 1). Viral (pathogen identified) meningitis The estimated annual number of inpatients with viral meningitis was 7,788 in 1989, 5,199 in 1990, and4,706 in The differences in these annual estimates relative to the total population were significant (Fig. 2). The relative ratios for each virus are shown in Table 4. Enteroviruses including mumps, echo, and Coxsackie viruses, were most frequently detected during the study period. However, the annual estimated values for these three types of viral meningitis varied from year to year (Fig. 2). There was a marked difference in the annual es- 896

4 Inpatients with Neurological Infections Table 3. Estimated Annual Etiologies for Inpatients with Neurological Infections in Japan (meanistandard deviation) timated values for inpatients with viral meningitis and in the frequency of each pathogenic virus. The regional distribution in the year when inpatients with the above-mentioned diseases were the most frequent, is illustrated in Fig. 3. In these types of viral meningitis, regional differences were clearly evident. Other types ofpathogen-identified meningitis The average estimated annual numberof inpatients with other types of pathogen-identified meningitis was and that per 106 population was 6.6±2.9 in the study period. This represented 2.6% of all patients of meningitis. Among them, post-vaccinal meningitis was the most frequent. The average estimated annual number of patients with this form of meningitis was 286±105. The responsible agent for this form of meningitis was MMRvaccine (mixed vaccine for mumps, measles, and rubella) in every patient. The annual numberof inpatients with post-mmr vaccinal meningitis was 300 in 1989, 384 in 1990, and 175 in There were no significant regional differences. Viral (pathogenic virus-identified) myelitis (including virusassociated myelopathy) The estimated annual number of inpatients with viral my- Internal Medicine Vol. 39, No. ll (November 2000) elitis (including virus- associated myelopathy) was 232 ±10, and that per 106 population was 1.9±0.08 in the study period. The proportion in all myelitis was 35.7%. Amongthe causes of viral myelitis, HTLV-I associated myelopathy (HAM) was the most frequent. The estimated annual number of inpatients with HAMwas 218±14 and that per 106 population was 1.8±0.1 during the survey period. Discussion The annual number of inpatients at large hospitals in Japan is considered to indicate the minimumannual prevalence of reliably-diagnosed diseases, excluding outpatients and inpatients at small hospitals. Within the Japanese medical system, most patients with encephalitis and myelitis are admitted or transferred to a large hospital for examination and treatment. Whenthese patients suffer severe sequelae after treatment in large hospitals, most of them are transferred to a small hospital for further care. The annual numberof inpatients with encephalitis and myelitis in the present survey may thus be very similar to the actual annual prevalence of encephalitis and myelitis in Japan. On the other hand, most patients with meningitis, especially viral meningitis, are thought to be treated in small 897

5 Kamei and Takasu Table 4. Estimated Annual Numberof Inpatients with Viral Neurological Infections in Japan (mean±standard deviation) Secondarysurvey _. _ 1#. c^ i à" i Ratioofpediatnc _. _. Etiological. F Patientsper106_...._..,. à" a. i u c.-. ^ u - patientstototal.. Relativeratio(%) diagnosis Actual _number Estimated number in n. /rri^ population inn a a Aii * of patients(%) in 377 departments 4,477 departments Viral encephalitis 82±21 678± ± (100)% herpes simplex virus 52±18 433± ± (63.9) varicella-zoster virus 7±3 54± (8.0) rubell virus 6±4 49± ± (7.2) measles virus 6±4 46± (6.8) influenza virus 3±3 28± (4.1) mumpus virus (3.0) Japanese B virus (3.0) other viruses (3.0) not described (0.1) Viral meningitis ,89811, (100)% mumps virus ,50013, (59.3) echo virus ,55811, (26.4) Coxsackies virus (3.6) varicella-zoster virus (1.5) entero 71 virus (1.1) herpes simplex virus (1. 1) other viruses (0.5) not described (6.1) Viral myelitis (100)% HTLV-I associated (94.0) myelophathy varicella-zoster virus (3.0) herpes simplex virus (3.0) r Table 5. Estimated Annual Etiologies for Inpatients with Other Neurologival Infections in Japan (meantstandard deviation) Secondarysurvey _. n.. Ratio ofpediatnc Pati r 1Q6 Etiological diagnosis Actual onumberin ^j Estimated aanna number in Pfents of t0 ^ patients(%) lation Relativeratio(%) 377 departments 4,477 departments F F Other encephalitis 12±4 98± ± (100)% acute cerebellitis 5±1 39± (39.8) Mycoplasma 3±1 24± ± (24.5) Parasite 1±1 7± ± (7.1) Other meningitis 86±9 821± ± (100)% post-vaccinal meningitis 30±2 286± ± (34.8) post infectious meningitis ± (33.1) Mycoplasma 5±3 42± ± (5.1) Other myelitis ± (100)% acute disseminated encephalomyelitis (spinal form) 24± ± (84.8) 898

6 Inpatients with Neurological Infections «rer «6 patients patients patients 250 -i å Annual 7^788 5^199 4)706 number of a A A inpatients f"* * *' à"* ^ *:p<0.01 I >jc I 8,000 -i -i loo- ^T t 7 (81),.,(34)I I (t q\ Measles / ::::::::::::S 5:$:$:-:$:$: 50- a8) (si) / wmmm - :$: Rubella ::::::j:: N.../ l$$i i Ji8K$ (Estimated annual number of inpatients) Figure 1. Estimated number of inpatients with types of identified viral encephalitis other than herpes simplex and Japanese B viruses in Japan during The total estimated annual number of inpatients with this form of viral encephalitis in the total population was not significantly different among the three years. The estimated annual number of inpatients with each of the viruses in the total population showed no significant differences among the three years (test for proportion with a Poisson distribution; p<0.05). However, there significant differences in the annual numberof inpatients with each viral encephalitis amongthe total number of inpatients with viral encephalitis over the three years (%2 test; p<0.05): rubella virus, 1989, 1990<1991; measles virus, 1989<1990, 1991; varicella-zoster virus, 1989>1990, 1991; influenza virus, 1989<1991; and mumps virus, 1989>1990, hospitals. For this reason, the numberof patients with meningitis in our survey could be underestimated. However, the annual number of patients with meningitis diagnosed from serial and extensive examination for pathogens could clearly indicate the relative ratio of each etiology of meningitis in Japan during the given period. Most previous epidemiological data concerning neurological infections in Japan have been based on nationwide one-day surveys that are carried out by the Japanese governmentevery five years. The reported estimates for meningitis and encephalitis (including myelitis according to the ICD classification) were 3,300-4,200 and 1,816, respectively (1, 2). The main reason for the difference in the estimated values for meningitis and encephalitis (including myelitis) between our survey and the one-day surveys is considered to be the difference in duration, i.e. the annual numbers of inpatients in our survey versus point prevalence in the one-day Figure 2. Estimated number of inpatients with identified viral meningitis in Japan during The differences in the annual estimated number of inpatients with each type of viral meningitis among the total population over the three years were significant (test for proportion with a Poisson distribution; p<0.05). Mumpsvirus and echo virus showed significant differences in each year, while Cocksackie virus showed 1990>1991. surveys. The one-day surveys provide useful information concerning the general and approximate point prevalence. However, the one-day surveys have certain problems including underestimation of acute benign illness, difficulty in evaluating rare illnesses, and incomplete reliability of the clinical diagnosis of neurological infections. Moreover, the one-day surveys are based on the ICD classification, and there are some differences in the classification of these diseases compared with their clinical classification. A previous report on the annual incidence of neurological diseases in the USA(3), gave annual incidences of meningitis and encephalitis of 150 and 150 per 106 population. It is considered surprising that the annual incidence of meningitis was equal to that of encephalitis. These rates were obtained from the previously reported data from the US Department of Health, Education, and Welfare (4). This survey thus not only covered neurological infections but also all kinds of illnesses according to the ICDclassification. The values were estimated by extrapolation from actual numbers of inpatients in 423 collected short-stay hospitals with six beds or more in This number of hospitals represented 0.02% of the total number of hospitals in USAat that time. Moreover, the hospitals with 200 beds or more in these 423 hospitals was 52%. These estimated values represent useful information concerning the general and 899

7 Kamei and Takasu Figure 3. Regional distribution of the annual estimated number of inpatients per 106 population in the epidemic years for mumps, Cocksackie, and echo meningitis. Regional differences in the estimated inpatient number per 106 population were evident for the three types of meningitis (test for proportion with a Poisson distribution; p<0.05): mumpsmeningitis in 1989, Chubu-Hokuriku, Kinki-Chugoku, Shikoku, Kyushu, Hokkaido>Tohoku, Kanto; Cocksackie meningitis in 1990, Kinki- Chugoku>Shikoku, Hokkaido; echo meningitis in 1991, Kinki-Chugoku, Chubu-Hokuriku, Kanto, Tohoku, Hokkaido>Shikoku, Kyushu. approximate annual incidence. As the diagnosis of neurological infections requires serial and extensive examinations of their pathogens, these estimated values may be involve the same problems as the nationwide one-day surveys in Japan. The previously reported annual incidence with HSVEin the USA was 2.0 to 4.0 per 106 population (5), while it was 2.3 per 106 population in Sweden (6) and 1.0 per 106 population in England (7). Our value for the estimated annual number of inpatients with HSVEin Japan over that period was very similar to the previously reported values given from other countries. In conclusion, weestimated the annual numberof inpatients with reliably-diagnosed viral and other neurological infections and their etiologies for the first time in Japan. Acknowledgements:Part of this study was performed under the auspices of the Research Group for Frequency, Risk Factors and Prevention of Mental, Nervous and Muscular Diseases (Chairman: Professor Kiyotaro Kondo, Department of Public Health, Hokkaido University School of Medicine, Japan) and was supported by a Grant for Nervous and Mental Disorders, No. 3A-3, from the National Center of Neurology and Psychiatry, the Ministry of Health and Welfare, Japan. References 1) Someya M, Isogai K, Onoda S, Fukushima Y. Estimated total number of patients in Japan based on the nationwide one-day survey in J Health Welfare Statistics 39 (5): 3-8, 1992 (in Japanese). 2) Sugaya Y, Isogai K, Ketsuya K, Kawaguchi T. Estimation of total number of patients in Japan at the surveyed day. J Health Welfare Statistics 37 (2): 7-1 1, 1990 (in Japanese). 3) Kurtzke JF. The current neurologic burden of illness and injury in the United States. Neurology 32: , ) Haupt BJ. Detailed diagnoses and surgical procedures for patients discharged from short-stay hospitals: United States Hyattsville, Maryland. US Department of Health, Education, and Welfare, Public Health Service (DHEWpublication no. [PHS] ): 1-164, ) Whitley RJ. Herpes simplex virus infections of the central nervous system. Areview. AmJ Med 85 (suppl 2A): 61-67, ) Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis: randomised multicentre study in consecutive Swedish patients. Lancet II: , ) Gulliford MC, Chandrasekera CP, Cooper RA, Murphy RP. Acyclovir treatment of herpes simplex encephalitis: experience in a district hospital. Postgrad Med J 63: ,