Protective effect of focal adhesion kinase against skeletal muscle reperfusion injury after acute limb ischemia.

OBJECTIVES: In cardiac muscle, ischemia reperfusion (IR) injury is attenuated by mitochondrial function, which may be upregulated by focal adhesion kinase (FAK). The aim of this study was to determine whether increased FAK levels reduced rhabdomyolysis in skeletal muscle too. MATERIAL AND METHODS: In a translational in vivo experiment, rat lower limbs were subjected to 4 hours of ischemia followed by 24 or 72 hours of reperfusion. FAK expression was stimulated 7 days before (via somatic transfection with pCMV-driven FAK expression plasmid) and outcomes were measured against non-transfected and empty transfected controls. Slow oxidative (i.e., mitochondria-rich) and fast glycolytic (i.e., mitochondria-poor) type muscles were analyzed separately regarding rhabdomyolysis, apoptosis, and inflammation. Severity of IR injury was assessed using paired non-ischemic controls. RESULTS: After 24 hours of reperfusion, marked rhabdomyolysis was found in non-transfected and empty plasmid-transfected fast-type glycolytic muscle, tibialis anterior. Prior transfection enhanced FAK concentration significantly (p = 0.01). Concomitantly, levels of BAX, promoting mitochondrial transition pores, were reduced sixfold (p = 0.02) together with a blunted inflammation (p = 0.01) and reduced rhabdomyolysis (p = 0.003). Slow oxidative muscle, m. soleus, reacted differently: although apoptosis was detectable after IR, rhabdomyolysis did not appear before 72 hours of reperfusion; and FAK levels were not enhanced in ischemic muscle despite transfection (p = 0.66). CONCLUSIONS: IR-induced skeletal muscle rhabdomyolysis is a fiber type-specific phenomenon that appears to be modulated by mitochondria reserves. Stimulation of FAK may exploit these reserves constituting a potential therapeutic approach to reduce tissue loss following acute limb IR in fast-type muscle.

Prolonged recovery of consciousness in children following symptomatic epileptic seizures.

INTRODUCTION: There is little published data on the duration of depressed consciousness following epileptic seizures. A prolonged recovery time may be a symptom of underlying brain pathology. This prospective paediatric cohort study investigates whether recovery is prolonged following symptomatic seizures. METHODS: Children aged 1-16 years, who had a witnessed seizure in which consciousness was impaired, were recruited. One hundred and twenty eight children (158 seizures) were studied. Seizure aetiology was classified as febrile, idiopathic, remote symptomatic, acute symptomatic and acute on remote symptomatic. At least hourly Paediatric Coma Scale recordings were used to assess recovery time. RESULTS: Recovery time was longest for children with acute on remote symptomatic seizures (4.0 h, range 0.89-10.5), followed by those with acute symptomatic seizures (1.94 h, range 0-35.27), remote symptomatic seizures (1.5h, range 0.07-85.5) and idiopathic seizures (0.83 h, range 0.07-13.13). Children with febrile seizures recovered the quickest (0.3h, range 0.05-9). Recovery time was significantly longer (p<0.001, CI 1.96-5.38) following seizures for which rescue antiepileptic drugs were administered compared to those for which it was not. Age, sex, type and duration of seizure did not independently affect recovery time. DISCUSSION: Symptomatic seizures take longer to recover than seizures of other aetiologies. It is recommended that a febrile child who presents with a seizure, who has not fully recovered within 30 min, should be investigated for an acute symptomatic aetiology. A high index of suspicion is also needed if children with apparent idiopathic seizures have not fully recovered within 1.5h.

Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).

OBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms.

BACKGROUND: Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the treatment of children with epilepsy and have significant adverse effects. Their efficacy and tolerability have not been not clearly established. OBJECTIVES: To determine the efficacy of corticosteroids in terms of seizure control, improvements in cognition and in quality of life and tolerability of steroids compared to placebo or other antiepileptic drugs. SEARCH STRATEGY: We searched the following databases: The Cochrane Epilepsy Group Specialized Register (September 2006); Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 2, 2006); MEDLINE (1966 - April 2004); EMBASE (1966 - December 2004); Database of Abstracts of Reviews of Effectiveness (DARE) (December 2004). We checked the reference lists of retrieved studies for additional reports of relevant studies. SELECTION CRITERIA: All randomized controlled trials of administration of corticosteroids to children (less than 16 years) with epilepsy. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion and extracted data. Outcomes included cessation of seizures, reduction in seizure frequency, improvement in cognition, quality of life and adverse effects of steroids. MAIN RESULTS: A single RCT was included that recruited five patients in double blind crossover trial. One was withdrawn prematurely from the study and another had infantile spasms and hence was excluded from further analysis. ACTH 4-9 was administered. The overall reduction in seizure frequency of more than 25% and less than 50% occurred in one child at low dose and in two children at higher dose. One child did not show any reduction in seizure frequency. No adverse effects were reported. AUTHORS' CONCLUSIONS: No evidence was found for the efficacy or safety of corticosteroids in treating childhood epilepsies. Clinicians using steroids in childhood epilepsies, other than for epileptic spasms, should take this into account before using these agents.

Recovery of consciousness after epileptic seizures in children.

OBJECTIVE: To investigate the duration of postictal impairment of consciousness and the factors that affect it. PATIENTS AND METHODS: 90 children aged 1-16 years (37 male, 53 female, median age 6 years), attending the accident and emergency department, and inpatients of Leeds General Infirmary, Leeds, UK, who had experienced seizures involving impairment of consciousness. Interventions-hourly modified paediatric coma scores were determined, until a coma score of 15 was obtained. Linear regression analysis was used to determine the factors influencing recovery time. RESULTS: 49 children were excluded owing to incomplete coma scoring, lost notes and refusal of consent. Median time for full recovery of consciousness was 38 min (0.63 h, range 0.05-17 h). Median recovery time was 18 min (0.3 h, range 0.05-9 h) from febrile seizures, which was significantly shorter than for seizures of other aetiologies (p<0.05), 1.35 h (range 0.07-13.13 h) from idiopathic seizures, 1.25 h (0.07-12.1 h) from remote symptomatic seizures and 4.57 h (0.25-17 h) from acute symptomatic seizures. Median recovery time after the use of benzodiazepines was 3.46 h (range 0.08-14.25 h), and was significantly longer (p<0.05) than for seizures not treated with benzodiazepines (median 0.47 h, range 0.05-17 h). Age, sex, seizure type and duration did not significantly affect recovery time. CONCLUSIONS: Most children experiencing febrile seizures recover within 30 min. An acute symptomatic aetiology should be considered if recovery takes >1 h.

The use of interferon beta in relapsing-remitting multiple sclerosis.

The use of interferon beta-1a to treat multiple sclerosis in a child of 7 years of age is discussed. To date, there is only one other published report of the use of interferon beta in a child as young as this. One year after commencing treatment she had shown significant clinical improvement, with a marked reduction in number of relapses. In her second year of treatment she suffered a major relapse from which she slowly recovered.

Juvenile Sandhoff disease--nine new cases and a review of the literature.

Juvenile Sandhoff disease (McKusick 268800) is a rare lysosomal storage disorder with only 12 cases recorded in the literature. This condition is also referred to as the subacute form of hexosaminidase deficiency. We describe 9 new cases of Pakistani origin and compare these with the other published cases. Ataxia and speech abnormalities were the commonest presentation. Constipation and urinary incontinence were frequent and may be due to autonomic neuropathy. Cherry-red spot was not noted in any of our cases. Increased lower limb reflexes were the commonest physical finding. Significant delay in diagnosis may be due to the nonspecific presentation of this condition. Diagnosis was on the basis of hexosaminidase deficiency. Residual enzyme activity did not correlate with the clinical picture. Emerging therapies make early diagnosis of this disorder important.

Two siblings with a new Aicardi-Goutières-like syndrome.

We present two siblings (male and female) with very similar characteristics comprising dysmorphic features, severe developmental delay, progressive microcephaly, tonic seizures, and hypothyroidism. The male also had micropenis and cryptorchidism. Both children developed pericardial effusions which caused the death of the female at age 16 months. The male's cardiac function was stable at last follow-up at the age of 15 months. Cerebral imaging showed widespread intracranial calcifications, delay in myelination, hypoplasia of the corpus callosum, and cerebral atrophy. CSF examination showed normal CSF white-cell count and was negative for interferon, although a cytotoxic antibody was thought to be present. Other causes of a neurodegenerative condition and congenital infection were excluded. The combination of these features has not been described before. We believe that these patients represent a new syndrome which has some of the features of Aicardi-Goutières syndrome but is distinct from it.

Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.

The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.

Idiopathic generalised epilepsy with phantom absences and absence status in a child.

A syndrome of idiopathic generalised epilepsy with phantom absences of undetermined onset has been recently described. This syndrome clinically becomes apparent in adulthood with generalised tonic clonic seizures and frequently absence status epilepticus. We report an 11 year-old normal girl with frequent episodes of absence status and no other overt clinical manifestations. However, appropriate video-EEG recordings documented that she had frequent absence seizures that were so mild as to escape recognition by her and the parents. These consisted of mild impairment of cognition and eyelid fluttering during brief generalised discharges of spike/multiple spike and slow waves. No further seizures occurred and the EEG normalised after appropriate drug treatment. Thus, it appears that this syndrome of phantom absences and absence status may start much earlier, in late childhood. Appropriate video-EEG documentation is needed for the recognition of these patients that may be more common than it appears from the few published cases (with Video).

Obstructive hydrocephalus following herpes simplex virus type 1 encephalitis treated by repeated third ventriculostomy.

A rare case of obstructive hydrocephalus due to aqueductal obstruction following neonatal herpes simplex virus type 1 encephalitis is presented. The child was treated by third ventriculostomy and vesicles were seen on the floor of the third ventricle. The stoma closed on two occasions and required repeat third ventriculostomy, which was successful in maintaining the child shunt-free.

Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21.

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

Neurovascular compression of the trigeminal and glossopharyngeal nerve: three case reports.

Trigeminal neuralgia (TN) is a frequent cause of paroxysmal facial pain and headache in adults. Glossopharyngeal neuralgia (GPN) is less common, but can cause severe episodic pain in the ear and throat. Neurovascular compression of the appropriate cranial nerve as it leaves the brain stem is responsible for the symptoms in many patients, and neurosurgical decompression of the nerve is now a well accepted treatment in adults with both TN and GPN who fail to respond to drug therapy. Neither TN nor GPN are routinely considered in the differential diagnosis when assessing children with paroxysmal facial or head pain, as they are not reported to occur in childhood. Case reports of three children with documented neurovascular compression causing severe neuralgic pain and disability are presented. The fact that these conditions do occur in the paediatric population, albeit rarely, is highlighted, and appropriate investigation and management are discussed.