udative pharyngitis andenlargement of the liver (it was ... are present early in the course of herpes encephalitis may ... by herpes simplex virus. This therapy.
Encephalitis during the prodromal stage of acute hepatitis A GREGORY W. HAMMOND, MD, FRCP[C] BRENDAN K. MACDOUGALL, MD, FRCP[C] FRANK PLUMMER, MD, FRCP[C] LAILA H. SEKLA, MD, PH D gave negative results for salicylate, alcoBecause the patient's encephalitis was hol and barbiturate in the serum and for observed to occur during the prodromal phenothiazine, imipramine hydrochlo- stage of acute hepatitis, a variety of tests ride and ethchlorvynol in the urine. A were performed to determine the cause lumbar puncture and computer-assisted of the hepatitis and to evaluate possible
Neurologic problems as prodromes of acute hepatitis A have been documented infrequently in the literature. The following report describes the occurrence of encephalitis in the late prodromal stage of an infection caused by hepatitis axial tomography were performed with A virus. the patient sedated. Tests of the cerebrospinal fluid showed the following levels: erythrocytes 1 I X 106/1, leukocytes 13 X Case report 106/1 (100% neutrophils), protein 0.48 g/l and glucose 3.3 mmol/1 (60 mg/dl). A 34-year-old man was admitted to blood glucose level was 6.33 mmol/l the emergency department of a general The (1 15 mg/dl). Gram-staining of the cerehospital following an incident in which brospinal revealed no microorganhe lost control of his car without suffer- isms, and fluid bacteria and acid-fast bacilli ing personal injury. His symptoms just could not be cultured. tomographic before this incident included fever, mild findings were reportedThe to be normal. upper abdominal discomfort, a steady However, because the abnormalities that headache in both temples and diffuse are present early in the course of herpes myalgia. Two days before his admission encephalitis may cause very subtle to hospital his appetite had decreased changes, as detected by computer-assistand his wife had noted a mild behaviour- ed tomography,' we elected to initiate al change. He became progressively treatment with adenine (15 more confused, delirious and agitated, mg/kg) for encephalitis arabinoside possibly caused and had just left work early on sick by simplex virus. This therapy leave when the incident that led to his was herpes to be re-evaluated in relation to the admission to hospital occurred. results of a radionuclear brain flow scan When admitted his temperature was and brain biopsy that were scheduled for 39°C and he was disoriented, combative the following day. and very restless. A general physical The morning after the patient entered examination revealed only a few small hospital his mental status showed posterior cervical lymph nodes, nonex- marked improvement: he was drowsy udative pharyngitis and enlargement of but oriented and cooperative. An electhe liver (it was palpable 2 cm below the troencephalogram showed periods of right costal margin and spanned 14 cm). high-amplitude and- slow-wave activity His fundi were normal and there was no consistent with a widespread subcortical neck stiffness or focal neurologic signs. Liver function tests showed a Initial tests of the blood showed a disorder. bilirubin level of 65.0 gmol/l (3.8 hemoglobin concentration of 2.17 mg/dl), a glutamic transamimmol/l (14 g/dl), a leukocyte count of 8 nase level of 1760 oxaloacetic and IU/I an alkaline X 1 09/l (41% mature neutrophils, 4% level phosphatase of 125 U/l the band cells, 28% atypical lymphocytes, serum, and a prothrombin time ofin 16.8 21% normal lymphocytes and 6% mono- seconds (control time 11.6 s). Other cytes) and a platelet count of 161 X biochemical abnormalities detected from 109/l. Biochemical analysis of the serum analysis of serum obtained in the first 3 gave the following concentrations: sodi- days the hospital stay included a um 137 mmol/l, potassium 3.3 mmol/l, lactateofdehydrogenase of 1300 U/l, urea 2.86 mmol/l (urea nitrogen 8 a creatinine level of level 168 gmol/l (1.9 mg/dl) and thyroxine 127.4 mmol/l (9.8 mg/dl) and a creatine kinase level of jsg/dl). Drug screening tests performed 2930 U/I. at the time the patient was admitted The adenine arabinoside infusion was and further neurologic invesstopped From the departments of medical microbiology and tigations were cancelled. The patient's medicine, University of Manitoba, and the Cadham temperature and mental status, and the Provincial Health Laboratory, Winnipeg results of repeated liver function tests Reprint requests to: Dr. Gregory W. Hammond, returned to normal within the next 14 Department of medical microbiology, University of Manitoba, Winnipeg, Man. R3E OW3
days.
concomitant causes of acute illness. However, cultures of throat swabs, urine and cerebrospinal fluid were negative for viruses, and extensive serologic tests* performed on blood specimens collected on the day of admission and 14 days later revealed that the only acute infection was hepatitis A, as established by a radioimmunoassay for IgM antibody specific to this virus. In the acute stage of the illness there were high serum titres of antibody to both the capsid antigen (1:320) and the nuclear antigen (> 1:80) of EBV. Discussion
Up to 70% of reported cases of encephalitis have no defined cause.2 In our patient the cause was not suspected until jaundice and abnormal findings from liver function tests were noted. The diagnosis was later confirmed by the detection in the serum of IgM antibody specific to hepatitis A virus. Other causes of encephalitis could not be found despite extensive serologic testing and cultures of throat swabs, urine and cerebrospinal fluid for other viruses. High static titres of IgG antibody to the capsid antigen of EBV may occur in 5% to 10% of healthy individuals, but the finding in our patient of such a titre along with antibody to EBV nuclear antigen early in the acute stage of his illness is consistent with previous EBV infection (W. Henle: personal communication, 1981). * For
antibodies to Mycoplasma pneumoniae and Toxoplasma gondii; hepatitis A, respiratory syncytial, influenza A, A/Brazil/I 1/78, A/Texas/l/77 and B, parainfluenza 1, 2 and 3, mumps, herpes simplex, western equine, St. Louis and California encephalitis, lymphocytic choriomeningitis and coxsackie B3 viruses; adenovirus; cytomegalovirus; echovirus 11; the capsid and nuclear antigens of Epstein-Barr virus (EBV); the heterophil antibody of infectious mononucleosis; and hepatitis B surface antigen and antibody.
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Encephalitis during the prodrome of hepatitis A virus infection has previously been reported.34 A review of the neurologic signs and symptoms in reported cases presumed to be caused by hepatitis A revealed that eight patients had neurologic manifestations of encephalitis immediately before the onset of clinical features of hepatitis.3 The average time between the onset of neurologic signs and the appearance of jaundice was 6 days. Other patients have showp involvement of the meninges, the spinal cord or peripheral nerves as a prodrome of hepatitis A.3'4 Two other reports documented single cases of encephalitis and of status epilepticus in association with a clinical diagnosis of viral hepatitis; in both cases serologic tests for hepatitis B antigen with the laboratory methods available at that time gave negative results.5" A 13-year-old patient was reported to have had symptoms of encephalitis with suspected basal ganglia involvement before the onset of suspected viral hepatitis of undetermined cause.7 Support for the possible systemic involvement of hepatitis A comes from observations that hepatitis A virus may be disseminated via the blood for up to 3 weeks before the onset of jaundice.This virus, like an enterovirus, is believed to contain ribonucleic acid,9 although studies with marmosets did not demonstrate an intestinal phase preceding the liver involvement in hepatitis A virus infections.0 The patient we have described experienced well recognized prodromal symptoms of hepatitis A, including fever, malaise, headache, myalgia and pharyngitis."" Knowledge of the full spectrum of symptoms and signs that hepatitis A virus can cause is being expanded through the use of sensitive serodiagnostic tests.'2 One study has shown that in 7 (29%) of 24 instances of family contact with acute hepatitis A an illness without jaundice resulted; two other patients (8%) showed seroconversion without being ill.'3 Serologic tests can detect specific 1gM antibody in serum obtained early in the course of hepatitis A."'7 Early diagnosis may assist those concerned with both patient and public health management. The diagnosis that acute hepatitis A is the cause of a patient's neurologic problems would be of value because the generally benign course of this disease would obviate the need for extensive or invasive diagnostic procedures and chemotherapy. Prophylactic therapy with immune serum globulin could be offered to those who had had contact with patients with confirmed hepatitis A. To our knowledge this is the first case of encephalitis as a prodrome of hepatitis A in which there has been labora270
tory documentation of an 1gM response to hepatitis A virus. With the increasing availability of this sensitive serologic test it may be useful to evaluate the role of the hepatitis A virus in patients with undiagnosed encephalitis, particularly to determine whether the encephalitis is due to symptomatic nonicteric hepatitis A. We gratefully acknowledge the assistance of Dr. L. Blecka for the hepatitis A 1gM radioimmunoassay test kit (Abbott Laboratories, Limited). We thank Dr. Werner Henle for the EBV serologic test results and Dr. John C. Wilt for his review of this article.
References 1. ENZMANN DR. RANSON B, NORMAN D, TALBERTH E: Computed tomography of herpes simplex encephali. tis. Radiology 1978; 129: 419-425 2. Center for Disease Control: Encephalitis Surveillance 1977, DHEW publ no (CDC) 80.8252, Center for Disease Control, Atlanta, 1979:17 3. FRIEDLANDER wi: Neurologic signs and symptoms as prodrome to virus hepatitis. Neurology (NY) 1956; 6: 574-579 4. WEINSTEIN L, DAVIsON wT: Neurologic manifesta. tions in she pre-icteric phase of infectious hepatitis. Am Pract 1946; 1:191-195 5. BLACK IA: Hepatitis with encephalitis: dystonic reactions from various drugs. Proc R Soc Med 1973; 66: 218 6. GORTYAI P. HASAN N: Status epilepticus in infective hepatitis. Br J Clin Pract 1973; 27: 139-140 7. RAYBAUD A, BONERAND ii, MASSIANI P: Apparition dun syndrome pallidostrih avec spasmes de torsion et athAtose A l'occssion d'une hApatite virale. Marseille Med 1965; 102: 583-585 8. KRUGMAN 5, GOCKE Di: Viral Hepatitis (Major Problenss in Internal Medicine ser, vol 15), Saunders, Philadelphia, 1978: 20-29, 30-47 9. BRADLEY DW, FIELDS HA, MCCAUSTLAND KA, COOK EH, GRAVELLE CR, MAYNARD JE: Biochemical and biophysical characterization of light and heavy density hepatitis A virus particles: evidence that HAV is an RNA virus. J Med Virol 1978; 2: 175-187 10. MATHIESEN LR, M0LLER AM, PURCELL RH, LON. DON WT, FEINSTONE SM: Hepatitis A virus in the liver and inteatine of marmoseta after oral inoculation. Infect Immun 1980; 28: 45-48 II. KOFF RS: Viral Hepatitis (Clinical Gastroenserology monogr), Wiley, New York, 1978: 134-151 12. vILLAREJOS vM, GUTIERREZ-DIERMISSEN A, AND. ERSON.vISONA K, RODRIGUEZ-ARAOONES A, AOYOST P3, HILL.MAN MR: Development of immunity against hepatitis A virus by subclinical infection. Proc Soc Exp Biol Med 1976; 153: 205-208 13. FROSNER GG, OVERBY LR, FLEHMIG B, GERTH Hi, HAAS H, DECKER RH, LING CM, ZUCKERMAN Al, FROSNER HR: Seroepidemiological investigation of patienta and family contacts in an epidemic of hepatitis A. JMed Virol 1977; 1:163-173 14. BRADLEY DW, FIELDS HA, MCCAUSTLAND KA, MAYNARD JE, DECKER RH, WHrrFINGTON R, OVERBY LR: Serodiagnosis of viral hepatitis A by s modified competitive binding radioimmunoassay for immunoglobulin M anti-hepatitis A virus. J Clin Microbiol 1979; 9: 120-127 15. BRADLEY DW, MAYNARD JE, HINDMAN SH, HORN. BECK CL, FIELDS HA, MCCAUSTLAND KA, COOK EH JR: Serodiagnosis of viral hepatitis A: detection of acute-phase immunoglobulin M anti-hepatitis A virus by radioimmunoassay. J Clin Microblol 1977; 5: 521-530 16. LOCARNINI SA, FERRIS AA, LEHMANN NI, GUST ID: The antibody response following hepatitis A infection. Intervirology 1977; 8: 309-318 17. ROGGENDoRF M, FROSNER GG, DEINHARDT F, SCHEID R: Comparison of solid phase test systems for demonstrating antibodies against hepatitis A virus (antiHAY) of the 1gM-class. J Med Virol 1980; 5: 47-62
CMA JOURNAL/FEBRUARY 1, 1982/VOL. 126
BOOKS This list is an acknowledgement of books received. It does not preclude review at a later date. ABSTRACTS OF HEALTH CARE MANAGEMENT STUDIES. Vol. XVII, June 1981. An International Journal with Abstracts of Studies of Management, Planning and Public Policy Related to the Delivery of Health Care. Published annually by Health Administration Press for the Cooperative Information Center for Health Care Management Studies, The University of Michi.an, Ann Arbor, Michigan, 1981. 351 pp. 60. ISSN 0194-4908
ALPERS AND MANCALL'S ESSENTIALS OF THE NEUROLOGIC EXAMI-
NATION. 2nd ed. Elliott L. Mancall. 228 pp. lIlust. F.A. Davis Company, Publishers, Philadelphia, 1981. $10.95, paperbound. ISBN 0-8036-5805-2
ATLAS OF HUMAN HISTOLOGY. 5th ed. ,Mariano S.H. di Fiore. 267 pp. Illust. Lea & Febiger, Philadelphia, 1981. $23.50. ISBN 0-8121-0756-X BAD BLOOD. The Tuskegee Syphilis Experiment. James H. Jones. 272 pp. Illust. Macmillan Publishing Co., Inc., New York, 1981. $20. ISBN 0-02-916670-5
BREAST CANCER MANAGEMENT. The
Experience of the Combined Breast Clinic, St. Georges Hospital/The Royal Marsden Hospital. Edited by R.C. Coombes, T.J. Powles, H.T. Ford and J.-C. Gazet. 317 pp. Illust. Academic Press Inc. (London) Ltd., London, England, 1981. $43.50. ISBN 0-12-790899-4
THE COLOR ATLAS OF HUMAN ANATOMY. Edited by Vanio Vannini and Giuliano Pogliani. Translated and revised by Dr. Richard T. Jolly. 108 pp. lIlust. Crown Publishers, Inc., New York, 1981. $9.25, paperbound. ISBN 0-517-545144 COMPUTERS IN THE PRACTICE OF MEDICINE. Vol. 1. Introduction to Computing Concepts. H. Dominic Covvey and Neil Harding McAlister. 266 pp. lIlust. Addison-Wesley Publishing Company, Don Mills, Ont., 1981. Price not stated. ISBN 0-201-01251-0
COMPUTERS IN THE PRACTICE OF MEDICINE. Vol. 2. Issues in Medical Computing. H. Dominic Covvey and Neil Harding McAlister. 205 pp. lIlust. AddisonWesley Publishing Company, Don Mills, Ont., 1981. Price not stated. ISBN 0-20101249-9
CONFERENCE - APPROPRIATE CARE FOR THE ELDERLY: SOME PROBLEMS. Held on 22nd October 1980 in the Hall of The Royal College of Physicians of Edinburgh. Edited by J.M.G. Wilson. 106 pp. Illust. George Stewart & Co. Ltd., Edinburgh, 1981. Price not stated. ISBN 0-85405-037-X
.LtMENTS DE NEUROLOGIE CLINIQUE. Guy Courtois. 279 pp. lIlust. Les Presses de 'Universite de Montreal, Montreal, 1981. Price not stated. ISBN 2-7606-0486-1
ELEMENTS OF PHARMACOLOGY. A Primer on Drug Action. P.J. Bentley. 154 pp. lIlust. Cambridge University Press, New York, 1981. $27.50, hardcover. ISBN 23617-7. $9.95, paperbound. ISBN 28074-5
