Peter Procopis

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

BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/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.

Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies.

Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new‐onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type.

Benign acute childhood myositis

Four school children, aged 6 to 9 years, had acute postinfectious myositis. The prodromal illness usually involved the upper respiratory tract, but gastrointestinal symptoms were also seen. Fever and nonspecific malaise were characteristic. After cessation of the illness, myalgia involved the calves and thighs. Arm and neck muscles were less frequently affected. Weakness was less marked than muscle pain. Serum creatine phosphokinase (CPK) was markedly increased in all cases. Myalgia and CPK levels subsided in less than a week, although one child was not back to normal for 4 weeks. Two children had electromyography, and patchy myopathic changes were found. Viral studies were not helpful in any of the cases.

Influenza a encephalitis with movement disorder

Influenza A is an uncommon but well-recognized cause of viral encephalitis in childhood, occurring most commonly during community influenza outbreaks. The authors report four cases of influenza A encephalitis that occurred during an Australian epidemic in 1997-1998. Choreoathetosis during the acute phase of infection or basal ganglia involvement on neuroimaging was observed in three of the four patients. These findings in pediatric encephalitis are suggestive of influenza A infection and may guide investigation and early diagnosis.

Mild encephalopathy with reversible splenial lesion: An important differential of encephalitis

Mild encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome characterized by a transient mild encephalopathy and a reversible lesion in the splenium of the corpus callosum on MRI. This syndrome has almost universally been described in children from Japan and East Asia. Here we describe seven cases of MERS occurring in Caucasian Australian children from one centre seen over a 3 year period. All patients had a fever-associated encephalopathy (n = 7), which presented with confusion (n = 4), irritability (n = 3), lethargy (n = 3), slurred speech (n = 3), drowsiness (n = 2) and hallucinations (n = 2). Other neurological symptoms included ataxia (n = 5) and seizures (n = 1). These symptoms resolved rapidly over 4-6 days followed by complete neurological recovery. In all patients, MRI performed within 1-3 days of onset of encephalopathy demonstrated a symmetrical diffusion-restricted lesion in the splenium of the corpus callosum. Three patients had additional lesions involving other parts of the corpus callosum and adjacent periventricular white matter. These same three patients had mild persisting white matter changes evident at followup MRI, while the other patients had complete resolution of radiological changes. A potential trigger was present in five of the seven cases: Kawasaki disease, Salmonella, cytomegalovirus, influenza B and adenovirus (all n = 1). Elevated white cell count (n = 4), elevated C reactive protein (n = 5) and hyponatremia (n = 6) were commonly observed. CSF was performed in four patients, which showed no pleocytosis. This case series of MERS demonstrates this condition occurs outside of East Asia and is an important differential to consider in children presenting with acute encephalopathy.

Application of oligonucleotide array CGH in the detection of a large intragenic deletion in POLG associated with Alpers Syndrome

Mutations in the polymerase γ (POLG) gene are among the most common causes of mitochondrial disease and more than 160 POLG mutations have been reported. However, a large proportion of patients suspected of having POLG mutations only have one (heterozygous) definitive pathogenic mutation identified. Using oligonucleotide array CGH, we identified a compound heterozygous large intragenic deletion encompassing exons 15-21 of this gene in a child with Alpers syndrome due to mtDNA depletion. This is the first large POLG deletion reported and the findings show the clinical utility of using array CGH in cases where a single heterozygous mutation has been identified in POLG.

Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy

PURPOSE To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants. RESULTS The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach (

Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

5990 Australian dollars (AUD) vs

Late-onset nonketotic hyperglycinemia with leukodystrophy and an unusual clinical course.

13069 AUD ; p = 0.02) among the patients with identified pathogenic variants. CONCLUSION Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.