Christopher Troedson

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.

A prospective study of acute movement disorders in children.

Aim  The purpose of this study was to report a prospective cohort of children with acute‐onset movement disorders.

Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies

Autoantibodies that bind to voltage‐gated potassium‐channel complex proteins (VGKC‐complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC‐complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile‐onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC‐complex antibodies were elevated (201pmol/L, normal<100), but extended antibody testing, including leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein 2 (CASPR2), was negative. The patient showed a partial response to steroid treatment, which was started late in the disease course. On review at 13 months of age, her development was consistent with an age of 5 to 6 months. These results suggest that VGKC‐complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy.

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.

Systemic lupus erythematosus due to C1q deficiency with progressive encephalopathy, intracranial calcification and acquired moyamoya cerebral vasculopathy.

We report a female with infantile onset of systemic lupus erythematosus secondary to C1q deficiency, in whom we identified a novel homozygous mutation in C1qB. The patient developed a progressive encephalopathy associated with spasticity, and suffered several arterial ischaemic strokes. Cerebral imaging demonstrated acquired intracranial calcification and a cerebral vasculopathy reminiscent of moyamoya. This case demonstrates overlap with some features of Aicardi-Goutières syndrome which, like C1q deficiency, is a monogenic cause of inflammation involving dysregulation of the innate immune system and stimulation of a type I interferon response.

Eye movement disorders are an early manifestation of CACNA1A mutations in children

The alpha‐1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary childrens hospital.

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.

Emergence of acute necrotising encephalopathy in Australia.

We report the first described cases of acute necrotising encephalopathy (ANE) in Australia. ANE is an acute onset enephalopathic illness associated with infectious agents, particularly influenza. ANE is well described in Japan and Taiwan but has been rarely reported elsewhere. ANE often presents with a fulminant encephalopathy and has characteristic imaging features with symmetrical oedema and enhancement of the thalami and posterior putamen. Pathological studies have shown no evidence of inflammatory infiltrate, but profound vasogenic oedema with extravasation of erythrocytes and plasma-like substance, and secondary necrosis. ANE has specific characteristics: infection induced acute encephalopathy with liver dysfunction, abnormal coagulation and deep grey matter imaging abnormalities. Despite the dramatic presentation, our patients improved surprisingly quickly associated with the use of early parenteral and then enteral steroid therapy. The 2007 influenza season was considered to be severe in Australia. Acute necrotising encephalopathy should be added to the complications of influenza infection in Australia. A previously well 7-year-old Caucasian girl presented initially with fever and upper respiratory tract infection. After 24 h she became rapidly drowsy and unresponsive. Within 6 h of neurological onset, her Glasgow coma score was 7/15 and she was intubated and ventilated. Her consciousness deteriorated further, and her examination revealed four limbed pyramidal signs with hyperreflexia. Blood examination revealed thrombocytopenia (46 ¥ 10 cells/L), abnormal coagulation (prolonged PT, APTT but normal fibrinogen) and elevated liver enzymes (AST 1957 U/L and ALT 1079 U/L). Her ammonia, lactate, glucose and urine metabolic screen were normal. Nasopharangeal aspirate was positive for Influenza A. All other serology was negative. Cerebro-spinal fluid (CSF) was not done because of the thrombocytopenia. Her magnetic resonance imaging (MRI) showed profound oedema and enhancement of the bilateral thalami, posterior putamen, brainstem tegmentum, hippocampal regions and cerebellar white matter (Fig. 1). The thalamic regions showed some diffusion restriction (Fig. 1b). The clinical and imaging features were compatible with acute necrotising encephalopathy. We commenced intravenous methyl-prednisolone within 24 h of neurological presentation (3 days intravenous 30 mg/kg, then oral prednisolone 2 mg/kg titrating down over 4 weeks). Our patient made rapid improvements and her examination was completely normal on Day 7. There were no residual motor, cognitive or behavioural residua apparent. Likewise, the liver dysfunction and coagulopathy normalised by Day 6. Her brother had a similar viral illness with positive Influenza A on nasopharyngeal aspirate, but no neurological symptoms. A previously well 22-month-old Australian boy of Chinese origin presented with neurological syndrome during a febrile illness with rhinorrhoea and diarrhoea. The parents were born in Australia, and the child had never travelled abroad. Two weeks previously, he had started at child care. On presentation, he was febrile, encephalopathic and had periodic dystonic posturing and hemiballismus. His consciousness deteriorated and he required intubation and ventilation. In addition, he had elevated liver enzymes and prolonged clotting with thrombocytopenia. Plasma ammonia and urine metabolic screen was normal. His MRI demonstrated dramatic T2weighted changes and oedema of the thalami and posterior putamen (Fig. 2). In addition, there were similar symmetrical lesions in the cerebellar grey matter and tegmentum, and one lesion in the subcortical white matter. The thalamic and posterior putamen lesions showed diffusion restriction (Fig. 2). CSF was acellular with a slightly raised protein (0.49 g/dL). CSF viral polymerase chain reaction was negative. Electroencephalogram result showed slowing but no epileptiform features. The patient had evidence of multiple concurrent infectious agents: adenovirus and rotavirus antigen positive (stool) and parainfluenza type 3 culture positive (nasopharyngeal aspirate). Our patient was treated with 30 mg/kg methylprednisolone per day (starting on the night of admission) for 5 days, followed by oral prednisolone 2 mg/kg/day titrating over the following month. Despite his aggressive presentation, within 2 weeks he was able to walk with aid, talk and feed himself. His repeat imaging at 2 weeks showed significant resolution of the thalamic and putamen oedema, and normalisation of the diffusion weighted images. Follow-up at 5 months revealed mild leftsided dystonia and oro-buccal incoordination. ANE is precipitated by infectious agents, particularly Influenza A and B, and occasionally other infections including parainfluenza. The clinical syndrome in ANE is typically a severe encephalopathy with mixed pyramidal and extrapyramidal signs. In addition, the presence of abnormal liver function and coagulation is typical of ANE and diagnostically important. ANE is predominantly described in Japan and Taiwan, although occasionally Caucasian cases from Europe and North America are reported. The acute MRI in our patients is typical of ANE, with severe thalamic and posterior putamen oedema, ring-like enhancement and diffusion restriction. The ring-like contrast enhancement points to a brain disorder involving blood brain barrier disruption and is diagnostically suggestive. Other biochemical support for the diagnosis of ANE include elevated CSF protein (but no cells) and derangement of liver function and clotting. In view of the liver and clotting dysfunction, the main differential diagnosis is of Reye’s syndrome, although a normal ammonia measurement makes this less likely. To help the clinician, diagnostic criteria exist for ANE. Mizuguchi and colleagues have proposed that ANE is a result of a local breakdown of the blood brain barrier and may be doi:10.1111/j.1440-1754.2008.01390-01395.x

Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation A Case Series and Review of the Literature

The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed. All three transplanted patients remain well, and the parameters evaluated remain stable. Of the treated patients, the two sisters had ongoing evidence of demyelinating sensorimotor neuropathy on nerve conduction tests, and with a early sensorimotor neuropathy in the older sister , and the other patient has mild intellectual impairment. One of the two un-transplanted controls, 15 years after MLD diagnosis, has relentlessly progressed to full dependency with epilepsy, severe mental retardation, dystonic movements, dysphagia and recurrent respiratory problems. Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. Our data show that, in comparison with their untreated siblings, UCBT significantly slowed the progression of the disease in the treated patients. We conclude that UCBT benefits children with pre-symptomatic early juvenile onset MLD by favourably altering the natural history of the disease.

Echovirus 19 associated with a case of acute flaccid paralysis

Acute flaccid paralysis can be caused by many members of the enterovirus genus, most notably the three poliviruses types 1 to 3. We report the case of acute flaccid paralysis caused by echovirus 19. The Western Pacific region has been declared polio free by the WHO since 2000. Australia is now using inactivated polio vaccine in the National Immunization Schedule. This vaccine does not carry the extremely rare risk of vaccine associated acute flaccid paralysis but it does leave our newly vaccinated population open gastrointestinal infection with polioviruses and the risk of circulation of the wild‐type virus. Continued surveillance of cases of acute flaccid paralysis is to detect polioviruses is essential until poliovirus is completely eradicated.