Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome Sekhar C. Pillai, FRACPa,b, Yael Hacohen, MRCPCHc, Esther Tantsis, FRACP, PhDa,b, Kristina Prelog, FRANZCRd, Vera Merheb, BSca, Alison Kesson, PhDe, Elizabeth Barnes, PhDf,g, Deepak Gill, FRACPb, Richard Webster, FRACPb, Manoj Menezes, FRACPb, Simone Ardern-Holmes, FRACPb, Sachin Gupta, FRACPb, Peter Procopis, FRACPb, Christopher Troedson, FRACPb, Jayne Antony, FRACPb, Robert A. Ouvrier, FRACPb, Yann Polfrit, MBBSh, Nicholas W. S. Davies, PhDi, Patrick Waters, PhDc, Bethan Lang, PhDc, Ming J. Lim, PhDc,j, Fabienne Brilot, PhDa, Angela Vincent, FRCPathc, Russell C. Dale, PhDa,b
abstract
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. BACKGROUND AND OBJECTIVES:
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).
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. RESULTS:
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.
CONCLUSIONS:
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.
ARTICLE
a
Neuroimmunology Group, Institute of Neuroscience and Muscle Research at the Kids Research Institute, Children’s Hospital at Westmead, University of Sydney, Australia; bTY Nelson Department of Neurology and Neurosurgery and Departments of dMedical Imaging, eInfectious Diseases and Microbiology, and fStatistics, the Children’s Hospital at Westmead, Sydney, Australia; cNuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, England; gNational Health Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia; hCentre Hospitalier Territorial Magenta, Service Pediatric, Nouméa, New Caledonia; iChelsea & Westminster Hospital, Department of Neurology, Imperial College Healthcare National Health Service Trust, London, England; and jEvelina Children’s Hospital, London, England
Dr Pillai acquired all clinical data, performed radiological phenotyping, retrieved investigation data, performed outcome assessments, performed statistical analysis, wrote the first draft, and edited subsequent drafts; Dr Hacohen, Ms Merheb, and Drs Waters, Lang, Lim, and Brilot performed and supervised all autoantibody testing and edited drafts; Dr Kesson performed infectious investigation supervision, edited drafts, and
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
Encephalitis is inflammation of the brain parenchyma and has many infectious and immune-mediated etiologies.1 Acute encephalitis can be life threatening and results in permanent neuropsychiatric and cognitive impairments in a significant proportion of survivors. Inflammatory forms of encephalitis such as acute disseminated encephalomyelitis (ADEM) have been known for some time, but in the past decade other autoimmune forms of encephalitis have been recognized, defined by the presence of autoantibodies against cell surface antigens. Autoantibody detection is important as immune suppression may improve outcomes, particularly when given early in the disease.2,3 A recent study suggested that Nmethyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis, the bestknown autoimmune form, is more common than herpes simplex virus (HSV) encephalitis in children and young adults,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.6–8 We studied clinical and radiologic features, serum autoantibodies in acute archived samples, and longterm outcomes in a large retrospective cohort of pediatric encephalitis from a single center.
METHODS Patients, Definitions, and Clinical Data Patients We report patients with encephalitis seen between January 1998 and October 2010 at the Children’s Hospital at Westmead, the largest tertiary children’s hospital in New
South Wales, Australia. Patients either presented directly to the hospital emergency department or were referred from district hospitals in western Sydney and New South Wales (referral base ∼4.5 million people). Patients were identified retrospectively from International Classification of Diseases, 10th Revision coding of encephalitis or encephalomyelitis at discharge, plus screening of consultant correspondence from the Department of Neurology database and review of cerebrospinal fluid (CSF) polymerase chain reaction testing from the Department of Infectious Diseases and Microbiology. The following patients were excluded: neonates (,1 month old), patients .16 years old, known or suspected cases of immunodeficiency, and viral or bacterial meningitis without encephalitis. Infectionassociated encephalopathy (influenza and rotavirus) cases were included. A total of 164 patients fulfilled the diagnostic criteria for acute encephalitis, according to the following definitions.
Definitions We used the Granerod encephalitis case definitions, with minor modifications.1 Encephalitis was defined as an acute encephalopathy with $2 of the following: fever $38°C, seizures or focal neurologic signs, CSF pleocytosis ($5 white blood cells/µL) or elevated CSF neopterin (.30 nmol/ L), EEG consistent with encephalitis (presence of slowing in this study), or MRI findings suggestive of encephalitis. CSF neopterin, which is produced secondary to a- or g-interferon stimulation, was included as an alternative to CSF pleocytosis because it has been shown to be a useful marker of central nervous system (CNS) inflammation.9 Encephalopathy was defined as an altered or reduced level of consciousness and a change in personality or behavior or confusion lasting .24 hours. We did not use lethargy and irritability as sole features
of encephalopathy because of the nonspecific nature of these features in sick children unless supported by EEG features of encephalopathy.
Clinical Data During Acute Encephalitis In total, 179 clinical or investigation variables were recorded in every patient (Supplemental Information). CSF results were available in 157 (96%) patients, and EEG reports from the first week of admission were available in 130 (79%) patients. We obtained follow-up information by telephone interview in 144 (88%) cases in 2011 and 2012 by using the Liverpool Outcome Score (LOS) questionnaire,10 supplemented by clinical records. All patients were followed up for a minimum of 12 months after encephalitis, and the LOS was recorded as follows: 1 = death, 2 = severe, 3 = moderate, 4 = mild, and 5 = normal, and specific domains of abnormal outcome were also recorded. The outcome score describes the patient’s abilities compared with peers, with mild describing impairments without dependence on carers, whereas severe describes complete dependence on carers. Clinical relapses were recorded separately.
MRI We had access to 1.5-Tesla MRI brain scans for review in 149 (91%) patients. MRI data were reviewed, blinded to clinical and diagnostic information, by pediatric neurologists (R.C.D., S.C.P.) and a pediatric neuroradiologist (K.P.), and consensus was reached on abnormalities. The mean and median duration of first MRI scan after admission were 4.8 days and 3 days, respectively (range 1–70 days).
Etiologic Investigation to Determine Encephalitis Causation Infectious Encephalitis and InfectionAssociated Encephalopathy The CSF, serological, and non-CNS specimen testing for infectious etiologies are summarized in Supplemental Table 3. Testing of up
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e975
to 42 different microorganisms was carried out as clinically indicated. The mean and median etiologic tests (including autoantibodies) per patient were 14 and 13 tests, respectively (range 0–36).
CSF Testing A CSF was obtained at a mean and median admission duration of 2.9 days and 2 days, respectively (range 1–48 days). Bacterial and viral cultures of the CSF were done on 155 (95%) and 152 (93%) patients, respectively. CSF polymerase chain reaction testing was obtained in 131 (80%) of the total cohort, with patients with ADEM less frequently tested (63%).
Serology Serological testing for $1 microorganisms was performed on 139 (85%) patients. Serological studies for microorganisms used complement fixation tests and immunoglobulin M (IgM) enzymelinked immunosorbent assays (Table 1).
Non-CNS Specimens These tests include blood culture (n = 144, 87.8%), nasopharyngeal aspirate (n = 69, 42%), stool and rectal swab (n = 68, 41%), throat swab (n = 47, 29%), and skin swab (n = 5, 3%) (Supplemental Table 3).
Immune-Mediated/AutoantibodyAssociated Encephalitis We used Granerod case definition for confirmed ADEM. Retrospective autoantibody testing on stored acute sera was performed in 103 of the 129 patients with non-ADEM encephalitis (80%). Patients with a preliminary diagnosis of ADEM were excluded from autoantibody testing (n = 35). Antibodies to NMDAR (n = 103), voltage-gated potassium channel complex (VGKC-complex) (n = 102), leucine-rich glioma-inactivated 1 (LGI1) (n = 99), contactin-associated protein-like 2 (CASPR2) (n = 99), glycine receptor (n = 102), and
e976
TABLE 1 Hierarchical Classification for the Etiology of Encephalitis Etiology of Encephalitisa
Confirmed
Probable
Infectious (N = 49, 30%) Enterovirus 17 Mycoplasma pneumoniae — 4 HSVb Cytomegalovirus — Other infectionsc — Infection-associated encephalopathy (N = 13, 8%) Influenza virus — Rotavirus — ANEd 3 Immune-mediated or autoantibody-associated (N = 56, 34%)e ADEM 35 NMDAR antibody 5 VGKC-complex antibody — Dopamine D2 receptor antibody — Unknown (N = 46, 28%) Total 64
Possible
— 11 1 — 1
3 — 4 3 5
— — —
5 5 —
— 5 7f 4
— — — —
29
25
Total N (%) 20 11 9 3 6
(12) (7) (5) (2) (4)
5 (3) 5 (3) 3 (2) 35 10 7 4 46 164
(21) (6) (4) (2) (28) (100)
ANE, acute necrotizing encephalopathy. Table adapted from Granerod et al. (2010).1 Serological testing for $1 microorganisms was performed on 139 (85%) patients. Serological studies for microorganisms used complement fixation tests (CFTs) and IgM enzyme-linked immunosorbent assays. Only 14 patients had paired acute and convalescent serology, and no patients had a diagnosis of infectious encephalitis based on a fourfold change in titer. A single raised anti-streptolysin O (group A Streptococcus, n = 1) and a positive IgM and IgG (HSV [n = 3] and Epstein–Barr virus, parvovirus B19 [each, n = 1]) result were used to diagnose probable or possible infectious encephalitis. A positive IgM provided a probable infectious diagnosis for Mycoplasma pneumoniae (n = 11). a 11 patients had $2 etiologic associations and are presented in Supplemental Table 4. b HSV-1 (n = 4, CSF PCR confirmed); HSV-2 (n = 1, skin swab polymerase chain reaction possible); 1 patient with probable HSV (relapsing) also had positive serum NMDAR and D2R antibodies. c Group A Streptococcus (n = 1, probable), adenovirus (n = 1, possible), Epstein–Barr virus (n = 1, possible), parainfluenza 3 virus (n = 1, possible), parvovirus B19 (n = 1, possible), varicella zoster virus (n = 1, possible). d Associated infections (probable/possible) in 2 of 3 patients. e 22 patients tested positive for $1 of the following antibodies: NMDAR (n = 11), VGKC (n = 7), D2R (n = 6), and glycine receptor (n = 1). LGI1, CASPR2, and glutamic acid decarboxylase antibodies were negative in all. One patient with a VGKCcomplex antibody titer of 421 pM had positive glycine receptor antibody. f 5 of the 7 VGKC-positive patients had Mycoplasma pneumoniae IgM detected (see Supplemental Table 4).
glutamic acid decarboxylase (n = 102) were tested as previously described.11–14 Only 5 patients had combined testing of CSF and serum for autoantibodies (NMDAR only). VGKC-complex antibody positivity was based on titers .150 pM, as suggested in children.15 Dopamine-2 receptor antibody testing (n = 103) was undertaken as described.16
Etiologic Causation The final etiologic diagnosis was determined by stringent application of the consensus guidelines proposed by Granerod et al.1 Cases were classified as confirmed, probable, or possible. Confirmed cases had detection of the organism or autoantibody in CSF or brain.1 A probable diagnosis was based on serological evidence of acute infection or autoantibody, and a possible
diagnosis was based on detection of the organism from a specimen sample outside the CNS, such as stool or nasopharyngeal aspirate.1 As accepted in the literature, we used the term infection-associated encephalopathy rather than encephalitis to denote encephalitis related to influenza virus or rotavirus.17–19 In cases with multiple etiologies (Supplemental Table 4), the agent with the strongest hierarchical association (confirmed . probable . possible) was designated as the etiology of encephalitis.
Ethics The study was ethically approved (09/CHW/56), and written consent was obtained from the families and patients for a follow-up telephone interview and testing of stored acute samples.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
Statistical Analysis
Demographics and Seasonality
For comparison of clinical variables between the different major etiologic groups, we used SAS version 9.3 (SAS Institute, Inc, Cary, NC). Categorical variables were compared with the exact x2 test and described in terms of proportions and Wilson confidence intervals (CIs); continuous variables were compared with the Kruskal–Wallis test and described in terms of median and range (Supplemental Tables 5–8). We assessed the relationship of clinical variables to outcome by using univariate and multivariate logistic regression analyses. All variables with a univariate P ,.05 were included as potential predictors in a multivariate model that used a stepwise backward selection procedure in SPSS (IBM SPSS Statistics, IBM Corporation). We described these associations by using odds ratios (ORs) and Wald CIs. We assessed the association between clinical variables to autoantibody status by using the x2 test and described it in terms of ORs and 95% CIs. We made no adjustment for multiple statistical testing.
The median age at presentation was 5.5 years (range 5 weeks–15.1 years), and 94 (57%) patients were male. Figure 1 demonstrates that young children are more frequently affected. The majority of encephalitis cases (n = 57, 35%) presented during the Australian winter season (June–August, data not shown).
Clinical Features, CSF, EEG, and MRI Figure 2 and Supplemental Table 5 compare the clinical features, which in descending order of frequency were fever (n = 126, 77%), seizures (n = 88, 54%), headache (n = 71, 43%), weakness or pyramidal signs (n = 61, 37%), any respiratory symptoms (n = 57, 35%), and agitation (n = 56, 34%). CSF pleocytosis was present in 110 out of 155 (71%) patients and elevated CSF protein in 50 out of 154 (33%) patients. CSF neopterin was elevated in 36/47 (77%) tested patients. Oligoclonal bands were measured in 53 (32%), and intrathecal oligoclonal bands were
detected in only 2 patients (1 with NMDAR encephalitis, 1 unknown) and mirrored oligoclonal bands in another 16 (5 infectious, 10 immunemediated [ADEM 4, NMDAR 4, dopamine receptor D2 {D2R} 2], 1 unknown). Five patients with positive serum NMDAR antibody also had CSF testing and were confirmed CSF NMDAR antibody positive. CSF findings by subgroup are presented in Supplemental Table 6. The EEG was abnormal in 115 out of 130 (88%) patients; EEG slowing was found in 111 out of 130 (85%) and epileptiform discharges in 27 out of 130 (21%) patients, respectively. Figure 3 and Supplemental Table 7 describe the MRI features. The MRI brain (T2-weighted fluid-attenuated inversion recovery) was abnormal in 121 out of 149 (81%) of patients.
Duration of Stay, Therapy, and Outcome The mean and median length of stay for patients were 27 and 13 days, respectively (range 1–618 days). Admission to the ICU was necessary in 66 (40%) patients, with the majority needing management of
RESULTS All Encephalitis (n = 164) Overview of Etiologies (Table 1) A total of 164 children were diagnosed with acute encephalitis. An etiology was proposed in 118 (72%) patients, of whom 64 (39%) were confirmed, 29 (18%) probable, and 25 (15%) possible. In 46 (28%) patients, the cause was unknown. The etiologic groups were infectious encephalitis, n = 49 (30%); infectionassociated encephalopathy, n = 13 (8%); and immune-mediated/ autoantibody-associated encephalitis, n = 56 (34%). Complete autoantibody and some infectious serological findings are presented in Table 1. Potential dual or multiple etiology occurred in 11 (7%) patients (Supplemental Table 4), including 8 with Mycoplasma pneumoniae.
FIGURE 1 Number of patients with acute encephalitis according to age at presentation and etiologic group. 11% of patients were ,1 year of age, and 54% of patients were #5 years old, with the frequency descending steadily at later ages.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e977
FIGURE 2
Clinical features at any stage in all encephalitis and major etiologic subgroups (n $ 7). Data including statistical significance is in Supplemental Table 5. EV, enterovirus; GI, gastrointestinal; MycoP, Mycoplasma pneumoniae; Unk, unknown.
e978
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
FIGURE 3
MRI features according to neuroanatomical location and sequence characteristics in all encephalitis and the major etiologic subgroups (n $ 7). Data including statistical significance are in Supplemental Table 7. EV, enterovirus; FLAIR, fluid-attenuated inversion recovery; MycoP, Mycoplasma pneumoniae; T1-W, T1-weighted; T2-W, T2-weighted; Unk, unknown.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e979
encephalopathy, seizures, or both. Of the 164 patients, 147 (87%) received antibiotics or antiviral therapy. The mean and median duration of followup were 6.6 years and 5.8 years, respectively (range 1.1–14.4 years). There were 5 deaths (4 in the hospital). Figure 4 compares the LOS measures. An abnormal outcome (LOS 1–4) was present in 71 out of 144 (49%) patients, including LOS 1 (death) (n = 5, 4%), LOS 2 (severe) (n = 11, 8%), LOS 3 (moderate) (n = 29, 20%), and LOS 4 (mild) (n = 26, 18%). The most common abnormal outcomes by category (Supplemental Table 8) were learning problems (n = 39, 28%), behavioral problems (n = 33, 24%), epilepsy (n = 25, 18%), and speech problems (n = 24, 17%). Clinical relapse occurred in 9 (5%) patients: HSV encephalitis (n = 1), ADEM (n = 1), NMDAR-Ab encephalitis (n = 3), D2R antibody encephalitis (n = 2), and unknown (n = 2). Patients with NMDAR and D2R antibodies were more likely to relapse (P = .01). Using univariate analysis, we found that an abnormal long-term outcome was associated with status epilepticus (seizure .30 minutes) (OR 7.74; 95% CI, 2.51–23.89), ICU admission (OR 3.83; 95% CI, 1.91–7.72), diffusion restriction on MRI (OR 2.47; 95% CI, 1.03–5.98), and a movement disorder (OR 2.44; 95% CI, 1.10–5.39). Patients with an infectious prodrome were less likely to have an abnormal outcome (OR 0.28; 95% CI, 0.12–0.63). On multivariate analysis, status epilepticus (OR 3.78; 95% CI, 1.07–13.41, P = .04), diffusion restriction (OR 2.47; 95% CI, 0.95–6.46, P = .06), and ICU admission (OR 2.27; 95% CI, 0.92–5.59, P = .08) each predicted an abnormal outcome.
Subgroup Analysis According to etiology, the following clinical characteristics were more common (Fig 2): Respiratory
e980
FIGURE 4
The LOS (1–5) in all encephalitis (n = 144, 88%) and the major etiologic subgroups (n $ 7). Data including statistical significance is in Supplemental Table 8.
symptoms (Mycoplasma, VGKCcomplex Ab), gastrointestinal symptoms (enterovirus), seizures (HSV, VGKC-complex Ab), weakness or pyramidal signs (ADEM), agitation and psychiatric symptoms (NMDAR), speech dysfunction (NMDAR), movement disorder (NMDAR), cerebellar (ADEM), sleep disturbance (NMDAR), brainstem (ADEM and enterovirus), and autonomic (NMDAR and enterovirus).
(any T2-weighted fluid-attenuated inversion recovery abnormality) in NMDAR encephalitis. Abnormalities detected with diffusion-weighted sequencing, T1 sequences, contrast enhancement, hemorrhage, and cystic necrosis were all more common in HSV (Fig 3 and Supplemental Table 7). HSV and unknown encephalitis had the worst outcomes, and ADEM had the best outcome (Fig 4).
According to etiology, the following MRI features were more common (Fig 3): abnormalities of white matter (HSV, ADEM), cortical gray matter (HSV), basal ganglia (Mycoplasma and ADEM), thalami (ADEM, HSV), cerebellum and brainstem (ADEM), and limbic encephalitis (NMDAR, VGKC-complex, Mycoplasma). The MRI was least likely to be abnormal
Of the smaller subgroups (Table 1), all 4 patients with D2R antibody–associated encephalitis had dystonia–Parkinsonism, and 3 out of 4 had localized basal ganglia involvement on MRI (basal ganglia encephalitis).16 Three patients had acute necrotizing encephalopathy with the typical radiologic features.18,20 There were no other
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
characteristic clinicoradiologic features in the other small subgroups.
Clinicoradiologic Correlation With Autoantibody Positivity Using univariate analysis in patients with non-ADEM encephalitis tested for autoantibody (n = 103), we found that an autoantibody-associated encephalitis was more likely (in descending order) with clinical relapse (OR 13.5; 95% CI, 2.46–74.04, P , .0001), movement disorder (OR 11.2; 95% CI, 3.82–32.9, P , .0001), CSF intrathecal or mirrored oligoclonal bands (OR 7.89; 95% CI, 1.53–40.5, P = .02), speech dysfunction (OR 5.92; 95% CI, 2.03–17.2, P , .0001), psychiatric symptoms (OR 4.79; 95% CI, 1.73–13.2, P = .002), agitation (OR 3.64; 95% CI, 1.34–9.94, P = .009), and MRI limbic encephalitis phenotype (OR 5.22; 95% CI, 1.27–21.5, P = .03). Antibodyassociated encephalitis was less common with headache (OR 0.35; 95% CI, 0.12–0.98, P = .04) or MRI thalamic involvement (OR 0.21; 95% CI, 0.05–0.98, P = .03).
Immunotherapy and Outcome A total of 60 out of 164 patients (37%) received immunotherapy (corticosteroids, n = 59; intravenous immunoglobulin, n = 16; rituximab, n = 2), most commonly for ADEM (27 out of 35), NMDAR-Ab encephalitis (6 out of 10), enterovirus (6 out of 20), and unknown (9 out of 46) subgroups. Abnormal outcome was not different in the patients who received immunotherapy compared with those who did not (OR 1.17; 95% CI, 0.60–2.31, P = .64). The mean length of stay was longer in patients who received immune therapy (41 days vs 19 days, P = .02).
DISCUSSION This single-center cohort, followed up for a median of 5.8 years, is the most comprehensive retrospective analysis of pediatric encephalitis to date. In
a resource-rich setting, we have defined the relative frequency of acute encephalitis syndromes by etiology, with emphasis on the emerging treatable autoantibodyassociated encephalitides. Despite long follow-up, the study confirms the high morbidity in survivors of encephalitis, the significant proportion who lack a diagnosis, the need to identify the autoantibodyassociated syndromes, and the need to improve the acute management and rehabilitation of these patients with the hope of reducing long-term residual neurocognitive impairments. Immune-mediated/autoantibodyassociated encephalitides were the most common etiologic group. Although by definition ADEM is an encephalomyelitis, it is notable that many previous encephalitis cohorts do not include ADEM but generally focus on infectious encephalitis alone.6–8,21 NMDAR-Ab encephalitis was diagnosed in 6% of patients, who had typical clinical features of the disease, with dominant movement, psychiatric, sleep, speech, and autonomic features. The number could be an underestimate, because serum testing was performed on only 103 out of 129 (81%) of the patients without ADEM. Indeed, 4 of the 46 patients with unknown encephalitis had a phenotype reminiscent of NMDAR-Ab encephalitis but were negative for serum antibody. CSF might have been helpful,14,22 although that is not our experience. VGKC-complex antibodies were first reported in adults with limbic encephalitis.11 Subsequently, it was found that the VGKC-complex antibodies bound not to the VGKC subunits themselves but to proteins, namely LGI1 and CASPR2,12,23 which are complexed with the VGKC subunits in vivo. In this report, 7 (4%) of children had VGKC-complex antibodies, but only 2 had evidence of limbic encephalitis on imaging, and they were not positive for LGI1 or CASPR2 antibodies, as is often true
for pediatric cases with positive VGKC-complex Ab.12,23–25 Although 150 pM has been proposed as a positive result for VGKC-complex Ab in children, levels .400 pM are more relevant in adults,15,26 and only 2 children had these levels. Nevertheless, VGKC-complex antibodies appear to be associated with inflammatory disorders (Hacohen et al in preparation). The association seen here of positive VGKC-complex Ab with Mycoplasma pneumoniae and with respiratory symptoms (5 out of 7) suggests that VGKC-complex Ab could be induced as part of the immune response to Mycoplasma pneumoniae. Mycoplasma pneumoniae–associated encephalitis occurred in 7% of our cohort, although the diagnostic specificity of mycoplasma IgM has been questioned.27 Antibodies to D2R were found in only 4 patients with dystonia–Parkinsonism and basal ganglia lesions, representing a small subgroup (2%).16 There were no patients with antibodies to glutamic acid decarboxylase and only 1 patient with glycine R antibody (who also had VGKC-complex antibodies and Mycoplasma), and reported pediatric cases with these antibodies are rare. Nine (20%) of the patients with unknown encephalitis did not have serum available for autoantibody testing, and comprehensive testing may help to ensure recognition of known autoantibodies and to define some of the “unknown” patients in the future. For example, g-aminobutyric acid A receptor antibodies have recently been found in patients with acute-onset severe epilepsy and encephalitis,28 and it will be interesting to test pediatric patients with encephalitis for this autoantibody. Infectious encephalitis was found in 30%, and the most common infection was enterovirus (12%). Even with broad testing for HSV (84% of patients), HSV encephalitis was
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e981
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.32 The emerging theme of postviral autoimmunity is increasingly recognized, and it emphasizes the importance of considering immunotherapies in post-HSV relapses.32–34 There were some patients with $2 etiologic associations (Supplemental Table 4), and these patients provide a challenge for diagnosis and illustrate the overlap between infectious and autoantibodyassociated syndromes.32,35–38 There were notable etiologic absences in this cohort, such as no Mycobacterium tuberculosis encephalitis. Unlike in the United Kingdom,5 Mycobacterium tuberculosis is rare in Australian children. We also did not observe any confirmed varicella encephalitis, a result probably related partly to the introduction of routine varicella vaccination during the study period. As is true for most resource-rich countries, we no longer observe measles or mumps encephalitis because of vaccination. Other
etiologies not seen in our cohort include arboviruses and Bartonella. There were small subgroups of infection-associated encephalopathy (8%) associated with influenza and rotavirus, and these were kept as a separate group, by convention.18,39 Acute necrotizing encephalopathy, which is an infection-associated encephalopathy, is observed more frequently in Japanese and East Asian children, presumably because of their differing genetic vulnerability.18 The main limitation of the study was the retrospective design and therefore incomplete investigation and the potential incomplete ascertainment of milder or atypical cases. Despite these limitations, the study confirms that encephalitis is a serious disease with an abnormal outcome in ∼50%, particularly in cognitive and behavioral domains, with 3% mortality. In general, the predictors of poor outcomes were ICU admission and status epilepticus, as in previous studies.40–42 In addition, we found diffusion restriction on MRI, a marker of cytotoxic injury, correlated with abnormal outcomes. The use of immunotherapy was not associated with better outcomes, but the patients receiving immune therapy had longer admissions, suggesting that these patients had a more complicated course. Immunotherapy has only recently become established in the treatment
of autoantibody-associated encephalitis (other than ADEM),3 and prospective studies are needed to determine the benefit of immunotherapy in patients with encephalitis irrespective of whether an autoantibody is detected. The percentage of unknown encephalitis (28%) in this study is the lowest among substantial pediatric cohorts,6–8,40,41 but it represents an important subgroup that is comparable in size to the prospective UK cohort in adults and children.5 There were no distinguishing clinical or radiologic characteristics of the unknown subgroup, mainly because of the likely heterogenous etiologies. The unknown encephalitis group may contain both encephalitis of viral origin (untested or unknown) and autoimmune etiologies. The poor outcome in this group emphasizes the importance of future research in this area.
ACKNOWLEDGMENTS We thank the patients, their families, and all health professionals who contributed to this study. S.C.P. has funding from the Australian Postgraduate Award scheme. Y.H. has funding from Oxford University Clinical Academic Graduate School and Oxford National Institute for Health Research Biomedical Research Centre. R.C.D. and F.B. have funding from NHMRC (Australia) for this work.
was involved in clinical data acquisition and analysis; Dr Davies was involved in study design and edited drafts; Dr Prelog performed radiological phenotyping and edited drafts; Drs Tantsis, Gill, Webster, Menzes, Ardern-Holmes, Gupta, Procopis, Troedson, Antony, Ouvrier, and Polfrit were involved in clinical data acquisition and analysis and edited drafts; Dr Barnes performed statistical analysis and edited drafts; Dr Vincent supervised autoantibody testing and edited first and subsequent drafts; Dr Dale conceived and designed the study, supervised all clinical aspects of the study, performed radiological phenotyping, wrote the first draft, and edited subsequent drafts; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2014-2702 DOI: 10.1542/peds.2014-2702 Accepted for publication Jan 6, 2015 Address correspondence to Russell C. Dale, PhD, Clinical School, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: russell. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2015 by the American Academy of Pediatrics
e982
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
FINANCIAL DISCLOSURE: S.C.P., F.B., and R.C.D. are funded by Australian Postgraduate Award, Star Scientific Foundation, Petre Foundation, and National Health and Medical Research Council. Y.H. has funding from Oxford University Clinical Academic Graduate School and Oxford National Institute for Health Research Biomedical Research Centre. The other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Dr Pillai has an Australian Postgraduate Award, and Drs Dale and Brilot have funding from Star Scientific Foundation, Petre Foundation, and National Health and Medical Research Council. No other authors have funding relevant to this project. POTENTIAL CONFLICT OF INTEREST: Dr Waters has received speaker honoraria from Euroimmun AG. The other authors have indicated they have no potential conflicts of interest to disclose.
REFERENCES 1. Granerod J, Cunningham R, Zuckerman M, et al. Causality in acute encephalitis: defining aetiologies. Epidemiol Infect. 2010;138(6):783–800
paediatric neurology: a marker of active central nervous system inflammation. Dev Med Child Neurol. 2009;51(4): 317–323
2. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83(2):142–150
10. Lewthwaite P, Begum A, Ooi MH, et al. Disability after encephalitis: development and validation of a new outcome score. Bull World Health Organ. 2010;88(8):584–592
3. 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(2):157–165 4. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7): 899–904 5. Granerod J, Ambrose HE, Davies NWS, et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835–844 6. Koskiniemi M, Korppi M, Mustonen K, et al. Epidemiology of encephalitis in children. A prospective multicentre study. Eur J Pediatr. 1997;156(7):541–545 7. Fowler A, Stödberg T, Eriksson M, Wickström R. Childhood encephalitis in Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12(6):484–490 8. Kolski H, Ford-Jones EL, Richardson S, et al. Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994–1995. Clin Infect Dis. 1998;26(2):398–409 9. Dale RC, Brilot F, Fagan E, Earl J. Cerebrospinal fluid neopterin in
11. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127(3): 701–712 12. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel–complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010; 133(9):2734–2748 13. Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology. 2008;71(16): 1291–1292 14. Dalmau J, Lancaster E, MartinezHernandez E, Rosenfeld MR, BaliceGordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63–74 15. Haberlandt E, Bast T, Ebner A, et al. Limbic encephalitis in children and adolescents. Arch Dis Child. 2011;96(2): 186–191 16. Dale RC, Merheb V, Pillai S, et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain. 2012;135(pt 11):3453–3468 17. Togashi T, Matsuzono Y, Narita M, Morishima T. Influenza-associated acute encephalopathy in Japanese children in
1994–2002. Virus Res. 2004;103(1–2): 75–78 18. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand. 2007;115(4 suppl):45–56 19. Lynch M, Lee B, Azimi P, et al. Rotavirus and central nervous system symptoms: cause or contaminant? Case reports and review. Clin Infect Dis. 2001;33(7): 932–938 20. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997; 19(2):81–92 21. Glaser CA, Gilliam S, Schnurr D, et al; California Encephalitis Project, 1998–2000. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998–2000. Clin Infect Dis. 2003;36(6): 731–742 22. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167–177 23. Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):776–785 24. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84(7):748–755 25. Suleiman J, Brenner T, Gill D, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology. 2011;76(14):1252–1255
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e983
26. Paterson RW, Zandi MS, Armstrong R, Vincent A, Schott JM. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry. 2014;85(6):625–630 27. Christie LJ, Honarmand S, Talkington DF, et al. Pediatric encephalitis: what is the role of Mycoplasma pneumoniae? Pediatrics. 2007;120(2):305–313 28. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 2014;13(3):276–286 29. Mailles A, Stahl JP; Steering Committee and Investigators Group. Infectious encephalitis in France in 2007: a national prospective study. Clin Infect Dis. 2009; 49(12):1838–1847 30. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease? Pediatrics. 2007;119(2). Available at: www.pediatrics.org/cgi/content/full/119/ 2/e399 31. Schleede L, Bueter W, Baumgartner-Sigl S, et al. Pediatric herpes simplex virus
e984
encephalitis: a retrospective multicenter experience. J Child Neurol. 2013;28(3): 321–331 32. Mohammad SS, Sinclair K, Pillai S, et al. Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-D-aspartate receptor or dopamine-2 receptor. Mov Disord. 2014; 29(1):117–122 33. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317–323 34. Hacohen Y, Deiva K, Pettingill P, et al. Nmethyl-D-aspartate receptor antibodies in post–herpes simplex virus encephalitis neurological relapse. Mov Disord. 2014;29(1):90–96 35. Prüss H, Finke C, Höltje M, et al. N-methylD-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72(6):902–911 36. Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75(3): 411–428 37. Hacohen Y, Absoud M, Woodhall M, et al; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group. Autoantibody biomarkers in
childhood-acquired demyelinating syndromes: results from a national surveillance cohort. J Neurol Neurosurg Psychiatry. 2014;85(4):456–461 38. Tsiodras S, Kelesidis I, Kelesidis T, Stamboulis E, Giamarellou H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J Infect. 2005;51(5):343–354 39. Amin R, Ford-Jones E, Richardson SE, et al. Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year review. Pediatr Infect Dis J. 2008;27(5): 390–395 40. DuBray K, Anglemyer A, LaBeaud AD, et al. Epidemiology, outcomes and predictors of recovery in childhood encephalitis: a hospital-based study. Pediatr Infect Dis J. 2013;32(8):839–844 41. Wang IJ, Lee PI, Huang LM, Chen CJ, Chen CL, Lee WT. The correlation between neurological evaluations and neurological outcome in acute encephalitis: a hospital-based study. Eur J Paediatr Neurol. 2007;11(2):63–69 42. Fowler A, Stödberg T, Eriksson M, Wickström R. Long-term outcomes of acute encephalitis in childhood. Pediatrics. 2010;126(4). Available at: www.pediatrics.org/cgi/content/full/126/ 4/e828
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony, Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang, Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale Pediatrics; originally published online March 23, 2015; DOI: 10.1542/peds.2014-2702 Updated Information & Services
including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/early/2015/03/17 /peds.2014-2702
Supplementary Material
Supplementary material can be found at: http://pediatrics.aappublications.org/content/suppl/2015/03/1 7/peds.2014-2702.DCSupplemental.html
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml
Reprints
Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony, Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang, Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale Pediatrics; originally published online March 23, 2015; DOI: 10.1542/peds.2014-2702
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2015/03/17/peds.2014-2702
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
abstract
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. BACKGROUND AND OBJECTIVES:
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).
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. RESULTS:
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.
CONCLUSIONS:
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.
ARTICLE
a
Neuroimmunology Group, Institute of Neuroscience and Muscle Research at the Kids Research Institute, Children’s Hospital at Westmead, University of Sydney, Australia; bTY Nelson Department of Neurology and Neurosurgery and Departments of dMedical Imaging, eInfectious Diseases and Microbiology, and fStatistics, the Children’s Hospital at Westmead, Sydney, Australia; cNuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, England; gNational Health Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia; hCentre Hospitalier Territorial Magenta, Service Pediatric, Nouméa, New Caledonia; iChelsea & Westminster Hospital, Department of Neurology, Imperial College Healthcare National Health Service Trust, London, England; and jEvelina Children’s Hospital, London, England
Dr Pillai acquired all clinical data, performed radiological phenotyping, retrieved investigation data, performed outcome assessments, performed statistical analysis, wrote the first draft, and edited subsequent drafts; Dr Hacohen, Ms Merheb, and Drs Waters, Lang, Lim, and Brilot performed and supervised all autoantibody testing and edited drafts; Dr Kesson performed infectious investigation supervision, edited drafts, and
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
Encephalitis is inflammation of the brain parenchyma and has many infectious and immune-mediated etiologies.1 Acute encephalitis can be life threatening and results in permanent neuropsychiatric and cognitive impairments in a significant proportion of survivors. Inflammatory forms of encephalitis such as acute disseminated encephalomyelitis (ADEM) have been known for some time, but in the past decade other autoimmune forms of encephalitis have been recognized, defined by the presence of autoantibodies against cell surface antigens. Autoantibody detection is important as immune suppression may improve outcomes, particularly when given early in the disease.2,3 A recent study suggested that Nmethyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis, the bestknown autoimmune form, is more common than herpes simplex virus (HSV) encephalitis in children and young adults,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.6–8 We studied clinical and radiologic features, serum autoantibodies in acute archived samples, and longterm outcomes in a large retrospective cohort of pediatric encephalitis from a single center.
METHODS Patients, Definitions, and Clinical Data Patients We report patients with encephalitis seen between January 1998 and October 2010 at the Children’s Hospital at Westmead, the largest tertiary children’s hospital in New
South Wales, Australia. Patients either presented directly to the hospital emergency department or were referred from district hospitals in western Sydney and New South Wales (referral base ∼4.5 million people). Patients were identified retrospectively from International Classification of Diseases, 10th Revision coding of encephalitis or encephalomyelitis at discharge, plus screening of consultant correspondence from the Department of Neurology database and review of cerebrospinal fluid (CSF) polymerase chain reaction testing from the Department of Infectious Diseases and Microbiology. The following patients were excluded: neonates (,1 month old), patients .16 years old, known or suspected cases of immunodeficiency, and viral or bacterial meningitis without encephalitis. Infectionassociated encephalopathy (influenza and rotavirus) cases were included. A total of 164 patients fulfilled the diagnostic criteria for acute encephalitis, according to the following definitions.
Definitions We used the Granerod encephalitis case definitions, with minor modifications.1 Encephalitis was defined as an acute encephalopathy with $2 of the following: fever $38°C, seizures or focal neurologic signs, CSF pleocytosis ($5 white blood cells/µL) or elevated CSF neopterin (.30 nmol/ L), EEG consistent with encephalitis (presence of slowing in this study), or MRI findings suggestive of encephalitis. CSF neopterin, which is produced secondary to a- or g-interferon stimulation, was included as an alternative to CSF pleocytosis because it has been shown to be a useful marker of central nervous system (CNS) inflammation.9 Encephalopathy was defined as an altered or reduced level of consciousness and a change in personality or behavior or confusion lasting .24 hours. We did not use lethargy and irritability as sole features
of encephalopathy because of the nonspecific nature of these features in sick children unless supported by EEG features of encephalopathy.
Clinical Data During Acute Encephalitis In total, 179 clinical or investigation variables were recorded in every patient (Supplemental Information). CSF results were available in 157 (96%) patients, and EEG reports from the first week of admission were available in 130 (79%) patients. We obtained follow-up information by telephone interview in 144 (88%) cases in 2011 and 2012 by using the Liverpool Outcome Score (LOS) questionnaire,10 supplemented by clinical records. All patients were followed up for a minimum of 12 months after encephalitis, and the LOS was recorded as follows: 1 = death, 2 = severe, 3 = moderate, 4 = mild, and 5 = normal, and specific domains of abnormal outcome were also recorded. The outcome score describes the patient’s abilities compared with peers, with mild describing impairments without dependence on carers, whereas severe describes complete dependence on carers. Clinical relapses were recorded separately.
MRI We had access to 1.5-Tesla MRI brain scans for review in 149 (91%) patients. MRI data were reviewed, blinded to clinical and diagnostic information, by pediatric neurologists (R.C.D., S.C.P.) and a pediatric neuroradiologist (K.P.), and consensus was reached on abnormalities. The mean and median duration of first MRI scan after admission were 4.8 days and 3 days, respectively (range 1–70 days).
Etiologic Investigation to Determine Encephalitis Causation Infectious Encephalitis and InfectionAssociated Encephalopathy The CSF, serological, and non-CNS specimen testing for infectious etiologies are summarized in Supplemental Table 3. Testing of up
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e975
to 42 different microorganisms was carried out as clinically indicated. The mean and median etiologic tests (including autoantibodies) per patient were 14 and 13 tests, respectively (range 0–36).
CSF Testing A CSF was obtained at a mean and median admission duration of 2.9 days and 2 days, respectively (range 1–48 days). Bacterial and viral cultures of the CSF were done on 155 (95%) and 152 (93%) patients, respectively. CSF polymerase chain reaction testing was obtained in 131 (80%) of the total cohort, with patients with ADEM less frequently tested (63%).
Serology Serological testing for $1 microorganisms was performed on 139 (85%) patients. Serological studies for microorganisms used complement fixation tests and immunoglobulin M (IgM) enzymelinked immunosorbent assays (Table 1).
Non-CNS Specimens These tests include blood culture (n = 144, 87.8%), nasopharyngeal aspirate (n = 69, 42%), stool and rectal swab (n = 68, 41%), throat swab (n = 47, 29%), and skin swab (n = 5, 3%) (Supplemental Table 3).
Immune-Mediated/AutoantibodyAssociated Encephalitis We used Granerod case definition for confirmed ADEM. Retrospective autoantibody testing on stored acute sera was performed in 103 of the 129 patients with non-ADEM encephalitis (80%). Patients with a preliminary diagnosis of ADEM were excluded from autoantibody testing (n = 35). Antibodies to NMDAR (n = 103), voltage-gated potassium channel complex (VGKC-complex) (n = 102), leucine-rich glioma-inactivated 1 (LGI1) (n = 99), contactin-associated protein-like 2 (CASPR2) (n = 99), glycine receptor (n = 102), and
e976
TABLE 1 Hierarchical Classification for the Etiology of Encephalitis Etiology of Encephalitisa
Confirmed
Probable
Infectious (N = 49, 30%) Enterovirus 17 Mycoplasma pneumoniae — 4 HSVb Cytomegalovirus — Other infectionsc — Infection-associated encephalopathy (N = 13, 8%) Influenza virus — Rotavirus — ANEd 3 Immune-mediated or autoantibody-associated (N = 56, 34%)e ADEM 35 NMDAR antibody 5 VGKC-complex antibody — Dopamine D2 receptor antibody — Unknown (N = 46, 28%) Total 64
Possible
— 11 1 — 1
3 — 4 3 5
— — —
5 5 —
— 5 7f 4
— — — —
29
25
Total N (%) 20 11 9 3 6
(12) (7) (5) (2) (4)
5 (3) 5 (3) 3 (2) 35 10 7 4 46 164
(21) (6) (4) (2) (28) (100)
ANE, acute necrotizing encephalopathy. Table adapted from Granerod et al. (2010).1 Serological testing for $1 microorganisms was performed on 139 (85%) patients. Serological studies for microorganisms used complement fixation tests (CFTs) and IgM enzyme-linked immunosorbent assays. Only 14 patients had paired acute and convalescent serology, and no patients had a diagnosis of infectious encephalitis based on a fourfold change in titer. A single raised anti-streptolysin O (group A Streptococcus, n = 1) and a positive IgM and IgG (HSV [n = 3] and Epstein–Barr virus, parvovirus B19 [each, n = 1]) result were used to diagnose probable or possible infectious encephalitis. A positive IgM provided a probable infectious diagnosis for Mycoplasma pneumoniae (n = 11). a 11 patients had $2 etiologic associations and are presented in Supplemental Table 4. b HSV-1 (n = 4, CSF PCR confirmed); HSV-2 (n = 1, skin swab polymerase chain reaction possible); 1 patient with probable HSV (relapsing) also had positive serum NMDAR and D2R antibodies. c Group A Streptococcus (n = 1, probable), adenovirus (n = 1, possible), Epstein–Barr virus (n = 1, possible), parainfluenza 3 virus (n = 1, possible), parvovirus B19 (n = 1, possible), varicella zoster virus (n = 1, possible). d Associated infections (probable/possible) in 2 of 3 patients. e 22 patients tested positive for $1 of the following antibodies: NMDAR (n = 11), VGKC (n = 7), D2R (n = 6), and glycine receptor (n = 1). LGI1, CASPR2, and glutamic acid decarboxylase antibodies were negative in all. One patient with a VGKCcomplex antibody titer of 421 pM had positive glycine receptor antibody. f 5 of the 7 VGKC-positive patients had Mycoplasma pneumoniae IgM detected (see Supplemental Table 4).
glutamic acid decarboxylase (n = 102) were tested as previously described.11–14 Only 5 patients had combined testing of CSF and serum for autoantibodies (NMDAR only). VGKC-complex antibody positivity was based on titers .150 pM, as suggested in children.15 Dopamine-2 receptor antibody testing (n = 103) was undertaken as described.16
Etiologic Causation The final etiologic diagnosis was determined by stringent application of the consensus guidelines proposed by Granerod et al.1 Cases were classified as confirmed, probable, or possible. Confirmed cases had detection of the organism or autoantibody in CSF or brain.1 A probable diagnosis was based on serological evidence of acute infection or autoantibody, and a possible
diagnosis was based on detection of the organism from a specimen sample outside the CNS, such as stool or nasopharyngeal aspirate.1 As accepted in the literature, we used the term infection-associated encephalopathy rather than encephalitis to denote encephalitis related to influenza virus or rotavirus.17–19 In cases with multiple etiologies (Supplemental Table 4), the agent with the strongest hierarchical association (confirmed . probable . possible) was designated as the etiology of encephalitis.
Ethics The study was ethically approved (09/CHW/56), and written consent was obtained from the families and patients for a follow-up telephone interview and testing of stored acute samples.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
Statistical Analysis
Demographics and Seasonality
For comparison of clinical variables between the different major etiologic groups, we used SAS version 9.3 (SAS Institute, Inc, Cary, NC). Categorical variables were compared with the exact x2 test and described in terms of proportions and Wilson confidence intervals (CIs); continuous variables were compared with the Kruskal–Wallis test and described in terms of median and range (Supplemental Tables 5–8). We assessed the relationship of clinical variables to outcome by using univariate and multivariate logistic regression analyses. All variables with a univariate P ,.05 were included as potential predictors in a multivariate model that used a stepwise backward selection procedure in SPSS (IBM SPSS Statistics, IBM Corporation). We described these associations by using odds ratios (ORs) and Wald CIs. We assessed the association between clinical variables to autoantibody status by using the x2 test and described it in terms of ORs and 95% CIs. We made no adjustment for multiple statistical testing.
The median age at presentation was 5.5 years (range 5 weeks–15.1 years), and 94 (57%) patients were male. Figure 1 demonstrates that young children are more frequently affected. The majority of encephalitis cases (n = 57, 35%) presented during the Australian winter season (June–August, data not shown).
Clinical Features, CSF, EEG, and MRI Figure 2 and Supplemental Table 5 compare the clinical features, which in descending order of frequency were fever (n = 126, 77%), seizures (n = 88, 54%), headache (n = 71, 43%), weakness or pyramidal signs (n = 61, 37%), any respiratory symptoms (n = 57, 35%), and agitation (n = 56, 34%). CSF pleocytosis was present in 110 out of 155 (71%) patients and elevated CSF protein in 50 out of 154 (33%) patients. CSF neopterin was elevated in 36/47 (77%) tested patients. Oligoclonal bands were measured in 53 (32%), and intrathecal oligoclonal bands were
detected in only 2 patients (1 with NMDAR encephalitis, 1 unknown) and mirrored oligoclonal bands in another 16 (5 infectious, 10 immunemediated [ADEM 4, NMDAR 4, dopamine receptor D2 {D2R} 2], 1 unknown). Five patients with positive serum NMDAR antibody also had CSF testing and were confirmed CSF NMDAR antibody positive. CSF findings by subgroup are presented in Supplemental Table 6. The EEG was abnormal in 115 out of 130 (88%) patients; EEG slowing was found in 111 out of 130 (85%) and epileptiform discharges in 27 out of 130 (21%) patients, respectively. Figure 3 and Supplemental Table 7 describe the MRI features. The MRI brain (T2-weighted fluid-attenuated inversion recovery) was abnormal in 121 out of 149 (81%) of patients.
Duration of Stay, Therapy, and Outcome The mean and median length of stay for patients were 27 and 13 days, respectively (range 1–618 days). Admission to the ICU was necessary in 66 (40%) patients, with the majority needing management of
RESULTS All Encephalitis (n = 164) Overview of Etiologies (Table 1) A total of 164 children were diagnosed with acute encephalitis. An etiology was proposed in 118 (72%) patients, of whom 64 (39%) were confirmed, 29 (18%) probable, and 25 (15%) possible. In 46 (28%) patients, the cause was unknown. The etiologic groups were infectious encephalitis, n = 49 (30%); infectionassociated encephalopathy, n = 13 (8%); and immune-mediated/ autoantibody-associated encephalitis, n = 56 (34%). Complete autoantibody and some infectious serological findings are presented in Table 1. Potential dual or multiple etiology occurred in 11 (7%) patients (Supplemental Table 4), including 8 with Mycoplasma pneumoniae.
FIGURE 1 Number of patients with acute encephalitis according to age at presentation and etiologic group. 11% of patients were ,1 year of age, and 54% of patients were #5 years old, with the frequency descending steadily at later ages.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e977
FIGURE 2
Clinical features at any stage in all encephalitis and major etiologic subgroups (n $ 7). Data including statistical significance is in Supplemental Table 5. EV, enterovirus; GI, gastrointestinal; MycoP, Mycoplasma pneumoniae; Unk, unknown.
e978
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
FIGURE 3
MRI features according to neuroanatomical location and sequence characteristics in all encephalitis and the major etiologic subgroups (n $ 7). Data including statistical significance are in Supplemental Table 7. EV, enterovirus; FLAIR, fluid-attenuated inversion recovery; MycoP, Mycoplasma pneumoniae; T1-W, T1-weighted; T2-W, T2-weighted; Unk, unknown.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e979
encephalopathy, seizures, or both. Of the 164 patients, 147 (87%) received antibiotics or antiviral therapy. The mean and median duration of followup were 6.6 years and 5.8 years, respectively (range 1.1–14.4 years). There were 5 deaths (4 in the hospital). Figure 4 compares the LOS measures. An abnormal outcome (LOS 1–4) was present in 71 out of 144 (49%) patients, including LOS 1 (death) (n = 5, 4%), LOS 2 (severe) (n = 11, 8%), LOS 3 (moderate) (n = 29, 20%), and LOS 4 (mild) (n = 26, 18%). The most common abnormal outcomes by category (Supplemental Table 8) were learning problems (n = 39, 28%), behavioral problems (n = 33, 24%), epilepsy (n = 25, 18%), and speech problems (n = 24, 17%). Clinical relapse occurred in 9 (5%) patients: HSV encephalitis (n = 1), ADEM (n = 1), NMDAR-Ab encephalitis (n = 3), D2R antibody encephalitis (n = 2), and unknown (n = 2). Patients with NMDAR and D2R antibodies were more likely to relapse (P = .01). Using univariate analysis, we found that an abnormal long-term outcome was associated with status epilepticus (seizure .30 minutes) (OR 7.74; 95% CI, 2.51–23.89), ICU admission (OR 3.83; 95% CI, 1.91–7.72), diffusion restriction on MRI (OR 2.47; 95% CI, 1.03–5.98), and a movement disorder (OR 2.44; 95% CI, 1.10–5.39). Patients with an infectious prodrome were less likely to have an abnormal outcome (OR 0.28; 95% CI, 0.12–0.63). On multivariate analysis, status epilepticus (OR 3.78; 95% CI, 1.07–13.41, P = .04), diffusion restriction (OR 2.47; 95% CI, 0.95–6.46, P = .06), and ICU admission (OR 2.27; 95% CI, 0.92–5.59, P = .08) each predicted an abnormal outcome.
Subgroup Analysis According to etiology, the following clinical characteristics were more common (Fig 2): Respiratory
e980
FIGURE 4
The LOS (1–5) in all encephalitis (n = 144, 88%) and the major etiologic subgroups (n $ 7). Data including statistical significance is in Supplemental Table 8.
symptoms (Mycoplasma, VGKCcomplex Ab), gastrointestinal symptoms (enterovirus), seizures (HSV, VGKC-complex Ab), weakness or pyramidal signs (ADEM), agitation and psychiatric symptoms (NMDAR), speech dysfunction (NMDAR), movement disorder (NMDAR), cerebellar (ADEM), sleep disturbance (NMDAR), brainstem (ADEM and enterovirus), and autonomic (NMDAR and enterovirus).
(any T2-weighted fluid-attenuated inversion recovery abnormality) in NMDAR encephalitis. Abnormalities detected with diffusion-weighted sequencing, T1 sequences, contrast enhancement, hemorrhage, and cystic necrosis were all more common in HSV (Fig 3 and Supplemental Table 7). HSV and unknown encephalitis had the worst outcomes, and ADEM had the best outcome (Fig 4).
According to etiology, the following MRI features were more common (Fig 3): abnormalities of white matter (HSV, ADEM), cortical gray matter (HSV), basal ganglia (Mycoplasma and ADEM), thalami (ADEM, HSV), cerebellum and brainstem (ADEM), and limbic encephalitis (NMDAR, VGKC-complex, Mycoplasma). The MRI was least likely to be abnormal
Of the smaller subgroups (Table 1), all 4 patients with D2R antibody–associated encephalitis had dystonia–Parkinsonism, and 3 out of 4 had localized basal ganglia involvement on MRI (basal ganglia encephalitis).16 Three patients had acute necrotizing encephalopathy with the typical radiologic features.18,20 There were no other
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
characteristic clinicoradiologic features in the other small subgroups.
Clinicoradiologic Correlation With Autoantibody Positivity Using univariate analysis in patients with non-ADEM encephalitis tested for autoantibody (n = 103), we found that an autoantibody-associated encephalitis was more likely (in descending order) with clinical relapse (OR 13.5; 95% CI, 2.46–74.04, P , .0001), movement disorder (OR 11.2; 95% CI, 3.82–32.9, P , .0001), CSF intrathecal or mirrored oligoclonal bands (OR 7.89; 95% CI, 1.53–40.5, P = .02), speech dysfunction (OR 5.92; 95% CI, 2.03–17.2, P , .0001), psychiatric symptoms (OR 4.79; 95% CI, 1.73–13.2, P = .002), agitation (OR 3.64; 95% CI, 1.34–9.94, P = .009), and MRI limbic encephalitis phenotype (OR 5.22; 95% CI, 1.27–21.5, P = .03). Antibodyassociated encephalitis was less common with headache (OR 0.35; 95% CI, 0.12–0.98, P = .04) or MRI thalamic involvement (OR 0.21; 95% CI, 0.05–0.98, P = .03).
Immunotherapy and Outcome A total of 60 out of 164 patients (37%) received immunotherapy (corticosteroids, n = 59; intravenous immunoglobulin, n = 16; rituximab, n = 2), most commonly for ADEM (27 out of 35), NMDAR-Ab encephalitis (6 out of 10), enterovirus (6 out of 20), and unknown (9 out of 46) subgroups. Abnormal outcome was not different in the patients who received immunotherapy compared with those who did not (OR 1.17; 95% CI, 0.60–2.31, P = .64). The mean length of stay was longer in patients who received immune therapy (41 days vs 19 days, P = .02).
DISCUSSION This single-center cohort, followed up for a median of 5.8 years, is the most comprehensive retrospective analysis of pediatric encephalitis to date. In
a resource-rich setting, we have defined the relative frequency of acute encephalitis syndromes by etiology, with emphasis on the emerging treatable autoantibodyassociated encephalitides. Despite long follow-up, the study confirms the high morbidity in survivors of encephalitis, the significant proportion who lack a diagnosis, the need to identify the autoantibodyassociated syndromes, and the need to improve the acute management and rehabilitation of these patients with the hope of reducing long-term residual neurocognitive impairments. Immune-mediated/autoantibodyassociated encephalitides were the most common etiologic group. Although by definition ADEM is an encephalomyelitis, it is notable that many previous encephalitis cohorts do not include ADEM but generally focus on infectious encephalitis alone.6–8,21 NMDAR-Ab encephalitis was diagnosed in 6% of patients, who had typical clinical features of the disease, with dominant movement, psychiatric, sleep, speech, and autonomic features. The number could be an underestimate, because serum testing was performed on only 103 out of 129 (81%) of the patients without ADEM. Indeed, 4 of the 46 patients with unknown encephalitis had a phenotype reminiscent of NMDAR-Ab encephalitis but were negative for serum antibody. CSF might have been helpful,14,22 although that is not our experience. VGKC-complex antibodies were first reported in adults with limbic encephalitis.11 Subsequently, it was found that the VGKC-complex antibodies bound not to the VGKC subunits themselves but to proteins, namely LGI1 and CASPR2,12,23 which are complexed with the VGKC subunits in vivo. In this report, 7 (4%) of children had VGKC-complex antibodies, but only 2 had evidence of limbic encephalitis on imaging, and they were not positive for LGI1 or CASPR2 antibodies, as is often true
for pediatric cases with positive VGKC-complex Ab.12,23–25 Although 150 pM has been proposed as a positive result for VGKC-complex Ab in children, levels .400 pM are more relevant in adults,15,26 and only 2 children had these levels. Nevertheless, VGKC-complex antibodies appear to be associated with inflammatory disorders (Hacohen et al in preparation). The association seen here of positive VGKC-complex Ab with Mycoplasma pneumoniae and with respiratory symptoms (5 out of 7) suggests that VGKC-complex Ab could be induced as part of the immune response to Mycoplasma pneumoniae. Mycoplasma pneumoniae–associated encephalitis occurred in 7% of our cohort, although the diagnostic specificity of mycoplasma IgM has been questioned.27 Antibodies to D2R were found in only 4 patients with dystonia–Parkinsonism and basal ganglia lesions, representing a small subgroup (2%).16 There were no patients with antibodies to glutamic acid decarboxylase and only 1 patient with glycine R antibody (who also had VGKC-complex antibodies and Mycoplasma), and reported pediatric cases with these antibodies are rare. Nine (20%) of the patients with unknown encephalitis did not have serum available for autoantibody testing, and comprehensive testing may help to ensure recognition of known autoantibodies and to define some of the “unknown” patients in the future. For example, g-aminobutyric acid A receptor antibodies have recently been found in patients with acute-onset severe epilepsy and encephalitis,28 and it will be interesting to test pediatric patients with encephalitis for this autoantibody. Infectious encephalitis was found in 30%, and the most common infection was enterovirus (12%). Even with broad testing for HSV (84% of patients), HSV encephalitis was
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e981
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.32 The emerging theme of postviral autoimmunity is increasingly recognized, and it emphasizes the importance of considering immunotherapies in post-HSV relapses.32–34 There were some patients with $2 etiologic associations (Supplemental Table 4), and these patients provide a challenge for diagnosis and illustrate the overlap between infectious and autoantibodyassociated syndromes.32,35–38 There were notable etiologic absences in this cohort, such as no Mycobacterium tuberculosis encephalitis. Unlike in the United Kingdom,5 Mycobacterium tuberculosis is rare in Australian children. We also did not observe any confirmed varicella encephalitis, a result probably related partly to the introduction of routine varicella vaccination during the study period. As is true for most resource-rich countries, we no longer observe measles or mumps encephalitis because of vaccination. Other
etiologies not seen in our cohort include arboviruses and Bartonella. There were small subgroups of infection-associated encephalopathy (8%) associated with influenza and rotavirus, and these were kept as a separate group, by convention.18,39 Acute necrotizing encephalopathy, which is an infection-associated encephalopathy, is observed more frequently in Japanese and East Asian children, presumably because of their differing genetic vulnerability.18 The main limitation of the study was the retrospective design and therefore incomplete investigation and the potential incomplete ascertainment of milder or atypical cases. Despite these limitations, the study confirms that encephalitis is a serious disease with an abnormal outcome in ∼50%, particularly in cognitive and behavioral domains, with 3% mortality. In general, the predictors of poor outcomes were ICU admission and status epilepticus, as in previous studies.40–42 In addition, we found diffusion restriction on MRI, a marker of cytotoxic injury, correlated with abnormal outcomes. The use of immunotherapy was not associated with better outcomes, but the patients receiving immune therapy had longer admissions, suggesting that these patients had a more complicated course. Immunotherapy has only recently become established in the treatment
of autoantibody-associated encephalitis (other than ADEM),3 and prospective studies are needed to determine the benefit of immunotherapy in patients with encephalitis irrespective of whether an autoantibody is detected. The percentage of unknown encephalitis (28%) in this study is the lowest among substantial pediatric cohorts,6–8,40,41 but it represents an important subgroup that is comparable in size to the prospective UK cohort in adults and children.5 There were no distinguishing clinical or radiologic characteristics of the unknown subgroup, mainly because of the likely heterogenous etiologies. The unknown encephalitis group may contain both encephalitis of viral origin (untested or unknown) and autoimmune etiologies. The poor outcome in this group emphasizes the importance of future research in this area.
ACKNOWLEDGMENTS We thank the patients, their families, and all health professionals who contributed to this study. S.C.P. has funding from the Australian Postgraduate Award scheme. Y.H. has funding from Oxford University Clinical Academic Graduate School and Oxford National Institute for Health Research Biomedical Research Centre. R.C.D. and F.B. have funding from NHMRC (Australia) for this work.
was involved in clinical data acquisition and analysis; Dr Davies was involved in study design and edited drafts; Dr Prelog performed radiological phenotyping and edited drafts; Drs Tantsis, Gill, Webster, Menzes, Ardern-Holmes, Gupta, Procopis, Troedson, Antony, Ouvrier, and Polfrit were involved in clinical data acquisition and analysis and edited drafts; Dr Barnes performed statistical analysis and edited drafts; Dr Vincent supervised autoantibody testing and edited first and subsequent drafts; Dr Dale conceived and designed the study, supervised all clinical aspects of the study, performed radiological phenotyping, wrote the first draft, and edited subsequent drafts; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2014-2702 DOI: 10.1542/peds.2014-2702 Accepted for publication Jan 6, 2015 Address correspondence to Russell C. Dale, PhD, Clinical School, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: russell. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2015 by the American Academy of Pediatrics
e982
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
FINANCIAL DISCLOSURE: S.C.P., F.B., and R.C.D. are funded by Australian Postgraduate Award, Star Scientific Foundation, Petre Foundation, and National Health and Medical Research Council. Y.H. has funding from Oxford University Clinical Academic Graduate School and Oxford National Institute for Health Research Biomedical Research Centre. The other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Dr Pillai has an Australian Postgraduate Award, and Drs Dale and Brilot have funding from Star Scientific Foundation, Petre Foundation, and National Health and Medical Research Council. No other authors have funding relevant to this project. POTENTIAL CONFLICT OF INTEREST: Dr Waters has received speaker honoraria from Euroimmun AG. The other authors have indicated they have no potential conflicts of interest to disclose.
REFERENCES 1. Granerod J, Cunningham R, Zuckerman M, et al. Causality in acute encephalitis: defining aetiologies. Epidemiol Infect. 2010;138(6):783–800
paediatric neurology: a marker of active central nervous system inflammation. Dev Med Child Neurol. 2009;51(4): 317–323
2. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83(2):142–150
10. Lewthwaite P, Begum A, Ooi MH, et al. Disability after encephalitis: development and validation of a new outcome score. Bull World Health Organ. 2010;88(8):584–592
3. 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(2):157–165 4. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7): 899–904 5. Granerod J, Ambrose HE, Davies NWS, et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835–844 6. Koskiniemi M, Korppi M, Mustonen K, et al. Epidemiology of encephalitis in children. A prospective multicentre study. Eur J Pediatr. 1997;156(7):541–545 7. Fowler A, Stödberg T, Eriksson M, Wickström R. Childhood encephalitis in Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12(6):484–490 8. Kolski H, Ford-Jones EL, Richardson S, et al. Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994–1995. Clin Infect Dis. 1998;26(2):398–409 9. Dale RC, Brilot F, Fagan E, Earl J. Cerebrospinal fluid neopterin in
11. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127(3): 701–712 12. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel–complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010; 133(9):2734–2748 13. Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology. 2008;71(16): 1291–1292 14. Dalmau J, Lancaster E, MartinezHernandez E, Rosenfeld MR, BaliceGordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63–74 15. Haberlandt E, Bast T, Ebner A, et al. Limbic encephalitis in children and adolescents. Arch Dis Child. 2011;96(2): 186–191 16. Dale RC, Merheb V, Pillai S, et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain. 2012;135(pt 11):3453–3468 17. Togashi T, Matsuzono Y, Narita M, Morishima T. Influenza-associated acute encephalopathy in Japanese children in
1994–2002. Virus Res. 2004;103(1–2): 75–78 18. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand. 2007;115(4 suppl):45–56 19. Lynch M, Lee B, Azimi P, et al. Rotavirus and central nervous system symptoms: cause or contaminant? Case reports and review. Clin Infect Dis. 2001;33(7): 932–938 20. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997; 19(2):81–92 21. Glaser CA, Gilliam S, Schnurr D, et al; California Encephalitis Project, 1998–2000. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998–2000. Clin Infect Dis. 2003;36(6): 731–742 22. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167–177 23. Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):776–785 24. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84(7):748–755 25. Suleiman J, Brenner T, Gill D, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology. 2011;76(14):1252–1255
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PEDIATRICS Volume 135, number 4, April 2015
e983
26. Paterson RW, Zandi MS, Armstrong R, Vincent A, Schott JM. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry. 2014;85(6):625–630 27. Christie LJ, Honarmand S, Talkington DF, et al. Pediatric encephalitis: what is the role of Mycoplasma pneumoniae? Pediatrics. 2007;120(2):305–313 28. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 2014;13(3):276–286 29. Mailles A, Stahl JP; Steering Committee and Investigators Group. Infectious encephalitis in France in 2007: a national prospective study. Clin Infect Dis. 2009; 49(12):1838–1847 30. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease? Pediatrics. 2007;119(2). Available at: www.pediatrics.org/cgi/content/full/119/ 2/e399 31. Schleede L, Bueter W, Baumgartner-Sigl S, et al. Pediatric herpes simplex virus
e984
encephalitis: a retrospective multicenter experience. J Child Neurol. 2013;28(3): 321–331 32. Mohammad SS, Sinclair K, Pillai S, et al. Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-D-aspartate receptor or dopamine-2 receptor. Mov Disord. 2014; 29(1):117–122 33. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317–323 34. Hacohen Y, Deiva K, Pettingill P, et al. Nmethyl-D-aspartate receptor antibodies in post–herpes simplex virus encephalitis neurological relapse. Mov Disord. 2014;29(1):90–96 35. Prüss H, Finke C, Höltje M, et al. N-methylD-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72(6):902–911 36. Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75(3): 411–428 37. Hacohen Y, Absoud M, Woodhall M, et al; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group. Autoantibody biomarkers in
childhood-acquired demyelinating syndromes: results from a national surveillance cohort. J Neurol Neurosurg Psychiatry. 2014;85(4):456–461 38. Tsiodras S, Kelesidis I, Kelesidis T, Stamboulis E, Giamarellou H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J Infect. 2005;51(5):343–354 39. Amin R, Ford-Jones E, Richardson SE, et al. Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year review. Pediatr Infect Dis J. 2008;27(5): 390–395 40. DuBray K, Anglemyer A, LaBeaud AD, et al. Epidemiology, outcomes and predictors of recovery in childhood encephalitis: a hospital-based study. Pediatr Infect Dis J. 2013;32(8):839–844 41. Wang IJ, Lee PI, Huang LM, Chen CJ, Chen CL, Lee WT. The correlation between neurological evaluations and neurological outcome in acute encephalitis: a hospital-based study. Eur J Paediatr Neurol. 2007;11(2):63–69 42. Fowler A, Stödberg T, Eriksson M, Wickström R. Long-term outcomes of acute encephalitis in childhood. Pediatrics. 2010;126(4). Available at: www.pediatrics.org/cgi/content/full/126/ 4/e828
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
PILLAI et al
Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony, Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang, Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale Pediatrics; originally published online March 23, 2015; DOI: 10.1542/peds.2014-2702 Updated Information & Services
including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/early/2015/03/17 /peds.2014-2702
Supplementary Material
Supplementary material can be found at: http://pediatrics.aappublications.org/content/suppl/2015/03/1 7/peds.2014-2702.DCSupplemental.html
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml
Reprints
Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony, Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang, Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale Pediatrics; originally published online March 23, 2015; DOI: 10.1542/peds.2014-2702
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2015/03/17/peds.2014-2702
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Suny Health Sciences Ctr on March 26, 2015
