Novel method for classification of prion diseases by detecting PrPres signal patterns from formalin-fixed paraffin-embedded samples.

Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.

Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study.

BACKGROUND: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. RESULTS: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0-46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. CONCLUSIONS: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.

Atrophy of the hippocampal CA1 subfield relates to long-term forgetting in focal epilepsy.

OBJECTIVE: The mechanisms underlying accelerated long-term forgetting (ALF) in patients with epilepsy are still under investigation. We examined the contribution of hippocampal subfields and their morphology to long-term memory performance in patients with focal epilepsy. METHODS: We prospectively assessed long-term memory and performed magnetic resonance imaging in 80 patients with focal epilepsy (61 with temporal lobe epilepsy and 19 with extratemporal lobe epilepsy) and 30 healthy controls. The patients also underwent electroencephalography recording. Verbal and visuospatial memory was tested 30 s, 10 min, and 1 week after learning. We assessed the volumes of the whole hippocampus and seven subfields and deformation of the hippocampal shape. The contributions of the hippocampal volumes and shape deformation to long-term forgetting, controlling for confounding factors, including the presence of interictal epileptiform discharges, were assessed by multiple regression analyses. RESULTS: Patients with focal epilepsy had lower intelligence quotients and route recall scores at 10 min than controls. The focal epilepsy group had smaller volumes of both the right and left hippocampal tails than the control group, but there were no statistically significant group differences for the volumes of the whole hippocampus or other hippocampal subfields. Multiple regression analyses showed a significant association between the left CA1 volume and the 1-week story retention (ß = 7.76; Bonferroni-corrected p = 0.044), but this was not found for the whole hippocampus or other subfield volumes. Hippocampal shape analyses revealed that atrophy of the superior-lateral, superior-central, and inferior-medial regions of the left hippocampus, corresponding to CA1 and CA2/3, was associated with the verbal retention rate. SIGNIFICANCE: Our results suggest that atrophy of the hippocampal CA1 region and its associated structures disrupts long-term memory consolidation in focal epilepsy. Neuronal cell loss in specific hippocampal subfields could be a key underlying cause of ALF in patients with epilepsy.

Clinical utility of serum prolactin and lactate concentrations to differentiate epileptic seizures from non-epileptic attacks in the emergency room.

PURPOSE: To evaluate the diagnostic utility of serum prolactin (PRL) and lactate (LAC) concentrations for patients presenting with either or both convulsions and transient loss of consciousness (TLOC) in the emergency room (ER). METHODS: This was a retrospective single-center study conducted in a tertiary care hospital ER. Medical records of consecutive patients who presented with convulsions or TLOC between January 2018 and December 2020 were reviewed. Patients with an ER diagnosis of epileptic seizures, psychogenic non-epileptic seizure (PNES), and syncope were selected for analysis. Serum PRL and LAC concentrations were measured within 3 h of the event and compared between groups. RESULTS: Among the 440 eligible patients, 173 (39.3%) were included for analysis. Serum PRL concentration was significantly higher in patients with epileptic seizures with convulsions than in those with PNES with convulsions (p < 0.001) and convulsive syncope (p = 0.023). Serum LAC concentration was not significantly elevated in patients with convulsive syncope. Using a PRL cut-off value of 24.0 ng/mL, serum PRL concentration had 100.0% sensitivity and 82.9% specificity for differentiating between PNES and other attacks without convulsions. CONCLUSION: Elevated serum PRL with normal serum LAC concentration in patients who have attacks with convulsions suggests convulsive syncope. Serum PRL concentration is useful in the diagnosis of PNES with convulsions. However, serum LAC concentration is not useful as a routine screening test for attacks without convulsions in the ER.

Paradoxical Cerebellar Embolism Associated with Platypnea-orthodeoxia Syndrome.

Platypnea-orthodeoxia syndrome is a rare clinical entity characterized by dyspnea and arterial blood deoxygenation in a sitting position. An 89-year-old woman was diagnosed with subacute cerebellar infarction. Her blood oxygen saturation decreased to 88% in a sitting position, resulting in dyspnea. Cardiological thoracic computed tomography revealed an unruptured aortic aneurysm, an enlarged ascending aorta, right atrial compression, and counterclockwise rotation of the heart. An anatomical distortion of the atrial septum induced by these abnormalities directed the atrial venous inflow such that the right-left shunt flow was exacerbated in a sitting position.

Cardiogenic cerebral infarction in the parietal lobe predicts the development of post-stroke epilepsy.

PURPOSE: Post-stroke epilepsy (PSE) is a major late complication of cardioembolic cerebral infarction. However, few studies have examined the epileptogenicity and characteristics of first-occurrence cardioembolic cerebral infarctions. METHODS: This retrospective study included 93 consecutive patients with old cardioembolic cerebral infarctions who were classified into two groups based on their epileptic history: patients presenting with PSE or stroke without seizure (SWS). Each patient was diagnosed with an epileptic seizure subtype and treated with appropriate anti-epileptic therapy after admission. We evaluated clinical characteristics, laboratory results, and intracranial infarct areas. The sizes of these areas were measured using MRI diffusion-weighted image (DWI) of each patient after their first stroke. The volume was calculated by multiplying the total slice area with the slice thickness. RESULTS: PSE was diagnosed in 43 (46.2 %) of 93 patients. The mean (± SD) time from infarction onset to the first seizure in the PSE group was 22.5 ±â€¯31.6 months. The PSE group exhibited significantly more atrial fibrillation (p = 0.022) and higher glucose levels (p < 0.001) compared with the SWS group. The most common PSE seizure type was focal to bilateral tonic-clonic seizure (61.0 %). Although DWI did not reveal any significant differences in the volume of infarctions between the two groups, the involvement of the parietal lobe in infarction of the PSE group (69.8 %) upon first admission was significantly higher (p = 0.006) than that of the SWS group (40.0 %). Multiple logistic regression analysis revealed that parietal lobe involvement in infarction (OR 4.95; 95 % CI 1.25-19.60; p = 0.023) was a significant independent predictor of PSE. CONCLUSION: The involvement of the parietal lobe in infarction was a significant independent predictor of PSE. Dysfunction of the parietal lobe might play a critical role in the epileptogenesis of PSE.

Modified diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score including deep white matter lesions predicts symptomatic intracerebral hemorrhage following intravenous thrombolysis.

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30-35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.

Differences between predictive factors for early neurological deterioration due to hemorrhagic and ischemic insults following intravenous recombinant tissue plasminogen activator.

Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (ENDh) or ischemic (ENDi) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with ENDh and ENDi were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6%), including 22 ENDh (3.0%) and 57 ENDi (7.7%), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.13) and pretreatment with antiplatelets (OR 2.84, 95% CI 1.08-7.72) were associated with ENDh. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95% CI 1.36-5.64) and large artery occlusions (OR 3.09, 95% CI 1.53-6.57) were associated with ENDi. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.

Temporal Trends in Clinical Characteristics and Door-to-Needle Time in Patients Receiving Intravenous Tissue Plasminogen Activator: A Retrospective Study of 4 Hospitals in Japan.

BACKGROUND: Intravenous recombinant tissue plasminogen activator (rt-PA) has become a common treatment for acute ischemic stroke and has highly time-dependent benefits. We aimed to clarify temporal trends regarding the frequency and characteristics of patients receiving rt-PA and explore factors associated with door-to-needle time (DNT) in Japanese emergency hospitals. METHODS: Consecutive patients who received intravenous rt-PA for acute ischemic stroke from October 2005 to December 2015 were retrospectively registered from 4 hospitals. Temporal trends in the frequency and characteristics of patients receiving rt-PA and factors associated with DNT were investigated. RESULTS: A total of 750 patients, including 688 (420 men, median 75 years old) with out-of-hospital stroke, were registered. The frequency of patients receiving intravenous rt-PA for acute ischemic stroke continuously increased from 1.8% in 2005 to 9.5% in 2015. The proportion of patients who were elderly or had prestroke disability increased over time, while pretreatment stroke severity declined. The DNT gradually decreased (median 105 minutes in 2005, 61 minutes in 2015). According to multivariate regression analysis with correction for multiple comparisons, activation of a code stroke system (standardized partial regression coefficient (ß) -.50, P < .001, q < .001), onset-to-door time (ß -.15, P < .001, q < .001), pretreatment with antithrombotic agents (ß .12, P < .001, q = .001), and year of treatment (ß .11, P = .007, q = .011) were associated with DNT. CONCLUSIONS: Intravenous rt-PA was widely adopted in Japanese emergency hospitals. Characteristics of patients receiving intravenous rt-PA have changed over the past decade. Several factors, including the year of treatment, were associated with DNT, which has shortened over time.

Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B: A case study.

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.

Clinical characteristics of atrial fibrillation-related cardioembolic stroke in patients aged 80 years or older.

AIM: Atrial fibrillation (AF)-related cardioembolic stroke is a serious problem in the aging society. The present study examined the clinical characteristics and outcomes of AF-related cardioembolic stroke in patients aged ≥80 years. METHODS: Between September 2011 and April 2014, consecutive patients with ischemic stroke and AF were retrospectively extracted from the multicenter database. Clinical characteristics were compared between patients aged ≥80 years and <80 years. Multivariate cox proportional hazard models were used to estimate hazard ratios and 95% confidential intervals on 90-day mortality for age of ≥80 years. RESULTS: A total of 253 patients aged ≥80 years (87 men, 86.4 ± 5.0 years) and 196 patients aged <80 years (134 men, 70.4 ± 7.1 years) were included. Patients aged ≥80 years were more frequently female, and more likely to have higher premorbid modified Rankin Scale score (mRS), lower body mass index, previous history of stroke, prior antiplatelet therapy, congestive heart failure, and persistent AF. Patients aged ≥80 years had higher initial National Institutes of Health Stroke Scale score and were more likely to have occlusion of the cervicocephalic arteries, but less likely to receive thrombolysis. Patients aged ≥80 years had a higher mRS and mortality after 3 months. Age of ≥80 years was a significant predictor of 90-day mortality after adjustment for sex (hazard ratio 2.20, 95% confidential interval 1.25-4.09), but was no longer significant after further adjustment for other clinical characteristics and stroke severity. CONCLUSIONS: In AF-related cardioembolic stroke, patients aged ≥80 years had different clinical characteristics and poorer outcome compared with patients aged <80 years. Geriatr Gerontol Int 2017; 17: 708-713.

Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation.

A 34-year-old man presented with an acute onset of upbeat nystagmus, slurred speech, and limb and truncal ataxias. The patient had a history of limb ataxia and gait disturbance previously treated as brainstem encephalitis with corticosteroids 3 years previously. Brain magnetic resonance imaging showed pontine developmental venous anomaly (DVA) and hemorrhagic infarction within the drainage territory of the DVA. Three months later, the patient exhibited recurrent limb ataxia, double vision, and numbness of the left side of the body. The brain magnetic resonance imaging revealed recurrent hemorrhagic venous infarction within the same territory of the pontine DVA. Laboratory tests disclosed a hypercoagulable state owing to a decrease of protein S activity despite the normal antigen level. Genetic testing indicated that the patient was a homozygous carrier of protein S Tokushima. The patient's severe disability remained unchanged in spite of treatment with anticoagulation therapy using warfarin. We propose that further research on hereditary coagulopathy be carried out in patients with recurrent episodes of DVA-related infarction.

Predictive Factors for Excellent or Extremely Poor Functional Outcome in Initial Atrial Fibrillation-Related Cardioembolic Stroke.

BACKGROUND: We aimed to determine the predictive factors for excellent or extremely poor functional outcome in patients with first-ever atrial fibrillation (AF)-related cardioembolic stroke. METHODS: Retrospective observational study from a database. Patients with AF-related cardioembolic stroke with a premorbid modified Rankin Scale (mRS) score of 0 or 1 and without a previous history of stroke were included. RESULTS: Factors associated with excellent functional outcome (mRS scores of 0 or 1; n = 77; 30.4% of patients) included age >78 years (OR 0.31, 95% CI 0.15-0.61), male sex (OR 2.16, 95% CI 1.04-4.60), absence of hypertension (OR 0.46, 95% CI 0.22-0.94) and initial National Institutes of Health Stroke Scale (NIHSS) score of >9 (OR 0.08, 95% CI 0.03-0.16). Factors associated with extremely poor functional outcome (mRS scores of 5 or 6; n = 63; 24.9%) included age >78 years (OR 3.30, 95% CI 1.54-7.39), initial NIHSS score of >9 (OR 12.38, 95% CI 5.40-32.56), congestive heart failure (OR 4.82, 95% CI 2.00-12.19) and ischemic heart disease (OR 4.02, 95% CI 1.18-14.69). CONCLUSIONS: Predictive factors exist to delineate excellent and extremely poor functional outcomes after a first-time stroke associated with AF.

Pure dysarthria and dysarthria-facial paresis syndrome due to internal capsule and/or corona radiata infarction.

BACKGROUND: Pure dysarthria (PD) and dysarthria-facial paresis syndrome (DFP) mainly result from lenticulostriate artery territory infarction. PD and DFP are rare clinical entities, often grouped without distinction. The purpose of this study was to examine clinical and radiographic differences between PD and DFP due to unilateral internal capsule and/or corona radiata infarction. METHODS: Using a database that included consecutive patients with ischemic stroke admitted to the neurological stroke units of three hospitals within 7 days from onset between September 2011 and April 2014, we retrospectively extracted first-ever stroke patient data, who presented with PD or DFP with a single ischemic lesion localized in the internal capsule and/or corona radiata. Patients with weakness, ataxia, sensory deficit, or cortical symptoms were excluded. Ischemic lesion volume was calculated by the ABC/2 method on diffusion-weighted imaging (DWI). DWI images were normalized and superimposed to the template for PD and DFP. We compared patients' characteristics between PD and DFP. RESULTS: A total of 2126 patients, including 65 patients (3.1%) with PD or DFP, were registered. Of these, 13 PD patients and 18 patients with DFP due to unilateral internal capsule and/or corona radiata infarction were included for analysis. Compared with DFP patients, PD patients had longer onset-to-door time (median 37.5 vs. 10.8 h, p = 0.031), shorter vertical length (C component) of ischemic lesions (median 12.0 vs. 18.8 mm, p = 0.007), and smaller ischemic lesion volume (median 285 vs. 828 mm(3), p = 0.023). Ischemic lesions causing PD were located more frequently in the left hemisphere than DFP (92% vs. 56%, p = 0.045). The superimposed lesion pattern indicated that DFP had lesions more medial and involving posterior portions of the putamen and the caudate body, as well as more of the genu and posterior limb of the internal capsule, than PD. Ninety days after onset, symptoms disappeared in 21 (72%) out of 29 patients. CONCLUSIONS: In cerebral infarction limited to the internal capsule and/or corona radiata, PD is derived from smaller and left-sided lesions with delay in diagnosis compared with DFP. The clinical course of those with PD and DFP might be benign.

Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 Scores on Severity and Functional Outcome in Acute Ischemic Stroke with Atrial Fibrillation.

BACKGROUND: We examined the association between pre-admission risk scores and severity on admission and functional outcome in acute ischemic stroke with atrial fibrillation (AF). METHODS: Between September 2011 and April 2014, we retrospectively extracted consecutive ischemic stroke patients with AF whose pre-admission modified Rankin Scale (mRS) score was 2 or less from our prospective database. Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were calculated in each patient, and their association with the National Institutes of Health Stroke Scale (NIHSS) score on admission or unfavorable outcome (mRS ≥ 3 at 3 months from the onset) was assessed. RESULTS: A total of 344 patients (189 were men; age, 77.7 ± 10.0 years) were included in the analysis. The median pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were 2, 4, and 4, respectively. NIHSS score on admission was positively correlated with pre-admission CHADS2 (ρ = .116, P = .031), CHA2DS2-VASc (ρ = .166, P = .020), and R2CHADS2 scores (ρ = .106, P = .049). Receiver operating characteristic (ROC) curve analysis revealed that pre-admission CHADS2 score of 2 or more (sensitivity, 80%; specificity, 45%; area under the ROC curve [AUC], .654), CHA2DS2-VASc score of 3 or more (sensitivity, 86%; specificity, 44%; AUC, .683), and R2CHADS2 score of 4 or more (sensitivity, 61%; specificity, 62%; AUC, .657) were associated with unfavorable outcome. The pre-admission CHA2DS2-VASc score was better than the pre-admission CHADS2 score in estimating unfavorable outcome (P = .017). In multivariate analysis, cutoffs of these scores, female sex, higher NIHSS score, and internal carotid artery occlusion were associated with unfavorable outcome. CONCLUSIONS: Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were associated with onset severity and functional outcome in acute ischemic stroke with AF.

[A case of Isaacs' syndrome causing various central nervous symptoms successfully treated with high-dose intravenous methylprednisolone therapy].

A 44-year-old man with a bilateral hand tremor suffered from a decline in concentration and abnormal vision for several months. He also complained of easily falling down because of muscle stiffness and cramps in his lower limbs. On admission, he demonstrated lower limb stiffness, muscle cramps, diplopia, hyperhidrosis, left upper limb ataxia and dysesthesia in all limbs. Laboratory examination showed a marked elevation in his serum creatine kinase level (26,890 U/l), and needle electromyography demonstrated myokymic discharges in the muscles of his lower extremities. Isaacs' syndrome was diagnosed based on a positive voltage-gated potassium channel antibody titer of 1,007 pM. Administration of an anticonvulsant (phenytoin, 200 mg/day) did not resolve his symptoms; however, high-dose intravenous methylprednisolone therapy (1 g/day for 3 days) resulted in marked clinical improvement. This case suggests that high-dose intravenous methylprednisolone therapy for Isaacs' syndrome might be as effective as other immunosuppressive therapies such as plasma exchange or intravenous immunoglobulin.

[Spontaneous seizures in a rat models of multiple prenatal lesioning].

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Eleven of 16 rats showed spontaneous seizures arising in the hippocampus from postnatal day47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. Alterations in the levels of glutamatergic and GABA-ergic receptors were investigated during growth. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. This model should enable better clarification of the mechanisms underlying the development of human epilepsy.

Spontaneous seizures in a rat model of multiple prenatal freeze lesioning.

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Electroencephalogram (EEG) and video recording were performed from postnatal day (P) 35 to P77. Brain tissues were examined immunohistochemically at P28 and P78 using semiquantitative densitometry. Eleven of 16 rats (68.8%) showed spontaneous seizures arising in the hippocampus from P47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. FCD was observed in the bilateral frontoparietal lobes. The expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits 1, 2A, 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 (GLT1) at FCD sites were increased at P28 and P78. There were no major histological abnormalities in the hippocampi compared with those in the cortex. However, the expression levels of NMDAR 2A and 2B were increased at P28. Levels of NMDAR1, 2A and 2B, the glutamate/aspartate transporter and GLT1 were also increased at P78. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. Alterations in the levels of glutamatergic and GABAergic receptors were investigated during growth. This model should enable better clarification of the mechanisms underlying the development of human epilepsy.