Six female patients with encephalitis, mean age 36.5 (17–60) years, were admitted to
the hospital during the 2000–2001 influenza A (H1N1) epidemic in the Osijek – Baranja
County. In three (50.0%) patients, the manifestation of encephalitis occurred on day 4 or
5, and in two (33.3%) patients within 24–48 hours of the onset of influenza symptoms.
The disease manifestations included headache, elevated body temperature, generalized
fatigue, and consciousness disturbance through coma. Three (50.0%) patients had
grand mal seizures. Pathologic electroencephalography findings were recorded in all six
(100%) patients, whereas computed tomography showed cerebral edema in three
(50.0%) patients. Elevated levels of hepatic enzymes and peripheral blood leukopenia
were found in two (33.3%) patients in whom encephalitis developed early upon the onset
of influenza. One (16.6%) of these patients died, whereas permanent sequels remained
in the other two (33.3%) patients

Dubravka Lišnjić

Ivan Soldo

Jasna Timarac

Ljiljana Perić

Mario Duvnjak

Ružica Palić

Silva Soldo-Butković

Željko Vranješ

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Coll. Antropol. 27 Suppl. 1 (2003) 19–22UDC 616.831-002:616.921.5Original scientific paperEncephalitis or EncephalopathyDuring an Influenza-A EpidemicIvan Soldo1, Mario Duvnjak1, Dubravka Li{nji}1, Jasna Timarac2,Ljiljana Peri}1, Ru`ica Pali}3, @eljko Vranje{4 and Silva Soldo-Butkovi}31 Department of Infectious Diseases, University Hospital »Osijek«, Osijek, Croatia2 School of Medicine, University »J. J. Strossmayer«, Osijek, Croatia3 University Department of Neurology, University Hospital »Osijek«, Osijek, Croatia4 ENT Department, University Hospital »Osijek«, Osijek, CroatiaA B S T R A C TSix female patients with encephalitis, mean age 36.5 (17–60) years, were admitted tothe hospital during the 2000–2001 influenza A (H1N1) epidemic in the Osijek – BaranjaCounty. In three (50.0%) patients, the manifestation of encephalitis occurred on day 4 or5, and in two (33.3%) patients within 24–48 hours of the onset of influenza symptoms.The disease manifestations included headache, elevated body temperature, generalizedfatigue, and consciousness disturbance through coma. Three (50.0%) patients hadgrand mal seizures. Pathologic electroencephalography findings were recorded in all six(100%) patients, whereas computed tomography showed cerebral edema in three(50.0%) patients. Elevated levels of hepatic enzymes and peripheral blood leukopeniawere found in two (33.3%) patients in whom encephalitis developed early upon the onsetof influenza. One (16.6%) of these patients died, whereas permanent sequels remainedin the other two (33.3%) patients.Key words: cerebral edema, influenza A, epilepsy, coma, encephalitis, encephalo-pathy.IntroductionInfluenza A epidemics have almost re-gularly been accompanied by reports ofcentral nervous system (CNS) impair-ments associated with influenza A1,2.CNS impairments usually occur in smallchildren under the age of 5–6 years, how-ever, they may also develop in adults.Encephalitis, encephalopathy and acutenecrotizing encephalopathy have been re-lated to the influenza virus invasion6,7.The interest in thorough research intothe CNS effects of influenza A virus has19Received for publication January 23, 2003been stimulated by recent reports fromJapan on the ever increasing rate of en-cephalitis or encephalopathy in pediatricpatients during the epidemics of influ-enza8. The CNS disease generally devel-oped within 12–48 hours of the onset ofinfluenza symptoms, and was accompa-nied by high body temperature, seizures,coma, and high mortality or permanentsequels in the survivors8,9. The patientshad elevated levels of serum creatine phos-phokinase (CPK), tumor necrosis factoralfa (TNF-) and interleukin (IL-6) inblood and cerebrospinal fluid (CSF), ab-normal hepatic enzyme findings, and CSFpleocytosis9,10.Brain radiological studies showed le-sions of the thalamus, brain stem andcerebellum bilaterally10,11. The influenzavirus (H3) genome was demonstrated inthe CSF of some patients with encephali-tis or encephalopathy10–12.The pathophysiology and pathogene-sis of encephalitis and encephalopathyassociated with influenza A virus has notyet been fully elucidated, however, thisinfluenza A complication obviously showsa rising tendency11,12. Some 150 to 200cases of encephalitis or encephalopathyper influenza epidemic are expected inJapan alone12.Methods and ResultsDuring the influenza A (H1N1) epi-demic in the Osijek, Baranja County,from the end of December 2000 till March2001, six female patients with encephali-tis were treated at the University Hospi-tal »Osijek«. The patients had neither re-ceived influenza A and B vaccination norsuffered from any neurological disorder.The clinical picture and epidemiologicaldata pointed to influenza, whereas en-cephalitis of another etiology (Leptospira,tick-borne meningoencephalitis, cytome-galovirus, herpes simplex virus 1 and 2,and enteroviruses) were ruled out in allsix patients. At least fourfold increase inthe influenza A virus antibody titer wasrecorded in paired sera of all these pa-tients.The patients were aged 17–60, meanage 36.5 years. In two (33.3%) patients,the symptoms of encephalitis manifestedwithin the first 48 hours, and in three(50.0%) patients on day 4 or 5 of the onsetof influenza. In one (16.6%) patient, en-cephalitis manifested on day 11 of initialinfluenza symptoms. A very severe mani-festation of encephalitis was recorded inthe patients in whom it developed earlyin the course of the underlying disease,i.e. influenza A. In two patients, the ini-tial abrupt manifestation of encephalitisincluded grand mal seizures and deepcoma. They both had marked leukopenia(L 1.8  109 and 1.9  109) without gra-nulocytopenia. One (16.6%) of these twopatients died, whereas two (33.3%) pa-tients sustained permanent sequels.20I. Soldo et al.: Encephalitis During Influenza-A, Coll. Antropol. 27 Suppl. 1 (2003) 19–22TABLE 1CLINICAL AND LABORATORY FINDINGSOF ENCEPHALITIS DURING INFLUENZA AEPIDEMIC IN OSIJEK 2000–2001Clinical and laboratoryfindingsNo. ofcases %Elevated body temperatureEpilepsyConsciousness disturbancesHeadacheVertigoCoughFatigueEEG abnormalityCT abnormalityALT/AST elevationLeukopeniaCSF pleocytosis6/63/64/66/65/65/66/66/63/62/62/64/6100.050.066.6100.083.383.3100.0100.050.033.333.366.6EEG = electroencephalogram; CT = computedtomography; ALT = alanine aminotransferase;AST = aspartate aminotransferase; CSF = ce-rebrospinal fluidThree (50.0%) patients were dischargedfrom the hospital as fully recovered. Allour patients (100%) had elevated bodytemperature (> 40 °C) (Table 1), and hadpreviously suffered headache and gener-alized fatigue. Vertigo and cough werepresent in five (83.3%), and conscious-ness disturbances up to deep coma in four(66.6%) patients. Electroencephalogram(EEG) was normal in all (100%) patients.Computed tomography (CT) of the brainrevealed severe cerebral edema and nor-mal finding in three (50.0%) patients each.Elevated serum levels of aspartate ami-notransferase (AST) and alanine amino-transferase (ALT) were recorded in two(33.3%), and CSF pleocytosis in four (66.6%)patients.DiscussionInfluenza viruses are obviously associ-ated with encephalitis, encephalopathyand acute necrotizing encephalopathy13.These severe complications of influenzamostly occur in small children under theage of 5–6 years, but are by no meansrare in adults either13,14. These CNS le-sions have frequently been reported dur-ing influenza A epidemics caused byH1N1 and H3N2 virus strains. The neu-rotropic properties of these viruses, in-cluding H5N1, have also been demon-strated experimentally15–17. In all ourpatients encephalitis developed duringthe influenza A (H1N1) epidemic, as veri-fied by clinical, epidemiological and sero-logic studies.In five patients, the symptoms of en-cephalitis occurred during the course ofinfluenza, whereas one patient probablydeveloped postinfectious encephalitis. In-terestingly enough, these were middle-aged women. This might be due to thehigher rate of influenza A and B vaccina-tion among men, because of more fre-quent travel and for occupational spe-cificities.Two of our patients with the onset ofencephalitis within 24–48 hours of influ-enza symptoms had elevated serum ASTand ALT levels, and marked peripheralblood leukopenia. There was no coagula-tion impairment, which is otherwise seenin small children with Reye's syndromethat has also been causally related withinfluenza virus. One of these patientsdied, whereas the others suffered perma-nent sequels. Three patients had severebrain edema, which has been associatedwith cytokines (TNF- and IL-6) thatlead to blood-brain barrier permeability,however, the contribution of local factorsshould also be taken in consideration17.The mechanism by which the influ-enza A virus penetrates the brain andcauses encephalopathy and encephalitishas not yet been completely clarified. Theinfluenza A virus is replicated in the na-sopharyngeal epithelium. The virus takesinvasive action to destroy the upper re-spiratory tract epithelium. Olfactory mu-cosa and its nerve endings are affectedwith the inflammation. The influenza Avirus probably reaches the brain via theolfactory nervous system18. The virus in-teraction with glial cells results in the re-lease of cytokines, especially TNF-.TNF- causes brain cell lesions by the in-hibition of intracellular mitochondrialrespiration18,19.Penetration of the influenza A virusinto the brain by this route appears quiteprobable, because it obviously does notoccur by the hematogenous route18–20. Itis of utmost importance to distinguishwhether these are manifestations of dif-ferent diseases or pathophysiological se-quels of the same disease entity.ConclusionIn the patients presented, the courseof disease, clinical picture analysis, labo-ratory findings and radiological study re-sults pointed to encephalitis or encepha-21I. Soldo et al.: Encephalitis During Influenza-A, Coll. Antropol. 27 Suppl. 1 (2003) 19–22lopathy caused by influenza A virus. Theexact pathogenetic mechanism of the as-sociation between influenza virus and ce-rebral manifestations remains an openquestion, however, it should be admittedthat a seemingly plain influenza couldcause severe, permanent and even life-threatening sequels. Therefore, caution iswarranted on approaching a patient withinfluenza A and B. Timely prevention ofthis seemingly simple but actually severeinfection is of utmost importance. Resultsof the study pointed to the need of addi-tional investigation aimed at a more dis-tinct differentiation of biologically recog-nizable and objective features of the di-sease.22I. Soldo et al.: Encephalitis During Influenza-A, Coll. Antropol. 27 Suppl. 1 (2003) 19–22R E F E R E N C E S1. DUBOWITZ, V., Lancet, 1 (1958) 140. — 2.HORNER, F. A., N. Engl. J. Med., 258 (1958) 983. —3. VASHCHENKO, M. A., L. V. MURAVSKAIA, L. F.KARASOSKAIA, V. G. MAKSIMETS, L. E. MOI-SEENKO, Varchebnoe Delo, 6 (1978) 132. — 4.SCHATER, M., Praxis, 58(2) (1969) 42. — 5. HER-TEL, G., Enceph. Clin. Neurops., 30 (1971) 271. — 6.YOSHIKAWA, H., S. YAMAZAKI, T. WATANABE, T.ABE, J. Child. Neurol., 16 (2001) 885. — 7.YOSHIKAWA, H., T. WATANABE, T. ABE, Y. ODA, J.Child. Neurol., 14 (1999) 249. — 8. FUJIMOTO, Y.,M. SHIBATA, M. TSUYUKI, M. OKADA, K. TSUZU-KI, Eur. J. Pediatr., 159 (2000) 319. — 9. PROTHE-ROE, S. M., D. H. MELLOR, Arch. Dis. Child., 66(1991) 702. — 10. AIBA, H., M. MOCHIZUKI, M. KI-MURA, H. HOJO, Neurology, 57 (2001) 295. — 11.SHINJOH, M., M. BAMBA, K. JOZAKI, E. TAKA-HASH, G. KOINUMA, N. SUGAYA, Clin. Infect. Dis.,31 (2000) 611. — 12. SUGAYA, N., Semin. Pediatr. In-fect. Dis., 13 (2002) 79. — 13. WEST, S. D., NJ.BRUNSKILL, Postgrad. Med. J., 78 (2002) 107. — 14.IIJIMA, H., K. WAKASUGI, M. AYABE, H. SHOJI, T.ABE, J. Neuroimaging, 12 (2002) 273. — 15. WARD,A. C., J. Neurovirol., 2 (1996) 139. — 16. REINA-CHER, M., J. BONIN, O. NARAYIN, C. SCHOLTIS-SEK, Lab. Invest., 49 (1983) 686. — 17. PARK, C. H.,M. ISHINAKA, A. TAKADA, H. KIDA, T. KIMURA,K. OCHIAI, T. UMEMURA, Arch. Virol., 147 (2002)1425. — 18. OZAWA, T., Y. NAKASHIMA, R. ITO, A.HIRANO, T. KONDO, Brain. Dev., 33 (2001) 63. —19. TOGASHI, T., Y. MATSUZONO, M. NARITA,Ped. Internat., 42 (2000) 192. — 20. ANI] K., I. SOL-DO, LJ. PERI], I. KARNER, B. BARAC, Scand. J. In-fect. Dis., 30 (1998) 509.I. SoldoDepartment of Infectious Diseases, University Hospital »Osijek«, J. Huttlera 4,31000 Osijek, CroatiaENCEFALITIS ILI ENCEFALOPATIJA TIJEKOM EPIDEMIJEINFLUENCE-AS A @ E T A KTijekom epidemije influence A (H1N1) u Osje~ko-baranjskoj `upaniji od 2000. do2001. godine lije~eno je 6 bolesnica s encefalitisom. Najmla|a bolesnica imala je 17, anajstarija 60 godina. Srednja `ivotna dob je 36.5 godina. Tri (50%) su bolesnice dobileencefalitis 4-tog i 5-tog dana od pojave simptoma influence, a dvije (33.3%) tijekom prvih24–48 sati od po~etka bolesti. Bolest se o~itovala glavoboljom, visokom temperaturom,op}om slabo{}u i poreme}ajem svijesti do kome. Tri (50%) su bolesnice imale epi napadtipa grand mal. U svih je bolesnica (100%) na|en patolo{ki EEG, u tri (50%) je na CT-una|en ja~i edem mozga. U dvije (33.3%) bolesnice u kojih se encefalitis javio prvih danainfluence na|ene su povi{ene vrijednosti jetrenih enzima i leukopenija u perifernojkrvi. Jedna (16.6%) je bolesnica umrla, a u dvije (33.3%) ostale su trajne sekvele.

Encephalitis or Encephalopathy During an Influenza-A Epidemic

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