Congenital myasthenic syndromes in childhood: diagnostic and management challenges.

The Congenital Myasthenic Syndromes (CMS), a group of heterogeneous genetic disorders of neuromuscular transmission, are often misdiagnosed as congenital muscular dystrophy (CMD) or myopathies and present particular management problems. We present our experience of 46 children with CMS, referred to us between 1992-2007 with provisional diagnoses of congenital myopathy (22/46), CMS or limb-girdle myasthenia (9/46), central hypotonia or neurometabolic disease (5/46), myasthenia gravis (4/46), limb-girdle or congenital muscular dystrophy (4/46) and SMA (2/46). Diagnosis was often considerably delayed (up to 18y4 m), despite the early symptoms in most cases. Diagnostic clues in the neonates were feeding difficulties (29/46), hypotonia with or without limb weakness (21/46), ptosis (19/46), respiratory insufficiency (12/46), contractures (4/46) and stridor (6/46). Twenty-five children had delayed motor milestones. Fatigability developed in 43 and a variable degree of ptosis was eventually present in 40. Over the period of the study, the mainstay of EMG diagnosis evolved from repetitive nerve stimulation to stimulation single fibre EMG. The patients were studied by several different operators. 66 EMGs were performed in 40 children, 29 showed a neuromuscular junction abnormality, 7 were myopathic, 2 had possible neurogenic changes and 28 were normal or inconclusive. A repetitive CMAP was detected in only one of seven children with a COLQ mutation and neither of the two children with Slow Channel Syndrome mutations. Mutations have been identified so far in 32/46 children: 10 RAPSN, 7 COLQ, 6 CHRNE, 7 DOK7, 1 CHRNA1 and 1 CHAT. 24 of 25 muscle biopsies showed myopathic changes with fibre size variation; 14 had type-1 fibre predominance. Three cases showed small type-1 fibres resembling fibre type disproportion, and four showed core-like lesions. No specific myopathic features were associated with any of the genes. Twenty children responded to Pyridostigmine treatment alone, 11 to Pyridostigmine with either 3, 4 DAP or Ephedrine and five to Ephedrine alone. Twenty one children required acute or chronic respiratory support, with tracheostomy in 4 and nocturnal or emergency non-invasive ventilation in 9. Eight children had gastrostomy. Another 11 were underweight for height indicative of failure to thrive and required dietetic input. A high index of clinical suspicion, repeat EMG by an experienced electromyographer and, if necessary, a therapeutic trial of Pyridostigmine facilitates the diagnosis of CMS with subsequent molecular genetic confirmation. This guides rational therapy and multidisciplinary management, which may be crucial for survival, particularly in pedigrees where previous deaths have occurred in infancy.

Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses.

Children with a mucopolysaccharidosis or mucolipidosis suffer progressive disability of the hands, particularly in relation to dysfunction of the median nerve. This is an increasing problem because bone-marrow transplantation has dramatically improved survival without apparently changing the musculoskeletal manifestations. We have reviewed 48 children with these syndromes who required carpal tunnel decompression, recording symptoms, signs, radiological, electrophysiological and operative findings, histology and upper-limb function. In these children the carpal tunnel syndrome differs from that seen in adults. Symptoms are rare but signs such as decreased sweating, pulp atrophy, thenar wasting and manual clumsiness are much more common. At operation, the flexor retinaculum was thickened and a mass of white tenosynovium engulfed the flexor tendons. Most patients had some definite nerve constriction with a thickened epineurium. Functional improvement was seen after early decompression, with some benefit from simultaneous tendon release. Regular physiotherapy helped to maintain increased hand movement. We describe our assessment protocol, the physiotherapy and operative regime and the standard functional review which helps to maximise function in the hands and upper limbs of these children.

Spinal cord monitoring in neuromuscular scoliosis.

This article reviews the use of spinal cord monitoring in neuromuscular scoliosis, a condition having a higher incidence of true positive results than idiopathic scoliosis. While somatosensory cortical evoked potentials (SCEP) are unreliable, somatosensory spinal evoked potentials (SSEP) are possible to obtain in most cases and a method using an epidural electrode is described. The '50% rule' is satisfactory having good specificity and sensitivity with it rare for post-operative paralysis to have occurred undetected. The spinal cord in these cases appears to have increased susceptibility particularly during the passage of sublaminar wires with the incidence of complications reduced using modern instrumentation.

A system-based study of the variation in the amplitude of the compound sensory nerve action potential recorded using surface electrodes.

This study arose from the impression that there is a wide variation in the amplitude of the compound sensory nerve action potential (SNAP) when recorded using surface electrodes. Both the physiological factors influencing the SNAP and the method of measurement itself can be viewed as inputs to a system that produces the recorded value as its output. Taking a systems approach to the analysis of the variation in the recorded value of the SNAP on repeat testing, the techniques of statistical process control and experimental design were used to study three electrodes. All showed wide variation of the results in a single control subject. Many different factors were studied but no single factor was found to be the cause for a significant amount of the variation. This finding, coupled to the wide variation demonstrated, has implications for the use of surface recording of the SNAP.

The use of weighted quadratic regression for the study of latencies of the P100 component of the visual evoked potential.

The aim of this study was to determine the range of normal values of the latency of the P100 component of the VEP from a control population. Weighted least squares polynomial regression analysis showed that a quadratic curve best described the relationship between age and latency and separate curves, along with normal ranges, are presented for males and females. We would recommend the use of this statistical method for all determinations of the normal range of P100 latencies.

The value of measuring saccadic eye movement in the investigation of non-compressive myelopathy.

Saccadic eye movement recording was performed in 53 patients with non-compressive myelopathy. Twenty one patients (40%) had subclinical abnormalities of saccadic movement, supporting a diagnosis of probable multiple sclerosis. When used in addition to the measurement of visual evoked potentials and brainstem auditory evoked responses, the detection of subclinical abnormalities increased from 40% to 57%. The detection rate of abnormalities by saccadic eye movement recording was equal to that of visual evoked responses, but more than of brainstem auditory evoked responses. Prolonged latency of gaze was the most common saccadic latency abnormality detected. The majority of saccadic velocity abnormalities could be explained by disease in the medial longitudinal bundle. An unusual finding was that abduction velocity was increased in six patients. It is concluded that the simple measurement of saccadic eye movement is a valuable addition to other ancillary investigations for the diagnosis of multiple sclerosis. It also allows analysis of oculomotor function, commonly disordered in multiple sclerosis, but rarely investigated.

EEG findings in hypomelanosis of Ito.

The EEG findings in 15 children with Hypomelanosis of Ito have been reviewed and related to the clinical and CT scan data. Although no consistent electroclinical associations were found in the group as a whole, there was some association between the presence of abnormal rhythmic EEG activity and the radiological appearances of neuronal migration defects. In addition, the possibility is raised that there may be a distinctive sub-group of children with Ito's syndrome who present with an early onset of intractable seizures and who have a neuronal migration defect.

Peripheral neuropathy and neuromuscular blockade presenting as prolonged respiratory paralysis following critical illness.

We report two patients who following critical illness presented with generalised paralysis associated with persistent failure to breathe. Both patients eventually recovered and were weaned from the ventilator. The cause of the paralysis was an unusual peripheral neuropathy in the first patient and persistent neuromuscular blockade secondary to vecuronium in the second. It is important to consider a reversible, possibly even iatrogenic, cause of this type of complication.

Disordered peripheral nerve conduction in DOOR(S) syndrome.

A case of DOOR(S) syndrome is detailed and the neurophysiological abnormalities observed in this patient and in other cases with this rare but recognisable autosomal recessive condition are considered. Particular emphasis is paid to the abnormal peripheral nerve conduction, which has not previously been recorded in the condition.

Median nerve compression in Proteus syndrome.

Proteus syndrome is a multi-organ disorder, a prime feature of which is localized gigantism, usually clinically obvious. Symptoms secondary to hypertrophy of nerves has not been previously recognized as a part of the syndrome.

EEG features of cortical dysplasia in children.

Two distinctive electroencephalographic abnormalities, very high amplitude rhythmic activity or prominent fast activity, have been described in children with extensive cortical dysplasia. Cases with cortical dysplasia identified on computerised tomography or magnetic resonance imaging, or a characteristic EEG were selected. One hundred and forty electroencephalograms from 94 cases were reviewed and related to the imaging findings. An EEG with very high amplitude rhythmic activity was found to have high specificity for severe cortical dysplasia but low sensitivity (< 50% cases). Abnormal fast activity was not specific and was seen with very diverse pathologies. The EEG features of most cases with localised cortical dysplasia were very variable. The EEG could be normal even when the cortical dysplasia was extensive.

Cortical dysgenesis: serial EEG findings in children and adults.

Cortical dysgenesis (CD) is becoming increasingly recognised as a cause of epilepsy in otherwise cryptogenic cases. We describe the serial EEG findings in 22 patients with focal/localised CD. The EEGs covered a minimum period of 5 years in each case (median = 13 years, range: 5-30 years), beginning in childhood. Median age at seizure onset was 3 years (range: 3 weeks-10 years, n = 21). The EEG was normal in the one patient, a 6 year old, who did not have epilepsy. Background rhythms appropriate for age were preserved in the majority of patients (18/22). Slow activity localised to the area of CD was seen in 11 patients; in 3 patients, this did not appear until the second decade of life. Epileptiform discharges were seen in at least one EEG in 20 patients: these were continuous or near-continuous (6 patients) or occurred recurrently in short runs (6 patients). In 6 patients, these discharges appeared only after the second decade of life and in 11 patients, they became more widespread over time. In the remaining patients, the EEG changes did not evolve. Sleep failed to produce new abnormalities (n = 15). None of the patients showed EEG features characteristic of lissencephaly or evolution to the Lennox-Gastaut syndrome. Even in this selected cohort of patients who had undergone serial clinical EEGs, the EEG abnormalities in focal/localised CD appeared relatively stable and showed only moderate changes over time. CD must be included in the differential diagnosis of any patient who presents with localised slow activity on EEG.

Early detection of abnormalities in partial epilepsy using magnetic resonance.

The incidence of brain abnormalities determined by magnetic resonance in 30 consecutive children presenting with intractable complex partial seizures is reported. Images were optimised to visualise the hippocampus and cortical grey matter. Abnormalities of the hippocampus or temporal lobe were seen in all 19 children with clinical features of temporal lobe epilepsy and in six of the seven children with clinically unlocalised epilepsy. By contrast, in the four children with a clinical diagnosis of extratemporal epilepsy, no temporal or hippocampal abnormalities were seen. Generalised cortical abnormalities of uncertain significance were found in a total of 14 children from all groups. The identification of focal brain abnormalities using optimised magnetic resonance imaging enables early non-invasive assessment of children with intractable seizure disorders and the identification of patients for whom epilepsy surgery may be appropriate. It may also lead to a better understanding of the structural basis of intractable epilepsy, and thereby contribute to early treatment decisions.