All that shakes is not epilepsy.

Experience from the clinic suggests that many people equate the term 'epilepsy' with the occurrence of convulsions, with the corollary that attacks involving shaking are likely to be due to epilepsy. However, just as many seizure types do not involve shaking, the differential diagnosis of intermittent shaking is wide and includes vasovagal syncope, cardiac disorders, concussive convulsions, psychogenic non-epileptic seizures, 'shaking transient ischaemic attacks', parasomnias, breath-holding attacks in children, hypoglycaemia and movement disorders.

Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space.

Biological systems that perform multiple tasks face a fundamental trade-off: A given phenotype cannot be optimal at all tasks. Here we ask how trade-offs affect the range of phenotypes found in nature. Using the Pareto front concept from economics and engineering, we find that best-trade-off phenotypes are weighted averages of archetypes--phenotypes specialized for single tasks. For two tasks, phenotypes fall on the line connecting the two archetypes, which could explain linear trait correlations, allometric relationships, as well as bacterial gene-expression patterns. For three tasks, phenotypes fall within a triangle in phenotype space, whose vertices are the archetypes, as evident in morphological studies, including on Darwin's finches. Tasks can be inferred from measured phenotypes based on the behavior of organisms nearest the archetypes.

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells.

AIMS/HYPOTHESIS: Pro-inflammatory cytokines induce death of pancreatic beta cells, leading to the development of type 1 diabetes. We sought to identify novel players and the underlying mechanisms involved in this process. METHODS: A high-throughput screen of 3,850 mouse small interfering RNAs (siRNAs) was performed in cytokine-treated MIN6 beta cells. Cells were transfected with the different siRNAs and then treated with a combination of TNFα, IL-1ß and IFNγ. Cellular apoptosis (caspase-3/7 activity), and changes in cellular reducing power and cell morphology were monitored. The resulting data were analysed and the corresponding z scores calculated. RESULTS: Several gene families were identified as promoting cytokine-induced beta cell apoptosis, the most prominent being those encoding ubiquitin ligases and serine/threonine kinases. Conversely, deubiquitinating enzymes appeared to reduce apoptosis, while protein phosphatases were mainly associated with lowering cellular reducing power. The screen suggested with high confidence the involvement of several novel genes in cytokine-induced beta cell death, including Camkk2, Epn3, Foxp3 and Tm7sf3, which encodes an orphan seven transmembrane receptor. siRNAs to Tm7sf3 promoted cytokine-induced death of MIN6 cells and human pancreatic islets, and abrogated insulin secretion in these cells. These findings implicate transmembrane 7 superfamily member 3 as a potential new player in the inhibition of cytokine-induced death and in the promotion of insulin secretion from pancreatic beta cells. CONCLUSIONS/INTERPRETATION: The signalling pathways and novel genes that we identified in this screen and that mediate beta cell death offer new possible targets for therapeutic intervention in diabetes and its adverse complications.

Transcallosal resection of hypothalamic hamartoma for gelastic epilepsy.

INTRODUCTION: Hypothalamic hamartomas (HHs) are commonly associated with severe epilepsy resistant to anticonvulsant therapy. Historically, surgical resection of HHs resulted in considerable morbidity. DISCUSSION: Two series of patients who successfully underwent resection using a transcallosal approach have now been published; we report the first UK experience of this technique in a series of five patients with HHs and gelastic epilepsy resistant to anticonvulsant therapy. Patients were assessed pre- and postoperatively for seizure activity, endocrine function, ophthalmology, and neurocognitive function. Two patients had precocious puberty and all had evidence of developmental delay and behavioral problems. Postoperatively, all children experienced at least a 50% reduction in seizure frequency with abolition of major seizure types; one child remains seizure-free. One child developed a mild postoperative right hemiparesis and one developed transient diabetes insipidus. CONCLUSION: There were no adverse developmental effects of surgery. Transcallosal resection of HHs ameliorates resistant epilepsy syndromes associated with HH.

Distinct right frontal lobe activation in language processing following left hemisphere injury.

Right hemisphere activation during functional imaging studies of language has frequently been reported following left hemisphere injury. Few studies have anatomically characterized the specific right hemisphere structures engaged. We used functional MRI (fMRI) with verbal fluency tasks in 12 right-handed patients with left temporal lobe epilepsy (LTLE) and 12 right-handed healthy controls to localize language-related activity in the right inferior frontal gyrus (RIFG). During the phonemic task, LTLE patients activated a significantly more posterior region of the right anterior insula/frontal operculum than healthy controls (P = 0.02). Activation of the left inferior frontal gyrus (LIFG) did not differ significantly between the two groups. This suggests that, following left hemisphere injury, language-related processing in the right hemisphere differs from that with a functionally normal left hemisphere. The localization of activation in the left and right inferior frontal gyri was determined with respect to the anatomical sub-regions pars opercularis (Pop), pars triangularis (Ptr) and pars orbitalis (Por). In the LIFG, both healthy controls (8 out of 12) and LTLE patients (9 out of 12) engaged primarily Pop during phonemic fluency. Activations in the RIFG, however, were located mostly in the anterior insula/frontal operculum in both healthy controls (8 out of 12) and LTLE patients (8 out of 12), albeit in distinct regions. Mapping the locations of peak voxels in relation to previously obtained cytoarchitectonic maps of Broca's area confirmed lack of homology between activation regions in the left and right IFG. Verbal fluency-related activation in the RIFG was not anatomically homologous to LIFG activation in either patients or controls. To test more directly whether RIFG activation shifts in a potentially adaptive manner after left hemisphere injury, fMRI studies were performed in a patient prior to and following anatomical left hemispherectomy for the treatment of Rasmussen's encephalitis. An increase in activation magnitude and posterior shift in location were found in the RIFG after hemispherectomy for both phonemic and semantic tasks. Together, these results suggest that left temporal lobe injury is associated with potentially adaptive changes in right inferior frontal lobe functions in processing related to expressive language.

Serum antibodies in epilepsy and seizure-associated disorders.

OBJECTIVE: To investigate whether autoantibodies to ion channels and other neural antigens are present in the sera of patients with epilepsy and seizure-related diseases. METHODS: Sera were obtained from 139 patients, including 26 with preexisting autoimmune disease, 46 in whom an autoimmune basis was suspected, and 67 with drug-resistant epilepsy. The sera were assayed for antibodies to voltage-gated potassium (VGKC) and calcium (VGCC) channels, glutamic acid decarboxylase (GAD), gangliosides, glutamate receptor type 3, cardiolipins, DNA, and nuclear antigens; the results were compared with results from a large cohort of healthy and disease controls. RESULTS: Increased titers of VGKC antibodies (>100 pM) were detected in 16 of 139 (11%) patients with seizures but only 1 control (0.5%). Eight VGKC-positive patients presented with an acute/subacute illness, and 5 of these had the highest VGKC antibodies; 3 patients improved spontaneously, another 5 patients responded well to immunomodulatory therapy. The other VGKC-positive patients had longer disease duration (>6 years) and intermediate levels of antibodies; immunotherapies have not been tested in this group. Very high levels of GAD antibodies (>1,000 U) were found in an additional 3 patients (2.1%) with long-standing drug-resistant epilepsy. CONCLUSIONS: The presence of autoantibodies to voltage-gated potassium channels and glutamic acid decarboxylase suggests that the immune system may contribute to certain forms of epilepsy or seizure-associated disorders. Further studies are needed to determine whether the antibodies are pathogenic.

Alpha7-acetylcholine receptor antibodies in two patients with Rasmussen encephalitis.

Rasmussen encephalitis (RE) sera were screened for antibodies to human alpha7 nicotinic acetylcholine receptors (nAChRs) using electrophysiology, calcium imaging, and ligand binding assays. Sera from two of nine patients with RE blocked ACh-induced currents through alpha7 nAChRs and the ACh-induced rise in intracellular free calcium ([Ca2+]i) and inhibited (125)I-alpha-bungarotoxin binding in cells expressing alpha7 nAChRs. Thus, the alpha7 nAChR is a potential target for pathogenic antibodies in patients with RE.

Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis.

OBJECTIVE: To determine the prevalence of serum antibodies to the ionotropic glutamate receptor 3 (GluR3) in patients with Rasmussen encephalitis (RE), a severe epileptic disorder, and to compare with serum from control subjects and patients with intractable epilepsy (IE). METHODS: The authors looked for serum immunoglobulin (Ig) G antibodies to GluR3 in 30 patients with RE, including two patients who had plasma exchange and 12 who had been treated with IV Igs with varying results, and 49 patients with IE and 23 healthy individuals, using ELISA with GluR3B peptide, Western blot analysis of recombinant full-length GluR3, immunoprecipitation of [35S]- and [125I]-labeled GluR3 extracellular domains, immunohistochemistry on rat brain sections, and electrophysiology of GluR3 expressed in Xenopus oocytes. RESULTS: Low levels of antibodies to the GluR3B peptide were detected using ELISA in only 4 of the 79 patients with epilepsy (2 with RE and 2 with IE); binding to GluR3B in other sera was shown to be nonspecific. One other patient with IE had antibodies to recombinant GluR3 on Western blot analysis. However, none of the sera tested precipitated either the [35S]- or the [125I]-labeled GluR3 domains; none bound to rat brain sections in a manner similar to rabbit antibodies to GluR3; and none of the nine sera tested affected the electrophysiologic function of GluR3. CONCLUSIONS: GluR3 antibodies were only infrequently found in Rasmussen encephalitis or intractable epilepsy.

Sarcoidosis presenting as palmar erythema.

Sarcoidosis, a multisystem disease of unknown aetiology, is characterized by the formation of non-caseating granulomas which may involve any organ of the body. The commonest sites of predilection are the lungs, skin and lymph nodes. We now report a patient who presented with palmar erythema which on biopsy confirmed the presence of non-caseating granulomas and who responded to systemic corticosteroids. We are unaware of any previous report in the literature of sarcoidosis presenting in this way.

Amyloid angiopathy causing widespread miliary haemorrhages within the brain evident on MRI.

The case of a 70-year-old woman with cerebral amyloid angiopathy (CAA) is presented. MRI of the head showed widespread miliary foci of haemorrhage within the cerebrum and cerebellum, with some additional linear lesions within the cerebral cortex and patchy lesions in the white matter. This is in contrast to the more usual pattern of intracranial haemorrhage in CAA, i.e., a lobar haematoma.

Double pathology in Rasmussen's syndrome: a window on the etiology?

The syndrome of chronic encephalitis with epilepsy (Rasmussen's syndrome) typically occurs in children and is characterized by the development of intractable focal seizures, progressive hemiparesis and intellectual deterioration. The etiology is unknown, and the pathological abnormalities vary from those of active disease, with numerous microglial nodules, with or without neuronophagia, perivascular round cells and glial scarring, to those of remote disease, demonstrated by neuronal loss, gliosis and perivascular round cells but few microglial nodules. We describe five patients presenting with clinical features typical of Rasmussen's syndrome, in whom pathological examination showed a second, previously unsuspected pathology in addition to the changes of chronic encephalitis. Two of the patients had vascular abnormalities bearing some resemblance to cavernous angiomata, one had a tumor, one had tuberous sclerosis, and one the forme fruste of tuberous sclerosis. The coexistence of a second pathology in these patients may provide information about the underlying mechanism of this rare condition.