Antonia Clarke

Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens

Objective To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens. Method Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase. Results Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect. Conclusions Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status

PURPOSE To delineate a catastrophic childhood epileptic syndrome of unknown cause presenting with persistent intractable multifocal status. METHODS Case note review. RESULTS Six children aged 5 months to 6 years presented with focal seizures that progressed within days to intractable multifocal seizures with or without secondary generalisation, which recurred every few minutes and persisted for weeks. One developed impaired consciousness shortly before seizures started. The two younger children showed mild developmental delay before onset but the others were normal. The seizures were unresponsive to all conventional anticonvulsants, steroids or pyridoxine and could only be controlled with doses of thiopentone sufficient to cause electrical suppression. MRI scans were initially normal but later showed focal cortical swelling followed by generalised atrophy. Two developed hepatomegaly, with a normal liver biopsy in one and steatosis in the other. No cause has been found even after neuropathological investigation. Three have died, two within 3 months of onset, while the three survivors have very severe neurological impairment and continued seizures. CONCLUSION The similarity of the clinical features suggests that this is a consistent clinical syndrome.

Use of melatonin to treat sleep disorders in tuberous sclerosis

The results of a therapeutic trial of the use of melatonin in patients with tuberous sclerosis complex who also have severe sleep problems are reported. We used a randomized double‐blind placebo‐controlled crossover design. Seven patients with confirmed diagnoses of tuberous sclerosis and significant sleep disorder were recruited. We employed three outcome measures: total sleep time, time to sleep onset, and number of awakenings. Patients treated with melatonin had a small but clinically significant improvement in total sleep time (mean improvement 0.55 hours, P<0.05). They also tended to have an improvement in sleep‐onset time but this did not reach statistical significance. Melatonin, in this trial, had no discernible effect on sleep fragmentation. We conclude that melatonin does have a beneficial effect in prolonging the total sleep time of patients with tuberous sclerosis and sleep disorder and that further trials are necessary to investigate the issues of optimal dosage, tolerance, and possible interactions with other medications.

Autistic regression associated with seizure onset in an infant with tuberous sclerosis.

We report here on a male diagnosed with tuberous sclerosis at 6 months of age. The child was treated with vigabatrin at age 6 months after an abnormal electroencephalogram but before onset of seizures. Vigabatrin was discontinued at age 13 months to avoid possible visual field defects. At 21 months, the child developed partial seizures with secondary generalization and infantile spasms. Standardized developmental assessments were performed at 12, 18, 24, 30, and 36 months of age. Cognitive and social development were normal until age 21 months and the onset of seizures. When assessed at 24 months, the child met criteria for autism and learning disability. This case indicates that the onset of epilepsy during an early stage in brain development can be associated with autistic regression and persistent developmental disorder. The case suggests the need to consider if possible visual field defects with vigabatrin outweigh the potentially deleterious effects of uncontrolled seizures.

Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family

Acute necrotizing encephalopathy (ANE) typically affects young, healthy children who develop rapid‐onset severe encephalopathy triggered by viral infections. This disease is more commonly reported in Japan but occurs worldwide, although it remains under‐recognized in Western countries. An autosomal dominant form, ANE1, was recently identified. We report the details of a 9‐year‐old Caucasian female who experienced recurrent ANE episodes at the ages of 9 months and 9 years. Brain magnetic resonance imaging findings were characteristic of ANE during both episodes, although more extensive in the recent episode, which resulted in severe neurological sequelae; influenza A was identified on bronchoalveolar lavage during this episode. Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE. Both the patient and her mother, who had also had postviral polyneuritis in the past, harbour a mutation in Ran‐binding protein 2 (RANBP2); this occurred de novo in the mother and confers genetic susceptibility to ANE. Our case suggests that recurrent disease and/or an expanded clinical phenotype raises the possibility of ANE1; positive family history, although supportive, is not necessary as the mutation can occur de novo. Increased awareness may lead to earlier recognition and better treatment options.

A new Nav1.7 sodium channel mutation I234T in a child with severe pain

Dominant gain‐of‐function mutations that hyperpolarize activation of the Nav1.7 sodium channel have been linked to inherited erythromelalgia (IEM), a disorder characterized by severe pain and redness in the feet and hands in response to mild warmth. Pharmacotherapy remains largely ineffective for IEM patients with cooling and avoidance of triggers being the most reliable methods to relieve pain. We now report a 5 year old patient with pain precipitated by warmth, together with redness in her hands and feet. Her pain episodes were first reported at 12 months, and by the age of 15–16 months were triggered by sitting as well as heat. Pain has been severe, inducing self‐mutilation, with limited relief from drug treatment. Our analysis of the patients genomic DNA identified a novel Nav1.7 mutation which replaces isoleucine 234 by threonine (I234T) within domain I/S4–S5 linker. Whole‐cell voltage‐clamp analysis shows a I234T‐induced shift of −18 mV in the voltage‐dependence of activation, accelerated time‐to‐peak, slowed deactivation and enhanced responses to slow ramp depolarizations, together with a −21 mV shift in the voltage‐dependence of slow‐inactivation. Our data show that I234T induces the largest activation shift for Nav1.7 mutations reported thus far. Although enhanced slow‐inactivation may attenuate the gain‐of‐function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient.

Pediatric Herpes Simplex Virus Encephalitis Complicated by N-Methyl-D-aspartate Receptor Antibody Encephalitis

N-methyl-D-aspartate receptor antibodies (NMDAR-Abs) can contribute to neurological relapse after herpes simplex virus encephalitis (HSE). We describe a child with NMDAR-Ab encephalitis after HSE, which was recognized and treated early. We discuss the case in the context of existing reports, and we propose a modified immunotherapy strategy to minimize risk of viral reactivation.

Acute life threatening cerebellitis presenting with no apparent cerebellar signs

Paediatric Neurology, St Georges Hospital NHS Foundation Trust, London, United Kingdom Paediatric Neurology, Evelina Children’s Hospital @ Guy’s & St Thomas’ Hospital NHS Foundation Trust, London, United Kingdom Neuroradiology, Evelina Children’s Hospital @ Guy’s & St Thomas’ Hospital NHS Foundation Trust, London, United Kingdom Paediatric Neuroscience, King’s College Hospital NHS Foundation Trust, London, United Kingdom Neurosurgery, Kings College Hospital NHS Foundation Trust, London, United Kingdom

Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults

This case series describes three children with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), an inflammatory condition characterized by a relapsing–remitting disease course responsive to steroids. The patients (two males, age 3y and 13y; one female, age 14y) presented with ataxia, dysarthria, and multiple cranial neuropathies. All patients demonstrated bilateral nodular lesions with contrast enhancement in the brainstem and cerebellum on magnetic resonance imaging, and perivascular lymphocytes and macrophages infiltrates on brain biopsies. Despite an initially good response to corticosteroids, all patients eventually became steroid‐dependent or ‐resistant, with frequent relapses on maintenance immunosuppressive therapy. Natalizumab and intravenous immunoglobulin stopped neurological disease progression in Patient 1 but he died at 17 years from respiratory complications. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein–Barr virus driven B‐cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. CLIPPERS disease in children is aggressive, with poor response to immunotherapy. Earlier use of newer immunotherapeutic agents such as natalizumab may be beneficial. Potential side effects need to be considered carefully.