REVIEW URRENT C OPINION
Epidemiology and outcomes of acute encephalitis Arun Venkatesan
Purpose of review This review seeks to describe recent advances in the epidemiology, outcomes, and prognostic factors in acute encephalitis. Recent findings Infectious causes continue to account for the largest proportion of encephalitis cases in which a cause is identified, although autoimmune causes are increasingly recognized. Type-A gamma-aminobutyric acid (GABAa) receptor antibodies have been recently identified in encephalitis with refractory seizures, whereas the roles of antibodies to the glycine receptor and dipeptidyl peptidase-like protein 6 have been defined in progressive encephalomyelitis with rigidity and myoclonus. Recent findings in the US cases of encephalomyelitis presenting with acute flaccid paralysis raise the possibility that enterovirus D68, a common respiratory pathogen, may cause central nervous system disease. Mortality from acute encephalitis occurs in about 10% of cases, with a large proportion of survivors suffering from cognitive or physical disability. In addition to delay in institution of appropriate antiviral or immune therapy, several potentially reversible factors associated with poor prognosis have been identified, including cerebral edema, status epilepticus, and thrombocytopenia. Summary Encephalitis imposes a significant worldwide health burden and is associated with poor outcomes. Supportive treatment and early institution of therapy may improve outcomes. Careful neurocognitive assessment of survivors of encephalitis is needed to better define long-term outcomes. Keywords acute flaccid paralysis, autoimmune encephalitis, herpes simplex virus, prognosis, viral encephalitis
INTRODUCTION Encephalitis, defined as inflammation of the parenchyma of the brain with associated neurologic dysfunction, manifests as a clinical syndrome characterized by a combination of encephalopathy, behavioral changes, fever, seizure, and focal neurologic deficits [1]. A myriad of causes can result in encephalitis, including infectious agents and an increasingly recognized number of autoimmune conditions. Outcomes are highly variable, although prognostic factors are beginning to be identified. Here we describe recent advances in our understanding of the epidemiology, prognostic factors, and outcome of acute encephalitis.
EPIDEMIOLOGY OF ENCEPHALITIS Broad strokes Several recent studies have utilized the US Nationwide Inpatient Sample (NIS), a nationally representative database of hospitalizations, to estimate numbers and rates of encephalitis-associated hospitalizations [2 ,3 ]. These studies report that over the &
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past decade, approximately 250 000 patients were admitted with a diagnosis of encephalitis, with a hospitalization rate of approximately seven per 100 000. Although higher than reported rates from other countries [4–8], this is comparable to the prior decade in the United States, suggesting that the overall incidence of encephalitis has not changed substantially over time [9]. Approximately half of all cases were associated with a known cause, congruent with many other large studies spanning the past several decades [9–12]. The leading identified cause was viral encephalitis and the most common specific cause was herpes encephalitis, which accounted for approximately 14% of all hospitalizations [2 ,3 ]. Other notable viral causes included &
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Department of Neurology, Johns Hopkins Encephalitis Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to Arun Venkatesan, MD, PhD, Department of Neurology, The Johns Hopkins University School of Medicine, Meyer 6-113 600 N, Wolfe Street, Baltimore, MD 21287, USA. Tel: +1 410 955 3730; fax: +1 410 955 6070; e-mail: [email protected] Curr Opin Neurol 2015, 28:277–282 DOI:10.1097/WCO.0000000000000199
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KEY POINTS
States, in which 50% had an infectious cause, 20% had autoimmune cause, and only 30% remained of unknown cause [14 ]. Several recent studies have also examined the epidemiology of encephalitis among critically ill populations. In one study composed of patients with encephalitis from the Johns Hopkins Hospital over the past decade with ICU stays greater than 48 h, approximately 40% had infectious causes (predominantly HSV and VZV) and 15% had immune-mediated causes, with close to 50% of unknown cause [15 ]. The similarity in frequency of causal groups (infectious, autoimmune, unknown) between ICU and noncritically ill patients with encephalitis is noteworthy, indicating that neither infectious nor autiommune causes as a whole are preferentially associated with encephalitis severity. A French study found similar percentages of immune-mediated causes but a higher percentage of infectious causes (over 50%). This was driven largely by M. tuberculosis (23% of cases) and Listeria monocytogenes (7% of cases) [16 ], the frequency of which have been previously recognized in encephalitis in France [11]. &
Infectious agents, including HSV and VZV, continue to account for a large proportion of cases of encephalitis. Ongoing identification of newer autoantibodies, including those directed against the GABAa receptor and the glycine receptor, has resulted in the expanding spectrum of recognized autoimmune encephalitis. Enterovirus D68 may be responsible for a recent surge in AFP-encephalitis cases in the United States.
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The recent identification of several potentially reversible risk factors for poor prognosis following encephalitis, including status epilepticus, cerebral edema, and thrombocytopenia, suggests the possibility of targeted intervention to improve outcomes. The incidence and magnitude of cognitive dysfunction following encephalitis is likely underappreciated and will require careful long-term follow-up.
enteroviruses, West Nile virus (WNV), and varicella zoster virus (VZV), which also account for substantial proportions of cases in other large studies [7,10,11,13]. Notably, the epidemiology of encephalitis as described in these large studies appears to be changing. Encephalitis-associated hospitalization rates for women were higher than for males [2 ,3 ], whereas in the previous decade, the rates were substantially higher in males [9]. A similar trend was noted in a study in Canada, where the relative increase in hospitalization rates was largely attributed to an increased incidence of VZV encephalitis in women [7], a finding not observed in the US NIS studies. It has been hypothesized that the increasing recognition of immune-mediated causes such as anti-Nmethyl-D-aspartate receptor (NMDAR) encephalitis, which may predominate in women and are not specifically coded for in the US NIS studies, accounts for the increase in encephalitis-associated hospitalization rates for women [2 ,3 ]. In support of this, it has recently been shown that systematic and extensive testing can result in the identification of additional specific causes – most notably autoimmune – that can substantially decrease the proportion of unknown causes of encephalitis to less than 40% [13]. In that study from the United Kingdom, approximately 40% of patients had infectious causes [including herpes simplex virus (HSV), VZV, and Mycobacterium tuberculosis], whereas 20% had immune-mediated cause, including acute disseminated encephalomyelitis, anti-NMDAR encephalitis, and anti-voltage-gated potassium channel (VGKC) encephalitis. These percentages are similar to a recent retrospective cohort study in the United &
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Expanding spectrum of autoantibodyassociated encephalitides Recognition of the spectrum of autoantibodymediated encephalitides continues to grow [17]. Although antibodies to the NMDAR and leucinerich, glioma inactivated 1 protein of the voltagegated potassium channel complex account for a substantial proportion of such cases, newer autoantibodies have been recently identified. In particular, high titer serum and/or cerebrospinal fluid (CSF) antibodies to the GABAa receptor were found in six patients who presented with rapidly progressive encephalopathy and refractory seizures [18 ]. Importantly, application of patient antibodies to neuronal cultures resulted in a selective reduction of synaptic GABAa receptor clusters, suggesting a pathogenic mechanism whereby disruption of GABA signaling contributes to the clinical syndrome. Another important recent advance has been the identification and characterization of autoantibodies in patients with progressive encephalomyelitis with rigidity and myoclonus (PERM). Similar to stiff-person syndrome, PERM is characterized by rigidity, myoclonus, stimulus-sensitive spasms, and autonomic disturbance; in addition, brainstem or other central nervous system manifestations arise. Previously identified autoantibodies included those directed against glutamic acid decarboxylase and amphiphysin [19,20]. Over the past 5–7 years, antibodies to the glycine receptor have also been identified in cases of PERM [21,22], &&
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Epidemiology and outcomes of acute encephalitis Venkatesan
with recent evidence suggesting that these antibodies can cause internalization and degradation of the glycine receptor [23 ]. Antibodies to the dipeptidyl peptidase-like protein 6, an extracellular component of neuronal potassium channels, have also recently been identified in three patients with a distinct PERM variant marked by cerebellar ataxia in addition to stiffness and hyperekplexia [24 ]. Although the most common autoantibody-associated encephalitides have likely been identified, it is anticipated that additional antibodymediated syndromes associated with small percentages of cases of encephalitis will continue to be identified. &&
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Update on causes of encephalomyelitis: acute flaccid paralysis Encephalomyelitis, in which patients typically develop mental status changes or cranial nerve deficits along with spinal cord manifestations such as acute flaccid paralysis (AFP), has long been recognized as a consequence of infection by polioviruses, other enteroviruses such as enterovirus-71, and WNV [25]. A recent surge in AFP in the United States, predominantly affecting children, has been found to be unrelated to both poliovirus and WNV [26 ,27 ]. These cases are preceded by a febrile and upper respiratory illness occurring approximately 1 week prior to the onset of neurologic illness and accompanied by a CSF pleocytosis. Although motor involvement is typically marked and can include ventilatory dysfunction, there is usually an absence of sensory deficits. Although CSF PCR for enteroviruses (as well as WNV and poliovirus) has been uniformly negative, PCRs from nasopharyngeal specimens have demonstrated the presence of enterovirus-D68 in some cases. Notably, enterovirus–D68 has been previously reported in the CSF of individuals with AFP, suggesting that it may cause neurologic disease [28,29]. Moreover, the surge in AFP cases has been temporally linked to an outbreak of enterovirus–D68 respiratory infections throughout the United States. Although circumstantial evidence is building, continued clinical and serological surveillance as well as testing of patients’ CSF will be needed to demonstrate a conclusive link between enterovirus–68 and AFP. &&
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PROGNOSIS, BIOMARKERS, AND OUTCOMES
information on long-term outcomes, although a recent Israeli study of 47 children with a mean follow-up of close to 6 years found that intelligence quotient is lower, behavioral impairments occur in over half of affected individuals, attention-deficit hyperactivity disorder is common (50%), and approximately 10% have residual motor deficits [30 ]. Previously reported poor prognostic factors in encephalitis include older age, immunosuppression, and other major medical comorbidities [11,31–35], findings that are corroborated by a recent analysis in hospitalized patients in the United States [2 ]. Several recent studies have attempted to further define clinical and paraclinical prognostic factors in acute encephalitis of all causes. In a study of 100 adults with all-cause encephalitis admitted to the ICU, the mortality rate was 20%, reflecting the severity of illness in this critically ill population. Notably, we found that several potentially reversible conditions, including cerebral edema, status epilepticus, and thrombocytopenia, were associated with in-hospital mortality [15 ], whereas normal electroencephalogram early in the admission was highly predictive of survival [36 ]. In a French study of critically ill patients with encephalitis, additionally identified poor prognostic factors included lower body temperature and elevated CSF protein levels [16 ]. Thrombocytopenia was also recently identified as a poor prognostic factor in a retrospective study of almost 200 patients with acute encephalitis, in which the population was not restricted to those requiring intensive care [14 ]. Taken together, these findings suggest that aggressive supportive therapies for seizures, hematologic derangements, and other comorbid conditions may improve outcomes in those with acute encephalitis. The presence of CSF proteins in acute encephalitis has also been investigated. In one study of children with acute encephalitis or encephalopathy, examination of admission CSF revealed that glialderived proteins S100B and glial fibrillary acidic protein as well as the neuronal protein tau were elevated in those with poor outcome as compared with those with favorable outcome or unaffected controls [37 ]. In another study of 56 adult patients with acute encephalitis of various causes, CSF levels of the neurofilament heavy chain, a structural component of axons, were increased in approximately 40% of patients, whereas S100B levels were increased in over 95% of patients. Notably, poor outcome was associated with increasing neurofilament heavy-chain levels over several weeks [38 ]. Overall, these findings suggest that increased levels of both glial and neuroaxonal proteins in the CSF, likely reflecting a combination of inflammation and neuronal damage, may serve as biomarkers of &&
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Acute encephalitis Mortality rates in encephalitis are typically reported to be 5–15%, with marked physical and cognitive morbidity among survivors. There is a paucity of
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prognosis in encephalitis. However, key issues such as timing and acquisition of CSF and standardization of laboratory testing will need to be further explored before such assays may be useful in a clinical setting.
Herpes simplex encephalitis Seminal studies of herpes simplex encephalitis (HSE) demonstrated that older age, poor level of consciousness at the time of initiation of therapy, and a delay of greater than 2 days between hospital admission and initiation of acyclovir were poor prognostic factors [34,39]. These findings were largely confirmed in a recent retrospective study of 106 patients admitted to several hospitals in Turkey, where follow-up information was available in over 90%. The mortality rate at 6 months was 8%, whereas only 23% had complete recovery [40 ]. Factors associated with unfavorable outcome included longer duration between onset of symptoms and hospitalization and extent of brain involvement on admission MRI, reinforcing the notion that early recognition and initiation of therapy is crucial. Several recent pediatric cohorts of HSE have also been described. In a retrospective study from the California Encephalitis Project, four of 21 pediatric cases (all adolescents) died during hospitalization [41 ], which contrasts with the surprising finding that none of 38 patients died in a recently reported German study [42 ]. In the latter, close to half (44%) were discharged with no apparent symptoms, and brain MRI remained normal in six patients more than 1 week after disease onset. However, eight patients experienced early relapses characterized by movement abnormalities and seizures; although not tested for, some or all of these cases were likely due to the development of anti-NMDAR encephalitis, which is now well documented to occur in a proportion of children and adults following HSE and has been recently reviewed [43,44]. &
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Antibody-associated encephalitis In a large observational study of over 500 patients with anti-NMDAR encephalitis, early treatment with steroids and/or immunosuppression and lack of admission to an ICU were associated with good outcome. Notably, improvement following initiation of immunotherapy was often delayed; almost half had no improvement in the first month, whereas substantial improvements occurred within 2 years of treatment in over 80% of patients [45 ]. Outcomes in another autoimmune condition, glycinereceptor antibody-associated PERM, also appear to be favorable, with the modified Rankin scale scores &&
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falling from a median of 5 during maximum severity of illness to a score of 1 over a median follow-up time of 3 years [23 ]. &&
West Nile virus West Nile virus encephalitis is associated with high in-hospital mortality (20%) and the majority of survivors have been found to experience persistent neurocognitive and functional impairments [46,47]. Recently, prospectively obtained outcomes have been reported from a trial of intravenous immunoglobulin in West Nile neuroinvasive disease (WNND) conducted between 2003 and 2006. Although the study was terminated early due to low enrolment and lack of study drug, outcome measures were obtained for up to 90 days in 55 patients. Pooled data from the three arms of the study suggested that older age and initial presentation of coma or with cranial nerve deficits were predictors of poor outcome [48 ]. Notably, substantial improvement occurred over the 90 days of the study, such that of the 14 patients who were initially comatose, only one remained in coma at follow-up. Similarly, of 25 patients who initially exhibited a cognitive deficit, only nine did so at their last evaluation [48 ]. These data underscore the potential for marked improvement over the months following an episode of WNND. &
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Other arboviral encephalitides Similar to other flaviviruses, Murray Valley encephalitis virus, endemic to Australia, can be associated with deep gray matter abnormalities on brain MRI [49,50]. A recent study found that thalamic involvement on MRI, found in approximately half of patients, was associated with at least moderate neurological deficits, whereas involvement of additional structures portended poorer prognosis [51]. Eastern equine encephalitis, a highly virulent arbovirus endemic to the eastern United States, has been associated with mortalities ranging from 25 to 70% [52]. In a cohort of 15 pediatric cases largely in Massachusetts, a short prodrome, suggestive of rapid disease progression, was associated with unfavorable outcomes [53]. Japanese encephalitis is the most commonly identified cause of encephalitis in Asia. In a cohort of 87 children in China with Japanese encephalitis, eight (9%) died, whereas 48 (55%) had full recovery at follow-up of at least 6 months [54]. Factors associated with poor outcome (death or severe sequelae) included at least two witnessed convulsions and abnormal breathing patterns, the latter of which may point to brainstem respiratory center involvement. Tick-borne encephalitis (TBE), an arboviral disease endemic to Europe and Asia, was Volume 28 Number 3 June 2015
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Epidemiology and outcomes of acute encephalitis Venkatesan
previously thought to cause mild illness in children [55]. In a recent Swedish study of 55 children with TBE, outcomes were assessed at a mean of 4 years after the acute illness [56]. Surprisingly, two-thirds of the children reported multiple symptoms, including headache, memory impairment, fatigue, irritability, and concentration problems. Cognitive function, as assessed by the Wechsler Intelligence Scale for Children-IV, was mildly to moderately impaired and involved deficits in executive function and working memory. Thus, neurocognitive dysfunction in the wake of pediatric TBE appears to be more widespread than previously recognized. Overall, careful neurocognitive assessment of survivors of encephalitis is needed to better define longterm outcomes and rehabilitation needs.
CONCLUSION Our understanding of the epidemiology of encephalitis continues to evolve, due in part to identification of new syndromes and broadening of the known clinical phenotype associated with established agents. Moreover, factors such as changes in climate and travel patterns have resulted in shifts in the geographic distribution of infectious agents. As a result, robust global surveillance measures that assess for both infectious and autoimmune causes will be necessary to define and update encephalitis epidemiology. Although encephalitis continues to be associated with significant morbidity and poor outcomes, early institution of disease-specific therapies and aggressive supportive treatment may be of benefit. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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Several of the patients described might have been classified as Hashimoto’s encephalopathy or stiff-person syndrome variants, when in actuality their clinical syndromes may have been driven by antibodies against the GABAa receptor. 19. De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of stiff-man syndrome with breast cancer. J Exp Med 1993; 178:2219–2223. 20. Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322: 1555–1560. 21. McKeon A, Martinez-Hernandez E, Lancaster E, et al. Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 2013; 70:44–50. 22. Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71:1291–1292. 23. Carvajal-Gonza´lez A, Leite MI, Waters P, et al. Glycine receptor antibodies in && PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014; 137:2178–2192. This article describes the clinical syndrome and outcomes of glycine-receptor antibody-associated PERM in 52 patients, the largest cohort described to date. Invitro studies suggest that patient antibodies can downregulate cell surface glycine receptor, thus providing a plausible mechanistic link between presence of antibodies and the autoimmune syndrome. 24. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity && and myoclonus: a new variant with DPPX antibodies. Neurology 2014; 82:1521–1528. This study describes a novel autoantibody associated with some cases of PERM.
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41. To TM, Soldatos A, Sheriff H, et al. Insights into pediatric herpes simplex encephalitis from a cohort of 21 children from the California Encephalitis Project, 1998–2011. Pediatr Infect Dis J 2014; 33:1287–1288. This study of 21 children with confirmed HSE found that a substantial proportion of patients had initial negative CSF HSV PCR and a majority had extratemporal involvement on brain MRI, suggesting that increased vigilance is needed to diagnose pediatric HSE. 42. Schleede L, Bueter W, Baumgartner-Sigl S, et al. Pediatric herpes simplex & virus encephalitis: a retrospective multicenter experience. J Child Neurol 2013; 28:321–331. This article highlights the difficulty in diagnosis of neonatal and pediatric HSE, as less than half of the 38 patients presented with neurologic symptoms, whereas six of 38 children had normal routine CSF studies. 43. Linnoila JJ, Rosenfeld MR, Dalmau J. Neuronal surface antibody-mediated autoimmune encephalitis. Semin Neurol 2014; 34:458–466. 44. Stahl JP, Mailles A. What is new about epidemiology of acute infectious encephalitis? Curr Opin Neurol 2014; 27:337–341. 45. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors && for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12:157–165. A large observational study of 577 patients, including 211 pediatric patients, with anti-NMDAR encephalitis, that provides the most detailed information to date on response to therapy, longitudinal outcomes, and prognostic factors. 46. Sejvar JJ, Curns AT, Welburg L, et al. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. J Neuropsychol 2008; 2:477–499. 47. Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis 2007; 44:1617–1624. 48. Hart J, Tillman G, Kraut MA, et al. West Nile virus neuroinvasive disease: & neurological manifestations and prospective longitudinal outcomes. BMC Infect Dis 2014; 14:248. A prospective study of WNND that suggests that outcomes may markedly improve over the first 3 months following disease onset. 49. Beattie GC, Glaser CA, Sheriff H, et al. Encephalitis with thalamic and basal ganglia abnormalities: etiologies, neuroimaging, and potential role of respiratory viruses. Clin Infect Dis 2013; 56:825–832. 50. Einsiedel L, Kat E, Ravindran J, et al. MR findings in Murray Valley encephalitis. AJNR Am J Neuroradiol 2003; 24:1379–1382. 51. Speers DJ, Flexman J, Blyth CC, et al. Clinical and radiological predictors of outcome for Murray Valley encephalitis. Am J Trop Med Hyg 2013; 88: 481–489. 52. Przelomski MM, O’Rourke E, Grady GF, et al. Eastern equine encephalitis in Massachusetts: a report of 16 cases, 1970–1984. Neurology 1988; 38:736–739. 53. Silverman MA, Misasi J, Smole S, et al. Eastern equine encephalitis in children, Massachusetts and New Hampshire,USA, 1970–2010. Emerg Infect Dis 2013; 19:194–201. 54. Ma J, Jiang L. Outcome of children with Japanese encephalitis and predictors of outcome in southwestern China. Trans R Soc Trop Med Hyg 2013; 107:660–665. 55. Logar M, Arnez M, Kolbl J, et al. Comparison of the epidemiological and clinical features of tick-borne encephalitis in children and adults. Infection 2000; 28:74–77. 56. Fowler A˚, Forsman L, Eriksson M, Wickstro¨m R. Tick-borne encephalitis carries a high risk of incomplete recovery in children. J Pediatr 2013; 163: 555–560. &
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Epidemiology and outcomes of acute encephalitis Arun Venkatesan
Purpose of review This review seeks to describe recent advances in the epidemiology, outcomes, and prognostic factors in acute encephalitis. Recent findings Infectious causes continue to account for the largest proportion of encephalitis cases in which a cause is identified, although autoimmune causes are increasingly recognized. Type-A gamma-aminobutyric acid (GABAa) receptor antibodies have been recently identified in encephalitis with refractory seizures, whereas the roles of antibodies to the glycine receptor and dipeptidyl peptidase-like protein 6 have been defined in progressive encephalomyelitis with rigidity and myoclonus. Recent findings in the US cases of encephalomyelitis presenting with acute flaccid paralysis raise the possibility that enterovirus D68, a common respiratory pathogen, may cause central nervous system disease. Mortality from acute encephalitis occurs in about 10% of cases, with a large proportion of survivors suffering from cognitive or physical disability. In addition to delay in institution of appropriate antiviral or immune therapy, several potentially reversible factors associated with poor prognosis have been identified, including cerebral edema, status epilepticus, and thrombocytopenia. Summary Encephalitis imposes a significant worldwide health burden and is associated with poor outcomes. Supportive treatment and early institution of therapy may improve outcomes. Careful neurocognitive assessment of survivors of encephalitis is needed to better define long-term outcomes. Keywords acute flaccid paralysis, autoimmune encephalitis, herpes simplex virus, prognosis, viral encephalitis
INTRODUCTION Encephalitis, defined as inflammation of the parenchyma of the brain with associated neurologic dysfunction, manifests as a clinical syndrome characterized by a combination of encephalopathy, behavioral changes, fever, seizure, and focal neurologic deficits [1]. A myriad of causes can result in encephalitis, including infectious agents and an increasingly recognized number of autoimmune conditions. Outcomes are highly variable, although prognostic factors are beginning to be identified. Here we describe recent advances in our understanding of the epidemiology, prognostic factors, and outcome of acute encephalitis.
EPIDEMIOLOGY OF ENCEPHALITIS Broad strokes Several recent studies have utilized the US Nationwide Inpatient Sample (NIS), a nationally representative database of hospitalizations, to estimate numbers and rates of encephalitis-associated hospitalizations [2 ,3 ]. These studies report that over the &
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past decade, approximately 250 000 patients were admitted with a diagnosis of encephalitis, with a hospitalization rate of approximately seven per 100 000. Although higher than reported rates from other countries [4–8], this is comparable to the prior decade in the United States, suggesting that the overall incidence of encephalitis has not changed substantially over time [9]. Approximately half of all cases were associated with a known cause, congruent with many other large studies spanning the past several decades [9–12]. The leading identified cause was viral encephalitis and the most common specific cause was herpes encephalitis, which accounted for approximately 14% of all hospitalizations [2 ,3 ]. Other notable viral causes included &
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Department of Neurology, Johns Hopkins Encephalitis Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to Arun Venkatesan, MD, PhD, Department of Neurology, The Johns Hopkins University School of Medicine, Meyer 6-113 600 N, Wolfe Street, Baltimore, MD 21287, USA. Tel: +1 410 955 3730; fax: +1 410 955 6070; e-mail: [email protected] Curr Opin Neurol 2015, 28:277–282 DOI:10.1097/WCO.0000000000000199
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KEY POINTS
States, in which 50% had an infectious cause, 20% had autoimmune cause, and only 30% remained of unknown cause [14 ]. Several recent studies have also examined the epidemiology of encephalitis among critically ill populations. In one study composed of patients with encephalitis from the Johns Hopkins Hospital over the past decade with ICU stays greater than 48 h, approximately 40% had infectious causes (predominantly HSV and VZV) and 15% had immune-mediated causes, with close to 50% of unknown cause [15 ]. The similarity in frequency of causal groups (infectious, autoimmune, unknown) between ICU and noncritically ill patients with encephalitis is noteworthy, indicating that neither infectious nor autiommune causes as a whole are preferentially associated with encephalitis severity. A French study found similar percentages of immune-mediated causes but a higher percentage of infectious causes (over 50%). This was driven largely by M. tuberculosis (23% of cases) and Listeria monocytogenes (7% of cases) [16 ], the frequency of which have been previously recognized in encephalitis in France [11]. &
Infectious agents, including HSV and VZV, continue to account for a large proportion of cases of encephalitis. Ongoing identification of newer autoantibodies, including those directed against the GABAa receptor and the glycine receptor, has resulted in the expanding spectrum of recognized autoimmune encephalitis. Enterovirus D68 may be responsible for a recent surge in AFP-encephalitis cases in the United States.
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The recent identification of several potentially reversible risk factors for poor prognosis following encephalitis, including status epilepticus, cerebral edema, and thrombocytopenia, suggests the possibility of targeted intervention to improve outcomes. The incidence and magnitude of cognitive dysfunction following encephalitis is likely underappreciated and will require careful long-term follow-up.
enteroviruses, West Nile virus (WNV), and varicella zoster virus (VZV), which also account for substantial proportions of cases in other large studies [7,10,11,13]. Notably, the epidemiology of encephalitis as described in these large studies appears to be changing. Encephalitis-associated hospitalization rates for women were higher than for males [2 ,3 ], whereas in the previous decade, the rates were substantially higher in males [9]. A similar trend was noted in a study in Canada, where the relative increase in hospitalization rates was largely attributed to an increased incidence of VZV encephalitis in women [7], a finding not observed in the US NIS studies. It has been hypothesized that the increasing recognition of immune-mediated causes such as anti-Nmethyl-D-aspartate receptor (NMDAR) encephalitis, which may predominate in women and are not specifically coded for in the US NIS studies, accounts for the increase in encephalitis-associated hospitalization rates for women [2 ,3 ]. In support of this, it has recently been shown that systematic and extensive testing can result in the identification of additional specific causes – most notably autoimmune – that can substantially decrease the proportion of unknown causes of encephalitis to less than 40% [13]. In that study from the United Kingdom, approximately 40% of patients had infectious causes [including herpes simplex virus (HSV), VZV, and Mycobacterium tuberculosis], whereas 20% had immune-mediated cause, including acute disseminated encephalomyelitis, anti-NMDAR encephalitis, and anti-voltage-gated potassium channel (VGKC) encephalitis. These percentages are similar to a recent retrospective cohort study in the United &
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Expanding spectrum of autoantibodyassociated encephalitides Recognition of the spectrum of autoantibodymediated encephalitides continues to grow [17]. Although antibodies to the NMDAR and leucinerich, glioma inactivated 1 protein of the voltagegated potassium channel complex account for a substantial proportion of such cases, newer autoantibodies have been recently identified. In particular, high titer serum and/or cerebrospinal fluid (CSF) antibodies to the GABAa receptor were found in six patients who presented with rapidly progressive encephalopathy and refractory seizures [18 ]. Importantly, application of patient antibodies to neuronal cultures resulted in a selective reduction of synaptic GABAa receptor clusters, suggesting a pathogenic mechanism whereby disruption of GABA signaling contributes to the clinical syndrome. Another important recent advance has been the identification and characterization of autoantibodies in patients with progressive encephalomyelitis with rigidity and myoclonus (PERM). Similar to stiff-person syndrome, PERM is characterized by rigidity, myoclonus, stimulus-sensitive spasms, and autonomic disturbance; in addition, brainstem or other central nervous system manifestations arise. Previously identified autoantibodies included those directed against glutamic acid decarboxylase and amphiphysin [19,20]. Over the past 5–7 years, antibodies to the glycine receptor have also been identified in cases of PERM [21,22], &&
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with recent evidence suggesting that these antibodies can cause internalization and degradation of the glycine receptor [23 ]. Antibodies to the dipeptidyl peptidase-like protein 6, an extracellular component of neuronal potassium channels, have also recently been identified in three patients with a distinct PERM variant marked by cerebellar ataxia in addition to stiffness and hyperekplexia [24 ]. Although the most common autoantibody-associated encephalitides have likely been identified, it is anticipated that additional antibodymediated syndromes associated with small percentages of cases of encephalitis will continue to be identified. &&
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Update on causes of encephalomyelitis: acute flaccid paralysis Encephalomyelitis, in which patients typically develop mental status changes or cranial nerve deficits along with spinal cord manifestations such as acute flaccid paralysis (AFP), has long been recognized as a consequence of infection by polioviruses, other enteroviruses such as enterovirus-71, and WNV [25]. A recent surge in AFP in the United States, predominantly affecting children, has been found to be unrelated to both poliovirus and WNV [26 ,27 ]. These cases are preceded by a febrile and upper respiratory illness occurring approximately 1 week prior to the onset of neurologic illness and accompanied by a CSF pleocytosis. Although motor involvement is typically marked and can include ventilatory dysfunction, there is usually an absence of sensory deficits. Although CSF PCR for enteroviruses (as well as WNV and poliovirus) has been uniformly negative, PCRs from nasopharyngeal specimens have demonstrated the presence of enterovirus-D68 in some cases. Notably, enterovirus–D68 has been previously reported in the CSF of individuals with AFP, suggesting that it may cause neurologic disease [28,29]. Moreover, the surge in AFP cases has been temporally linked to an outbreak of enterovirus–D68 respiratory infections throughout the United States. Although circumstantial evidence is building, continued clinical and serological surveillance as well as testing of patients’ CSF will be needed to demonstrate a conclusive link between enterovirus–68 and AFP. &&
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PROGNOSIS, BIOMARKERS, AND OUTCOMES
information on long-term outcomes, although a recent Israeli study of 47 children with a mean follow-up of close to 6 years found that intelligence quotient is lower, behavioral impairments occur in over half of affected individuals, attention-deficit hyperactivity disorder is common (50%), and approximately 10% have residual motor deficits [30 ]. Previously reported poor prognostic factors in encephalitis include older age, immunosuppression, and other major medical comorbidities [11,31–35], findings that are corroborated by a recent analysis in hospitalized patients in the United States [2 ]. Several recent studies have attempted to further define clinical and paraclinical prognostic factors in acute encephalitis of all causes. In a study of 100 adults with all-cause encephalitis admitted to the ICU, the mortality rate was 20%, reflecting the severity of illness in this critically ill population. Notably, we found that several potentially reversible conditions, including cerebral edema, status epilepticus, and thrombocytopenia, were associated with in-hospital mortality [15 ], whereas normal electroencephalogram early in the admission was highly predictive of survival [36 ]. In a French study of critically ill patients with encephalitis, additionally identified poor prognostic factors included lower body temperature and elevated CSF protein levels [16 ]. Thrombocytopenia was also recently identified as a poor prognostic factor in a retrospective study of almost 200 patients with acute encephalitis, in which the population was not restricted to those requiring intensive care [14 ]. Taken together, these findings suggest that aggressive supportive therapies for seizures, hematologic derangements, and other comorbid conditions may improve outcomes in those with acute encephalitis. The presence of CSF proteins in acute encephalitis has also been investigated. In one study of children with acute encephalitis or encephalopathy, examination of admission CSF revealed that glialderived proteins S100B and glial fibrillary acidic protein as well as the neuronal protein tau were elevated in those with poor outcome as compared with those with favorable outcome or unaffected controls [37 ]. In another study of 56 adult patients with acute encephalitis of various causes, CSF levels of the neurofilament heavy chain, a structural component of axons, were increased in approximately 40% of patients, whereas S100B levels were increased in over 95% of patients. Notably, poor outcome was associated with increasing neurofilament heavy-chain levels over several weeks [38 ]. Overall, these findings suggest that increased levels of both glial and neuroaxonal proteins in the CSF, likely reflecting a combination of inflammation and neuronal damage, may serve as biomarkers of &&
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Acute encephalitis Mortality rates in encephalitis are typically reported to be 5–15%, with marked physical and cognitive morbidity among survivors. There is a paucity of
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prognosis in encephalitis. However, key issues such as timing and acquisition of CSF and standardization of laboratory testing will need to be further explored before such assays may be useful in a clinical setting.
Herpes simplex encephalitis Seminal studies of herpes simplex encephalitis (HSE) demonstrated that older age, poor level of consciousness at the time of initiation of therapy, and a delay of greater than 2 days between hospital admission and initiation of acyclovir were poor prognostic factors [34,39]. These findings were largely confirmed in a recent retrospective study of 106 patients admitted to several hospitals in Turkey, where follow-up information was available in over 90%. The mortality rate at 6 months was 8%, whereas only 23% had complete recovery [40 ]. Factors associated with unfavorable outcome included longer duration between onset of symptoms and hospitalization and extent of brain involvement on admission MRI, reinforcing the notion that early recognition and initiation of therapy is crucial. Several recent pediatric cohorts of HSE have also been described. In a retrospective study from the California Encephalitis Project, four of 21 pediatric cases (all adolescents) died during hospitalization [41 ], which contrasts with the surprising finding that none of 38 patients died in a recently reported German study [42 ]. In the latter, close to half (44%) were discharged with no apparent symptoms, and brain MRI remained normal in six patients more than 1 week after disease onset. However, eight patients experienced early relapses characterized by movement abnormalities and seizures; although not tested for, some or all of these cases were likely due to the development of anti-NMDAR encephalitis, which is now well documented to occur in a proportion of children and adults following HSE and has been recently reviewed [43,44]. &
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Antibody-associated encephalitis In a large observational study of over 500 patients with anti-NMDAR encephalitis, early treatment with steroids and/or immunosuppression and lack of admission to an ICU were associated with good outcome. Notably, improvement following initiation of immunotherapy was often delayed; almost half had no improvement in the first month, whereas substantial improvements occurred within 2 years of treatment in over 80% of patients [45 ]. Outcomes in another autoimmune condition, glycinereceptor antibody-associated PERM, also appear to be favorable, with the modified Rankin scale scores &&
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falling from a median of 5 during maximum severity of illness to a score of 1 over a median follow-up time of 3 years [23 ]. &&
West Nile virus West Nile virus encephalitis is associated with high in-hospital mortality (20%) and the majority of survivors have been found to experience persistent neurocognitive and functional impairments [46,47]. Recently, prospectively obtained outcomes have been reported from a trial of intravenous immunoglobulin in West Nile neuroinvasive disease (WNND) conducted between 2003 and 2006. Although the study was terminated early due to low enrolment and lack of study drug, outcome measures were obtained for up to 90 days in 55 patients. Pooled data from the three arms of the study suggested that older age and initial presentation of coma or with cranial nerve deficits were predictors of poor outcome [48 ]. Notably, substantial improvement occurred over the 90 days of the study, such that of the 14 patients who were initially comatose, only one remained in coma at follow-up. Similarly, of 25 patients who initially exhibited a cognitive deficit, only nine did so at their last evaluation [48 ]. These data underscore the potential for marked improvement over the months following an episode of WNND. &
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Other arboviral encephalitides Similar to other flaviviruses, Murray Valley encephalitis virus, endemic to Australia, can be associated with deep gray matter abnormalities on brain MRI [49,50]. A recent study found that thalamic involvement on MRI, found in approximately half of patients, was associated with at least moderate neurological deficits, whereas involvement of additional structures portended poorer prognosis [51]. Eastern equine encephalitis, a highly virulent arbovirus endemic to the eastern United States, has been associated with mortalities ranging from 25 to 70% [52]. In a cohort of 15 pediatric cases largely in Massachusetts, a short prodrome, suggestive of rapid disease progression, was associated with unfavorable outcomes [53]. Japanese encephalitis is the most commonly identified cause of encephalitis in Asia. In a cohort of 87 children in China with Japanese encephalitis, eight (9%) died, whereas 48 (55%) had full recovery at follow-up of at least 6 months [54]. Factors associated with poor outcome (death or severe sequelae) included at least two witnessed convulsions and abnormal breathing patterns, the latter of which may point to brainstem respiratory center involvement. Tick-borne encephalitis (TBE), an arboviral disease endemic to Europe and Asia, was Volume 28 Number 3 June 2015
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previously thought to cause mild illness in children [55]. In a recent Swedish study of 55 children with TBE, outcomes were assessed at a mean of 4 years after the acute illness [56]. Surprisingly, two-thirds of the children reported multiple symptoms, including headache, memory impairment, fatigue, irritability, and concentration problems. Cognitive function, as assessed by the Wechsler Intelligence Scale for Children-IV, was mildly to moderately impaired and involved deficits in executive function and working memory. Thus, neurocognitive dysfunction in the wake of pediatric TBE appears to be more widespread than previously recognized. Overall, careful neurocognitive assessment of survivors of encephalitis is needed to better define longterm outcomes and rehabilitation needs.
CONCLUSION Our understanding of the epidemiology of encephalitis continues to evolve, due in part to identification of new syndromes and broadening of the known clinical phenotype associated with established agents. Moreover, factors such as changes in climate and travel patterns have resulted in shifts in the geographic distribution of infectious agents. As a result, robust global surveillance measures that assess for both infectious and autoimmune causes will be necessary to define and update encephalitis epidemiology. Although encephalitis continues to be associated with significant morbidity and poor outcomes, early institution of disease-specific therapies and aggressive supportive treatment may be of benefit. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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