Journalof Infection(1991) 23, 169-174 CASE REPORTS Herpes zoster associated encephalitis in dialysis patients W. C. C h e u n g , * K. Y. Y u e n , ~ C. M. Chang* a n d K. P. Cheng*
* University Medical Unit and t Microbiology Unit, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Accepted for publication 27 February I99I
Summary Two patients on dialysis because of chronic renal failure who developed herpes zoster associated encephalitis are reported. Both developed overt encephalopathy despite treatment with oral acyclovir for the preceding herpes zoster eruption. The encephalopathy responded rapidly to intravenous acyclovir.
Introduction Reactivation of previous varicella zoster virus (VZV) infection gives rise to dermatomal cutaneous herpes zoster (HZ). Occasionally H Z may be complicated by neurological sequelae including neuralgia, cranial and peripheral nerve palsies, myelitis, encephalitis, leukoencephalopathy and hemiplegia. 1 Herpes zoster associated encephalitis (HZAE) is notably an unusual complicationfl T h o u g h H Z A E has been reported in healthy individuals, 3 dissemination of herpetic lesions, advanced age and underlying immunosuppressed states such as may occur in lymphoreticular diseases, haematological malignancies and anticancer or steroid therapy, are the major risk factors. 2 Uraemia has been associated with lymphopenia and depression of both cellmediated and humoral responses. 4 T h e defective cellular immunity, which is more affected than the humoral immunity, is not completely rectified by dialysis. Recently, in uraemic patients on maintenance haemodialysis, impairment of the macrophage Fc-gamma receptor function has been d e m o n s t r a t e d ) T h e significant mortality (2o %) caused by infection and the increased prevalence of mycobacterial infection in the chronic dialysis population,6.7 is further presumptive evidence of their immunocompromised state. Despite the large number of such patients enjoying a longer life expectancy as a result of the introduction of dialysis programmes and potent antibiotics, H Z A E has not been reported in dialysis patients. We report two cases of H Z A E in such patients whose diagnosis and management are discussed. ~: Addresscorrespondenceto: Dr K. Y. Yuen, ClinicalMicrobiologist,UniversityMicrobiologyUnit, PathologyBuilding~QueenMaryHospital, Pokfulam,Hong Kong. oi63-4453/9I/O5OI69 +o6 $03.00/0
© 1991The British Societyfor the Studyof Infection
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ET AL.
Case reports
Case I A 55-year-old Chinese woman with a past history of asthma, hypertension and chronic renal failure of unknown aetiology had been well-maintained on chronic ambulatory peritoneal dialysis (CAPD) for 3 years. She presented to our outpatient dialysis clinic with typical H Z eruptions over the left T I o dermatome. Oral acyclovir 4oo mg t.d.s, was prescribed. T h r e e days later she was admitted because of visual hallucinations. Physical examination showed a typical H Z rash, but her nervous system was normal and she was orientated and coherent. She was euvolaemic with a heart rate of IOO min and a BP of 140/80 m m H g . Other systems were essentially unremarkable. Laboratory investigations were as follows: haemoglobin 5"8 g/dl, WBCs 4"6× lO9/1, neutrophils 81.5 %, lymphocytes 9"7 %, monocytes 4" 1%, platelets 172 x IO9/1, ESR 7 o m m in the first hour, glucose 6"7mmol/1, Na I32mmol/1, K 4"3 mmol/1, urea 29"7 mmol/1, creatinine 112o #tool/l, Ca 2"48 mmol/1, PO 4 2"33 mmol/1, albumin 38 g/l, globulin 23 g/1. C T scan of the brain was normal. At lumbar puncture the opening pressure was 15-5 cm water. T h e CSF WBC count was 24 × lO6/1 of which 76 % were lymphocytes and 24 % were monocytes. T h e protein and glucose values were within normal limits. E E G showed marked bilateral slow waves compatible with infective or metabolic encephalopathy. Acyclovir was now given by the intravenous route in a dose of 250 mg daily (5 m g / k g / d a y ) and was continued for 12 days. Her visual hallucinations resolved 9 days after admission. Neurological evaluation and E E G during the sixth week was normal. Case 2 A 65-year-old Chinese woman with hypertension and chronic renal failure of unknown aetiology had been maintained on CAPD since 1987. In May 1989 she was started on haemodialysis because of ultra-filtration failure after an episode of candidal peritonitis. She was admitted because of vomiting and dizziness immediately after the haemodialysis session and was found to be euvolaemic with a heart rate of 9o/min and a BP of 22O/lOO m m H g . No neurological deficit was noted. T h e electrolytes and liver function tests were normal. Her blood pressure was stabilised with nifedipine retard 2o mg b.d. On the second day she developed a low grade fever and typical H Z eruptions over the left r i 2 dermatome. She was discharged on oral acyclovir 400 mg t.d.s. Four days later the patient was readmitted because of a fluctuating mental state. On examination she was disoriented and had a temperature of 38 °C. T h e r e was no focal neurological deficit or meningism. Active H Z lesions were still confined to her left T I2 dermatome. Her pulse was 9o/min and BP 130/90 m m H g . Other systems were unremarkable. T h e results of laboratory investigation were as follows: haemoglobin 5"6g/dl, WBCs 9"52 lO9/1, platelets 250 × lO3/1, glucose 8"9 mmol/1, Na 134 retool/l, K 5"4 mmol/1, C1 88 mmol/1, urea 44"5 retool/l, creatinine 149o/zmol/1, Ca 2-23 mmol/1, PO 4 3"64 retool/1. C T Scan of the brain was normal. At lumbar puncture the CSF opening pressure was 18 cm water. T h e WBC count was 7o x lO6/1 of which
Zoster encephalitis in dialysis patients
17I
89 % were lymphocytes and Io % were monocytes. T h e protein value was o'75 g/1 while the glucose content was normal. E E G performed on the second day after admission showed periodic delta waves in both hemispheres anteriorly which were compatible with infective or metabolic encephalopathy. Acyclovir was changed from the oral to the intravenous route at a dose of 250 mg daily with supplementary doses of 25o mg after each haemodialysis session. T h e patient became afebrile and oriented on the second day. However her clinical course was subsequently complicated by severe aspiration pneumonia and stress-induced gastro-intestinal bleeding. Despite intensive care and antibiotic coverage, she died I5 days after her second admission. Permission for post-mortem examination was refused. In both cases, the initial sepsis workup, CSF culture for bacteria, mycobacteria, fungi and viruses, CIE for common bacterial antigens (meningitis panel) and latex agglutination test for cryptococcal antigen were negative. Viral antibody titres by complement fixation tests for influenza, mumps, herpes simplex, varicella zoster, lymphocytic choriomeningitis, adenovirus, measles and enteroviruses were also negative on the CSF. T h e serum complement fixation antibody titre for VZV in both cases was I6O on admission and was negative for the viruses listed above and for Japanese B encephalitis virus. T h e r e was no recent use of desferrioxamine or other new medication. T h e r e was no clinical evidence of aluminium toxicity or underdialysis. After treatment with acyclovir for I week further CSFs were examined. T h e y were normal in both patients.
Discussion
Herpes zoster associated encephalitis has not been reported in association with dialysis patients. Both of our cases satisfied the diagnostic criteria of H Z A E which were defined by Jemsek as follows : (I) clinical evidence of H Z with or without virological confirmation; (2) an encephalopathic clinical state; (3) a diffusely abnormal E E G (4) CSF findings compatible with encephalitis; and (5) exclusion of other known toxic or metabolic-induced encephalopathies. 2 Certain factors should be considered, especially in dialysis patients. T h e y are apt to develop confusion, contributory factors are their increased susceptibility to infection, fluid or electrolyte imbalance, hypertension, nutritional deficiency, aluminium toxicity and Wernicke's encephalopathy. It is always difficult to establish a direct relationship between H Z eruption and confusion as the H Z infection can be coincidental or can be the triggering event of the above-mentioned complications. Moreover, the H Z eruption may antedate the H Z A E by 3 months or may not be observed at all. 8' 9 U n d e r such circumstances, the diagnosis of H Z A E might be missed. E E G abnormalities are rather non-specific and can be present in many conditions. T w e n t y - o n e per cent of patients with apparently uncomplicated H Z had abnormal EEGs which were qualitatively similar but quantitatively less severe than those found in patients with HZAE. 1° It is not certain whether such a high percentage of E E G abnormalities merely reflects the high prevalence of undiagnosed subclinical H Z A E or the fact that the E E G is less
172
W. C. C H E U N G E T A L .
specific as a diagnostic tool than has been supposed. Indeed E E G abnormalities were also noted in other neurotropic virus infections without overt signs of encephalitis, e.g. 30% patients with measles and 22% patients with varicella.11,1~ Uraemic patients often have abnormal EEGs with superimposed slow waves and loss of normal alpha rhythm. T h e abnormality may persist for up to 6 months after dialysis is commenced but usually it eventually resolves. 13 Moreover, abnormal EEGs and encephalopathy have been reported in patients with acyclovir induced neurotoxicity. 14 Lymphocytic pleocytosis in the CSF may not necessarily indicate involvement of the central nervous system by VZV. In patients with uncomplicated HZ, as many as 38 % were found to have mild pleocytosis or elevated CSF protein. 15 Moreover, iO~/o uraemic patients had more than 5 leucocytes m m 3 (range 7-6oo) in the CSF and 2o % had a protein concentration greater than I g/1. This was attributed to alteration of the blood-brain barrier in the uraemic state. 12 Laboratory methods used to confirm infection of the central nervous system by VZV have been described but were either insensitive or not readily available. Demonstration of VZV in the CSF or brain tissue by electron microscopy and the recovery of VZV by CSF culture offer direct evidence of invasion into the central nervous system. 16 However, there are few reports in the literature of successful diagnosis by these methods. 2'~7 VZV antibody detection in CSF by indirect immunofluorescence (FAMA) was reported to have high sensitivity and specificity in the diagnosis of HZAE. 8 However, other workers demonstrated that in patients with herpes simplex virus (HSV) encephalitis or H Z A E , 'cross reacting' antibodies, including IgM and IgG, to both HSV and VZV were detected simultaneously by enzyme-linked immunosorbent assay (ELISA). This was attributed to epitopes common to HSV and VZV. 9' 18 Thus, the mere detection of intrathecal anti-VZV-IgG or IgM does not necessarily indicate diagnostic specificity. Mathiesen 9 showed that H Z A E was associated with intrathecal synthesis of two or more V Z V - I g G subclasses which might be diagnostic of HZAE. These sophisticated methods would certainly help in the diagnosis of H Z A E but the absence of a CSF viral antibody titre does not exclude the diagnosis. Ophir 17 reported one case of culture-proven H Z A E in which the serum and CSF were negative for antibodies against VZV. As rightly pointed out by Jemsek, the diagnosis of H Z A E is largely clinical and is made by exclusion. In both our patients, the close temporal relationship between the H Z eruptions and the onset of the encephalopathic state (3 and 4 days respectively) together with the good response to intravenous acyclovir are strong supporting evidence for the diagnosis of HZAE. T h e negative CSF viral culture is in accord with the experience of many other workers in the literature. T h e negative CSF antibody for VZV could be attributed to the low sensitivity of the complement fixation method employed in our laboratory. Uraemic encephalopathy is excluded as these patients had been wellmaintained on dialysis for 6 months to 3 years before the confusional state. Dialysis encephalopathy is unlikely in view of the relatively short history of dialysis, the use of aluminium free dialysate and the absence of characteristic E E G and neurological features. Neurotoxicity due to accumulation of acyclovir
Zoster encephalitis in dialysis patients
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is unlikely as both patients i m p r o v e d after it was changed from the oral to the intravenous route. Acyclovir has been d e m o n s t r a t e d to be effective in the t r e a t m e n t of HZAE.3,16,lg,20 It penetrates the b l o o d - b r a i n - b a r r i e r well giving a p l a s m a / C S F ratio of approximately 2 : I. Its plasma half life, n o r m a l l y 2"7 h increases to 2o h with renal failure which requires the dose to be adjusted. 2~ Acyclovir is readily haemodialysable and a single 6 h session will reduce acyclovir concentration by 60 %. A n extra dose of acyclovir should therefore be given after haemodialysis. ~ Acyclovir clearance during C A P D is only 4"4 m l / m i n and no s u p p l e m e n t is required. 23 It is striking to note that both patients had been receiving oral acyclovir, 4oo m g t.d.s., for a few days before they developed H Z A E . T h e r e is no clinical s t u d y that has examined the pharmacokinetics of oral acyclovir in uraemic patients t h o u g h a r e c o m m e n d a t i o n of dosage based on pharmacokinetic analysis of oral acyclovir was published. 24 T h e bioavailability of oral acyclovir varies between 15 and 3 0 % in the normal host. 25 I m p a i r e d intestinal absorption of various substances due to uraemic toxins, vitamin D deficiency, intestinal ileus and bacterial overgrowth has been reported in renal failure. 26 T h u s , absorption of acyclovir m i g h t have been erratic, allowing H Z A E to develop as a result of subtherapeutic acyclovir values in the plasma. Both patients i m p r o v e d after changing to intravenous acyclovir. In s u m m a r y , we have reported two cases of H Z A E in patients on dialysis. T h e diagnosis of H Z A E remains a clinical one and can only be m a d e by exclusion. Both patients had been receiving oral acyclovir before developing H Z A E and i m p r o v e d after changing to the intravenous route. H Z eruption in dialysis patients, as in others who are i m m u n o s u p p r e s s e d , should be treated by intravenous acyclovir so that the rare complication of H Z A E m a y be prevented. References
I. Chang CM, Woo E, Yu YL, Q'Huang CY, Chiu D. Herpes zoster and its neurological complications. Postgrad Med J I987; 63 : 85-89. 2. Jemsek J, Greenberg SB, Taber L, Harvey D, Gershon A, Couch RB. Herpes zosterassociated encephalitis : clinicopathologic report of ~2 cases and review of the literature. Medicine (Baltimore) I983 ; 62: 81-97. 3. Johns DR, Gress DR. Rapid response to acyclovir in herpes zoster-associated encephalitis. Am J Med I987; 82: 560-562. 4. Goldblum SE, Read WP. Host defenses and immunologic alterations associated with chronic haemodialysis. Ann Intern Med I98O; 93: 597-613. 5- Ruiz P, Gomez F. Impaired function of macrophage Fc gamma receptors in end-stage renal disease. N Engl J Med I99o; 322(I I) : 717-722. 6. Santiago A, Chazan JA. Factors associated with mortality among 405 chronic haemodialysis patients who died between I973 and i985. Kidney Int I987; 3I: 245. 7. Belcon MC, Smith EKM, Kahana LM, Shimizu AG. Tuberculosis in dialysis patients. Clin Nephrol I982; x7: I4. 8. Gershon A, Steinberg S, Greenberg S, Taber L. Varicella zoster associated encephalitis: detection of specific antibody in CSF. J Clin Microbiol I98o; I2: 764-767. 9- Mathiesen T, Linde A, Stenkvist EO, Wahren B. Antiviral IgM and IgG subclasses in varicella zoster associated neurological syndromes. J Neurol Neurosurg Psychiatry I989; 52 : 578-582. IO. 7
Peterslund NA, Hansen JH. Electroencephalographic changes in patients with herpes zoster. Acta Neurol Scand I989; 79: 4o7-4II. JI N 23
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I I. Grossman HJ, Gibbs EL, Lepper M H , Spies HW. Electroencephalographic studies on children with measles with no clinical evidence of C N S involvement. Elektroenceph Clin Neurophysiol r955; 7: 3x5. I2. Gibbs FA, Gibbs EL, Carpenter PR. Electroencephalographic abnormality in ' u n complicated' childhood diseases. J A M A I959; I 7 I : IO5O-IO55 . I3. Morrison G, Geheb MA, Earley LE, Seldin PW, Giebisch G, Eds. Chronic renal failure in the kidney physiology and pathophysiology. Vol. 2 New York: Raven Press, r985: I928. x4. Arndt KA. Adverse reactions to acyclovir: topical, oral and intravenous, ff A m Acad Derrnatol I988; I8 (Ipt2): I88-I9O. I5. Gold E. Serologic and virus isolation studies of patients with varicella or herpes zoster infection. N Engl ff Med I966; 274(4): r 8 I - I 8 5 . I6. Steele RW, Keeney RE, Bradsher RW, Moses EB, SoloffBL. Treatment of varicella-zoster meningo-encephalitis with acyclovir---demonstration of virus in C S F by electron microscopy. A m J Clin Pathol I983 ; 8o : 57--6o. x7. Ophir O, Siegman-Igra Y, Vardinon N, Liron M. Herpes zoster encephalitis : isolation of virus from cerebrospinal fluid. Isr ff Med Sci I984; 2o: I I89~I I92. I8. Dennin RH, Herb E. Immunological diagnosis in viral infections of the C N S : course of antibody titres against homo- and heterologous viruses. Med Microbiol Imrnunol I989; I78 : 255-268. r 9. Cheesbrough J S, Finch R G , W a r d MJ. A case of herpes zoster associated encephalitis with rapid response to acyclovir. Postgrad Med ff I985 ; 6I : I45-x46. 2o. Bowan RV, Lythall DA, D e W y t t CN. A case of herpes zoster associated encephalitis treated with acyclovir. ,,lust N Z f f Med I985; I5: 43-442I. Blum M R , Liao S, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. A m ff Med I982; 73: I86--I92. 22. Krasny HC, Liao S H T , Miranda PD. Influence of haemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. A m ff Med r982; 73: 2o2-2o4. 23. Shah G M , Winer RL, Krasny HC. Acyclovir pharmacokinetics in a patient on CAPD. Am ff Kidney Dis I986; 6: 5o7-5Io. 24. Fletcher CV, Chinnock BJ, Chace B, Balfour H H . Pharmacokinetics and safety of high dose oral acyclovir for suppression of CMV disease after renal transplantation. Clin pharrnacol Ther I988; 44: 158-163. 25. D e Miranda P, Blum, MR. Pharmacokinetics of acyclovir after intravenous and oral administration, ff Amirnicrob Chernother I983 ; x2 (Suppl B) : 29-37. 26. Adler M, Toussaint C. Gastrointestinal complications of renal failure. In: Maher JF, Ed. Replacement of renal function by dialysis. 3rd ed. Holland: Kluwer Academic Publishers, I989 : 843.
* University Medical Unit and t Microbiology Unit, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Accepted for publication 27 February I99I
Summary Two patients on dialysis because of chronic renal failure who developed herpes zoster associated encephalitis are reported. Both developed overt encephalopathy despite treatment with oral acyclovir for the preceding herpes zoster eruption. The encephalopathy responded rapidly to intravenous acyclovir.
Introduction Reactivation of previous varicella zoster virus (VZV) infection gives rise to dermatomal cutaneous herpes zoster (HZ). Occasionally H Z may be complicated by neurological sequelae including neuralgia, cranial and peripheral nerve palsies, myelitis, encephalitis, leukoencephalopathy and hemiplegia. 1 Herpes zoster associated encephalitis (HZAE) is notably an unusual complicationfl T h o u g h H Z A E has been reported in healthy individuals, 3 dissemination of herpetic lesions, advanced age and underlying immunosuppressed states such as may occur in lymphoreticular diseases, haematological malignancies and anticancer or steroid therapy, are the major risk factors. 2 Uraemia has been associated with lymphopenia and depression of both cellmediated and humoral responses. 4 T h e defective cellular immunity, which is more affected than the humoral immunity, is not completely rectified by dialysis. Recently, in uraemic patients on maintenance haemodialysis, impairment of the macrophage Fc-gamma receptor function has been d e m o n s t r a t e d ) T h e significant mortality (2o %) caused by infection and the increased prevalence of mycobacterial infection in the chronic dialysis population,6.7 is further presumptive evidence of their immunocompromised state. Despite the large number of such patients enjoying a longer life expectancy as a result of the introduction of dialysis programmes and potent antibiotics, H Z A E has not been reported in dialysis patients. We report two cases of H Z A E in such patients whose diagnosis and management are discussed. ~: Addresscorrespondenceto: Dr K. Y. Yuen, ClinicalMicrobiologist,UniversityMicrobiologyUnit, PathologyBuilding~QueenMaryHospital, Pokfulam,Hong Kong. oi63-4453/9I/O5OI69 +o6 $03.00/0
© 1991The British Societyfor the Studyof Infection
170
W . C. C H E U N G
ET AL.
Case reports
Case I A 55-year-old Chinese woman with a past history of asthma, hypertension and chronic renal failure of unknown aetiology had been well-maintained on chronic ambulatory peritoneal dialysis (CAPD) for 3 years. She presented to our outpatient dialysis clinic with typical H Z eruptions over the left T I o dermatome. Oral acyclovir 4oo mg t.d.s, was prescribed. T h r e e days later she was admitted because of visual hallucinations. Physical examination showed a typical H Z rash, but her nervous system was normal and she was orientated and coherent. She was euvolaemic with a heart rate of IOO min and a BP of 140/80 m m H g . Other systems were essentially unremarkable. Laboratory investigations were as follows: haemoglobin 5"8 g/dl, WBCs 4"6× lO9/1, neutrophils 81.5 %, lymphocytes 9"7 %, monocytes 4" 1%, platelets 172 x IO9/1, ESR 7 o m m in the first hour, glucose 6"7mmol/1, Na I32mmol/1, K 4"3 mmol/1, urea 29"7 mmol/1, creatinine 112o #tool/l, Ca 2"48 mmol/1, PO 4 2"33 mmol/1, albumin 38 g/l, globulin 23 g/1. C T scan of the brain was normal. At lumbar puncture the opening pressure was 15-5 cm water. T h e CSF WBC count was 24 × lO6/1 of which 76 % were lymphocytes and 24 % were monocytes. T h e protein and glucose values were within normal limits. E E G showed marked bilateral slow waves compatible with infective or metabolic encephalopathy. Acyclovir was now given by the intravenous route in a dose of 250 mg daily (5 m g / k g / d a y ) and was continued for 12 days. Her visual hallucinations resolved 9 days after admission. Neurological evaluation and E E G during the sixth week was normal. Case 2 A 65-year-old Chinese woman with hypertension and chronic renal failure of unknown aetiology had been maintained on CAPD since 1987. In May 1989 she was started on haemodialysis because of ultra-filtration failure after an episode of candidal peritonitis. She was admitted because of vomiting and dizziness immediately after the haemodialysis session and was found to be euvolaemic with a heart rate of 9o/min and a BP of 22O/lOO m m H g . No neurological deficit was noted. T h e electrolytes and liver function tests were normal. Her blood pressure was stabilised with nifedipine retard 2o mg b.d. On the second day she developed a low grade fever and typical H Z eruptions over the left r i 2 dermatome. She was discharged on oral acyclovir 400 mg t.d.s. Four days later the patient was readmitted because of a fluctuating mental state. On examination she was disoriented and had a temperature of 38 °C. T h e r e was no focal neurological deficit or meningism. Active H Z lesions were still confined to her left T I2 dermatome. Her pulse was 9o/min and BP 130/90 m m H g . Other systems were unremarkable. T h e results of laboratory investigation were as follows: haemoglobin 5"6g/dl, WBCs 9"52 lO9/1, platelets 250 × lO3/1, glucose 8"9 mmol/1, Na 134 retool/l, K 5"4 mmol/1, C1 88 mmol/1, urea 44"5 retool/l, creatinine 149o/zmol/1, Ca 2-23 mmol/1, PO 4 3"64 retool/1. C T Scan of the brain was normal. At lumbar puncture the CSF opening pressure was 18 cm water. T h e WBC count was 7o x lO6/1 of which
Zoster encephalitis in dialysis patients
17I
89 % were lymphocytes and Io % were monocytes. T h e protein value was o'75 g/1 while the glucose content was normal. E E G performed on the second day after admission showed periodic delta waves in both hemispheres anteriorly which were compatible with infective or metabolic encephalopathy. Acyclovir was changed from the oral to the intravenous route at a dose of 250 mg daily with supplementary doses of 25o mg after each haemodialysis session. T h e patient became afebrile and oriented on the second day. However her clinical course was subsequently complicated by severe aspiration pneumonia and stress-induced gastro-intestinal bleeding. Despite intensive care and antibiotic coverage, she died I5 days after her second admission. Permission for post-mortem examination was refused. In both cases, the initial sepsis workup, CSF culture for bacteria, mycobacteria, fungi and viruses, CIE for common bacterial antigens (meningitis panel) and latex agglutination test for cryptococcal antigen were negative. Viral antibody titres by complement fixation tests for influenza, mumps, herpes simplex, varicella zoster, lymphocytic choriomeningitis, adenovirus, measles and enteroviruses were also negative on the CSF. T h e serum complement fixation antibody titre for VZV in both cases was I6O on admission and was negative for the viruses listed above and for Japanese B encephalitis virus. T h e r e was no recent use of desferrioxamine or other new medication. T h e r e was no clinical evidence of aluminium toxicity or underdialysis. After treatment with acyclovir for I week further CSFs were examined. T h e y were normal in both patients.
Discussion
Herpes zoster associated encephalitis has not been reported in association with dialysis patients. Both of our cases satisfied the diagnostic criteria of H Z A E which were defined by Jemsek as follows : (I) clinical evidence of H Z with or without virological confirmation; (2) an encephalopathic clinical state; (3) a diffusely abnormal E E G (4) CSF findings compatible with encephalitis; and (5) exclusion of other known toxic or metabolic-induced encephalopathies. 2 Certain factors should be considered, especially in dialysis patients. T h e y are apt to develop confusion, contributory factors are their increased susceptibility to infection, fluid or electrolyte imbalance, hypertension, nutritional deficiency, aluminium toxicity and Wernicke's encephalopathy. It is always difficult to establish a direct relationship between H Z eruption and confusion as the H Z infection can be coincidental or can be the triggering event of the above-mentioned complications. Moreover, the H Z eruption may antedate the H Z A E by 3 months or may not be observed at all. 8' 9 U n d e r such circumstances, the diagnosis of H Z A E might be missed. E E G abnormalities are rather non-specific and can be present in many conditions. T w e n t y - o n e per cent of patients with apparently uncomplicated H Z had abnormal EEGs which were qualitatively similar but quantitatively less severe than those found in patients with HZAE. 1° It is not certain whether such a high percentage of E E G abnormalities merely reflects the high prevalence of undiagnosed subclinical H Z A E or the fact that the E E G is less
172
W. C. C H E U N G E T A L .
specific as a diagnostic tool than has been supposed. Indeed E E G abnormalities were also noted in other neurotropic virus infections without overt signs of encephalitis, e.g. 30% patients with measles and 22% patients with varicella.11,1~ Uraemic patients often have abnormal EEGs with superimposed slow waves and loss of normal alpha rhythm. T h e abnormality may persist for up to 6 months after dialysis is commenced but usually it eventually resolves. 13 Moreover, abnormal EEGs and encephalopathy have been reported in patients with acyclovir induced neurotoxicity. 14 Lymphocytic pleocytosis in the CSF may not necessarily indicate involvement of the central nervous system by VZV. In patients with uncomplicated HZ, as many as 38 % were found to have mild pleocytosis or elevated CSF protein. 15 Moreover, iO~/o uraemic patients had more than 5 leucocytes m m 3 (range 7-6oo) in the CSF and 2o % had a protein concentration greater than I g/1. This was attributed to alteration of the blood-brain barrier in the uraemic state. 12 Laboratory methods used to confirm infection of the central nervous system by VZV have been described but were either insensitive or not readily available. Demonstration of VZV in the CSF or brain tissue by electron microscopy and the recovery of VZV by CSF culture offer direct evidence of invasion into the central nervous system. 16 However, there are few reports in the literature of successful diagnosis by these methods. 2'~7 VZV antibody detection in CSF by indirect immunofluorescence (FAMA) was reported to have high sensitivity and specificity in the diagnosis of HZAE. 8 However, other workers demonstrated that in patients with herpes simplex virus (HSV) encephalitis or H Z A E , 'cross reacting' antibodies, including IgM and IgG, to both HSV and VZV were detected simultaneously by enzyme-linked immunosorbent assay (ELISA). This was attributed to epitopes common to HSV and VZV. 9' 18 Thus, the mere detection of intrathecal anti-VZV-IgG or IgM does not necessarily indicate diagnostic specificity. Mathiesen 9 showed that H Z A E was associated with intrathecal synthesis of two or more V Z V - I g G subclasses which might be diagnostic of HZAE. These sophisticated methods would certainly help in the diagnosis of H Z A E but the absence of a CSF viral antibody titre does not exclude the diagnosis. Ophir 17 reported one case of culture-proven H Z A E in which the serum and CSF were negative for antibodies against VZV. As rightly pointed out by Jemsek, the diagnosis of H Z A E is largely clinical and is made by exclusion. In both our patients, the close temporal relationship between the H Z eruptions and the onset of the encephalopathic state (3 and 4 days respectively) together with the good response to intravenous acyclovir are strong supporting evidence for the diagnosis of HZAE. T h e negative CSF viral culture is in accord with the experience of many other workers in the literature. T h e negative CSF antibody for VZV could be attributed to the low sensitivity of the complement fixation method employed in our laboratory. Uraemic encephalopathy is excluded as these patients had been wellmaintained on dialysis for 6 months to 3 years before the confusional state. Dialysis encephalopathy is unlikely in view of the relatively short history of dialysis, the use of aluminium free dialysate and the absence of characteristic E E G and neurological features. Neurotoxicity due to accumulation of acyclovir
Zoster encephalitis in dialysis patients
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is unlikely as both patients i m p r o v e d after it was changed from the oral to the intravenous route. Acyclovir has been d e m o n s t r a t e d to be effective in the t r e a t m e n t of HZAE.3,16,lg,20 It penetrates the b l o o d - b r a i n - b a r r i e r well giving a p l a s m a / C S F ratio of approximately 2 : I. Its plasma half life, n o r m a l l y 2"7 h increases to 2o h with renal failure which requires the dose to be adjusted. 2~ Acyclovir is readily haemodialysable and a single 6 h session will reduce acyclovir concentration by 60 %. A n extra dose of acyclovir should therefore be given after haemodialysis. ~ Acyclovir clearance during C A P D is only 4"4 m l / m i n and no s u p p l e m e n t is required. 23 It is striking to note that both patients had been receiving oral acyclovir, 4oo m g t.d.s., for a few days before they developed H Z A E . T h e r e is no clinical s t u d y that has examined the pharmacokinetics of oral acyclovir in uraemic patients t h o u g h a r e c o m m e n d a t i o n of dosage based on pharmacokinetic analysis of oral acyclovir was published. 24 T h e bioavailability of oral acyclovir varies between 15 and 3 0 % in the normal host. 25 I m p a i r e d intestinal absorption of various substances due to uraemic toxins, vitamin D deficiency, intestinal ileus and bacterial overgrowth has been reported in renal failure. 26 T h u s , absorption of acyclovir m i g h t have been erratic, allowing H Z A E to develop as a result of subtherapeutic acyclovir values in the plasma. Both patients i m p r o v e d after changing to intravenous acyclovir. In s u m m a r y , we have reported two cases of H Z A E in patients on dialysis. T h e diagnosis of H Z A E remains a clinical one and can only be m a d e by exclusion. Both patients had been receiving oral acyclovir before developing H Z A E and i m p r o v e d after changing to the intravenous route. H Z eruption in dialysis patients, as in others who are i m m u n o s u p p r e s s e d , should be treated by intravenous acyclovir so that the rare complication of H Z A E m a y be prevented. References
I. Chang CM, Woo E, Yu YL, Q'Huang CY, Chiu D. Herpes zoster and its neurological complications. Postgrad Med J I987; 63 : 85-89. 2. Jemsek J, Greenberg SB, Taber L, Harvey D, Gershon A, Couch RB. Herpes zosterassociated encephalitis : clinicopathologic report of ~2 cases and review of the literature. Medicine (Baltimore) I983 ; 62: 81-97. 3. Johns DR, Gress DR. Rapid response to acyclovir in herpes zoster-associated encephalitis. Am J Med I987; 82: 560-562. 4. Goldblum SE, Read WP. Host defenses and immunologic alterations associated with chronic haemodialysis. Ann Intern Med I98O; 93: 597-613. 5- Ruiz P, Gomez F. Impaired function of macrophage Fc gamma receptors in end-stage renal disease. N Engl J Med I99o; 322(I I) : 717-722. 6. Santiago A, Chazan JA. Factors associated with mortality among 405 chronic haemodialysis patients who died between I973 and i985. Kidney Int I987; 3I: 245. 7. Belcon MC, Smith EKM, Kahana LM, Shimizu AG. Tuberculosis in dialysis patients. Clin Nephrol I982; x7: I4. 8. Gershon A, Steinberg S, Greenberg S, Taber L. Varicella zoster associated encephalitis: detection of specific antibody in CSF. J Clin Microbiol I98o; I2: 764-767. 9- Mathiesen T, Linde A, Stenkvist EO, Wahren B. Antiviral IgM and IgG subclasses in varicella zoster associated neurological syndromes. J Neurol Neurosurg Psychiatry I989; 52 : 578-582. IO. 7
Peterslund NA, Hansen JH. Electroencephalographic changes in patients with herpes zoster. Acta Neurol Scand I989; 79: 4o7-4II. JI N 23
174
W. C. G H E U N G E T AL.
I I. Grossman HJ, Gibbs EL, Lepper M H , Spies HW. Electroencephalographic studies on children with measles with no clinical evidence of C N S involvement. Elektroenceph Clin Neurophysiol r955; 7: 3x5. I2. Gibbs FA, Gibbs EL, Carpenter PR. Electroencephalographic abnormality in ' u n complicated' childhood diseases. J A M A I959; I 7 I : IO5O-IO55 . I3. Morrison G, Geheb MA, Earley LE, Seldin PW, Giebisch G, Eds. Chronic renal failure in the kidney physiology and pathophysiology. Vol. 2 New York: Raven Press, r985: I928. x4. Arndt KA. Adverse reactions to acyclovir: topical, oral and intravenous, ff A m Acad Derrnatol I988; I8 (Ipt2): I88-I9O. I5. Gold E. Serologic and virus isolation studies of patients with varicella or herpes zoster infection. N Engl ff Med I966; 274(4): r 8 I - I 8 5 . I6. Steele RW, Keeney RE, Bradsher RW, Moses EB, SoloffBL. Treatment of varicella-zoster meningo-encephalitis with acyclovir---demonstration of virus in C S F by electron microscopy. A m J Clin Pathol I983 ; 8o : 57--6o. x7. Ophir O, Siegman-Igra Y, Vardinon N, Liron M. Herpes zoster encephalitis : isolation of virus from cerebrospinal fluid. Isr ff Med Sci I984; 2o: I I89~I I92. I8. Dennin RH, Herb E. Immunological diagnosis in viral infections of the C N S : course of antibody titres against homo- and heterologous viruses. Med Microbiol Imrnunol I989; I78 : 255-268. r 9. Cheesbrough J S, Finch R G , W a r d MJ. A case of herpes zoster associated encephalitis with rapid response to acyclovir. Postgrad Med ff I985 ; 6I : I45-x46. 2o. Bowan RV, Lythall DA, D e W y t t CN. A case of herpes zoster associated encephalitis treated with acyclovir. ,,lust N Z f f Med I985; I5: 43-442I. Blum M R , Liao S, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. A m ff Med I982; 73: I86--I92. 22. Krasny HC, Liao S H T , Miranda PD. Influence of haemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. A m ff Med r982; 73: 2o2-2o4. 23. Shah G M , Winer RL, Krasny HC. Acyclovir pharmacokinetics in a patient on CAPD. Am ff Kidney Dis I986; 6: 5o7-5Io. 24. Fletcher CV, Chinnock BJ, Chace B, Balfour H H . Pharmacokinetics and safety of high dose oral acyclovir for suppression of CMV disease after renal transplantation. Clin pharrnacol Ther I988; 44: 158-163. 25. D e Miranda P, Blum, MR. Pharmacokinetics of acyclovir after intravenous and oral administration, ff Amirnicrob Chernother I983 ; x2 (Suppl B) : 29-37. 26. Adler M, Toussaint C. Gastrointestinal complications of renal failure. In: Maher JF, Ed. Replacement of renal function by dialysis. 3rd ed. Holland: Kluwer Academic Publishers, I989 : 843.
