Functional Recovery in Autoimmune Encephalitis: A Prospective Observational Study.

Background: Prospective observations of functional recovery are lacking in patients with autoimmune encephalitis defined by antibodies against synaptic proteins and neuronal cell surface receptors. Methods: Adult patients with a diagnosis of autoimmune encephalitis were included into a prospective registry. At 3, 6 and 12 months of follow-up, the patients' modified Rankin Scale (mRS) was obtained. Results: Patients were stratified into three groups according to their antibody (Ab) status: anti-NMDAR-Ab (n=12; group I), anti-LGI1/CASPR2-Ab (n=35; group II), and other antibodies (n=24; group III). A comparably higher proportion of patients in group I received plasma exchange/immunoadsorption and second line immunosuppressive treatments at baseline. A higher proportion of patients in group II presented with seizures. Group III mainly included patients with anti-GABABR-, anti-GAD65- and anti-GlyR-Ab. At baseline, one third of them had cancer. Patients in groups I and III had much higher median mRS scores at 3 months compared to patients in group II. A median mRS of 1 was found at all follow-up time points in group II. Conclusions: The different dynamics in the recovery of patients with certain autoimmune encephalitides have important implications for clinical trials. The high proportion of patients with significant disability at 3 months after diagnosis in groups I and III points to the need for improving treatment options. More distinct scores rather than the mRS are necessary to differentiate potential neurological improvements in patients with anti-LGI1-/CASPR2-encephalitis.

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

BACKGROUND: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. METHODS: Within the period of 2014-2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. RESULTS: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. CONCLUSIONS: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.

Management of Autoimmune Encephalitis: An Observational Monocentric Study of 38 Patients.

Over the last years the clinical picture of autoimmune encephalitis has gained importance in neurology. The broad field of symptoms and syndromes poses a great challenge in diagnosis for clinicians. Early diagnosis and the initiation of the appropriate treatment is the most relevant step in the management of the patients. Over the last years advances in neuroimmunology have elucidated pathophysiological basis and improved treatment concepts. In this monocentric study we compare demographics, diagnostics, treatment options and outcomes with knowledge from literature. We present 38 patients suffering from autoimmune encephalitis. Antibodies were detected against NMDAR and LGI1 in seven patients, against GAD in 6 patients) one patient had coexisting antibodies against GABAA and GABAB), against CASPR2, IGLON5, YO, Glycine in 3 patients, against Ma-2 in 2 patients, against CV2 and AMPAR in 1 patient; two patients were diagnosed with hashimoto encephalitis with antibodies against TPO/TG. First, we compare baseline data of patients who were consecutively diagnosed with autoimmune encephalitis from a retrospective view. Further, we discuss when to stop immunosuppressive therapy since how long treatment should be performed after clinical stabilization or an acute relapse is still a matter of debate. Our experiences are comparable with data from literature. However, in contrary to other experts in the field we stop treatment and monitor patients very closely after tumor removal and after rehabilitation from first attack.

Psychoses in epilepsy: A comparison of postictal and interictal psychoses.

We retrospectively analyzed data of patients with epilepsy (n=1434) evaluated with prolonged EEG monitoring in order to estimate the prevalence of postictal psychosis (PP) and interictal psychosis (IP), to investigate a potential association of psychosis subtype with epilepsy type, and to assess differences between PP and IP. The overall prevalence of psychosis was 5.9% (N=85); prevalence of PP (N=53) and IP (N=32) was 3.7% and 2.2%, respectively. Of patients with psychosis, 97.6% had localization-related epilepsy (LRE). Prevalence of psychosis was highest (9.3%) in patients with temporal lobe epilepsy (TLE). When comparing PP with IP groups on demographic, clinical, and psychopathological variables, patients with IP were younger at occurrence of first psychosis (P=0.048), had a shorter interval between epilepsy onset and first psychosis (P=0.002), and more frequently exhibited schizophreniform traits (conceptual disorganization: P=0.008; negative symptoms: P=0.017) than those with PP. Postictal psychosis was significantly associated with a temporal seizure onset on ictal EEG (P=0.000) and a higher incidence of violent behavior during psychosis (P=0.047). To conclude, our results support the presumption of a preponderance of LRE in patients with psychosis and that of a specific association of TLE with psychosis, in particular with PP. Given the significant differences between groups, PP and IP may represent distinct clinical entities potentially with a different neurobiological background.

Association of the chromosome 11q13.5 variant with atopic dermatitis in Austrian patients.

BACKGROUND: Recently, the two single nucleotide polymorphisms, rs7927894 on chromosome 11q13.5 and rs877776 within the region of the hornerin gene, were identified as novel susceptibility variants for atopic dermatitis in the first genome wide association study in atopic dermatitis. OBJECTIVE: The aim of our study was to evaluate the influence of these two genetic variants on atopic dermatitis and disease-related phenotypes in the Austrian population. METHODS: 275 atopic dermatitis patients and 243 controls were genotyped for the two variants rs7927894 and rs877776 by using Taqman based allelic discrimination assays. RESULTS: When comparing patients with controls we found a significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis (OR: 1.71; CI 1.14-2.59; p=0.010). Subgroup analysis revealed no significant association of rs7927894 with early age of onset of the disease, concomitant asthma and allergic rhinoconjunctivitis, total serum IgE levels and family history of atopy. The analysis of the rs877776 variant showed neither a relevant difference in the allelic distribution between patients and controls nor a statistically significant association with any of the analyzed atopic dermatitis phenotypes. CONCLUSIONS: In summary our data show a statistically significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis but not with other disease-related phenotypes. Therefore, we assume that the rs7927894 single nucleotide polymorphism selectively influences eczema development. More investigations in distinct study populations are needed to assess the role of this interesting polymorphism in atopic dermatitis.

Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2.

We characterize a consanguineous Egyptian family with an autosomal recessively inherited familial cortical myoclonic tremor and epilepsy. We used multipoint linkage analysis to map the causative mutation to a 12.7 megabase interval within 1q31.3-q32.2 with a log of odds score of 3.6. For further investigation of the linked region in an efficient and unbiased manner, we performed exome sequencing. Within the suspected region we identified a homozygous single base pair deletion (c.503_503delG) leading to a frameshift in the coding region of the sixth exon of CNTN2 alias TAG-1 (p.Trp168fs), which segregated in the respective family. Many studies point towards an important role of the CNTN2 product contactin 2 in neuronal excitability. Contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, and another transmembrane protein called contactin associated protein-like 2 (CNTNAP2 alias CASPR2) are together necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. CNTN2 knockout mice were previously reported to suffer from spontaneous seizures and mutations in the CNTNAP2 gene have been described to cause epilepsy in humans. To further delineate the role of CNTN2 in patients with epilepsy, we sequenced the coding exons in 189 Caucasian patients with epilepsy. No recessive mutation was detected and heterozygote carriers of rare CNTN2 variants do not seem to be predisposed to epilepsy. Given the severity of the mutation and the proposed function of the gene, we consider this mutation as the most likely cause for cortical myoclonic tremor and epilepsy in this family.

Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.

BACKGROUND: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. METHODS: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. RESULTS: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). CONCLUSIONS: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.

A novel mutation in the VCP gene (G157R) in a German family with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia.

Mutations in the valosin-containing protein (VCP) are known to cause autosomal-dominant inclusion-body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N-terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD.

Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil.

PURPOSE AND METHODS: Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[(11)C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[(11)C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus. RESULTS: Among different VOIs, radioactivity was highest in the choroid plexus. The hippocampal VOI could not be used for data analysis because it was contaminated by spill-in of radioactivity from the adjacent choroid plexus. In several other temporal lobe regions that are known to be involved in seizure generation and propagation ipsilateral influx rate constants K(1) and efflux rate constants k(2) of R-[(11)C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus (K(1), range: -3.8% to +22.3%; k(2), range: -2.3% to +43.9%), amygdala (K(1), range: -20.6% to +31.3%; k(2), range: -18.0% to +38.9%), medial anterior temporal lobe (K(1), range: -8.3% to +14.5%; k(2), range: -14.5% to +31.0%) and lateral anterior temporal lobe (K(1), range: -20.7% to +16.8%; k(2), range: -24.4% to +22.6%). In contrast to temporal lobe VOIs, asymmetries were minimal in a region presumably not involved in epileptogenesis located outside the temporal lobe (superior parietal gyrus, K(1), range: -3.7% to +4.5%; k(2), range: -4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux (k(2)) increases were more pronounced than ipsilateral influx (K(1)) increases, which resulted in ipsilateral reductions (10%-26%) of R-[(11)C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K(1), k(2) and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p > 0.05, Wilcoxon matched pairs test). CONCLUSIONS: Even though we failed to detect statistically significant differences in R-[(11)C]verapamil model parameters between epileptogenic and nonepileptogenic brain regions, it cannot be excluded from our pilot data in a small sample size of patients that regionally enhanced P-gp activity might contribute to drug resistance in some patients with temporal lobe epilepsy.