Aciclovir induced posterior leucoencephalopathy
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神经科学杂志 2005年第9期
1 Department of Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK
2 Department of Neuroradiology, Newcastle General Hospital
3 Division of Clinical Pharmacology, Karolinska Institute, Stockholm, Sweden
Keywords: aciclovir; encephalopathy; 9-carboxymethoxymethylguanine
Aciclovir is an extremely effective agent for the treatment of herpes simplex encephalitis and varicella–zoster infections in immunocompromised individuals.1 Encephalopathy induced by aciclovir is an infrequent but well recognised adverse effect of aciclovir.2 The predisposing factors to aciclovir induced encephalopathy (AIE) include age, acute or chronic renal failure, and other neurotoxic drugs.2 Tremors (40–58%), disorientation (40–50%), agitation (22–38%), hallucinations (25%), and delirium (25%) are common presentations of AIE, whereas seizures (10%), cerebellar ataxia (11%), sensory symptoms (9%), speech disorders (9%), fever (3%), and cranial nerve palsies (0%) are much less frequent.2 The supportive diagnostic criteria for AIE include a temporal association between the symptoms and aciclovir use, as well as acellular cerebrospinal fluid (CSF) in cases without herpes simplex or varicella–zoster encephalitis. In the majority of cases symptoms develop within 72 hours of starting aciclovir treatment, although up to 120 days has been reported.2 The clinical recovery may take several days (five days in 57% of cases) following discontinuation of aciclovir.2 The EEG typically shows diffuse slow wave activity rather than focal abnormalities.2
The radiological features are not well described in AIE. Case reports have identified multifocal white matter signal abnormalities involving the cerebellum, pons, and periventricular region as well as evidence of vascular encephalopathy on MRI.2,3 We report a case of AIE with MRI features consistent with posterior leucoencephalopathy with clinical and radiological improvement following the discontinuation of aciclovir, along with raised serum and CSF concentrations of aciclovir and 9-carboxymethoxymethylguanine (CMMG), the main metabolite of aciclovir.
Case report
A 47 year old women with a 15 month history of cANCA+ glomerulonephritis and chronic end stage renal failure (serum creatinine 957 μmol/l), managed on continuous ambulatory peritoneal dialysis, azathioprine (100 mg/day), and prednisolone (10 mg/day), developed a mid-thoracic varicella–zoster rash. She was given a reduced dose of intravenous aciclovir (250 mg three times daily). Within 48 hours she became agitated, developed visual hallucinations and drowsiness (Glasgow coma scale (GCS): overall 6; eye 1, motor 4, verbal 1). On admission to the intensive care unit she was apyrexial, the highest blood pressure recorded was 180/104 while agitated, and fundoscopy was unremarkable. The tendon reflexes were exaggerated, with extensor plantar responses. Oculocephalic and corneal reflexes as well as spontaneous respiration were present.
Laboratory investigations showed a haemoglobin of 9.7 g/l, white cell count 5.8x109/l, urea 22 mmol/l, ESR 90 mm/h, C reactive protein 27 mg/l, albumin 22 g/l, ammonia 10 mmol/l, and cANCA negative. Computed tomography of the head, done immediately after she became obtunded, showed posterior white matter hypodensities. The lumbar CSF contained no white cells and four red blood cells per mm3, with a protein of 0.63 g/l and a CSF/serum glucose ratio of 3.9/6.4. The opening pressure was 41 cm. CSF cultures, including culture for acid fast bacilli, were negative. CSF testing by polymerase chain reaction was negative for herpes simplex virus I and II, varicella–zoster virus, cryptococcal antigen, and JC virus. An EEG showed excessive slow wave activity. Magnetic resonance imaging (MRI) of the brain and an MR venogram (done after five days on aciclovir) showed symmetrical posterior white matter changes predominantly in the occipital and parietal lobes (fig 1A and 1B) without evidence of venous sinus thrombosis, gadolinium enhancement, or matched defects in diffusion weighted images.
On admission, azathioprine was stopped and intravenous methylprednisolone (500 mg/day for three days) was started for presumed CNS vasculitis. There was no improvement 72 hours after this treatment and after eight days of aciclovir. Aciclovir was discontinued when AIE was suspected, and peritoneal dialysis was maintained. Within 48 hours of discontinuation of aciclovir, the GCS improved (eye score 3, motor score 6, verbal score 3) and neurological examination showed bilateral upper limb postural tremor, which resolved over 24 hours. The Addenbrooke’s score was 77/100. Repeat MRI (fig 1C, 1D) showed a significant improvement. Analysis of aciclovir and CMMG levels in the serum and CSF showed high values, at levels generally associated with neurotoxicity.4 The serum aciclovir and CMMG concentrations were, respectively, as follows:
5 days post-aciclovir initiation: 34.9 μmol/l and 91.7 μmol/l;
6 days post-aciclovir: 35.4 μmol/l and 148.5 μmol/l;
7 days post-aciclovir: 17.2 μmol/l and 141 μmol/l.
The CSF aciclovir and CMMG concentrations four days post-aciclovir initiation were, respectively, 5.99 μmol/l and 2.25 μmol/l (CMMG levels are not detectable in CSF unless there is neurotoxicity (Helldén A, submitted for publication)), supporting a diagnosis of AIE.4
Comment
The clinical presentation of our patient, her rapid recovery, and the CSF and EEG findings are characteristic of AIE in cases without herpes simplex or varicella–zoster encephalitis.2,5 The lack of significantly raised blood pressure or papilloedema excludes hypertensive posterior leucoencephalopathy. ANCA+ vasculitis causing posterior leucoencephalopathy has been reported but only in the presence of severe hypertension. AIE, an infrequent but well recognised adverse effect of aciclovir, has until now been diagnosed mainly on clinical features.2,5 Factors predisposing to AIE include age, acute or chronic renal failure, and other neurotoxic drugs.5 The diagnosis is facilitated by analysis of aciclovir and CMMG in serum and CSF. In cases with renal failure, the half life of aciclovir extends from 3 to 20 hours and as a result aciclovir is metabolised to CMMG by alcohol and aldehyde dehydrogenases.4 At present, reliable dose recommendations are not available for patients with renal failure.
In a case study of 93 patients, mainly with renal failure,4 we found mean (SD) serum aciclovir concentrations of 21.0 (30.7) μmol/l (in 49 patients with neurotoxicity) and 7.2 (6.7) μmol/l (in 44 asymptomatic patients receiving aciclovir), while CMMG concentrations were 34.1 (39.4) μmol/l in patients with neurotoxicity and 4.7 (4.7) μmol/l in asymptomatic patients. CMMG levels of >10 μmol/l seemed to be associated with neurotoxicity. A high CMMG level is a strong predictor of AIE in patients with renal failure.4 Haemodialysis is effective in clearing aciclovir and CMMG, and to a lesser extent so is peritoneal dialysis.4
This case highlights the difficulties in diagnosing AIE and the value of measuring aciclovir and CMMG levels in making the diagnosis.4 In cases with renal failure and herpes simplex or varicella–zoster encephalitis, aciclovir should not be discontinued prematurely, but a total daily dose exceeding 400 mg is not generally recommended in patients with renal impairment. Pharmacokinetic studies of aciclovir and CMMG are being undertaken at Karolinska University Hospital, Sweden, with the aim of achieving dose recommendations for patient with renal failure.
ACKNOWLEDGEMENTS
We are grateful to Dr M Snow, Department of Infectious Diseases, Newcastle General Hospital (NGH) for the clinical input and helpful comments, and Dr T J Walls (NGH) for financial support.
References
Dorsky DI. Clyde S, Crumpacker S. Drugs five years later: acyclovir, Ann Intern Med 1987;107:859–74.
Rashiq S, Briewa L, Mooney M, et al. Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med 1993;234:507–11.
Braun JS, Apel I. Schaffer S, et al. Delirium during oral therapy of herpes zoster with acyclovir: case report and brief review of central nervous system side-effects of acyclovir. Nervenarzt 1998;69:1015–18.
Hellden A, Odar-Cederlof I, Diener P, et al. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study. Nephrol Dial Transplant 2003;18:1135–41.
Cohen SM, Minkove JA, Zebley JW, et al. Severe but reversible neurotoxicity from acyclovir. Ann Intern Med 1984;100:920.(D Mahad, J Jarvis, P F Ch)
2 Department of Neuroradiology, Newcastle General Hospital
3 Division of Clinical Pharmacology, Karolinska Institute, Stockholm, Sweden
Keywords: aciclovir; encephalopathy; 9-carboxymethoxymethylguanine
Aciclovir is an extremely effective agent for the treatment of herpes simplex encephalitis and varicella–zoster infections in immunocompromised individuals.1 Encephalopathy induced by aciclovir is an infrequent but well recognised adverse effect of aciclovir.2 The predisposing factors to aciclovir induced encephalopathy (AIE) include age, acute or chronic renal failure, and other neurotoxic drugs.2 Tremors (40–58%), disorientation (40–50%), agitation (22–38%), hallucinations (25%), and delirium (25%) are common presentations of AIE, whereas seizures (10%), cerebellar ataxia (11%), sensory symptoms (9%), speech disorders (9%), fever (3%), and cranial nerve palsies (0%) are much less frequent.2 The supportive diagnostic criteria for AIE include a temporal association between the symptoms and aciclovir use, as well as acellular cerebrospinal fluid (CSF) in cases without herpes simplex or varicella–zoster encephalitis. In the majority of cases symptoms develop within 72 hours of starting aciclovir treatment, although up to 120 days has been reported.2 The clinical recovery may take several days (five days in 57% of cases) following discontinuation of aciclovir.2 The EEG typically shows diffuse slow wave activity rather than focal abnormalities.2
The radiological features are not well described in AIE. Case reports have identified multifocal white matter signal abnormalities involving the cerebellum, pons, and periventricular region as well as evidence of vascular encephalopathy on MRI.2,3 We report a case of AIE with MRI features consistent with posterior leucoencephalopathy with clinical and radiological improvement following the discontinuation of aciclovir, along with raised serum and CSF concentrations of aciclovir and 9-carboxymethoxymethylguanine (CMMG), the main metabolite of aciclovir.
Case report
A 47 year old women with a 15 month history of cANCA+ glomerulonephritis and chronic end stage renal failure (serum creatinine 957 μmol/l), managed on continuous ambulatory peritoneal dialysis, azathioprine (100 mg/day), and prednisolone (10 mg/day), developed a mid-thoracic varicella–zoster rash. She was given a reduced dose of intravenous aciclovir (250 mg three times daily). Within 48 hours she became agitated, developed visual hallucinations and drowsiness (Glasgow coma scale (GCS): overall 6; eye 1, motor 4, verbal 1). On admission to the intensive care unit she was apyrexial, the highest blood pressure recorded was 180/104 while agitated, and fundoscopy was unremarkable. The tendon reflexes were exaggerated, with extensor plantar responses. Oculocephalic and corneal reflexes as well as spontaneous respiration were present.
Laboratory investigations showed a haemoglobin of 9.7 g/l, white cell count 5.8x109/l, urea 22 mmol/l, ESR 90 mm/h, C reactive protein 27 mg/l, albumin 22 g/l, ammonia 10 mmol/l, and cANCA negative. Computed tomography of the head, done immediately after she became obtunded, showed posterior white matter hypodensities. The lumbar CSF contained no white cells and four red blood cells per mm3, with a protein of 0.63 g/l and a CSF/serum glucose ratio of 3.9/6.4. The opening pressure was 41 cm. CSF cultures, including culture for acid fast bacilli, were negative. CSF testing by polymerase chain reaction was negative for herpes simplex virus I and II, varicella–zoster virus, cryptococcal antigen, and JC virus. An EEG showed excessive slow wave activity. Magnetic resonance imaging (MRI) of the brain and an MR venogram (done after five days on aciclovir) showed symmetrical posterior white matter changes predominantly in the occipital and parietal lobes (fig 1A and 1B) without evidence of venous sinus thrombosis, gadolinium enhancement, or matched defects in diffusion weighted images.
On admission, azathioprine was stopped and intravenous methylprednisolone (500 mg/day for three days) was started for presumed CNS vasculitis. There was no improvement 72 hours after this treatment and after eight days of aciclovir. Aciclovir was discontinued when AIE was suspected, and peritoneal dialysis was maintained. Within 48 hours of discontinuation of aciclovir, the GCS improved (eye score 3, motor score 6, verbal score 3) and neurological examination showed bilateral upper limb postural tremor, which resolved over 24 hours. The Addenbrooke’s score was 77/100. Repeat MRI (fig 1C, 1D) showed a significant improvement. Analysis of aciclovir and CMMG levels in the serum and CSF showed high values, at levels generally associated with neurotoxicity.4 The serum aciclovir and CMMG concentrations were, respectively, as follows:
5 days post-aciclovir initiation: 34.9 μmol/l and 91.7 μmol/l;
6 days post-aciclovir: 35.4 μmol/l and 148.5 μmol/l;
7 days post-aciclovir: 17.2 μmol/l and 141 μmol/l.
The CSF aciclovir and CMMG concentrations four days post-aciclovir initiation were, respectively, 5.99 μmol/l and 2.25 μmol/l (CMMG levels are not detectable in CSF unless there is neurotoxicity (Helldén A, submitted for publication)), supporting a diagnosis of AIE.4
Comment
The clinical presentation of our patient, her rapid recovery, and the CSF and EEG findings are characteristic of AIE in cases without herpes simplex or varicella–zoster encephalitis.2,5 The lack of significantly raised blood pressure or papilloedema excludes hypertensive posterior leucoencephalopathy. ANCA+ vasculitis causing posterior leucoencephalopathy has been reported but only in the presence of severe hypertension. AIE, an infrequent but well recognised adverse effect of aciclovir, has until now been diagnosed mainly on clinical features.2,5 Factors predisposing to AIE include age, acute or chronic renal failure, and other neurotoxic drugs.5 The diagnosis is facilitated by analysis of aciclovir and CMMG in serum and CSF. In cases with renal failure, the half life of aciclovir extends from 3 to 20 hours and as a result aciclovir is metabolised to CMMG by alcohol and aldehyde dehydrogenases.4 At present, reliable dose recommendations are not available for patients with renal failure.
In a case study of 93 patients, mainly with renal failure,4 we found mean (SD) serum aciclovir concentrations of 21.0 (30.7) μmol/l (in 49 patients with neurotoxicity) and 7.2 (6.7) μmol/l (in 44 asymptomatic patients receiving aciclovir), while CMMG concentrations were 34.1 (39.4) μmol/l in patients with neurotoxicity and 4.7 (4.7) μmol/l in asymptomatic patients. CMMG levels of >10 μmol/l seemed to be associated with neurotoxicity. A high CMMG level is a strong predictor of AIE in patients with renal failure.4 Haemodialysis is effective in clearing aciclovir and CMMG, and to a lesser extent so is peritoneal dialysis.4
This case highlights the difficulties in diagnosing AIE and the value of measuring aciclovir and CMMG levels in making the diagnosis.4 In cases with renal failure and herpes simplex or varicella–zoster encephalitis, aciclovir should not be discontinued prematurely, but a total daily dose exceeding 400 mg is not generally recommended in patients with renal impairment. Pharmacokinetic studies of aciclovir and CMMG are being undertaken at Karolinska University Hospital, Sweden, with the aim of achieving dose recommendations for patient with renal failure.
ACKNOWLEDGEMENTS
We are grateful to Dr M Snow, Department of Infectious Diseases, Newcastle General Hospital (NGH) for the clinical input and helpful comments, and Dr T J Walls (NGH) for financial support.
References
Dorsky DI. Clyde S, Crumpacker S. Drugs five years later: acyclovir, Ann Intern Med 1987;107:859–74.
Rashiq S, Briewa L, Mooney M, et al. Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med 1993;234:507–11.
Braun JS, Apel I. Schaffer S, et al. Delirium during oral therapy of herpes zoster with acyclovir: case report and brief review of central nervous system side-effects of acyclovir. Nervenarzt 1998;69:1015–18.
Hellden A, Odar-Cederlof I, Diener P, et al. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study. Nephrol Dial Transplant 2003;18:1135–41.
Cohen SM, Minkove JA, Zebley JW, et al. Severe but reversible neurotoxicity from acyclovir. Ann Intern Med 1984;100:920.(D Mahad, J Jarvis, P F Ch)