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1.  Double seronegative myasthenia gravis with antiphospholipid syndrome: a case report 
Introduction
Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness. It is often associated with other autoimmune disorders, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Many aspects of autoimmune diseases are not completely understood, particularly when they occur in association, which suggests a common pathogenetic mechanism.
Case presentation
We report a case of a 42-year-old Caucasian woman with antiphospholipid syndrome, in whom myasthenia gravis developed years later. She tested negative for both antibodies against the acetylcholine receptor and against muscle-specific receptor tyrosine-kinase, but had typical decremental responses at the repetitive nerve stimulation testing, so that a generalized myasthenia gravis was diagnosed. Her thromboplastin time and activated partial thromboplastin time were high, anticardiolipin and anti-β2 glycoprotein-I antibodies were slightly elevated, as a manifestation of the antiphospholipid syndrome. She had a good clinical response when treated with a combination of pyridostigmine, prednisone and azathioprine.
Conclusions
Many patients with myasthenia gravis test positive for a large variety of auto-antibodies, testifying of an immune dysregulation, and some display mild T-cell lymphopenia associated with hypergammaglobulinemia and B-cell hyper-reactivity. Both of these mechanisms could explain the occurrence of another autoimmune condition, such as antiphospholipid syndrome, but further studies are necessary to shed light on this matter.
Clinicians should be aware that patients with an autoimmune diagnosis such as antiphospholipid syndrome who develop signs and neurological symptoms suggestive of myasthenia gravis are at risk and should prompt an emergent evaluation by a specialist.
doi:10.1186/1752-1947-8-2
PMCID: PMC3917420  PMID: 24380508
Antibodies against acetylcholine receptor; Antibodies against muscle-specific receptor tyrosine-kinase; Antibodies against ryanodine receptor; Antibodies against titin; Antiphospholipid syndrome; Autoimmune disorders; Seronegative myasthenia gravis
2.  Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A 
Kasperavičiūtė, Dalia | Catarino, Claudia B. | Matarin, Mar | Leu, Costin | Novy, Jan | Tostevin, Anna | Leal, Bárbara | Hessel, Ellen V. S. | Hallmann, Kerstin | Hildebrand, Michael S. | Dahl, Hans-Henrik M. | Ryten, Mina | Trabzuni, Daniah | Ramasamy, Adaikalavan | Alhusaini, Saud | Doherty, Colin P. | Dorn, Thomas | Hansen, Jörg | Krämer, Günter | Steinhoff, Bernhard J. | Zumsteg, Dominik | Duncan, Susan | Kälviäinen, Reetta K. | Eriksson, Kai J. | Kantanen, Anne-Mari | Pandolfo, Massimo | Gruber-Sedlmayr, Ursula | Schlachter, Kurt | Reinthaler, Eva M. | Stogmann, Elisabeth | Zimprich, Fritz | Théâtre, Emilie | Smith, Colin | O’Brien, Terence J. | Meng Tan, K. | Petrovski, Slave | Robbiano, Angela | Paravidino, Roberta | Zara, Federico | Striano, Pasquale | Sperling, Michael R. | Buono, Russell J. | Hakonarson, Hakon | Chaves, João | Costa, Paulo P. | Silva, Berta M. | da Silva, António M. | de Graan, Pierre N. E. | Koeleman, Bobby P. C. | Becker, Albert | Schoch, Susanne | von Lehe, Marec | Reif, Philipp S. | Rosenow, Felix | Becker, Felicitas | Weber, Yvonne | Lerche, Holger | Rössler, Karl | Buchfelder, Michael | Hamer, Hajo M. | Kobow, Katja | Coras, Roland | Blumcke, Ingmar | Scheffer, Ingrid E. | Berkovic, Samuel F. | Weale, Michael E. | Delanty, Norman | Depondt, Chantal | Cavalleri, Gianpiero L. | Kunz, Wolfram S. | Sisodiya, Sanjay M.
Brain  2013;136(10):3140-3150.
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
doi:10.1093/brain/awt233
PMCID: PMC3784283  PMID: 24014518
mesial temporal lobe epilepsy; mesial temporal sclerosis; SCN1A; association; complex genetics
3.  Atypical face shape and genomic structural variants in epilepsy 
Brain  2012;135(10):3101-3114.
Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
doi:10.1093/brain/aws232
PMCID: PMC3470710  PMID: 22975390
epilepsy; dysmorphism; structural variants; genomics; dense surface models
4.  Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome? 
BMJ Case Reports  2009;2009:bcr12.2008.1363.
We report on a 70-year-old woman with partial complex status epilepticus who was initially diagnosed with herpes simplex-2 (HSV-2) encephalitis, based on brain magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) lymphocytic pleocytosis and HSV-2 DNA detection by polymerase chain reaction (PCR) in the CSF, but without improvement on intravenous acyclovir. Anti-Ri antibodies were positive and computed tomography (CT) investigations revealed a small cell carcinoma at biopsy suggesting paraneoplastic encephalitis. The outcome was unfavourable and the autopsy showed typical features of paraneoplastic encephalitis but no evidence of viral inclusions. This case report is interesting because: (1) it is the first report of an autopsy proven paraneoplastic widespread encephalitis with anti-Ri antibodies; (2) despite a positive HSV-2 PCR in the CSF, there was no sign of herpetic infections of the nervous system; and (3) it illustrates the fact that if paraneoplastic antibodies are usually good markers of the underlying tumour, they are not always predictive of neurological deficits.
doi:10.1136/bcr.12.2008.1363
PMCID: PMC3029830  PMID: 21833342

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