A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a Broader Spectrum of Disease?

Elbers, Jorina; Bitnun, Ari; Richardson, Susan E.; Ford-Jones, E. Lee; Tellier, Raymond; Wald, Rachel M.; Petric, Martin; Kolski, Hanna; Heurter, Helen; MacGregor, Daune

doi:10.1542/peds.2006-1494

Cited by 132 publications

(120 citation statements)

References 32 publications

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“…Even with broad testing for HSV (84% of patients), HSV encephalitis was diagnosed in only 5%, confirming recent reports that HSV encephalitis is less common in children than adults with encephalitis. 4,29,30 Despite early acyclovir therapy (not described), the outcomes after HSV encephalitis were poor, as described in recent pediatric cohorts. 30,31 Interestingly, 1 patient with HSV encephalitis relapsed with chorea and had NMDAR and D2R antibodies.…”

Section: Discussionmentioning

confidence: 97%

“…4,29,30 Despite early acyclovir therapy (not described), the outcomes after HSV encephalitis were poor, as described in recent pediatric cohorts. 30,31 Interestingly, 1 patient with HSV encephalitis relapsed with chorea and had NMDAR and D2R antibodies. 32 The emerging theme of postviral autoimmunity is increasingly recognized, and it emphasizes the importance of considering immunotherapies in post-HSV relapses.…”

Section: Discussionmentioning

confidence: 97%

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Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

et al. 2015

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BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immunemediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome.METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis).RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS:We have defined clinical and radiologic phenotypes of infectious and immunemediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/ autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority. WHAT'S KNOWN ON THIS SUBJECT:Encephalitis is a serious and disabling condition. There are infectious and immune-mediated causes of encephalitis, but many cases remain undiagnosed. WHAT THIS STUDY ADDS:This large single-center study on childhood encephalitis provides insight into the relative frequency and clinicoradiologic phenotypes of infectious, autoantibody-associated, and unknown encephalitis. Risk factors for an abnormal outcome are also defined. 4 and a prospective study of adults (n = 134) and children (n = 69) with encephalitis found that infectious encephalitis and immunemediated forms were identified in 42% and 21% of the cohort, respectively. 5 However, most of the previous larger studies of encephalitis in children were undertaken before the advent of neuronal autoantibody testing. [6][7][8] We studied clinical and radiologic features, serum autoantibodies in acute archived samples, and longterm outcomes in a large ret...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

et al. 2015

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“…Although standard treatment for viral encephalitis involves acyclovir, an inhibitor of DNA polymerase (Whitley et al, 1986), poor long-term neurologic and cognitive outcomes still occur (Elbers et al, 2007;Hokkanen et al, 1996;Lahat et al, 1999). However, some have reported that although acyclovir can reduce CNS viral titres to undetectable levels, inflammatory markers remain unaffected (Lund-berg et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

Galic

Riazi

Henderson

et al. 2009

Neurobiology of Disease

101

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Viral infections of the CNS and their accompanying inflammation can cause long-term neurological effects, including increased risk for seizures. To examine the effects of CNS inflammation, we infused polyinosinic: polycytidylic acid, intracerebroventricularly to mimic a viral CNS infection in 14 day-old rats. This caused fever and an increase in the pro-inflammatory cytokine, interleukin (IL)-1β in the brain. As young adults, these animals were more susceptible to lithium-pilocarpine and pentylenetetrazol-induced seizures and showed memory deficits in fear conditioning. Whereas there was no alteration in adult hippocampal cytokine levels, we found a marked increase in NMDA (NR2A and C) and AMPA (GluR1) glutamate receptor subunit mRNA expression. The increase in seizure susceptibility, glutamate receptor subunits, and hippocampal IL-1β levels were suppressed by neonatal systemic minocycline. Thus, a novel model of viral CNS inflammation reveals pathophysiological relationships between brain cytokines, glutamate receptors, behaviour and seizures, which can be attenuated by anti-inflammatory agents like minocycline.

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“…PCR for HSV-1 and HSV-2, which has supplanted viral cultures and other studies as the test of choice, should be obtained from the CSF and has high sensitivity (96 %) and specificity (99 %) [67,68]. False-negative PCR can occur early in the illness [98][99][100], and if the clinical suspicion is high, aciclovir should be continued empirically and repeat CSF HSV PCR obtained within 3-7 days [43].…”

Section: Laboratory Studiesmentioning

confidence: 99%

“…3) Falsenegative PCR studies. HSV-1 PCR may yield a false-negative, particularly early in the course of the HSVE and among children [98][99][100]. When suspicion is high, patients should be treated empirically, despite a negative PCR, and HSV PCR from the CSF should be repeated within 3-7 days [43].…”

Section: Diagnostic Pitfallsmentioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be lifesaving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

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A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a Broader Spectrum of Disease?

Cited by 132 publications

References 32 publications

Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

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