Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis

Stockholm University, Tukholma, Stockholm, Sweden
Journal of Neurology (Impact Factor: 3.38). 03/2006; 253(2):163-70. DOI: 10.1007/s00415-005-0941-6
Source: PubMed


To study the occurrence of relapse of herpes simplex encephalitis (HSE) and to find out whether soluble activity markers in cerebrospinal fluid (CSF) indicate direct viral or immune- mediated events.
A consecutive series of 32 adult survivors of HSE were followed to determine the incidence of clinical relapse of HSE. Four patients had neurological deterioration interpreted as relapsing HSE. Four non-relapsing HSE cases were selected as matched controls. Fifty nine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon-gamma, soluble CD8, tumour necrosis factor-alpha, and interleukin-10), amount of HSV-DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S-100-beta, and neuron specific enolase).
Relapse of HSE was diagnosed in 3 of 26 (12 %) acyclovir-treated patients (5 episodes during 6.1 years of followup) and in 1 of 6 vidarabine-recipients. All relapses occurred from 1 to 4 months after acute HSE, except for a second relapse after 3.3 years in one patient. Computer tomography at relapses revealed few abnormalities apart from those found during the primary disease. Intravenous acyclovir and corticosteroids were given for 7-21 days in all the relapse patients. All relapse patients seemed to recover to the pre-relapse condition. HSV-DNA was demonstrated in CSF in all patients during the acute stage but not in any of 13 CSF samples taken during relapse phases. The HSV viral load during the acute stage of HSE was not higher or of longer duration in the relapsing patients than in the non-relapsing HSE controls. The levels of sCD8 were increased in nearly all CSF samples tested with peaks of sCD8 at one month of acute HSE. In all episodes of relapse, sCD8 peaks were detected during the first week at high levels. CSF levels of neuron-specific enolase, S-100 and glial fibrillary acidic protein were markedly lower at relapse than at the acute stage of HSV-1 encephalitis.
The lack of demonstrable HSV DNA in CSF, the lack of acute CSF signs and the lack of signs of neural and glia cells destruction indicate that a direct viral cytotoxicity is not the major pathogenic mechanism in relapse. Instead, the pronounced CSF proinflammatory immunological response and the relative lack of CSF anti-inflammatory cytokine IL-10 response suggest immunologically-mediated pathogenicity.

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    • "Children frequently have dyskinesia and choreoathetosis that typically develop 4 – 6 weeks after the initial HSVE episode. In adult relapse cases, cognitive and psychiatric symptoms are more prominent and movement disorders have not been described [13, 16]. The CSF PCR for HSV is no longer positive, the MRI does not show new necrotic lesions, and symptoms do not respond to antiviral therapy. "
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    ABSTRACT: Classic herpes simplex virus encephalitis (HSVE) is an acute viral infection that usually follows a monophasic disease course; however some patients, mainly children, experience a relapse within weeks or months after the initial event. In a subset of these patients a viral reactivation is unlikely because the CSF PCR for HSV is negative, repeated MRI does not show new necrotic lesions, and the symptoms are refractory to antiviral therapy. These patients often develop choreoathetosis variably accompanied by behavioral changes and seizures, and a postinfectious immune-mechanism has been postulated. Recent studies demonstrated that 7% of patients with HSVE harbor NR1 N-methyl-D-aspartate receptor (NMDAR) IgG antibodies. Moreover, a child with post- HSVE choreoathetosis was found to have NMDAR antibodies; the patient did not improve with antiviral therapy but recovered after aggressive immunotherapy. Based on these findings, evidence is increasing that a subgroup of post-HSVE represents a separate disease entity, which in fact is anti-NMDAR encephalitis. Patients with relapsing HSVE or prolonged atypical symptoms, who have negative CSF PCR for HSV should routinely be tested for NMDAR IgG antibodies in CSF and serum. It is important to be aware of this differential diagnosis because patients respond to immunotherapy.
    Full-text · Article · Jul 2013 · Clinical neuropathology
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    • "The ideal length of treatment recommended for adults and children with HSV encephalitis is still unknown. Initial trials suggested 10 days [17], but since then, relapses have been reported, so 14 – 21 days is now recommended [18,19]. Additionally, many would recommend repeating the LP to ensure that the CSF is negative for HSV by PCR before stopping treatment and this is supported by a European consensus statement and recently published UK guidelines on the management of children with viral encephalitis [19]. "
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    ABSTRACT: We aimed to audit the regional management of central nervous system (CNS) infection in children. The study was undertaken in five district general hospitals and one tertiary paediatric hospital in the Mersey region of the UK. Children admitted to hospital with a suspected CNS infection over a three month period were identified. Children were aged between 4 weeks and 16 years old. Details were recorded from the case notes and electronic records. We measured the appropriateness of management pathways as outlined by national and local guidelines. Sixty-five children were identified with a median age of 6 months (range 1 month to 15 years). Ten had a CNS infection: 4 aseptic meningitis, 3 purulent meningitis, 3 encephalitis [2 with herpes simplex virus (HSV) type 1]. A lumbar puncture (LP) was attempted in 50 (77%) cases but only 43 had cerebrospinal fluid (CSF) available for analysis. Of these 24 (57%) had a complete standard set of tests performed. Fifty eight (89%) received a third generation cephalosporin. Seventeen (26%) also received aciclovir with no obvious indication in 9 (53%). Only 11 (65%) of those receiving aciclovir had CSF herpes virus PCR. Seventeen had cranial imaging and it was the first management step in 14. Treatment lengths of both antibiotics and aciclovir were highly variable: one child with HSV encephalitis was only treated with aciclovir for 7 days. The clinical management of children with suspected CNS infections across the Mersey region is heterogeneous and often sub-optimal, particularly for the investigation and treatment of viral encephalitis. National guidelines for the management of viral encephalitis are needed.
    Full-text · Article · Sep 2012 · BMC Pediatrics
    • "This may have been the basis of the early relapse in the case presented. HSV-DNA may or may not be demonstrable in the CSF during relapse[1012] The role of corticosteroids in HSE is not well defined. Neurological damage in HSE results not only from viral invasion, but also from intense inflammatory changes and cerebral edema secondary to the immune response to the virus.[213] "
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    ABSTRACT: A 2-month-old infant presented to our emergency department with fever, altered consciousness, and focal seizures of acute onset. He had vesicular skin lesions over the right preauricular region. CT brain showed a large hypodense lesion involving the left temporo-parietal region, left basal ganglia and left thalamus. MRI brain revealed bilateral multifocal corticomedullary lesions suggestive of encephalitis. CSF-PCR was positive for herpes simplex virus (HSV) type I. He was treated with standard dose intravenous acyclovir for 15 days along with a trial of pulse methylprednisolone, but was readmitted within a week with features of an early relapse. The infant survived but developed significant neurological sequelae. Although treatment of HSV is available, the neurological outcome is guarded even with adequate antiviral therapy. Adjunct corticosteroid therapy did not appear to attenuate the neurological sequelae.
    No preview · Article · Nov 2011 · Indian Journal of Dermatology
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