Originalia U. W i n t e r g e r s t , B. H. B e l o h r a d s k y
Acyclovir Monotherapy versus Acyclovir plus Beta-Interferon in Focal Viral Encephalitis in Children Summary: Severe focal viral encephalitis is most commonly caused by herpes simplex virus (HSV), but other viruses may act as etiologic agents as well. Acyclovir (ACV) is the standard therapy for HSV encephalitis, but the mortality of 28% and defect healing rate of about 35% are still unsatisfactory. Furthermore, ACV has virtually no effect on other pathogens of viral encephalitis, except for varicella-zoster virus (VZV). It is well known that [5-interferon (~-IFN) has a broad antiviral spectrum, and it has been demonstrated in vitro that 13-IFN in combination with acyclovir has synergistic inhibitory effects on HSV. To investigate if the combination of ACV with and without 13-IFN might also be of significance for the treatment of severe viral encephalitis, we performed a retrospective study. A case record form was sent to all 278 West German
children's hospitals. The response rate was 78%. A total of 301 patients were reported, of whom 214 received specific antiviral therapy with either ACV alone (n = 179) or ACV plus [3-IFN (n = 35). No overall differences between ACV monotherapy and the combination therapy were observed. However, in a subgroup of 41 patients (ACV n = 30, ACV plus ~-IFN n = 11) who had low-density areas of the temporal lobes on cranial computed tomography scans, compatible with severe focal encephalitis, sequelae due to defect formation and mortality were significantly (p=0.014) reduced in patients who had received combination therapy. These data are the first indication that combination treatment with ACV and [3-IFN may be of advantage in patients with focal viral encephalitis and should be controlled in a prospective trial.
Zusammenfassung:Acyclovir allein oder kombiniert mit Beta-Interferon bei fokaler Virusenzephalitis. Die schwere fokale virale Enzephalitis wird meist durch Herpes-simplex-Viren verursacht, aber auch andere Viren kommen fitiologisch in Betracht. Die Standardtherapie der Herpes-simplex-Enzephalitis ist Acyclovir (ACV), wobei die Letalitgt von 28% und Defekt-Heilungsrate von 35% immer noch unbefriedigend ist. Dartiberhinaus hat Acyclovir mit Ausnahme von Varizella-zoster-Virus (VZV) keinen Effekt bei Enzephalitiden durch andere Erreger. [3-Interferon ([3-IFN) hat ein breites antivirates Spektrum und hat in vitro in der Kombination mit Acyclovir eine synergistische Wirkung gegen HSV. Wir ffihrten deshalb eine retrospektive Studie mit der Fragestellung dutch, ob die Kombination von ACV und [3-IFN in der Behandlung der viralen Enzephalitis einen therapeutischen Vorteil gegentiber der Monotherapie mit ACV erbringt. Hierzu wurde ein Fragebogen an alle 278 westdeutschen Kinderkliniken versandt. Die Rticklaufquote betrug 78%, 301
Patienten wurden mitgeteilt. 214/301 Patienten erhielten eine antivirale Therapie, wobei 179 mit ACV-Monotherapie und 35 mit der Kombinationstherapie (ACV plus [3-IFN) behandeit wurden. In der Gesamtgruppe der behandelten Patienten wurden keine Unterschiede hinsichtlich Morbidit~it und Letalitfit zwischen der Mono- und der Kombinationstherapie beobachtet. In einer Untergruppe von 41 Patienten allerdings (ACV n = 30, ACV plus [3-IFN n = l l ) , die in der cranialen Computertomographie hypodense Zonen in den Temporallappen aufwiesen (vereinbar mit fokaler Enzephalitis), war die Defekt-Heilungsrate und die Letalitfit in der Patientengruppe mit Kombinationstherapie signifikant niedriger (p = 0,014) als mit ACV-Monotherapie. Diese Beobachtung k6nnte ein erster Hinweis sein, dal3 eine Kombinationstherapie bei der fokalen viralen Enzephalitis einen therapeutischen Vorteil bringen k6nnte und sollte in einer kontrollierten prospektiven Studie geprfift werden.
Introduction Severe focal viral encephalitis is a rare but life-threatening disease with an incidence of 2 to 3/1,000,000 per year. Most frequently caused by herpes simplex virus (HSV) [1], the disease can also be caused by Arbo-, Epstein Barr-, and enteroviruses [1]. Early diagnosis and early onset of therapy are crucial for the outcome of the illness [2]. Untreated herpes-simplex encephalitis has a mortality
of 70%, with sequelae of defect formation in a further 25% [3]. In two controlled studies in adults [4, 5] and one in neonates [6], it has previously been shown that mortality Received: t0 February 1992/Revisionaccepted: 20 April 1992 Dr. U. Wintergerst, Prof. Dr. B. H. Belohradsky, UniversitfitsKinderklinik, Ludwig-Maximilians-Universit~it,Lindwurmstr. 4, W-8000 Mtinchen, Germany.
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U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis and sequelae of herpes-simplex encephalitis can be significantly r e d u c e d with acyclovir (ACV). T h e remaining mortality o f 28% and the rate o f sequelae of defect formation of about 35% in H S V encephalitis are still unsatisfactory [2]. Therefore, and because of the lack of effect o f A C V on o t h e r pathogens except varicella- zoster virus ( V Z V ) , there is a n e e d for alternative therapeutical approaches. Interferons are interesting putative therapeutic agents because of their potent i m m u n o m o d u l a t i n g and antiviral effects [7-10]. Moreover, deficient p r o d u c t i o n of e n d o g e n o u s interferon has b e e n d e m o n s t r a t e d in patients with H S V encephalitis [11, 12]. In vitro synergistic inhibitory effects of A C V in c o m b i n a t i o n with beta-interferon ([3-IFN) [13, 14] or alpha-interferon [15] on H S V have b e e n described. A n i m a l studies and clinical trials with a few patients receiving alpha-interferon [16-18] and the combination of A C V plus t3-IFN in H S V encephalitis have also shown encouraging results [19-21]. In p r e p a r a t i o n for a prospective multicenter study, we retrospectively analysed 301 patients with viral encephalitis with regard to antiviral t r e a t m e n t and outcome.
Patients and Methods
Data collection: Standardised case record forms were sent to all West German children's hospitals (n =278). Data on clinical symptoms, diagnostic tests and therapy were requested (Table 1). We were particularly interested in symptoms (e.g. fever, headache and signs of focal neurological defects, coma) and their duration prior to the administration of specific antiviral therapy, diagnostic procedures, therapeutic regimen, outcome and follow-up. All cases of viral encephalitis in children in the period from January 1983 to December 1988 were to be reported. Oiteria for the evaluation of therapy: Table 2 lists the criteria for the evaluation of the therapeutic outcome. Criteria previously used in adult studies were adapted to children [22] (e.g. down-ranking in school). Encephalitis was defined as a febrile illness with central nervous symptoms such as focal or grand mal seizures, altered consciousness, changes in personality, focal neurological signs, elevation of protein and cell count in cerebrospinal fluid and disturbances shown on the electroencephalogram (EEG). Other causes of the neurological disorder, such as bacterial infections, tumors, intoxication and metabolic disorders, had to be excluded. Low-density areas detected by cranial computed tomography (CCT) were considered indicative of inflamed or necrotic areas in the cerebrum when other reasons (e.g. infarction, tumor) were not evident [23-26]. Infarction is unlikely in the context of the sudden onset of high fever, and tumors differ in the course of the disease. Treatment schedules: Patients were treated with ACV monotherapy or with a combination of ACV and 13-IFN. The dose of ACV was 30-50 mg/kg bw/d in 70% of the patients and 15-30 mg/kg bw/d in the remaining 30% for 10.9 + 4.8 (mean + 1 SD) days. I3-IFN was administered in all patients who received combination therapy in a dose of 500,000 IU/kg bw/d for at least five days (Fiblaferon ®, Rentschler Ltd., Germany) if tolerated. All patients received additional supportive therapy depending on the severity of their disease.
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Table 1 : Data on viral encephalitis requested per questionnaire from 278 West German children's hospitals. a) General data and clinical symptoms before the beginning of therapy: age, sex, weight, year of treatment, occurrence and duration of the symptoms, fever, restlessness, personality change, speech disorders, seizures (focal or generalized) and altered states of consciousness (confusion, obtundation, stupor, coma, [38]) as well as other symptoms before the onset of antiviral therapy; b) Neurological diseases before the onset of therapy; c) Serological and virological diagnostic tests; d) Laboratory tests and physical diagnostics: CSF findings, electroencephalography, cranial computed tomography (CCT), magnetic resonance imaging (MRI); e) Treatment: duration and dose of antiviral therapy, use of beta-interferon, symptomatic therapy (artificial ventilation, therapy of raised intracerebral pressure, sedation, antiepileptic therapy, other) f) Treatment outcome (at discharge and follow-up)
Table 2: Evaluation of therapy results. 1. Cure: complete restoration of neurologic function. 2. Defect syndromes: motor or affective disorders, or disorders of concentration owing to intellectual defects, divided into: - slight defects: little impairment of motor, psychological or intellectual function, e.g. asymptomatic epilepsy under antiepileptic therapy. -moderate defects: functions in accordance with age still possible, but major motor or intellectual restrictions that hampered daily life (hemiparesis, persistent seizure disorder), transfer to a special school for disabled children or a medical pedagogic kindergarten necessary. -severe defects: need for complete nursing care, spastic quadriptegia, serious developmental delay, severe intellectual defects, no longer feasible to attend school. 3. Death: up to 15 months after the illness when attributable to the disease, e.g. aspiration pneumonia in acquired swallowing disorder.
Statistics: The case record forms were evaluated by means of frequency tables in accordance with therapy schedules (patient group with ACV monotherapy versus combination therapy, ACV + [3-IFN). Data were analysed both for the two treatment groups in total and also for the following specific subgroups: 1. patients with proven HSV infection (as based on a four-fold elevation of HSV IgG in serum or HSV IgM in serum or CSF, or autochthonous production of specific IgG in CSF. Brain biopsies were not performed) (n = 97) 2. patients with initial coma (n = 103) 3. patients with focal abnormalities shown on the EEG (n = 76) 4. patients with low-density areas in the temporal lobes demonstrated by CCT (n = 41). Considerable overlapping of the subgroups occurred. Statistical analysis was carried out using Fisher's exact test (SAS program). With respect to the retrospective nature of this study, p values must be interpreted descriptively.
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U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis 140
c--
130. 120
I I
110. 100
~
9o 80. 70. 60. 50 40 30. 20 10
l
0
no
HSV
Varicella
Measles
Rubella
Coxsackle
EBV
I Echo
CMV
pathogen
Figure 1' Suspected e t i o l o g y of 301 recorded cases of viral encephalitis.
IFN+Acyclovlr = (n=35) Acyclovlr
(n=179)
cure
sflght defect
moderate defect
severe defect
death
Figure 2: Therapeutic outcome in 214 patients with viral encephalitis in relation to treatment regimen. * p = n.s.
Results
Seventy-eight percent of the children's hospitals responded to our inquiry. Ninety-eight hospitals reported on 301 patients. One hundred eighteen hospitals did not treat any child with encephalitis during the study period. Figure 1 shows the suspected different etiologies in the reported 301 patients. The etiology of the infection was not established in 46.5% of the cases. In 33% serological or cerebrospinal findings for an acute HSV infection were demonstrated. The remaining cases were diagnosed as specified. Since brain biopsies were not performed, the true incidence of HSV encephalitis remained unclear. Two hundred fourteen of 301 patients received antiviral therapy with either ACV or ACV plus [3-IFN. Eighty-seven patients did not receive any antiviral therapy because they had a very mild course of disease, showed signs characteristic of specific etiologies (e.g. measles exanthema) and therefore were not treated with ACV, or developed the disease before 1983 (i.e. before the introduction of ACV in Germany). The data of these patients are not considered here. Figure 2 shows the clinical outcome of the remaining 214 patients. One hundred seventy-nine patients were treated
with ACV monotherapy and 35 with the combination of ACV plus [3-IFN. The average age was 4 years 9 months ( + 4 years 6 months) in the patients who received ACV monotherapy and 5 years 1 month ( + 4 years 5 months) in the group who received combination therapy. The sex ratio (male to female) was 1.2:1. The analysis of the 214 patients in total did not show any significant differences in outcome between therapy with ACV alone and therapy with ACV plus [3-IFN. In the combination treatment group, both the percentage of pretreatment coma - a poor prognostic sign - (42.8% vs. 32.9%) and the percentage of patients with acute HSV infection (54.3% vs. 40.3%) were slightly higher. In subgroups 1-3 (patients with proven HSV infection, patients with initial coma, patients with disturbances in EEG) there were also no significant differences in therapeutic outcome, with similar initial conditions in both treatment groups. In patients with proven HSV infection who received combination therapy (n=17), 23.5% were cured, 23.5% had slight defects, 17.6% had moderate defects, 29.4% had severe defects and 5.8% died, whereas in patients who received ACV monotherapy (n = 69), 24.6% were cured, 8.6% had slight defects, 20.3% had moderate defects, 33.3% had severe defects and 13% died (not significant). CCT scans were performed in 219 patients. Low-density areas in one or both temporal lobes were found in 41 (18.7%) patients. Of these, 31 had proven HSV infection, one had VZV infection and in nine patients no pathogen was identified. Interestingly, patients with low-density areas in the temporal lobes had a significantly better response (p = 0.014, response classified as healed, slight-, moderate-, severe-defect and death, absolute case numbers in 2 columns [therapy groups] x 5 lines [response], Fisher's exact test) to the combination therapy of ACV plus [3-IFN than to ACV monotherapy (Figure 3). Complete restoration of health was achieved in 27% of patients compared to 10% in the monotherapy group, mild defects occurred in 36.5% versus 16%, moderate defects in 36.5% versus 21%, no severe defects versus 43% and no deaths versus 10% in monotherapy group. 50
40
3O
[]
~,IFN+Acyclovlr x
[]
Acyclovlr
(n=11) (n=30)
1
,
I
i Cure
mild defect
l moderate defect
s e v e r e defect
death
Figure 3: Therapeutic outcome in patients with low-density in the temporal lobes (as shown by CCT) in relation to treatment regimen (n =41). * p=0.014. areas
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U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis Table 3: Comparision of prognostic factors in the two therapy groups (acyclovir [ACV] versus ACV plus f-interferon [B-IFN]) of patients with low-density areas in the temporal lobes.
Comatosepatients Duration of coma before onset of therapy Acute HSV-1 infection Acute HSV-2 infection ACV dose Duration of ACV therapy Duration of B-IFN therapy Percentage of infants < 6 months of age Percentage of infants < 4 weeks of age Further CCT findings~ Mean period of follow-up Focal abnormalities in EEG
7 (23%)
3 (27%)
0.9 d (0.5-2) 21 (70%)
1.8 d (0.5-4) 8 (73%)
2 (7%)
0
28.4 mg/kgbw/d (15-50 mg/kg/d) 9.6 d (6-13 d)
31.2 mg/kgbw/d (15-40 m~,~tt) 15.5 d (I0-32 d) 5.1d
-
(1-11)
9 (30%)
3 (27%)
4 (13%)
1 (9%)
14 (46%) 13 months (2-44 months)
5 (45%) 6.2 months (1.5-6 months)
11 (37%)
1 (11%)
"Low-densityareas in other parts of the cerebrum,generalizedcerebral edema. Both treatment groups were comparable with regard to the major prognostic criteria (Table 3). They differed neither in the percentage of comatose patients nor in the average duration and severity of the disturbance of consciousness. Moreover, the percentage of young infants (< 6 months), with a predominance of HSV-2 encephalitis (with a poorer prognosis than HSV-1 [270, was the same in the two groups. Two newborns with documented HSV-2 infection were treated with ACV monotherapy. One was cured and the other had a slight defect. In the group of four newborns (no differentiation between HSV-1 and HSV-2) who received ACV monotherapy, two slight and one severe defect occurred and one newborn died. One newborn in the combination therapy group survived with a slight defect. Mean duration of ACV therapy in the ACV monotherapy group was only 9.6 days compared to 15.5 days in the combination treatment group. This difference is mainly due to a 32-day treatment course with ACV in one patient who received combination therapy. In patients who received ACV plus [5-IFN treatment, there were no differences in therapeutic outcome regarding the ACV dose and the duration of ACV therapy. In the ACV monotherapy group, the mean ACV dose in patients who 34 / 210
died or had severe sequelae was 27 mg/kg bw/d (15-50 mg/kg bw/d) for a mean duration of 9.8 days (8-13 d) versus 29.4 mg/kg bw/d (15-40 mg/kg bw/d) and 9.4 days (6-10 d) in patients who were cured or had only mild or moderate sequelae. Ninety-three percent of severely affected patients versus 71% of mildly affected patients had acute HSV infection according to the criteria presented in the Methods section. The side effects of [3-IFN therapy were reversible in all patients and consisted of fever (62.6%), chills (22.2%), leukopenia (< 4000/ram 3, 44.4%), elevation of transaminases (ALT, AST~ 26.6%), thrombopenia (< 100,000/mm 3, 20%), prolongation of partial thromboplastin time (15.5%), anemia (6.6%), diarrhoea (4.4%), an allergic reaction in one patient and a cerebral hemorrhage in one patient. The cerebral hemorrhage occurred in an area already previously shown to be necrotic by CCT before the onset of the [~-IFN therapy and caused no further deterioration. Discussion
The introduction of ACV has recently ameliorated the outcome of HSV encephalitis. However, mortality and sequelae are still high and there is no specific antiviral therapy available for most other etiologies of severe focal encephalitis. Acyclovir and [3-IFN have shown a synergistic inhibitory effect on HSV in vitro [13,14], and ~-IFN itself has a broad antiviral spectrum. In our study therapeutic outcome did not differ significantly between ACV monotherapy and the combination therapy (ACV plus [3-IFN) if all patients are included. This group as a whole was heterogenous and poorly defined, but one conclusion may be that there is not a strong beneficial effect of [3-IFN in unselected patients with viral encephalitis. Even in the subgroup of patients with signs of acute HSV infection, there was no significant difference in therapeutic outcome. However, in patients with low-absorption areas in the temporal lobes as demonstrated by CCT, the therapeutic outcome was significantly better with the drug combination than with ACV monotherapy, independent of the etiologic agent. There were no severe sequelae or deaths among the 11 patients treated with ACV plus [3-IFN, whereas 16 of 30 patients (53%) treated with ACV alone had severe sequelae or died. It is unlikely that the different duration of ACV therapy is responsible for this difference because the longer mean duration of ACV therapy in the patient group treated with ACV plus ~-IFN was mainly due to one patient who was treated for 32 days, and there was no correlation in either treatment group between duration of ACV therapy and therapeutic outcome. What could explain the effect of this drug combination in patients with temporal low-density areas demonstrated by CCT? Exogenous interferons penetrate the intact blood-brain barrier only to a small extent [28,29]. Indeed,
Infection20 (1992) No. 4 © MMV MedizinVerlag GmbHMfinchen,Mfinchen1992
U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis intracerebral interferon production is raised in inflamed CNS areas [12, 30-32], but it is too low to sufficiently inhibit viral replication in H S V encephalitis [11,12]. Disturbances of the blood-brain barrier could locally enhance the concentration of exogenous interferon in inflamed areas, and this exogenous interferon may act synergistically with A C V against H S V or other viruses. In patients with cerebral low:density regions other than the temporal lobes, the differences in disease outcome were not statistically significant, but there was a positive trend in favour of combination therapy (data not shown). Furthermore, in the subgroup with H S V infection (subgroup 1), a considerably higher proportion of patients treated with the combination therapy had low-absorption areas in the temporal lobes (47%) compared to those treated with A C V monotherapy (33%), but nevertheless therapeutic outcome was similar in both treatment groups. The poor penetration into the neuronal tissue in patients with an intact blood-brain barrier could be one further explanation for the lack of effect in the subgroup with HSV infection and in the other subgroups. This raises the question whether interferon should be administered intrathecally. Only few data are available with regard to this question, and the results of therapeutic outcome are contradictory [33,34]. It is evident that attention should be paid to the differential diagnosis of low-density areas on the CCT scan [1,26]. All efforts were undertaken to rule out other causes of hypodense lesions in this series of patients. The
close similarity of the initial disease parameters of the patients with temporal low-density areas in C C T in both treatment groups allows the notion that the combination therapy may have a positive effect on disease outcome. O f course the limitations of retrospective analysis of patient data have to be considered. However, this finding may constitute a basis for new regimens to treat this devastating disease and should be tested in a controlled prospective study. Meanwhile, inflamed areas in the temporal lobes can be detected earlier and m o r e sensitively with magnetic resonance imaging ( M R I ) [35] or with single photon emission computed tomography (SPECT) [36,37] than with CCT. In the present study M R I was performed in 24 patients, but usually only after (in 22/24 patients) C C T scans. CCT results were confirmed by M R I in all cases, but we cannot make any appraisal with regard to the higher sensitivity of MRI. The M R I and S P E C T imaging techniques should be employed in a prospective study, the results of which may then further substantiate the idea that earlier diagnosis followed by combination therapy" with A C V plus I3-IFN may improve the prognosis of patients with severe focal viral encephalitis. Acknowledgements
We are indepted to W. Gaus, J. Hasford and S. Schmid for statistical help and to P. Heinz-Erian for reviewing the manuscript.
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30. Degr6, M., Dahl, H., Vandvik, B.: Interferon in the serum and cerebrospinal fluid in patients with multiple sclerosis and other neurological disorders. Acta Neurol. Scand. 53 (1976) 152-160. 31. Dussaix, E., Lebon, P., Ponsot, G., Huault, G., Tardieu, M.: Intrathecal synthesis of different alpha-interferons in patients with various neurological diseases. Acta Neurol. Scand. 71 (1985) 504-509. 32. Ho-Yen, D. O., Carrington, D.: Alpha-interferon responses in cerebrospinal fluid of patients with suspected meningitis. J. Clin. Pathol. 40 (1987) 83-86. 33. De Clerq, E., Edy, V. G., De Vlieger, H., Eeckeis, R., Desmyter, J.: Intrathecal administration of interferon in neonatal herpes. J. Pediatr. 86 (1975) 736-739. 34. Prange, H. W., Weber, T., Wismann, H.: Treatment of viral encephalitis with systemic and intrathecal beta-interferon. Antiviral Res, 3 (1984) 92. 35. Schroth, G., Gawehn, J., Thron, A., Vallbraeht, A., Voigt, K.: Early diagnosis of herpes-simplex encephalitis by MRI. Neurology 37 (1987) 179-183. 36. Bfill, U., Braun, H., Ferbert, A., Stirner, H., Weiiler, C., Ringeistein, E.: Combined Spect imaging of regional cerebral blood flow (99mTc-hexamethyl-prophylenamine oxime. HMPAO) and blood volume (~mTc-RBC) to assess regional cerebral perfusion reserve in patients with cerebrovascular disease. Nucl. Med. 27 (1988) 51-57, 37. Launes, J., Niiddnen, P., Lindroth, L, Brownel, A. L., Lievendahl, tC, Iivanainen, M.: Diagnosis of acute herpes simplex encephalitis by brain perfusion single photon emission computed tomography. Lancet i (1988) 1188- 1191. 38. Nellhaus, G., Stumpf, D. A., Moe, P. G.: Neurologic and muscular disorders. In: Kempe. H., Silver, 14. K., O'Brien, D.. Fulginiti, V. A. (eds,): Current pediatric diagnosis and treatment. Appleton & Lange, Norwalk, Conn. 1987, p. 652.
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Infection 20 (1992) No. 4
© MMV Medizin Verlag GmbH Mfinchen, Miinchen 1992
Acyclovir Monotherapy versus Acyclovir plus Beta-Interferon in Focal Viral Encephalitis in Children Summary: Severe focal viral encephalitis is most commonly caused by herpes simplex virus (HSV), but other viruses may act as etiologic agents as well. Acyclovir (ACV) is the standard therapy for HSV encephalitis, but the mortality of 28% and defect healing rate of about 35% are still unsatisfactory. Furthermore, ACV has virtually no effect on other pathogens of viral encephalitis, except for varicella-zoster virus (VZV). It is well known that [5-interferon (~-IFN) has a broad antiviral spectrum, and it has been demonstrated in vitro that 13-IFN in combination with acyclovir has synergistic inhibitory effects on HSV. To investigate if the combination of ACV with and without 13-IFN might also be of significance for the treatment of severe viral encephalitis, we performed a retrospective study. A case record form was sent to all 278 West German
children's hospitals. The response rate was 78%. A total of 301 patients were reported, of whom 214 received specific antiviral therapy with either ACV alone (n = 179) or ACV plus [3-IFN (n = 35). No overall differences between ACV monotherapy and the combination therapy were observed. However, in a subgroup of 41 patients (ACV n = 30, ACV plus ~-IFN n = 11) who had low-density areas of the temporal lobes on cranial computed tomography scans, compatible with severe focal encephalitis, sequelae due to defect formation and mortality were significantly (p=0.014) reduced in patients who had received combination therapy. These data are the first indication that combination treatment with ACV and [3-IFN may be of advantage in patients with focal viral encephalitis and should be controlled in a prospective trial.
Zusammenfassung:Acyclovir allein oder kombiniert mit Beta-Interferon bei fokaler Virusenzephalitis. Die schwere fokale virale Enzephalitis wird meist durch Herpes-simplex-Viren verursacht, aber auch andere Viren kommen fitiologisch in Betracht. Die Standardtherapie der Herpes-simplex-Enzephalitis ist Acyclovir (ACV), wobei die Letalitgt von 28% und Defekt-Heilungsrate von 35% immer noch unbefriedigend ist. Dartiberhinaus hat Acyclovir mit Ausnahme von Varizella-zoster-Virus (VZV) keinen Effekt bei Enzephalitiden durch andere Erreger. [3-Interferon ([3-IFN) hat ein breites antivirates Spektrum und hat in vitro in der Kombination mit Acyclovir eine synergistische Wirkung gegen HSV. Wir ffihrten deshalb eine retrospektive Studie mit der Fragestellung dutch, ob die Kombination von ACV und [3-IFN in der Behandlung der viralen Enzephalitis einen therapeutischen Vorteil gegentiber der Monotherapie mit ACV erbringt. Hierzu wurde ein Fragebogen an alle 278 westdeutschen Kinderkliniken versandt. Die Rticklaufquote betrug 78%, 301
Patienten wurden mitgeteilt. 214/301 Patienten erhielten eine antivirale Therapie, wobei 179 mit ACV-Monotherapie und 35 mit der Kombinationstherapie (ACV plus [3-IFN) behandeit wurden. In der Gesamtgruppe der behandelten Patienten wurden keine Unterschiede hinsichtlich Morbidit~it und Letalitfit zwischen der Mono- und der Kombinationstherapie beobachtet. In einer Untergruppe von 41 Patienten allerdings (ACV n = 30, ACV plus [3-IFN n = l l ) , die in der cranialen Computertomographie hypodense Zonen in den Temporallappen aufwiesen (vereinbar mit fokaler Enzephalitis), war die Defekt-Heilungsrate und die Letalitfit in der Patientengruppe mit Kombinationstherapie signifikant niedriger (p = 0,014) als mit ACV-Monotherapie. Diese Beobachtung k6nnte ein erster Hinweis sein, dal3 eine Kombinationstherapie bei der fokalen viralen Enzephalitis einen therapeutischen Vorteil bringen k6nnte und sollte in einer kontrollierten prospektiven Studie geprfift werden.
Introduction Severe focal viral encephalitis is a rare but life-threatening disease with an incidence of 2 to 3/1,000,000 per year. Most frequently caused by herpes simplex virus (HSV) [1], the disease can also be caused by Arbo-, Epstein Barr-, and enteroviruses [1]. Early diagnosis and early onset of therapy are crucial for the outcome of the illness [2]. Untreated herpes-simplex encephalitis has a mortality
of 70%, with sequelae of defect formation in a further 25% [3]. In two controlled studies in adults [4, 5] and one in neonates [6], it has previously been shown that mortality Received: t0 February 1992/Revisionaccepted: 20 April 1992 Dr. U. Wintergerst, Prof. Dr. B. H. Belohradsky, UniversitfitsKinderklinik, Ludwig-Maximilians-Universit~it,Lindwurmstr. 4, W-8000 Mtinchen, Germany.
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH M/inchen, Mtinchen 1992
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U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis and sequelae of herpes-simplex encephalitis can be significantly r e d u c e d with acyclovir (ACV). T h e remaining mortality o f 28% and the rate o f sequelae of defect formation of about 35% in H S V encephalitis are still unsatisfactory [2]. Therefore, and because of the lack of effect o f A C V on o t h e r pathogens except varicella- zoster virus ( V Z V ) , there is a n e e d for alternative therapeutical approaches. Interferons are interesting putative therapeutic agents because of their potent i m m u n o m o d u l a t i n g and antiviral effects [7-10]. Moreover, deficient p r o d u c t i o n of e n d o g e n o u s interferon has b e e n d e m o n s t r a t e d in patients with H S V encephalitis [11, 12]. In vitro synergistic inhibitory effects of A C V in c o m b i n a t i o n with beta-interferon ([3-IFN) [13, 14] or alpha-interferon [15] on H S V have b e e n described. A n i m a l studies and clinical trials with a few patients receiving alpha-interferon [16-18] and the combination of A C V plus t3-IFN in H S V encephalitis have also shown encouraging results [19-21]. In p r e p a r a t i o n for a prospective multicenter study, we retrospectively analysed 301 patients with viral encephalitis with regard to antiviral t r e a t m e n t and outcome.
Patients and Methods
Data collection: Standardised case record forms were sent to all West German children's hospitals (n =278). Data on clinical symptoms, diagnostic tests and therapy were requested (Table 1). We were particularly interested in symptoms (e.g. fever, headache and signs of focal neurological defects, coma) and their duration prior to the administration of specific antiviral therapy, diagnostic procedures, therapeutic regimen, outcome and follow-up. All cases of viral encephalitis in children in the period from January 1983 to December 1988 were to be reported. Oiteria for the evaluation of therapy: Table 2 lists the criteria for the evaluation of the therapeutic outcome. Criteria previously used in adult studies were adapted to children [22] (e.g. down-ranking in school). Encephalitis was defined as a febrile illness with central nervous symptoms such as focal or grand mal seizures, altered consciousness, changes in personality, focal neurological signs, elevation of protein and cell count in cerebrospinal fluid and disturbances shown on the electroencephalogram (EEG). Other causes of the neurological disorder, such as bacterial infections, tumors, intoxication and metabolic disorders, had to be excluded. Low-density areas detected by cranial computed tomography (CCT) were considered indicative of inflamed or necrotic areas in the cerebrum when other reasons (e.g. infarction, tumor) were not evident [23-26]. Infarction is unlikely in the context of the sudden onset of high fever, and tumors differ in the course of the disease. Treatment schedules: Patients were treated with ACV monotherapy or with a combination of ACV and 13-IFN. The dose of ACV was 30-50 mg/kg bw/d in 70% of the patients and 15-30 mg/kg bw/d in the remaining 30% for 10.9 + 4.8 (mean + 1 SD) days. I3-IFN was administered in all patients who received combination therapy in a dose of 500,000 IU/kg bw/d for at least five days (Fiblaferon ®, Rentschler Ltd., Germany) if tolerated. All patients received additional supportive therapy depending on the severity of their disease.
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Table 1 : Data on viral encephalitis requested per questionnaire from 278 West German children's hospitals. a) General data and clinical symptoms before the beginning of therapy: age, sex, weight, year of treatment, occurrence and duration of the symptoms, fever, restlessness, personality change, speech disorders, seizures (focal or generalized) and altered states of consciousness (confusion, obtundation, stupor, coma, [38]) as well as other symptoms before the onset of antiviral therapy; b) Neurological diseases before the onset of therapy; c) Serological and virological diagnostic tests; d) Laboratory tests and physical diagnostics: CSF findings, electroencephalography, cranial computed tomography (CCT), magnetic resonance imaging (MRI); e) Treatment: duration and dose of antiviral therapy, use of beta-interferon, symptomatic therapy (artificial ventilation, therapy of raised intracerebral pressure, sedation, antiepileptic therapy, other) f) Treatment outcome (at discharge and follow-up)
Table 2: Evaluation of therapy results. 1. Cure: complete restoration of neurologic function. 2. Defect syndromes: motor or affective disorders, or disorders of concentration owing to intellectual defects, divided into: - slight defects: little impairment of motor, psychological or intellectual function, e.g. asymptomatic epilepsy under antiepileptic therapy. -moderate defects: functions in accordance with age still possible, but major motor or intellectual restrictions that hampered daily life (hemiparesis, persistent seizure disorder), transfer to a special school for disabled children or a medical pedagogic kindergarten necessary. -severe defects: need for complete nursing care, spastic quadriptegia, serious developmental delay, severe intellectual defects, no longer feasible to attend school. 3. Death: up to 15 months after the illness when attributable to the disease, e.g. aspiration pneumonia in acquired swallowing disorder.
Statistics: The case record forms were evaluated by means of frequency tables in accordance with therapy schedules (patient group with ACV monotherapy versus combination therapy, ACV + [3-IFN). Data were analysed both for the two treatment groups in total and also for the following specific subgroups: 1. patients with proven HSV infection (as based on a four-fold elevation of HSV IgG in serum or HSV IgM in serum or CSF, or autochthonous production of specific IgG in CSF. Brain biopsies were not performed) (n = 97) 2. patients with initial coma (n = 103) 3. patients with focal abnormalities shown on the EEG (n = 76) 4. patients with low-density areas in the temporal lobes demonstrated by CCT (n = 41). Considerable overlapping of the subgroups occurred. Statistical analysis was carried out using Fisher's exact test (SAS program). With respect to the retrospective nature of this study, p values must be interpreted descriptively.
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mfinchen, Mtinchen 1992
U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis 140
c--
130. 120
I I
110. 100
~
9o 80. 70. 60. 50 40 30. 20 10
l
0
no
HSV
Varicella
Measles
Rubella
Coxsackle
EBV
I Echo
CMV
pathogen
Figure 1' Suspected e t i o l o g y of 301 recorded cases of viral encephalitis.
IFN+Acyclovlr = (n=35) Acyclovlr
(n=179)
cure
sflght defect
moderate defect
severe defect
death
Figure 2: Therapeutic outcome in 214 patients with viral encephalitis in relation to treatment regimen. * p = n.s.
Results
Seventy-eight percent of the children's hospitals responded to our inquiry. Ninety-eight hospitals reported on 301 patients. One hundred eighteen hospitals did not treat any child with encephalitis during the study period. Figure 1 shows the suspected different etiologies in the reported 301 patients. The etiology of the infection was not established in 46.5% of the cases. In 33% serological or cerebrospinal findings for an acute HSV infection were demonstrated. The remaining cases were diagnosed as specified. Since brain biopsies were not performed, the true incidence of HSV encephalitis remained unclear. Two hundred fourteen of 301 patients received antiviral therapy with either ACV or ACV plus [3-IFN. Eighty-seven patients did not receive any antiviral therapy because they had a very mild course of disease, showed signs characteristic of specific etiologies (e.g. measles exanthema) and therefore were not treated with ACV, or developed the disease before 1983 (i.e. before the introduction of ACV in Germany). The data of these patients are not considered here. Figure 2 shows the clinical outcome of the remaining 214 patients. One hundred seventy-nine patients were treated
with ACV monotherapy and 35 with the combination of ACV plus [3-IFN. The average age was 4 years 9 months ( + 4 years 6 months) in the patients who received ACV monotherapy and 5 years 1 month ( + 4 years 5 months) in the group who received combination therapy. The sex ratio (male to female) was 1.2:1. The analysis of the 214 patients in total did not show any significant differences in outcome between therapy with ACV alone and therapy with ACV plus [3-IFN. In the combination treatment group, both the percentage of pretreatment coma - a poor prognostic sign - (42.8% vs. 32.9%) and the percentage of patients with acute HSV infection (54.3% vs. 40.3%) were slightly higher. In subgroups 1-3 (patients with proven HSV infection, patients with initial coma, patients with disturbances in EEG) there were also no significant differences in therapeutic outcome, with similar initial conditions in both treatment groups. In patients with proven HSV infection who received combination therapy (n=17), 23.5% were cured, 23.5% had slight defects, 17.6% had moderate defects, 29.4% had severe defects and 5.8% died, whereas in patients who received ACV monotherapy (n = 69), 24.6% were cured, 8.6% had slight defects, 20.3% had moderate defects, 33.3% had severe defects and 13% died (not significant). CCT scans were performed in 219 patients. Low-density areas in one or both temporal lobes were found in 41 (18.7%) patients. Of these, 31 had proven HSV infection, one had VZV infection and in nine patients no pathogen was identified. Interestingly, patients with low-density areas in the temporal lobes had a significantly better response (p = 0.014, response classified as healed, slight-, moderate-, severe-defect and death, absolute case numbers in 2 columns [therapy groups] x 5 lines [response], Fisher's exact test) to the combination therapy of ACV plus [3-IFN than to ACV monotherapy (Figure 3). Complete restoration of health was achieved in 27% of patients compared to 10% in the monotherapy group, mild defects occurred in 36.5% versus 16%, moderate defects in 36.5% versus 21%, no severe defects versus 43% and no deaths versus 10% in monotherapy group. 50
40
3O
[]
~,IFN+Acyclovlr x
[]
Acyclovlr
(n=11) (n=30)
1
,
I
i Cure
mild defect
l moderate defect
s e v e r e defect
death
Figure 3: Therapeutic outcome in patients with low-density in the temporal lobes (as shown by CCT) in relation to treatment regimen (n =41). * p=0.014. areas
Infection 20 (1992) No. 4 © MMV MedizinVerlag GmbH Mfinchen, Mfinchen 1992
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U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis Table 3: Comparision of prognostic factors in the two therapy groups (acyclovir [ACV] versus ACV plus f-interferon [B-IFN]) of patients with low-density areas in the temporal lobes.
Comatosepatients Duration of coma before onset of therapy Acute HSV-1 infection Acute HSV-2 infection ACV dose Duration of ACV therapy Duration of B-IFN therapy Percentage of infants < 6 months of age Percentage of infants < 4 weeks of age Further CCT findings~ Mean period of follow-up Focal abnormalities in EEG
7 (23%)
3 (27%)
0.9 d (0.5-2) 21 (70%)
1.8 d (0.5-4) 8 (73%)
2 (7%)
0
28.4 mg/kgbw/d (15-50 mg/kg/d) 9.6 d (6-13 d)
31.2 mg/kgbw/d (15-40 m~,~tt) 15.5 d (I0-32 d) 5.1d
-
(1-11)
9 (30%)
3 (27%)
4 (13%)
1 (9%)
14 (46%) 13 months (2-44 months)
5 (45%) 6.2 months (1.5-6 months)
11 (37%)
1 (11%)
"Low-densityareas in other parts of the cerebrum,generalizedcerebral edema. Both treatment groups were comparable with regard to the major prognostic criteria (Table 3). They differed neither in the percentage of comatose patients nor in the average duration and severity of the disturbance of consciousness. Moreover, the percentage of young infants (< 6 months), with a predominance of HSV-2 encephalitis (with a poorer prognosis than HSV-1 [270, was the same in the two groups. Two newborns with documented HSV-2 infection were treated with ACV monotherapy. One was cured and the other had a slight defect. In the group of four newborns (no differentiation between HSV-1 and HSV-2) who received ACV monotherapy, two slight and one severe defect occurred and one newborn died. One newborn in the combination therapy group survived with a slight defect. Mean duration of ACV therapy in the ACV monotherapy group was only 9.6 days compared to 15.5 days in the combination treatment group. This difference is mainly due to a 32-day treatment course with ACV in one patient who received combination therapy. In patients who received ACV plus [5-IFN treatment, there were no differences in therapeutic outcome regarding the ACV dose and the duration of ACV therapy. In the ACV monotherapy group, the mean ACV dose in patients who 34 / 210
died or had severe sequelae was 27 mg/kg bw/d (15-50 mg/kg bw/d) for a mean duration of 9.8 days (8-13 d) versus 29.4 mg/kg bw/d (15-40 mg/kg bw/d) and 9.4 days (6-10 d) in patients who were cured or had only mild or moderate sequelae. Ninety-three percent of severely affected patients versus 71% of mildly affected patients had acute HSV infection according to the criteria presented in the Methods section. The side effects of [3-IFN therapy were reversible in all patients and consisted of fever (62.6%), chills (22.2%), leukopenia (< 4000/ram 3, 44.4%), elevation of transaminases (ALT, AST~ 26.6%), thrombopenia (< 100,000/mm 3, 20%), prolongation of partial thromboplastin time (15.5%), anemia (6.6%), diarrhoea (4.4%), an allergic reaction in one patient and a cerebral hemorrhage in one patient. The cerebral hemorrhage occurred in an area already previously shown to be necrotic by CCT before the onset of the [~-IFN therapy and caused no further deterioration. Discussion
The introduction of ACV has recently ameliorated the outcome of HSV encephalitis. However, mortality and sequelae are still high and there is no specific antiviral therapy available for most other etiologies of severe focal encephalitis. Acyclovir and [3-IFN have shown a synergistic inhibitory effect on HSV in vitro [13,14], and ~-IFN itself has a broad antiviral spectrum. In our study therapeutic outcome did not differ significantly between ACV monotherapy and the combination therapy (ACV plus [3-IFN) if all patients are included. This group as a whole was heterogenous and poorly defined, but one conclusion may be that there is not a strong beneficial effect of [3-IFN in unselected patients with viral encephalitis. Even in the subgroup of patients with signs of acute HSV infection, there was no significant difference in therapeutic outcome. However, in patients with low-absorption areas in the temporal lobes as demonstrated by CCT, the therapeutic outcome was significantly better with the drug combination than with ACV monotherapy, independent of the etiologic agent. There were no severe sequelae or deaths among the 11 patients treated with ACV plus [3-IFN, whereas 16 of 30 patients (53%) treated with ACV alone had severe sequelae or died. It is unlikely that the different duration of ACV therapy is responsible for this difference because the longer mean duration of ACV therapy in the patient group treated with ACV plus ~-IFN was mainly due to one patient who was treated for 32 days, and there was no correlation in either treatment group between duration of ACV therapy and therapeutic outcome. What could explain the effect of this drug combination in patients with temporal low-density areas demonstrated by CCT? Exogenous interferons penetrate the intact blood-brain barrier only to a small extent [28,29]. Indeed,
Infection20 (1992) No. 4 © MMV MedizinVerlag GmbHMfinchen,Mfinchen1992
U. Wintergerst, B. H. Belohradsky: Therapy of Severe Viral Encephalitis intracerebral interferon production is raised in inflamed CNS areas [12, 30-32], but it is too low to sufficiently inhibit viral replication in H S V encephalitis [11,12]. Disturbances of the blood-brain barrier could locally enhance the concentration of exogenous interferon in inflamed areas, and this exogenous interferon may act synergistically with A C V against H S V or other viruses. In patients with cerebral low:density regions other than the temporal lobes, the differences in disease outcome were not statistically significant, but there was a positive trend in favour of combination therapy (data not shown). Furthermore, in the subgroup with H S V infection (subgroup 1), a considerably higher proportion of patients treated with the combination therapy had low-absorption areas in the temporal lobes (47%) compared to those treated with A C V monotherapy (33%), but nevertheless therapeutic outcome was similar in both treatment groups. The poor penetration into the neuronal tissue in patients with an intact blood-brain barrier could be one further explanation for the lack of effect in the subgroup with HSV infection and in the other subgroups. This raises the question whether interferon should be administered intrathecally. Only few data are available with regard to this question, and the results of therapeutic outcome are contradictory [33,34]. It is evident that attention should be paid to the differential diagnosis of low-density areas on the CCT scan [1,26]. All efforts were undertaken to rule out other causes of hypodense lesions in this series of patients. The
close similarity of the initial disease parameters of the patients with temporal low-density areas in C C T in both treatment groups allows the notion that the combination therapy may have a positive effect on disease outcome. O f course the limitations of retrospective analysis of patient data have to be considered. However, this finding may constitute a basis for new regimens to treat this devastating disease and should be tested in a controlled prospective study. Meanwhile, inflamed areas in the temporal lobes can be detected earlier and m o r e sensitively with magnetic resonance imaging ( M R I ) [35] or with single photon emission computed tomography (SPECT) [36,37] than with CCT. In the present study M R I was performed in 24 patients, but usually only after (in 22/24 patients) C C T scans. CCT results were confirmed by M R I in all cases, but we cannot make any appraisal with regard to the higher sensitivity of MRI. The M R I and S P E C T imaging techniques should be employed in a prospective study, the results of which may then further substantiate the idea that earlier diagnosis followed by combination therapy" with A C V plus I3-IFN may improve the prognosis of patients with severe focal viral encephalitis. Acknowledgements
We are indepted to W. Gaus, J. Hasford and S. Schmid for statistical help and to P. Heinz-Erian for reviewing the manuscript.
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