Catherine DeVile

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.

Clinical Neuroimaging Features and Outcome in Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency predominantly affects the central nervous system. There are limited data on long-term outcome or brain magnetic resonance imaging (MRI) features. We examined the clinical, brain MRI, biochemical, genetic, and electroencephalographic features and outcome in 8 children with a diagnosis of molybdenum cofactor deficiency observed in our institution over 10 years. Two modes of presentation were identified: early (classical) onset with predominantly epileptic encephalopathy in 6 neonates, and late (atypical) with global developmental impairment in 2 children. Children in both groups had varying degrees of motor, language, and visual impairment. There were no deaths. Brain MRI demonstrated cerebral infarction in all but one child in the atypical group. Distinctive features were best observed on early brain MRI: acute symmetrical involvement of the globus pallidi and subthalamic regions coexisting with older cerebral hemisphere infarction, chronic lesions suggestive of a prenatal insult, pontocerebellar hypoplasia with retrocerebellar cyst, and presence of a distinctive band at the cortical/subcortical white matter. Sequential imaging revealed progressive pontine atrophy and enlargement of retrocerebellar cyst. The brain MRI of one child with atypical presentation (verbal dyspraxia, lens dislocation) showed symmetrical cerebellar deep nuclei signal abnormality without cerebral infarction. Imaging pattern on early brain MRI (<1 week) may prompt the diagnosis, potentially allowing early treatment and disease modifications.

Severe cerebellitis following methadone poisoning.

We report a 3-year-old girl with an unusual presentation of cerebellitis following ingestion of methadone. CT showed diffuse symmetrical swelling and oedema of the cerebellum resulting in compression of the fourth ventricle and hydrocephalus. The changes were confirmed on MRI with the addition of watershed injuries. These findings represent a toxic encephalopathy and have been reported in previous cases of heroin intoxication by inhalation, but rarely following opioid ingestion. The aetiology of the watershed infarcts is discussed.

DOK7 congenital myasthenic syndrome in childhood: Early diagnostic clues in 23 children

Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life.

Fracture and non‐fracture pain in children with osteogenesis imperfecta

AIMnTo describe and compare the characteristics of acute fracture and chronic non-fracture pain in children with osteogenesis imperfecta (OI).nnnMETHODSnA questionnaire about fracture-related pain and prospective 7-d diary about non-fracture-related pain was completed by a random sample of 35 children aged 5-18 from a UK national OI service. Main outcome measures included pain intensity, location, frequency, quality, coping strategies and analgesia use.nnnRESULTSnMost children reported moderate to severe pain associated with fractures and less intense non-fracture pain (p<0.001). Pain intensity was significantly higher in the children who used analgesics (p<0.001). The quality of fracture and non-fracture pain differed only for affective words, which were less frequently used to describe non-fracture pain (p=0.002). More activities of daily living (ADLs) were affected by fracture pain than by non-fracture pain (p<0.001). Children reported more frequent use of approach coping strategies with fracture pain and more frequent use of distraction for non-fracture pain (p<0.01). There were no differences in non-fracture pain intensity, duration, quality, effect on ADLs or coping between children who did or did not take bisphosphonates.nnnCONCLUSIONSnPain is a common occurrence for children with OI and is both acute and chronic in nature, interfering with childrens daily living activities. OI pain may not be optimally treated because many children experienced moderate to severe pain despite use of analgesics and/or coping strategies.

Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta

BACKGROUNDnOsteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit.nnnREPORTnWhole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency.nnnDISCUSSIONnHomozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from Classical OI.nnnCONCLUSIONSnHere we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

Experience of using electromyography of the genioglossus in the investigation of paediatric dysphagia

Aim The aim of the study was to assess, retrospectively, the utility of genioglossus electromyography (gEMG) in evaluating children with suspected neurogenic feeding and swallowing difficulties.

Understanding the Information Needs of General Practitioners Managing a Rare Genetic Disorder (Osteogenesis Imperfecta)

Background: Lack of adequate knowledge is a common problem in medicine, but is a particular problem in a rapidly advancing field like genetics. This study uses the example of a rare genetic disorder (osteogenesis imperfecta) to understand the information needs of primary care physicians (GPs). Objectives: To determine whether a knowledge gap is recognised, how GPs currently attempt to overcome it, and what features of an information resource are preferred by GPs. Methods: GPs of children affected by osteogenesis imperfecta in and around Greater London were interviewed, using both questionnaire-based semi-structured interview and a qualitatively analysed open-ended discussion. Consultations in both primary and tertiary care settings over a 5-year period were compared. Results: Problems due to osteogenesis imperfecta were presented to GPs in about one third of consultations with these patients. GPs reported finding such patients difficult to manage due to lack of knowledge. Knowledge from tertiary sources, which was authoritative, accessible and relevant, was preferred, particularly when reasoning was explained. Primary literature and clinical guidelines were not favoured. Conclusions: Empirical evidence supports and elaborates theoretical models for provision of clinically useful information. A model for improved information services using authoritative web-based information linked to electronic patient records is suggested.

Fracture and non-fracture pain in children with osteogenesis imperfecta: Pain in children with osteogenesis imperfecta

Aim: To describe and compare the characteristics of acute fracture and chronic non‐fracture pain in children with osteogenesis imperfecta (OI). Methods: A questionnaire about fracture‐related pain and prospective 7‐d diary about non‐fracture‐related pain was completed by a random sample of 35 children aged 5–18 from a UK national OI service. Main outcome measures included pain intensity, location, frequency, quality, coping strategies and analgesia use. Results: Most children reported moderate to severe pain associated with fractures and less intense non‐fracture pain (p<0.001). Pain intensity was significantly higher in the children who used analgesics (p<0.001). The quality of fracture and non‐fracture pain differed only for affective words, which were less frequently used to describe non‐fracture pain (p=0.002). More activities of daily living (ADLs) were affected by fracture pain than by non‐fracture pain (p<0.001). Children reported more frequent use of approach coping strategies with fracture pain and more frequent use of distraction for non‐fracture pain (p<0.01). There were no differences in non‐fracture pain intensity, duration, quality, effect on ADLs or coping between children who did or did not take bisphosphonates.