Ilan Blatt

Non-stroke neurological syndromes associated with antiphospholipid antibodies: Evaluation of clinical and experimental studies

Although many types of neurological disorders and events have been described in association with antiphospholipidantibodies(aPL) and the antiphospholipidsyndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurologicaldisordersor events such as epilepsy, psychiatricdisease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrèsyndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.

Extracranial metastases of medulloblastoma in adults: literature review.

A consecutive series of 30 cases of extracranial medulloblastoma metastases in adults is analysed. The majority of the patients were males with a 3:1 male/female ratio. Bone was the most frequent site of metastases in adults (77%) and children (78%), followed by lymph nodes (33%) in both children and adults. Lung metastases were more common in adults (17%), but liver metastases occurred more frequently in children (15%). Possible routes of spread and development of metastases are discussed, with special emphasis on the role of shunts in tumour seeding. Distant extracranial metastatic spread of medulloblastoma occurs at the rate of 7.1%. Mean interval between operation of the primary tumour and the discovery of metastases was shorter in children (20 months) than in adults (36 months). Survival after the discovery of metastases was also shorter in children (5 months) than in adults (9.5 months). Shunts were associated with an earlier appearance of metastases and with a poorer prognosis. A detailed review of the literature of 119 cases of medulloblastoma with extracranial metastases is provided.

Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect.

A 6-year-old boy with partial complex seizures developed recurrent episodes of hyperthermia 2 months after topiramate was introduced into his antiepilepsy drug regimen. Further investigation revealed that the febrile episodes were related to environmental temperature and physical activity. A pilocarpine iontophoresis sweat test showed that the amount of sweat produced by the child was 5% that of age-matched controls. Topiramate discontinuation resulted in the disappearance of febrile episodes and normalization of sweat quantity in repeat sweat testing. Based on this observation and the previous data on zonisamide and isolated case reports on topiramate-related hyperthermia and the effect on sweat production, topiramate was suspected of causing oligohydrosis. A pilot study was carried out involving 13 additional children and young adults (age range 1—37 years) receiving topiramate. All patients were directly questioned regarding symptoms of decreased sweating and heat intolerance, went through a pilocarpine iontophoresis sweat test, and were compared with 14 age-matched controls who went through the sweat test for unrelated reasons. Nine of the patients were found to have reduced sweat quantity on the pilocarpine iontophoresis sweat test (including index case) (mean 0.089 g/30 minutes, SD 0.082; age-matched control: mean 0.21 g/30 minutes, SD 0.06). Eight of them were children (below 16 years). However, only three patients revealed symptoms related to heat intolerance. Topiramate is most likely responsible for decreased sweat production as detected by a pilocarpine iontophoresis sweat test. The effect seems to be more significant in children than in adults. There is a discrepancy between test results and clinical symptoms. Interestingly, oligohydrosis was found to be a relatively common side effect of zonisamide. Both zonisamide and topiramate share a carbonic anhydrase inhibitor activity. The significance of oligohydrosis in hot climates should not be underestimated. Its extent, the role of sweat test prediction, and clinical significance during topiramate treatment should be further estimated. (J Child Neurol 2003;18:254—257).

Autosomal recessive form of periventricular heterotopia

Background: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. Objective: To classify cortical malformation syndromes associated with PH. Methods: Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. Results: Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. Conclusions: Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.

Thrombin regulation of synaptic transmission: Implications for seizure onset

Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of thrombin and a PAR-1 agonist on neuronal excitability and synaptic currents was assessed by whole cell-patch recordings of pyramidal neurons in rat hippocampal slices. In addition, PAR-1 distribution in different hippocampal regions was assessed using immunohistochemistry. We found that thrombin caused an increase in spontaneous action potential discharges of CA3 but not of CA1 pyramidal neurons. When excitatory synaptic activity was blocked, thrombin caused a marked reduction in spontaneous IPSCs in CA3 neurons and a marked increase in the frequency of IPSCs in CA1 neurons. These effects are likely to be local, as they were reproduced in TTX-treated slices. In parallel, thrombin increased both the frequency and the amplitude of mEPSCs only in CA3 neurons. These effects were blocked by a selective PAR-1 antagonist. The higher expression of PAR-1 in stratum lucidum of CA3 is correlated with the effects of thrombin in this region. These results suggest that thrombin triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons, providing a novel insight to the pathophysiology of seizures following cerebrovascular events and present new avenues for therapeutic intervention.

Novel Pathogenic Mutations and Copy Number Variations in the VPS13A Gene in Patients With Chorea-Acanthocytosis

Chorea‐acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult‐onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real‐time quantitative PCR and long‐range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Thrombin regulation of synaptic plasticity: implications for physiology and pathology.

Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on long term potentiation (LTP) in mice hippocampal slices. Surprisingly, different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. High thrombin concentrations induced an NMDA dependent, slow onset LTP, whereas low concentrations of thrombin promoted a VGCCs, mGluR-5 dependent LTP through activated Protein C (aPC). Remarkably, aPC facilitated LTP by activating PAR1 through an Endothelial Protein C Receptor (EPCR)-mediated mechanism which involves intracellular calcium stores. These findings reveal a novel mechanism by which PAR1 may regulate the threshold for synaptic plasticity in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions.

Treatment of porphyric convulsions with magnesium sulfate.

Summary: We report a 16‐year‐old girl with acute intermittent porphyria who had abdominal pain, generalized tonic‐clonic and simple partial seizures, and inappropriate antidiuretic hormone secretion. Because most antiepileptic drugs are contraindicated in porphyria, she was treated with magnesium sulfate i.v. Soon after starting treatment, seizures stopped, returned, and then again responded in several trials with discontinuation and reinstitution of i.v. magnesium sulfate. Our experience encourages the use of magnesium sulfate for treatment of seizures in patients with porphyria.

Occurrence of seizures in association with work‐related stress in young male army recruits

Purpose: To examine the risk of undergoing an epileptic seizure as a function of differing levels of occupational stress (physical and mental) in new military recruits with no previous history of epilepsy or with epilepsy in remission for over 2 years.

Treating seizures and epilepsy with anticoagulants

Thrombin is a serine protease playing an essential role in the blood coagulation cascade. Recent work, however, has identified a novel role for thrombin-mediated signaling pathways in the central nervous system. Binding of thrombin to protease-activated receptors (PARs) in the brain appears to have multiple actions affecting both health and disease. Specifically, thrombin has been shown to lead to the onset of seizures via PAR-1 activation. In this perspective article, we review the putative mechanisms by which thrombin causes seizures and epilepsy. We propose a potential role of PAR-1 antagonists and novel thrombin inhibitors as new, possible antiepileptic drugs.