Male patients affected by mosaic PCDH19 mutations: five new cases.

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years).

High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.

Normal-pressure hydrocephalus. Is cisternography still useful in selecting patients for a shunt?

The clinical usefulness of cisternography in selecting patients with presumed normal-pressure hydrocephalus for shunting was investigated in 76 patients. The predictive value of a scale based on combined clinical and computed tomographic criteria was first established, followed by an assessment of the predictive value of cisternography. Predictions based on cisternograms were identical to those of the clinical/computed tomographic scale in 43%, better in 24%, and worse in 33%. Our findings suggest that cisternography does not improve the diagnostic accuracy of combined clinical and computed tomographic criteria in patients with presumed normal-pressure hydrocephalus.

Shunting normal-pressure hydrocephalus: do the benefits outweigh the risks? A multicenter study and literature review.

We performed a multicenter retrospective study in 166 consecutive patients shunted for presumed normal-pressure hydrocephalus (NPH) in the four neurosurgical departments of Amsterdam. Overall improvement occurred in 36%, substantial improvement in 21%. In the subgroup of idiopathic NPH (N = 127), marked improvement was only 15%. The incidence of shunt-responsive NPH in our area was 2.2/million/year. The rate of severe and moderate shunt-related complications was 28%, leading to death or severe residual morbidity in 7%. The substantial benefit/serious harm ration in the whole group was only three (21%/7%), decreasing to 1.7 in idiopathic NPH. By excluding patients at high surgical risk, this ratio might have risen to 10 in the whole group and to six in idiopathic NPH. Our experience is much less favorable than that encountered in the literature, reporting overall improvement in 74% and marked improvement in 55% of the shunted patients. We conclude that NPH is probably a very rare and still overdiagnosed syndrome and that the overall morbidity rate for each patient demonstrating meaningful improvement is high.

Ring chromosome 20 epilepsy syndrome in children: electroclinical features.

Ring chromosome 20 mosaicism is associated with dysmorphic features, mental retardation, and intractable seizures, including recurrent episodes of nonconvulsive status epilepticus. The authors' findings in four children, all without dysmorphic features, indicate that mental deterioration and frequent subtle nocturnal frontal lobe seizures, associated with a characteristic EEG pattern, represent prominent additional clinical features not previously described in this syndrome. This emphasizes the importance of full-night video-EEG in children with frontal lobe seizures and cognitive deterioration.

Chronic spinal arachnoiditis following intracranial subarachnoid haemorrhage.

A 54-year-old woman presented with progressive gait imbalance and increased urinary frequency, associated with spinal arachnoiditis. The symptoms started after the occurrence of communicating hydrocephalus as a sequel of subarachnoid haemorrhage (SAH), and were initially attributed to post-SAH vasospasm, decompensating hydrocephalus and/or periventricular leuko-encephalopathy. Further clinical deterioration led to the diagnosis of thoracic spinal arachnoiditis, as a second complication of SAH.

The tarsal tunnel syndrome after a proximal lesion.

Three patients in whom the first symptoms of the tarsal tunnel syndrome (TTS) emerged after an acute event proximal to but not affecting the ankle are described. These patients suggest that a pre-existing asymptomatic TTS may become manifest after a mechanism akin to that described in the "double crush" syndrome.

The rigid spine syndrome in two sisters.

Two half-sisters aged 14 and 18 years are described with a rigid spine syndrome as the cardinal clinical feature of an autosomal dominant neuromuscular disorder. Ten years previously, a diagnosis of multicore disease had been made from the clinical signs and muscle biopsy findings. Long term follow-up revealed a non-specific muscular dystrophy with axial predominance and a rigid spine in the younger girl; the older sister presented at the age of 18 with a rigid spine as the only myopathic sign. Computed tomography of the muscles showed severe involvement of the paraspinal musculature, in contrast with either less or no involvement of the other muscles.

Shunting normal pressure hydrocephalus: the predictive value of combined clinical and CT data.

The value of an ordinal global scale derived from combined clinical and CT data (clin/CT scale) to predict the clinical outcome in 112 patients shunted for presumed normal pressure hydrocephalus (NPH) was analysed. The clinical data were retrospectively collected, all CT scans were re-evaluated, and the clin/CT scale was determined blind to the results of further ancillary tests and to the post-surgical outcome. The scale ranked three classes of prediction: on the basis of clinical and CT characteristics, improvement after shunting was probable, possible, or improbable. The predictive value of the clin/CT scale for the subgroup of communicating NPH was established for two different strategies, depending on the strictness of selection criteria for shunting. In the subgroup of patients with presumed communicating NPH, the prevalence of shunt responsiveness was 29%; the best strategy was to shunt only patients with probable shunt-responsive NPH: the sensitivity was 0.54, the specificity 0.84, and the predictive accuracy 0.75, with a limited number of ineffective shunts (11%) and missed improvements (13%). The study illustrates its need to assess the pre-test probability of NPH based on combined clinical and CT data, before establishing the clinical usefulness of an ancillary test.

Classification of epileptic seizures: a comparison of two systems.

PURPOSE: Extensive experience with video-EEG seizure monitoring, notably in the setting of epilepsy surgery programs, has exposed the limited value of the current International Classification of Epileptic Seizures (ICES) for providing relevant localizing information. To overcome this limitation, a Semiologic Seizure Classification (SSC) has recently been proposed. This study aimed to assess and to compare the usefulness and reliability of both systems in the setting of a tertiary epilepsy center. METHODS: Three epileptologists independently reviewed video-taped seizures, randomly selected from the archive of the Epilepsy Monitoring Unit. They were blinded to the EEG findings and final diagnosis and classified all seizures according to both classifications. RESULTS: One hundred thirty-eight seizures from 60 patients (age range, 2-59 years) were reviewed (maximum, three seizures per patient). Fifty-five seizures from 20 patients were recorded in the setting of presurgical evaluations, and the remainder as part of regular diagnostic evaluations. The average interobserver agreement was higher for SSC (63.3%, kappa = 0. 56) than for ICES (38.6%, kappa = 0.41). Some categories of SSC, such as hypermotor or automotor, had the best interobserver agreement, and were strongly correlated with the anatomic localization of the seizures (frontal and temporal lobe, respectively). All reviewers agreed that SSC provided a better description of the seizures than did ICES, in 60% of the patients. CONCLUSIONS: SSC provides a more comprehensive picture of epileptic seizures than does ICES, notably in patients with localized epilepsy syndromes, and appears to be very useful and reliable, particularly in the setting of specialized epilepsy centers.

A special case of congenital adrenal hypoplasia and acute bilateral infantile striatal necrosis.

Isolated mineralocorticoid deficiency is described in a 5-week-old boy. The deficiency progressed to general adrenal insufficiency during the boy's first year of life. The family history suggested X-linked inheritance. At 18 months of age the patient developed acute bilateral infantile striatal necrosis, which might suggest a possible relationship between both entities.

Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study.

The authors describe 12 pregnancies in women with epilepsy using lamotrigine (LTG) monotherapy. A seizure increase in nine pregnancies was probably related to a gradual decline of LTG level-to-dose ratio to 40% of baseline. After delivery, LTG kinetics returned swiftly to baseline, causing toxic side effects in some women. Frequent LTG level monitoring and appropriate dose adjustments are advised in the period before and during pregnancy and after delivery, especially in women on LTG monotherapy.

A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).

Progressive myoclonus epilepsy of the Lafora type or Lafora disease (EPM2; McKusick no. 254780) is an autosomal recessive disorder characterized by epilepsy, myoclonus, progressive neurological deterioration and glycogen-like intracellular inclusion bodies (Lafora bodies). A gene for EPM2 previously has been mapped to chromosome 6q23-q25 using linkage analysis and homozygosity mapping. Here we report the positional cloning of the 6q EPM2 gene. A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase). The gene, denoted EPM2, presents alternative splicing in the 5' and 3' end regions. Mutational analysis revealed that EPM2 patients are homozygous for loss-of-function mutations in EPM2. These findings suggest that Lafora disease results from the mutational inactivation of a PTPase activity that may be important in the control of glycogen metabolism.