Kumaran Deiva

N-Methyl-D-Aspartate Receptor Antibodies in Post-Herpes Simplex Virus Encephalitis Neurological Relapse

Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune‐mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N‐methyl‐D‐aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody–positive, 2 were negative (1 with HSV‐positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody–positive. In 2 of the NMDAR antibody–positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune‐mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.

Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children

Objective: To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) were predictive of a demyelination phenotype in children presenting with acquired demyelinating syndrome (ADS). Method: Sixty-five children with a first episode of ADS (12 acute disseminated encephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) were identified from 2 national demyelination programs in the United Kingdom and France. Acute serum samples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis of multiple sclerosis (MS) at 1 year. Results: Twenty-three of 65 (35%) children had MOG-Abs. Antibody-positive and antibody-negative patients were not clinically different at presentation, but identification of MOG-Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%) MOG-Ab–positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab–negative patients (p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS disease course, with a positive predictive value of 91% (95% confidence interval [CI] 72–99), negative predictive value of 38% (95% CI 24–54), positive likelihood ratio of 4.02 (CI 1.0–15.4), and odds ratio of 6.5 (CI 1.3–31.3). Conclusions: MOG-Abs are found at presentation in 35% of patients with childhood ADS, across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MS disease course at onset.

HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era

HAART therapy has led to a significant reduction of general and neurological morbidity, and mortality among HIV‐1 infected patients. It can also decrease HIV‐1 RNA titres in plasma and CSF towards undetectable level. However, the initial hope of achieving total eradication of the virus from the body has vanished. Even in patients who do not develop viral resistance or treatment intolerance, two kinds of viral persistence have been demonstrated both in lymphoid and central nervous system. The first one is a smoldering infection that persists, despite prolonged and apparently efficient HAART, in monocytes, tissue macrophages and most probably microglia. The second one is an integration of proviral DNA in the genome of subpopulations of CD4 lymphocytes of patients receiving efficient HAART. A similar viral integration in astrocytes and less likely in resting microglia is suggested by several studies, although it has yet to be demonstrated conclusively

CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis

Objectives: To differentiate onset of CNS involvement in primary hemophagocytic lymphohistiocytosis (HLH) from that of other CNS inflammatory diseases and to identify early symptoms linked to abnormal cognitive outcome. Methods: Forty-six children with primary HLH who had neurologic evaluation within 2 weeks and brain MRI within 6 months of diagnosis were included. Initial symptoms, CSF study, brain MRI, and neurologic outcome were assessed. Brain MRIs were compared with those of 44 children with acute disseminated encephalomyelitis (ADEM). Results: At disease onset, 29 children (63%) had neurologic symptoms and 7 (15%) had microcephaly. Twenty-three (50%) children had abnormal CSF study, but only 15 (33%) had abnormal brain MRI. The latter showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1. At the end of follow-up (3.6 ± 3.6 years), 17 of the 28 (61%) surviving patients had normal neurologic status, 5 (18%) had a severe neurologic outcome, and 6 (21%) had mild cognitive difficulties. Abnormal neurologic outcome was not influenced by age or type of genetic defect, but by the presence of neurologic symptoms, MRI lesions, or abnormal CSF study at onset. Early clinical and MRI symptoms may regress after treatment. Conclusion: Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI. In cases of abnormal brain MRI, the observed lesions differ from those of ADEM.

Treatment and outcome of children and adolescents with N-methyl-d-aspartate receptor encephalitis

The objective of this study is to describe the treatment and outcome of children and adolescents with N-methyl-d-aspartate receptor (NMDA-R) encephalitis. A retrospective study of children and adolescents with NMDA-R encephalitis was performed by the French Paraneoplastic Neurological Syndrome Reference Center between January 1, 2007 and December 31, 2012. The modified Rankin scale (mRS) was used to assess outcome. Thirty-six children and adolescents with NMDA-R encephalitis were studied. All of the patients received first-line immunotherapy (corticosteroids, intravenous immunoglobulins or plasma exchange), and 81xa0% received second-line immunotherapy (rituximab or cyclophosphamide). Median time between first-line and second-line treatment was 26xa0days. During the first 24xa0months, 30 of 36 patients (83xa0%) achieved a good outcome (mRSxa0≤xa02) and 20 of 36 patients (56xa0%) achieved complete recovery (mRSxa0=xa00). Median time to good outcome and to complete recovery was 6 and 24xa0months, respectively. Three patients (8xa0%) relapsed, one patient died. In multivariate analysis, agexa0>12xa0years was a predictor of good outcome and initial mRSxa0≤xa03 was a predictor of complete recovery. Despite a higher rate of patients who received second-line immunotherapy, the outcome of the patients in the present series was very similar to the outcome reported in previous series. The present study highlights the need for clinical trials to determine the optimal treatment of NMDA-R encephalitis.

Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation

Our purpose was to investigate in human neurons the neuroprotective pathways induced by Fractalkine (FKN) against glutamate receptor‐induced excitotoxicity. CX3CR1 and FKN are expressed constitutively in the tested human embryonic primary neurons and SK‐N‐SH, a human neuroblastoma cell line. Microfluorometry assay demonstrated that CX3CR1 was functional in 44% of primary neurons and in 70% of SK‐N‐SH. Fractalkine induced ERK1/2 phosphorylation within 1u2003min and Akt phosphorylation after 10u2003min, and both phosphorylation decreased after 20u2003min. No p38 and SAPK/JNK activation was observed after FKN treatment. Application of FKN triggered a 53% reduction of the NMDA‐induced neuronal calcium influx, which was insensitive to pertussis toxin and LY294002 an inhibitor of Akt pathway, but abolished by PD98059, an ERK1/2 pathway inhibitor. Moreover, FKN significantly reduced neuronal NMDA‐induced apoptosis, which was pertussis toxin insensitive and abolished in presence of PD98059 and LY294002. In conclusion, FKN protected human neurons from NMDA‐mediated excitotoxicity in at least two ways with different kinetics: (i) an early ERK1/2 activation which reduced NMDA‐mediated calcium flux; and (ii), a late Akt activation associated with the previously induced ERK1/2 activation.

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer

Objective: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). Methods: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. Results: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34–72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. Conclusion: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell–directed immunotherapies may improve its prognosis.

Acute idiopathic transverse myelitis in children: Early predictors of relapse and disability

Objective: To identify early prognostic factors of relapse and disability in children presenting with an acute idiopathic transverse myelitis (TM). Methods: Ninety-five children with acute idiopathic TM from 2 national European cohorts (France and United Kingdom) of CNS demyelinating diseases in children were identified and studied for early factors that predict relapse and disability using logistic regression models. Results: Sixteen (17%) relapsed, with a diagnosis of multiple sclerosis in 13 (14%) and neuromyelitis optica in 3 (3%). Logistic regression revealed 2 main criteria as risk factors for relapse: female sex (odds ratio [OR] 3.21, 95% confidence interval [CI] 0.88–11.78) and presence of associated brain lesions (OR 14.0, 95% CI 2.8–69.3). Twenty-eight (30%) children had a poor outcome defined by a Kurtzke Expanded Disability Status Scale score ≥4 or an American Spinal Injury Association impairment (ASIA) scale <D at last follow-up. Five factors were associated with poor outcome: female sex (OR 5.8, 95% CI 0.99–32.7), severe ASIA scale at onset (OR 33.5, 95% CI 1.8–618), gadolinium enhancement on spinal MRI (OR 24.1, 95% CI 3.78–153.88), absence of pleocytosis (OR 4.6, 95% CI 0.87–26.0), and absence of cervical or cervico-thoracic lesion on spinal MRI (OR 3.9, 95% CI 0.78–19.6). Conclusions Early predictors of relapse and disability identified in this large childhood study of acute idiopathic TM have important utility for clinical management. Larger prospective collaborative studies are required to validate these findings, which may improve the design of clinical trials.

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses.