Cortical plasticity induced by different degrees of peripheral nerve injuries: a rat functional magnetic resonance imaging study under 9.4 Tesla.

BACKGROUND: Major peripheral nerve injuries not only result in local deficits but may also cause distal atrophy of target muscles or permanent loss of sensation. Likewise, these injuries have been shown to instigate long-lasting central cortical reorganization. METHODS: Cortical plasticity changes induced after various types of major peripheral nerve injury using an electrical stimulation technique to the rat upper extremity and functional magnetic resonance imaging (fMRI) were examined. Studies were completed out immediately after injury (acute stage) and at two weeks (subacute stage) to evaluate time affect on plasticity. RESULTS: After right-side median nerve transection, cortical representation of activation of the right-side ulnar nerve expanded intra-hemispherically into the cortical region that had been occupied by the median nerve representation After unilateral transection of both median and ulnar nerves, cortical representation of activation of the radial nerve on the same side of the body also demonstrated intra-hemispheric expansion. However, simultaneous electrical stimulation of the contralateral uninjured median and ulnar nerves resulted in a representation that had expanded both intra- and inter-hemispherically into the cortical region previously occupied by the two transected nerve representations. CONCLUSIONS: After major peripheral nerve injury, an adjacent nerve, with similar function to the injured nerve, may become significantly over-activated in the cortex when stimulated. This results in intra-hemispheric cortical expansion as the only component of cortical plasticity. When all nerves responsible for a certain function are injured, the same nerves on the contralateral side of the body are affected and become significantly over-activated during a task. Both intra- and inter-hemispheric cortical expansion exist, while the latter dominates cortical plasticity.

Transhemispheric cortical plasticity following contralateral C7 nerve transfer: a rat functional magnetic resonance imaging survival study.

PURPOSE: To perform contralateral C7 nerve transfer in a controlled, survival rat functional magnetic resonance imaging model, so as to understand the extent of cortical plasticity after brachial plexus injury and surgical manipulation with this procedure. METHODS: A total of 24 rats divided into 3 groups underwent surgery followed by functional magnetic resonance imaging in this study. Group I rats served as sham controls. Group II injury rats underwent complete right brachial plexus root avulsion. Group III repair rats underwent complete right brachial plexus root avulsion and then contralateral C7 nerve transfer to the right median nerve. We assessed cortical response to median nerve stimulation at 0, 3, and 5 months after injury using functional magnetic resonance imaging at 9.4 T. We concurrently performed sensory and motor functional testing. RESULTS: We noted a progression in cortical activation in the repair rats over 0, 3, and 5 months. Initially, right median nerve stimulation in the repair group showed complete loss of activation in the contralateral somatosensory cortex. Nerve stimulation at 3 months produced primarily ipsilateral cortical activation; at 5 months, 3 patterns of cortical activation emerged: ipsilateral, bilateral, and contralateral activation. After right median nerve stimulation, injury rats maintained a lack of cortical activation and control rats maintained exclusive contralateral activation throughout all time points. Functional testing revealed a degree of return of sensory and motor function over time in the repair group compared with the injured group. CONCLUSIONS: A high degree of transhemispheric cortical plasticity occurred after contralateral C7 nerve transfer. There appears to be a predilection for the rat brain to restore the preinjury somatotopic representation of the brain. CLINICAL RELEVANCE: Understanding the cortical changes after nerve injury and repair may lead to specific pharmacologic or behavioral interventions that can improve functional outcomes.

Distraction rate and latency: factors in the outcome of paediatric maxillary distraction.

BACKGROUND/PURPOSE: Over 50 years ago, current tenets of distraction osteogenesis were developed through work on the lower extremity; however, the application of these tenets in the paediatric craniofacial skeleton remains questionable. Prompted by recent concern that traditional aspects of distraction may be either outdated or wholly inapplicable to the paediatric maxilla, we retrospectively evaluated maxillary distraction protocol using a 24-h latency period in conjunction with a distraction rate of 2mm/day. METHODS: Following maxillary advancement via a distraction protocol consisting of a 24-h latency period and a distraction rate of 2mm/day, seven consecutive paediatric cases were evaluated. Standard profile photos and cephalometric films taken preoperatively, at device removal and at 1-year follow-up were compared. With the sella as the point of registration, pre- and post-distraction films were superimposed on the sella-nasion plane. Sella-nasion-subspinale, the angle of convexity, the distance from incisal edges to the y-axis, and angulation of the upper incisor to the sella-nasion plane were analysed to evaluate hard-tissue changes. RESULTS: Patient age ranged from 3 to 14 years (mean=7.43 years). Maxillary distraction length averaged 11 mm (range=10-12 mm). Interval from device application to removal averaged 98 days (range=75-180 days). The interval of the active distraction ranged from 11 to 65 days (mean=24 days). From distraction completion to device removal averaged 85 days (range=60-150). Follow-up intervals ranged from 52 to 24 months (mean=34 months). All patients demonstrated substantial clinical advancement of the maxilla with correction of midfacial deficiencies. A single patient developed mild cellulitis at one skin-device interface; no other complications were noted. Cephalometric and clinical evaluations at 1 year post-distraction demonstrated stable results, and parental satisfaction was qualitatively high. CONCLUSIONS: The surgical dogma of lower-extremity distraction osteogenesis is not absolute and may not be optimal for use in the paediatric maxilla. Our results demonstrate effective maxillary correction following application of a 24-h latency period coupled with rapid distraction at 2mm/day. Our success with a short latency period and more rapid device expanse may be a product of the significant vascularity and improved healing potential of the paediatric maxilla.

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC).

Extensive intracranial calcifications and leukoencephalopathy are seen in both Coats plus and leukoencephalopathy with calcifications and cysts (LCC; Labrune syndrome). Coats plus syndrome is additionally characterized by the presence of bilateral retinal telangiectasia and exudates while LCC shows the progressive formation of parenchymal brain cysts. Despite these apparently distinguishing features, recent evidence suggests that Coats plus and LCC represent the same clinical entity with a common primary pathogenesis involving a small vessel obliterative microangiopathy. Here, we describe eight previously unreported cases, and present an update on one of the original Coats plus patients to highlight the emerging core clinical features of the "cerebroretinal microangiopathy with calcification and cysts" (CRMCC) phenotype.

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.

Cerebral palsy after maternal trauma in pregnancy.

Ten children (six males, four females) with spastic (n=9) and mixed spastic-dyskinetic (n=1) cerebral palsy were born at term to mothers who earlier in the pregnancy had been involved in accidents without suffering overt abdominal injury, placental abruption, or premature onset of labour. At follow-up (at ages 2-24y), Gross Motor Function Classification System levels were II (n=7) and V (n=3). Cognitive level was normal in five patients, while learning disability was mild to moderate in two and severe in three. Magnetic resonance imaging of the brain in all children, assessed blind to the dates of maternal trauma in pregnancy, showed lesions consistent with prenatal vascular insult at the time of the trauma. Feasible mechanisms of brain injury include reduced placental blood flow and/or placental embolization.

Anoxic-epileptic seizures: observational study of epileptic seizures induced by syncopes.

AIMS: To describe a large series of children with anoxic-epileptic seizures (AES)--that is, epileptic seizures induced by syncopes. METHODS: Retrospective case-note review in a tertiary paediatric neurology unit. For all 27 children seen with a definite diagnosis of AES between 1972 and 2002, a review of clinical histories, videotapes, and EEG/ECG studies was undertaken. Main outcome measures were: age of onset, frequency and type of syncopes; age of onset and frequency of AES; type and duration of induced epileptic seizures; effect of treatment of syncopal and epileptic components. RESULTS: Median age of onset of syncopes was 8 months (range 0.2-120), frequency 2 in total to 40/day, median total approximately 200. Syncopes were predominantly reflex asystolic (RAS), prolonged expiratory apnoea (cyanotic breath-holding spells), or of mixed or uncertain origin; there was one each of ear piercing and hair grooming vasovagal syncope and one of compulsive Valsalva. Median age of onset of AES was 17 months (range 7-120), frequency from total 1 to 3/day, median total 3. The epileptic component was almost always bilateral clonic; three had additional epilepsy, one each with complex partial seizures, myoclonic absences, and febrile seizures plus. Median duration of epileptic component was 5 minutes (range 0.5-40, mean 11). Cardiac pacing prevented RAS in two patients: most other anti-syncope therapies were ineffective. Diazepam terminated the epileptic component in 6/8. Valproate or carbamazepine abolished AES in 5/7 without influencing syncope frequency. CONCLUSIONS: Although uncommon compared with simple syncopes, syncope triggered epileptic seizures (AES) are an important treatable basis of status epilepticus.

Coats' plus: a progressive familial syndrome of bilateral Coats' disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument.

In 1988 we reported two sisters with bilateral Coats' disease, sparse hair, dystrophic nails, and primeval splashes of intracranial calcification. We now provide an update on this family documenting the occurrence of skeletal defects comprising abnormal bone marrow, osteopenia, and sclerosis with a tendency to fractures, a mixed cerebellar and extrapyramidal movement disorder, infrequent epileptic seizures, leukodystrophic changes, and postnatal growth failure. Additionally, we present two previously unreported individuals from Ireland and Switzerland with the identical disorder which we designate Coats' plus. Since our original publication a number of other authors have described, frequently as a "new" syndrome, cases with a variable combination of the same features observed in our patients. We review this literature and suggest that the phenotypic overlap with dyskeratosis congenita may provide a clue to the molecular aetiology of this multisystem disorder.

Gratification disorder ("infantile masturbation"): a review.

BACKGROUND: Little has been published on gratification disorder ("infantile masturbation") in early childhood. AIMS: To expand on the profile of patients diagnosed with this condition. METHODS: Retrospective case note review; Fraser of Allander Neurosciences Unit paediatric neurology outpatient department 1972-2002. RESULTS: Thirty one patients were diagnosed (11 males and 20 females). Twenty one were referred for evaluation of possible epileptic seizures or epilepsy. The median age at first symptoms was 10.5 months (range 3 months to 5 years 5 months). The median age at diagnosis was 24.5 months (range 5 months to 8 years). The median frequency of events was seven times per week, and the median length 2.5 minutes. Events occurred in any situation in 10 children, and in a car seat in 11. Types of behaviour manifested were dystonic posturing in 19, grunting in 10, rocking in 9, eidetic imagery in 7, and sweating in 6. Two children had been previously diagnosed as having definite epilepsy. In nine cases home video was invaluable in allowing confident diagnosis. CONCLUSION: Gratification disorder, otherwise called infantile masturbation, is an important consideration in the differential diagnosis of epilepsy and other paroxysmal events in early childhood. Home video recording of events often prevents unnecessary investigations and treatments.

Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism.

Aicardi-Goutiéres syndrome (AGS) is an early onset, progressive encephalopathy characterised by calcification of the basal ganglia, white matter abnormalities, and a chronic cerebrospinal fluid (CSF) lymphocytosis. Cree encephalitis shows phenotypic overlap with AGS although the conditions have been considered distinct because of immunological abnormalities observed in Cree encephalitis. We report that levels of interferon alpha (IFN-alpha), a marker of AGS, are raised in Cree encephalitis. Moreover, linkage analysis indicates that the disorders are allelic and refines the AGS1 locus to a 3.47 cM critical interval. Our data show that a CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder. Recognition of immunological dysfunction as part of the AGS phenotype provides further evidence of a primary pathogenic role for abnormal IFN-alpha production in AGS.

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.

Anoxic seizures: self-terminating syncopes.

This review focuses on anoxic seizures induced by self terminating syncopes in the young. Anoxic seizures are nonepileptic events consequent upon abrupt interruption of the energy supply to metabolically active cerebral neurones. Anoxic seizures are the most common paroxysmal events misdiagnosed as epilepsy. Neurally mediated syncopes have numerous appellations, especially in the young. This proliferation of terminology likely results from uncertainty regarding pathophysiology. The most important type of self-limiting syncope from the point of view of diagnostic difficulty has been called neurocardiogenic or vasovagal syncope and reflex anoxic seizure, amongst other names: this review includes a video clip of such a child with prolonged asystole. It also includes a detailed case history emphasising the feelings of a patient with this type of syncope who was misdiagnosed as having epilepsy for many years. The second class of self-terminating syncope discussed and illustrated on video is the so-called breath-holding spell of young children. The third example illustrated is the compulsive Valsalva manoeuvre of individuals with autistic spectrum disorder, in which anoxic seizures - as shown on the video clips - are easily misdiagnosed as epileptic seizures, with unfortunate consequences.

Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability.

Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous system potassium channelopathy characterized by brief attacks of cerebellar ataxia and continuous interictal myokymia. Point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome 12p associate with EA1. We have studied 4 families and identified three new and one previously reported heterozygous point mutations in this gene. Affected members in Family A (KCNA1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supporting the suggestion that there is an association between mutations of KCNA1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymia alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkably drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an apparently unrelated family, although no functional studies were attempted. Heterologous expression of the proteins encoded by the mutant KCNA1 genes suggest that the four point mutations impair delayed-rectifier type potassium currents by different mechanisms. Increased neuronal excitability is likely to be the common pathophysiological basis for the disease in these families. The degree and nature of the potassium channel dysfunction may be relevant to the new phenotypic observations reported in this study.

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.

Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures.

OBJECTIVE: To determine whether permanent cardiac pacing could prevent syncope and seizures in children with frequent severe neurally mediated syncope, and if so whether dual chamber pacing was superior to single chamber ventricular pacing. METHODS: Dual chamber pacemakers were implanted into 12 children (eight male, four female) aged 2-14 years (median 2.8 years) with frequent episodes of reflex anoxic seizures and a recorded prolonged asystole during an attack. The pacemaker was programmed to sensing only (ODO), single chamber ventricular pacing with hysteresis (VVI), and dual chamber pacing with rate drop response (DDD) for four month periods, with each patient allocated to one of the six possible sequences of these modes, according to chronological order of pacemaker implantation. The parent and patient were blinded to the pacemaker mode and asked to record all episodes of syncope or presyncope ("near miss" events). The doctor analysing the results was blinded to the patient and pacemaker mode. RESULTS: One patient was withdrawn from the study after the pacemaker was removed because of infection. In the remaining children, both dual chamber and single chamber pacing significantly reduced the number of syncopal episodes compared with sensing only (p = 0.0078 for both). VVI was as effective as DDD for preventing syncope, but DDD was superior to VVI in reducing near miss events (p = 0.016). CONCLUSIONS: Permanent pacing is an effective treatment for children with severe neurally mediated syncope and reflex anoxic seizures. VVI is as effective as DDD in preventing syncope and seizures, but DDD is superior in preventing overall symptoms.

Muscle ultrasound in the assessment of suspected neuromuscular disease in childhood.

One hundred paediatric, muscle ultrasound examinations performed in the evaluation of suspected neuromuscular disease were reviewed. The results were related to the presence or absence of neuromuscular disease in each child assessed. The group comprised 66 males and 34 females, age range 2 months to 16 years (mean 5.3 years). Scans were graded I-IV, according to muscle echogenicity, using Heckmatt's criteria. Thirty-two children had a final diagnosis of neuromuscular disease. The sensitivity of ultrasound in detecting neuromuscular disease was 78% with 91% specificity. The test was more reliable in the sub-group of > 3 years with a sensitivity of 81% and specificity of 96%. There was a significant difference in disease status, (with and without neuromuscular disease), between children with a normal, grade I, scan and those with an abnormal, grade II, III, IV, image (chi-square, P < 0.001, 95% confidence limits 0.54-0.86). Muscle ultrasound is a specific and sensitive investigation for suspected neuromuscular disease in children.

A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy.

Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.