Long term outcome in non-multiple sclerosis paediatric acquired demyelinating syndromes.

OBJECTIVES: We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). METHODS: In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. RESULTS: A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5-14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. CONCLUSION: The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype.

Facial Dysmorphism, Hirsutism, and Failure to Thrive as Manifestation of Leigh Syndrome in a Child with SURF1 Mutation.

Leigh syndrome (or subacute necrotizing encephalomyelopathy) is a rare neurodegenerative disorder characterized by psychomotor retardation or regression, typically occurring in stepwise decrements. Onset is typically between ages 3 and 12 months. Neurological manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy, whereas extraneurological manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness. Approximately 50% of affected individuals die by age 3 years, most often as a result of respiratory or cardiac failure. We report a case of 22-month-old female child presenting to us with severe failure to thrive, dysmorphic features, hirsutism, external ophthalmoplegia epilepsy, and neuroregression with characteristic findings of Leigh's syndrome on neuroimaging and her muscle biopsy revealed evidence of mitochondrial respiratory chain defect involving complex IV and SURF1 mutation.

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures.

OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Phenotypical Variation with Same Genetic Mutation in Familial Hypokalemic Periodic Paralysis.

Hypokalemic periodic paralysis is a genetic neuromuscular disorder characterized by episodes of painless muscle paralysis associated with low serum potassium, exclusively, during the attack. This may be precipitated by heavy exercise, fasting, or high-carbohydrate meals. We report two siblings, presenting at different ages with varying symptomatology-older sibling with episodic weakness in the morning associated with reduced physical exercise and consumption of large carbohydrate meal, whereas younger sibling complained of muscle stiffness following large carbohydrate meal and at the end of physical exercise. Molecular genetic study showed both siblings and their father were positive for calcium channel alpha-1S subunit (CACNA1S) C3716G>A; p.Arg1239His mutation. It is important to check serum potassium in a child presenting with muscle stiffness or weakness after a carbohydrate meal or vigorous exercise. This condition responds with potassium supplement. Often relevant family history and trigger factors with clinical correlation and blood results can lead to its diagnosis.

Neuropsychological Difficulties Associated with Dopa Responsive Dystonia.

A young girl with L-dopa responsive dystonia showed significant improvements in motor function but had ongoing complaints of neuropsychological difficulties. A neuropsychological evaluation was undertaken to understand the nature of her difficulties. Intellectual function, attention, executive function, and academic attainment were assessed using published psychometric tests. Verbal and non-verbal reasoning was found to be age appropriate. Particular difficulties were identified with working memory, visual selective attention, dual attention, and processing speed which were having a significant impact upon the child and her family. The importance of a thorough neuropsychological evaluation is discussed in helping to appropriately manage and support the child with this chronic but rare health condition.

Fifteen-minute consultation: an approach to a child presenting to the emergency department with acute psychotic symptoms.

Presentation of a child in the A&E with altered behaviour including psychotic features is not unusual. New-onset psychotic symptoms in children pose a significant diagnostic challenge due to several reasons. First, primary psychotic conditions are uncommon in pre-pubertal children. Second, differentiating between delirium and psychosis can be difficult in children, more so in infants, toddlers and young children. Third, intervening and managing a secondary cause of psychosis can significantly optimise outcome. Prompt recognition of a possible underlying cause for a child's psychotic behaviour is essential, and at the same time challenging, in the emergency department. This article attempts to present a systematic approach to a child with acute onset of psychotic symptoms in an emergency setting.

Prolonged expiratory apnoea with cyanosis in Arnold Chiari II malformation.

Apnoea associated with Arnold Chiari malformation is a known entity and can be obstructive or central. Differentiating between two types is vital to deciding management pathway and prognosticating disease process.

Neuroimaging in Menkes Disease.

Menkes disease (MD) is a rare infantile onset neurodegenerative disorder due to mutations in the X linked ATP7A gene. These patients can present with failure to thrive, severe psychomotor retardation, seizures and hypopigmented hair, which is characteristic of this condition. A number of neuro-radiological findings have been reported in this condition. We report the spectrum of neuro-radiological findings in three affected boys being treated at our centre. We suggest that magnetic resonance imaging (MRI) and, in particular magnetic resonance angiography (MRA) when taken in the context of the clinical presentation may be helpful in making an early diagnosis of this devastating condition.

A structured approach to the assessment of a floppy neonate.

Hypotonia in a newborn presents a diagnostic challenge for clinicians. It is an important clinical feature that may indicate an underlying systemic illness or neurological problem at the level of the central or peripheral nervous system. It is important to know the different presentations of hypotonia and to have the knowledge of the diagnostic work up which requires multidisciplinary assessment and input and the prognostic implications of these disorders. This review article presents a structured approach highlighting initial assessment, examination, and management of a neonate with generalized hypotonia.

Prolonged video-EEG in identifying paroxysmal nonepileptic events in children with epilepsy: a useful tool.

PURPOSE: Habitual events, behaviors, and nonepileptic events can be easily confused with epileptic seizures in children in the absence of clear description and can be challenging, even for an experienced clinician. The aim was to report on the usefulness of adding video-EEG to routine EEG studies of infants and children with frequent atypical paroxysmal events. METHODS: A retrospective analysis of video-EEG carried over a 2-year period in a tertiary pediatric neurology center. Outcomes were classified as: "conclusive epileptic," "conclusive nonepileptic," "unremarkable," and "inconclusive." RESULTS: Forty-four children (M:F 19:25) with an age range of 1 to 15 years (mean: 7 years, median: 8.5 years) were analyzed. Thirty (68%) children had successful epilepsy classification. A diagnosis of a specific nonepileptic event was reached in 55% of cases. Antiepileptic drugs were discontinued completely in 8 patients (20%), and the total number of antiepileptic drugs was reduced in 13 others (33%). CONCLUSIONS: Paroxysmal nonepileptic events can cause diagnostic confusion, particularly in children with developmental delay, epilepsy (especially refractory epilepsy), or those with previous "abnormal" EEG. Accurate diagnosis can be reached in the majority of cases using prolonged video-EEG monitoring.

Cataplectic facies: clinical marker in the diagnosis of childhood narcolepsy-report of two cases.

BACKGROUND: Narcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition. PATIENTS: We present two children who presented with "cataplectic facies," an unusual facial feature only recently described in children with narcolepsy with cataplexy. RESULT: The diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay. CONCLUSION: The diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies.

Carers' express positive views on the acceptability, efficacy and safety of buccal midazolam for paediatric status epilepticus.

AIM: Buccal midazolam has emerged as an effective alternative to rectal diazepam in the management of paediatric status epilepticus. This study aimed to identify carers' views on the safety, efficacy and acceptability of buccal midazolam in the management of this common neurological emergency. METHODS: Community-based, face-to-face interviews were carried out with 34 carers to evaluate the effectiveness, adverse effects and convenience of buccal midazolam as a rescue treatment for prolonged seizures. All children received 2.5 to 10 mg of Epistatus, a proprietary oral solution (10 mg/mL). We evaluated therapeutic success, time taken for seizures to cease and the need to attend the emergency department, together with the development of side effects, namely respiratory depression and sedation. RESULTS: Most of the families (91%) found that buccal midazolam was always, or usually, effective in stopping seizures and it prevented hospital admission in 65% of cases. The majority (96%) of those who had used both buccal midazolam and rectal diazepam preferred the former as it was easier to administer, more socially acceptable and did not sedate the child as much. CONCLUSION: Carers felt that buccal midazolam was an effective, safe and more acceptable alternative to rectal diazepam in the management of paediatric status epilepticus.

Voltage gated potassium channel antibodies positive autoimmune encephalopathy in a child: A case report and literature review of an under-recognized condition.

Autoimmune limbic encephalitis (LE) associated with voltage gated potassium channel antibodies (VGKC-Abs) in children is more common than previously thought and is not always paraneoplastic. Non-neoplastic, autoimmune LE associated with VGKC-Abs has been described recently. However, only few case reports in children as the disease is predominantly described in the adult population. It is likely that this type of autoimmune encephalitis is currently under-diagnosed and hence, under-treated, especially in children. We present a 13-year-old previously fit and healthy African girl diagnosed with LE and we reviewed the literature for its current management.

Atypical juvenile neuronal ceroid lipofuscinosis: A report of three cases.

The diagnosis of juvenile neuronal ceroid lipofuscinosis (JNCL) is usually based on age of onset, initial clinical symptoms, clinical progression, and pathologic findings. Our cases manifested atypical clinical symptomatology and/or pathologic findings and therefore, represent variant forms of JNCL. Case 1 and 2 presented with slow developmental regression from the age of 4 years and became blind and wheelchair bound at around 8 years. Pathologic finding of lymphocytes showed fingerprint inclusion which was consistent with JNCL. Mutational analysis was positive for CLN5 which usually presents as variant late infantile NCL (LINCL) and more common in Finnish population. Case 3 presented with progressive visual loss from the age of 8 years. Clinical symptomatology and age of onset were similar to that of JNCL but was found to have low palmitoyl protein thioesterase, granular inclusion body, and CLN1 mutation, thus representing milder form of INCL. These three cases demonstrated phenotypic-genotypic variations. Pertinent issues relating diagnostic difficulties, ophthalmologic, neuroradiological, and laboratory aspects are discussed.

Phenotypic heterogeneity in skeletal muscle sodium channelopathies: A case report and literature review.

Skeletal muscle sodium channelopathies (SMSCs) including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PC), and sodium channel myotonia are caused by sodium channel gene (SCN4A) mutations, with altered sarcolemal excitability, and can present as episodes of skeletal muscle weakness, paralysis, and myotonia. We report a teenage boy, who presented with features of HyperPP, PC, myotonia congenita, and sodium channel myotonia. His electromyography (EMG) revealed myopathic changes, myotonia, and Fournier EMG pattern I, and posed a diagnostic challenge. Genetic analysis showed Thr704Met mutation in SCN4A gene. While with typical clinical phenotypes, the electromyographic patterns can be used to direct genetic testing, atypical phenotypes may pose diagnostic dilemmas. Clinicians dealing with neuromuscular disorders in children need to be aware of the unusual clinical presentations of SMSC, so that focused genetic testing can be carried out.

Acute longitudinal myelitis as the first presentation in child with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system auto-immune disorder that is characterized by widespread immune dysregulation, formation of auto-antibodies, and immune complexes, resulting in inflammation and potential damage to variety of organs. It is complicated by neurological manifestations in 25-95% of the patients. Acute transverse myelitis (ATM) may be a complication in 1-2% of patients with SLE but in some patients it may be the initial manifestation of SLE. This sub-group of patients where ATM is the presenting feature may not fulfil the ACR criteria for the diagnosis of SLE which may delay the diagnosis and may affect the outcome. In those patients where the involvement is more than four segments of the spine are believed to have poor prognosis, but early diagnosis and treatment may alter the course and lead to a better outcome. We describe a young Polish girl where ATM was the initial manifestation of SLE involving almost the whole length of spine but she had a reasonably good outcome following early diagnosis and aggressive treatment.