Jo M. Wilmshurst

Definitive neuroradiological diagnostic features of tuberculous meningitis in children.

Background: Although CT scanning is used widely for making the diagnosis and detecting the complications of tuberculous meningitis (TBM) in children, the radiological features are considered non-specific. CT is particularly suggestive of the diagnosis when there is a combination of basal enhancement, hydrocephalus and infarction, and even then the diagnosis may be in doubt. In this paper we introduce a new CT feature for making the diagnosis of TBM, namely, hyperdensity in the basal cisterns on non-contrast scans, and we assess which of the recognized CT features is most sensitive and specific. Objective: To determine the sensitivity and specificity of the presence of high-density exudates in the basal cisterns (on non-contrast CT) and basal enhancement (on contrast-enhanced CT) for the diagnosis of TBM in children, and to correlate these with the complications of infarction and hydrocephalus. Materials and methods: Retrospective review of CT scans with readers blinded to the diagnosis, which was based on a definitive culture of cerebrospinal fluid (CSF) for TBM or other bacteria. Computer-aided conversion of hard-copy film density to Hounsfield units was employed as well as a density threshold technique for determining abnormally high densities. Results: The most specific feature for TBM is hyperdensity in the basal cisterns prior to IV contrast medium administration (100%). The most sensitive feature of TBM is basal enhancement (89%). A combination of features (hydrocephalus, infarction and basal enhancement) is as specific as pre-contrast hyperdensity, but has a lower sensitivity (41%). There were statistically significant differences in the presence of hydrocephalus (p=0.0016), infarcts (P=0.0014), basal enhancement (P<0.0001) and pre-contrast density (P<0.0001) between the negative and positive TBM patient groups. The presence of granulomas was not statistically significant between the two groups (P=0.44). Conclusions: The presence of high density within the basal cisterns on non-contrast CT scans is a very specific sign for TBM in children. This will enhance diagnostic confidence, allow early institution of therapy and could reduce expenditure on contrast medium, scan time and radiation exposure. With the use of threshold techniques we believe that the pre-contrast hyperdensity may be detectable by a computer program that will facilitate diagnosis, and may also be modified to detect abnormal enhancement. Basal enhancement is a sensitive sign for the diagnosis of TBM and should be sought after contrast medium administration when no hyperdensity is seen in the basal cisterns or when this finding needs to be confirmed. The CT scan feature of hyperdense exudates on pre-contrast scans should be added to the inclusion criteria for the diagnosis of TBM in children.

Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics

Evidence‐based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or “state of the art” interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video‐EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile‐onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short‐term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short‐term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long‐term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits.

Neurologic and Neurobehavioral Sequelae in Children With Human Immunodeficiency Virus (HIV-1) Infection

The range and extent of neurologic and neurobehavioral complications of human immunodeficiency virus (HIV-1) infection in children are under-described. Seventy-eight children with HIV-1 infection (32 females) were assessed for neurologic complications. Forty-six children had abnormal neurology examinations. Thirty-three children had global pyramidal tract signs, 5 had a hemiparesis, 4 had peripheral neuropathy, 18 had visual impairment, and 5 had hearing impairment. Thirty-nine of 63 children over 1 year of age had neurobehavioral problems. Of 24 children with HIV encephalopathy, 74% had severe immunosuppression and 45% were not receiving antiretroviral therapy. Twelve children had prior opportunistic central nervous system infections, and 9 had epilepsy. Diverse neurologic and neurobehavioral deficits are common in children with HIV-1 infection. Children with severe immunosuppression, who were not receiving antiretroviral therapy, were growth impaired and less than 1 year of age, were at greatest risk for developing neurologic complications.

Severe infantile axonal neuropathy with respiratory failure

We describe 5 infants (4 male, 1 female) with a severe intractable form of motor‐sensory axonal neuropathy. All became ventilator‐dependent, 4 have since died and 1 remains static. Diaphragmatic paralysis was an early feature with generalized neuropathy evolving rapidly. Nerve conduction studies and biopsies were consistent with axonal disease. This disorder could be a new condition or part of the spectrum of inherited neuropathies of the axonal degenerative type. It may be that there is a “switching‐off” in the infants Schwann cell–axonal interactions in utero or in the early postnatal period, resulting in severe progressive deterioration and then a static period without recovery.

An update on the treatment of Sydenham's chorea: the evidence for established and evolving interventions.

Over 320 years after Thomas Sydenham described the condition labelled Sydenham’s chorea, it remains poorly understood. The disorder is an antineuronal antibody-mediated neuropsychiatric disorder caused by a poststreptococcal, autoimmune condition affecting control of movement, mood, behaviour and potentially the heart. The treatment remains empirical, and is less than optimal. There are few large clinically controlled trials. Recommendations for optimal management remain inconsistent and are hampered by the side effects from pharmacotherapy. Care for patients should be targeted at primary treatment (penicillin and bed rest), secondary palliation (symptomatic medication) and supportive (social) care. Small studies have demonstrated trends to support the use of immunoglobulins and steroids as therapeutic interventions for children affected by Sydenham’s chorea.

Treatment of sydenham chorea with intravenous immunoglobulin.

Sydenham chorea is a post-streptococcal, autoimmune, neuropsychiatric, movement disorder. There is no effective treatment. In a randomized study, comparison was made of the outcomes of 10 children treated with standard management alone compared to 10 who received additional intravenous immunoglobulin. The outcomes were assessed using a clinical rating scale, brain single-photon emission computed tomography, and the duration of symptomatic treatment. All three outcome measurement tools found improved outcomes in the group that received intravenous immunoglobulin.

Migrating Partial Seizures in Infancy: Two New Cases:

Two infants presented at 3 weeks and 3 months of age with intractable partial seizures. Extensive investigations failed to identify an underlying cause. There was no response to antiepileptic drug therapy and no developmental progress following the onset of the seizures. In both infants there was a distinctive pattern of seizures that arose independently from multiple regions of both hemispheres. Interictal electroencephalograms revealed multifocal epileptiform activity. The infants died aged 9 and 12 months. One underwent postmortem examination, which was normal with no hippocampal sclerosis. These infants fulfill the diagnostic criteria of the syndrome of migrating partial seizures in infancy described by Coppola and colleagues in 1995. (J Child Neurol 2000;15:717-722).

Peripheral neuropathies of infancy

Over a 33-year period, 260 patients (< 17 years of age; 119 males, 141 females) from New South Wales, Australia who had peripheral neuropathies confirmed by nerve biopsy, were studied. Of these, 50 infants presented with symptoms or signs of neuropathy under 1 year of age: including 24 patients with demyelinating neuropathies and 21 axonal neuropathies; a further five patients had spinal muscular atrophy with associated secondary sensory axonopathy. Nineteen infants had hereditary motor sensory neuropathy, of whom 13 had myelin protein mutations confirmed by molecular genetic studies. Peripheral neuropathy is not an unusual diagnosis in infancy. Awareness of this association will aid early diagnosis and prognosis as well as facilitate interventional patient management.

MRI findings in acute idiopathic transverse myelopathy in children

ObjectiveTo describe the clinical and MRI findings in three children with acute idiopathic myelopathy (AIM).Materials and methodsRetrospective review of the clinical presentation, MRI findings and outcome of three patients diagnosed with acute idiopathic transverse myelitis.ResultsOf note was the swift onset of symptoms in all patients, without any preceding illness or history of vaccination in two of the patients, and the rapid resolution of symptoms on steroid therapy in all the patients. MRI showed T2-weighted hyperintensity and patchy enhancement with gadolinium, but the extensive cord involvement did not correlate with the severity of presentation or outcome.ConclusionsOur findings do not support that MRI evidence alone of diffuse myelopathy is a predictor of poor outcome in childhood AIM.

RyR1 Deficiency in Congenital Myopathies Disrupts Excitation-Contraction Coupling

In skeletal muscle, excitation–contraction (EC) coupling is the process whereby the voltage‐gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca2+ channels located on the terminal cisternae. This subcellular membrane specialization is necessary for proper intracellular signaling and any alterations in its architecture may lead to neuromuscular disorders. In this study, we present evidence that patients with recessive RYR1‐related congenital myopathies due to primary RyR1 deficiency also exhibit downregulation of the alfa 1 subunit of the DHPR and show disruption of the spatial organization of the EC coupling machinery. We created a cellular RyR1 knockdown model using immortalized human myoblasts transfected with RyR1 siRNA and confirm that knocking down RyR1 concomitantly downregulates not only the DHPR but also the expression of other proteins involved in EC coupling. Unexpectedly, this was paralleled by the upregulation of inositol‐1,4,5‐triphosphate receptors; functionally however, upregulation of the latter Ca2+ channels did not compensate for the lack of RyR1‐mediated Ca2+ release. These results indicate that in some patients, RyR1 deficiency concomitantly alters the expression pattern of several proteins involved in calcium homeostasis and that this may influence the manifestation of these diseases.