Apolipoprotein E ε4 Is Associated With the Development of Incident Dementia in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients With p.Arg544Cys Mutation.

BACKGROUND AND PURPOSE: To identify clinical, laboratory, and magnetic resonance imaging (MRI) features in predicting incident stroke and dementia in Korean patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). MATERIALS AND METHODS: We enrolled 87 Korean CADASIL patients who had undergone baseline clinical, laboratory, and MRI examinations between March 2012 and February 2015. The primary outcome of this study is the occurrence of stroke and dementia during the study period. The occurrence of incident stroke was confirmed by neuroimaging study, and dementia was defined by the diagnostic and statistical manual of mental disorders, fourth edition, criteria. RESULTS: Of the 87 patients, 57.5% were men, and the mean age was 63 ± 13 years (range 34-90 years), and 82 patients (94.3%) had p.Arg544Cys mutation. During an average follow-up of 67 months (interquartile range: 53-69 months), incident stroke occurred in 14 of 87 patients (16.1%) and incident dementia in 7 of 70 non-demented patients (10.0%). In adjusted analysis, increased systolic blood pressure was associated with increased risk of incident stroke [for every 10-mmHg increase; hazard ratio, 1.44 (1.02-2.03)]. Apolipoprotein E ε4 genotype was associated with an increased risk of incident dementia [hazard ratio, 10.70 (1.27-89.88)]. CONCLUSION: In this study, apolipoprotein E ε4 genotype was associated with the development of incident dementia, and higher blood pressure was associated with increased risk of incident stroke in CADASIL patients with predominant p.Arg544Cys mutation.

Low serum vitamin D levels in patients with myasthenia gravis.

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease. Vitamin D has important roles both in the autoimmune response and in skeletal muscles. We investigated the levels of 1,25-dihydroxy vitamin D [1,25(OH)2D] and 25-hydroxy vitamin D [25(OH)D] in patients with MG and healthy subjects. MG patients were classified by disease stage, age of onset and treatment status whether or not to taking immunosuppressive agents. MG patients had lower plasma 25(OH)D levels (mean, 18.8 ±â€¯8.4 ng/mL) than healthy controls (26.3 ±â€¯6.1 ng/mL) (p < .05). 1,25(OH)2D levels showed slightly high in MG patients than healthy controls, but had no significant difference between two groups. In addition, no significant differences were observed between two groups divided by clinical characteristics. Serum 25(OH)D levels significantly lower in patients with MG compared with healthy controls. We recommend monitoring of vitamin D status in patients with MG to avoid direct negative effects on the muscles or autoimmune response.

A prognostic factor in focal hand dystonia: typist's cramp cases and literature review.

The prognosis of focal hand dystonia (FHD) remains unclear. We retrospectively studied six patients with typist's cramp in our hospitals, and five cases in the PubMed database. All of them were right-handed. We compared clinical features between simple (dystonia in only one specific task), and dystonic/progressive groups (dystonia in several and/or new tasks). The initially affected right hand ratio was significantly higher in dystonic/progressive groups than in simple group (p=0.015). Initially affected hand may be a predictor for the progression, implying that the progression may be associated with the amount of daily routine hand movements.

Characteristics of the Drip-and-Ship Paradigm for Patients with Acute Ischemic Stroke in South Korea.

BACKGROUND: Data on the drip-and-ship paradigm in Korea are limited. The present study aimed to evaluate the use of the drip-and-ship paradigm and the time delays and outcomes associated with the paradigm in Korea. METHODS: We used data from the Clinical Research Center for Stroke-5 registry between January 2011 and March 2014. Among patients treated with tissue-type plasminogen activator (tPA), the use of the drip-and-ship paradigm was evaluated, and time delays and functional outcomes at 3 months were compared between patients treated with the paradigm and those treated directly at visits. RESULTS: Among 1843 patients who met the eligibility criteria, 244 patients (13.2%) were treated with the drip-and-ship paradigm. Subsequent endovascular recanalization therapy was used in 509 patients (27.6%). The median time from symptom onset to groin puncture was greater in patients treated with the paradigm than in those treated directly at visits (305 versus 200 minutes, P < .001). In multivariate analysis, the risks of unfavorable functional outcomes and symptomatic intracranial hemorrhage were higher inpatients treated with the paradigm than in those directly treated at visits (odds ratio [OR] 2.15; 95% confidence interval [CI], 1.50-3.08; P < .001 and OR 1.78; 95% CI, 1.02-3.12; P = .041, respectively). CONCLUSIONS: In Korea, the drip-and-ship paradigm was used in less than 15% of all patients treated with tPA. The use of the paradigm might cause an increase in the onset-to-groin puncture time. Additionally, clinical outcomes might be worse in patients treated with the paradigm than in those treated directly at visits.

Both binding and blocking antibodies correlate with disease severity in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease associated with antibodies directed to the postsynaptic muscle components of the neuromuscular junction. The heterogeneous nature of the acetylcholine receptor (AChR) antibody response had led to the categorization of AChR antibodies into 3 types: binding, blocking, and modulating antibodies. The purpose of this study is to compare the AChR antibodies' type with the clinical severity of MG patients. The patients enrolled in the study had been tested for both binding and blocking antibodies and had disease duration exceeding 2 years since diagnosis. The patients were divided into five main classes by the Myasthenia Gravis Foundation of America clinical classification. Again, the enrolled patients were divided into ocular and generalized group. We compared the type and titer of antibodies and the thymus status between the ocular and generalized group. Thirty-five patients met the inclusion criteria. Of these, 16 patients (47 %) had both blocking and binding AChR antibodies, 11 patients (31 %) had only binding antibodies, and 8 patients (22 %) had only blocking antibodies. By defined clinical classification, the ocular and generalized groups included 10 and 25 patients, respectively. Sixteen patients in the generalized group possessed both AChR antibodies, with the remaining patients displaying only the binding antibody. All the patients with only blocking antibody were classified into ocular group. Use of binding and blocking antibodies' tests may, therefore, be more helpful in predicting the prognosis and diagnoses of MG patient.

Lying-down nystagmus and head-bending nystagmus in horizontal semicircular canal benign paroxysmal positional vertigo: are they useful for lateralization?

BACKGROUND: Lateralization of horizontal semicircular canal benign paroxysmal positional vertigo (HSC-BPPV) is very important for successful repositioning. The directions of lying-down nystagmus (LDN) and head-bending nystagmus (HBN) have been used as ancillary findings to identify the affected sites. This retrospective study was performed to evaluate the lateralizing values of LDN and HBN using clinical and laboratory findings for lateralizing probabilities in patients with HSC-BPPV. METHODS: For 50 HSC-BPPV patients with asymmetric direction-changing horizontal nystagmus (DCHN) during the head-rolling test (HRT) using Frenzel goggles, the directions of LDN and HBN were evaluated and compared to those determined by video-oculography. Directional LDN was defined as the contralesional direction of nystagmus in geotropic types and the ipsilesional direction in apogeotropic types. Directional HBN was defined as the opposite direction relative to directional LDN. We also analyzed LDN and HBN in 14 patients with a history of ipsilesional peripheral vestibulopathy, caloric abnormality or conversion from other types of BPPV (such as probable localized HSC-BPPV, pro-BPPV). RESULTS: LDN and HBN were seen in 68% (34/50) and 76% (38/50) of patients, respectively. Of these, 19 (55.9%), and 28 (73.7%) patients showed directional LDN and HBN, respectively. The proportion of patients with directional LDN and HBN was much smaller among the pro-BPPV patients (4/12 for LDN, 3/10 for HBN). CONCLUSIONS: LDN and HBN did not seem to predict lateralization in patients with HSC-BPPV. To improve the prediction of lateralization of HSC-BPPV, it is necessary to modify the maneuvers used to elicit LDN or HBN, especially in cases of symmetric DCHN during HRT.

Headache among CADASIL patients with R544C mutation: prevalence, characteristics, and associations.

BACKGROUND AND AIM: There are variations of migraine prevalence in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) among different regions of the world. Previous studies on Asian CADASIL patients have not provided detailed descriptions of the characteristics of their headaches. The aims of this study were to determine prevalence and characteristics of headaches and to investigate associations between headache and other clinical symptoms or brain magnetic resonance imaging (MRI) findings among homogenous group of patients having the same R544C mutation. METHODS: In this cross-sectional study, we enrolled 53 CADASIL patients with the R544C mutation between May 2010 and April 2011. We obtained the history of headache using a structured questionnaire and detailed interview. Other clinical features and brain MRI findings were also assessed for potential associations. RESULTS: Overall headache prevalence was 45.3% (24 patients). Among them, 21 patients (87.5%) were classified as having tension-type headache, followed by migraine (two patients) and unclassifiable headaches (one patient). Except for alcohol consumption, no significant associations were observed between the headaches and other clinical features or brain MRI findings. CONCLUSION: Migraine was found in only 3.8% of CADASIL patients with the R544C mutation. Such a low prevalence of migraine may hinder clinical detection of CADASIL among ethnically Asian patients.

Adult Sandhoff disease with 2 mutations in the HEXB gene presenting as brachial amyotrophic diplegia.

Sandhoff disease is a rare autosomal recessive metabolic disorder of GM2 gangliosides. It is caused by a lack of functional N-acetyl-ß-D-glucosaminidase A and B because of mutations in the HEXB gene. We describe a 55-year-old woman with adult Sandhoff disease presenting as brachial amyotrophic diplegia. The assay of total hexosaminidase involving A and B showed decreased level of these activities. Hex-A was 4.6 nmol·min·mL (normal: 7.0-20.0 nmol·min·mL) and Hex-B was 0.1 nmol·min·mL (normal: 1.0-10.0 nmol·min·mL), respectively. Analysis of HEXB gene demonstrated 2 point mutations that were located at the exon 5 (c.619A>G) and exon 11 (c.1250C>T). Compound heterozygosity of these 2 mutations may trigger the development of distinct adult Sandhoff disease phenotype. Sandhoff disease should be considered in the differential diagnosis of lower motor neuron disease, such as brachial amyotrophic diplegia, even if the age at onset is more than 50 years.

Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of cerebral small blood vessels caused by mutations in the NOTCH3 gene. The initial detection of CADASIL may be more difficult among Asian populations because common clinical phenotypes and neuroimaging findings are not frequently found in these populations. The purpose of this study was to screen the NOTCH3 gene for mutations among consecutive patients with acute ischemic stroke from our region in Korea. METHODS: Between April 2008 and March 2009, 151 consecutive patients with acute ischemic stroke were screened for NOTCH3 mutations. All patients underwent a detailed clinical examination and structured interview for clinical symptoms and family history. We reviewed brain magnetic resonance imaging data from stroke patients to assess the severity of white-matter hyperintensity lesions, the number of cerebral microbleeds, and the number of lacunar infarctions. Polymerase chain reaction was used to screen exons 3, 4, 6, 11, and 18 of the NOTCH3 gene. RESULTS: Among 151 consecutive patients with acute ischemic stroke, 6 patients (4.0%; 95% confidence interval [CI] 0.9-7.1) possessed a NOTCH3 gene mutation. All patients exhibited the same R544C mutation in exon 11. Four of these 6 patients presented with large artery atherosclerosis. The prevalence of CADASIL in patients with neuroimaging features consistent with advanced small-vessel disease was 36.0% (95% CI 8.0-64.8). CONCLUSIONS: In this region, NOTCH3 gene mutations are frequently found in acute stroke patients who present with neuroimaging features consistent with advanced small-vessel disease.

Is progressive upper-body apraxia a corticobasal syndrome?

Corticobasal degeneration (CBD) is characterized by various clinical manifestations including corticobasal syndrome, progressive supranuclear palsy-like syndrome and frontotemporal dementia. Focal cortical atrophy syndrome as the initial manifestation rarely occurs in CBD. Here, we present a 62-year-old man and a 70-year-old man who were admitted due to clumsiness in the arms. On initial neurological examination, they showed asymmetric limb apraxia without parkinsonism or global cognitive dysfunction. Brain MRI showed focal atrophy in the frontal and prefrontal cortices, and brain positron emission tomography scan revealed decreased metabolism in these same brain locations. Although these patients developed parkinsonism and dystonia within several years, the neurological signs were limited to the arms for a long period. "Progressive upper-body apraxia" may be a rare clinical manifestation of CBD which shows a benign clinical outcome. The patients described may enhance our understanding of the clinical heterogeneity of this disease.

Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the NOTCH3 gene. Several characteristic population-specific clinical phenotypes and neuroimaging features have been reported in CADASIL. This study investigated the clinical stroke presentation and cranial magnetic resonance imaging (MRI) findings in a group of patients with CADASIL. We reviewed the clinical stroke presentation and brain MRI findings in 73 consecutive Korean patients aged >18 years diagnosed with CADASIL between May 2004 and April 2009. Brain MRI images were also scored for lacunar infarction and cerebral microbleeds. Intracranial atherosclerosis (ICAS) was assessed by magnetic resonance angiography. Disability was measured with the modified Rankin scale (mRS) and classified as good (mRS score 0-2) or poor (mRS score 3-5). In this study, 65 of the 73 patients (90.3%) had the same R544C genotype. A total of 40 episodes of cerebral infarction were confirmed in 31 patients, with a mean age at onset of 58.8 ± 11.4 years (range, 38-76 years). Twelve patients (16.9%) had ICAS, and 5 of these patients had symptomatic stenoses. Intracerebral hemorrhage occurred in 9 patients (12.3%). Both intracerebral hemorrhage and ICAS were associated with poor clinical outcome. Our data demonstrate the diversity of clinical stroke presentation according to ethnicity and vascular risk factors.

Cognitive impairments in multiple system atrophy of the cerebellar type.

BACKGROUND AND PURPOSE: We investigated the cognitive profiles in a large sample of patients with multiple system atrophy-cerebellar ataxia (MSA-C) and compared directly them in patients with clinical diagnosis of probable MSA-C without dementia and control subjects with intact cognition. METHODS: We prospectively enrolled 26 patients with clinical diagnosis of probable MSA-C. All patients underwent a standardized neuropsychological test of the Seoul Neuropsychological Screening Battery. RESULTS: The score of Korean version of the Mini- Mental State Examination was significantly lower in patients with MSA-C (27.2 ± 2.5) than in control subjects (28.9 ± 1.0, p = 0.003). Patients with MSA-C showed a significantly worse performance in visuospatial function, 3 words recall, verbal immediate, delayed and recognition memory, visual delayed memory, phonemic and sementic Controlled Oral Word Association Test, and ideomotor praxis (p < 0.05). CONCLUSIONS: Patients with MSA-C show more severe and more widespread cognitive dysfunctions than controls. Our results also indicate that cognitive dysfunction in patients with MCA-C is suggestive of disruption of the cerebellocortical circuits.

Simple Partial Status of Forced Thinking Originated in the Mesial Temporal Region: Intracranial Foramen Ovale Electrode Recording and Ictal PET.

Forced thinking (FT) is a rare epileptic phenomenon which is usually seen in patients with frontal lobe epilepsy. We report a rare case of mesial temporal lobe epilepsy presenting FT as simple partial status epilepticus. A 50-year-old woman with left hippocampal sclerosis developed a prolonged episode of continuous FT for five days after she experienced a clustering of complex partial seizures during the period of preoperative video-electroencephalography (EEG) monitoring. The EEG demonstrated continuous focal ictal discharges in the left foramen ovale electrodes. Positron emission tomography showed focal glucose hypermetabolism in the left mesial temporal region. This case indicates that the anatomical substrate for the development of FT is located in the mesial temporal region as well as the frontal lobe, and prolonged FT can occur as a seizure manifestation.

Palilalia, echolalia, and echopraxia-palipraxia as ictal manifestations in a patient with left frontal lobe epilepsy.

Palilalia is a relatively rare pathologic speech behavior and has been reported in various neurologic and psychiatric disorders. We encountered a case of palilalia, echolalia, and echopraxia-palipraxia as ictal phenomena of left frontal lobe epilepsy. A 55-year-old, right-handed man was admitted because of frequent episodes of rapid reiteration of syllables. Video-electroencephalography monitoring revealed stereotypical episodes of palilalia accompanied by rhythmic head nodding and right-arm posturing with ictal discharges over the left frontocentral area. He also displayed echolalia or echopraxia-palipraxia, partially responding to an examiner's stimulus. Magnetic resonance imaging revealed encephalomalacia on the left superior frontal gyrus and ictal single photon emission computed tomography showed hyperperfusion just above the lesion, corresponding to the left supplementary motor area (SMA), and subcortical nuclei. This result suggests that the neuroanatomic substrate involved in the generation of these behaviors as ictal phenomena might exist in the SMA of the left frontal lobe.

A Novel PANK2 Mutation in a Patient with Atypical Pantothenate-Kinase-Associated Neurodegeneration Presenting with Adult-Onset Parkinsonism.

BACKGROUND: Pantothenate-kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder that is characterized by progressive extrapyramidal signs, visual loss, and cognitive impairment. PKAN is caused by mutations in the pantothenate kinase gene (PANK2), which is located on chromosome 20p13 and encodes pantothenate kinase, the key regulatory enzyme in coenzyme-A biosynthesis. CASE REPORT: In this report we describe a case of atypical PKAN with a novel PANK2 mutation, presenting with a 10-year history of postural tremor involving both hands. Upon neurological examination, the patient's face was masked and he spoke in a monotonous voice. The patient presented with mild bradykinesia and rigidity that involved all of the extremities. Horizontal saccadic eye movements were slow and fragmented. Brain MRI revealed a typical "eye-of-the-tiger" sign. A mutation analysis revealed three PANK2 mutations: two in exon 3 (Asp 378Gly and Leu385CysfsX13) and one in exon 4 (Arg440Pro). CONCLUSIONS: Parkinsonism is not an unusual presenting symptom in patients with atypical PKAN, and so it is important for physicians to consider PKAN in the differential diagnosis of patients presenting with young-onset parkinsonism.

Unilateral standing leg tremor as the initial manifestation of Parkinson disease.

BACKGROUND: The aim of this study was to analyze the different forms of leg tremors exhibited while standing in patients with Parkinson disease (PD), and to determine if the type of leg tremor exhibited is indicative of prognosis or treatment response in PD patients. METHODS: We studied the clinical characteristics of five PD patients (all women; mean age, 59 years, range, 53-64 years) with unilateral standing leg tremor as the initial manifestation of PD, including their electrophysiological findings and the results of long-term follow-up. RESULTS: For each patient, parkinsonism either existed at the time of onset of the initial symptoms or developed later. Patient responses to drugs were generally good, but one patient showed a poor response to drugs, even though she had only a low frequency leg tremor. For two patients whom we could observe during the 10-year follow-up period, neither the leg tremor nor parkinsonism was aggravated. CONCLUSIONS: There are two forms of unilateral standing leg tremor in PD. One form is high frequency, similar to the primary orthostatic tremor. The other is low frequency and similar to the parkinsonian resting tremor. Based on these observations, it appears that progression might be slow if PD patients have standing leg tremor as the initial manifestation.

Parkinsonsim due to a Chronic Subdural Hematoma.

Subdural hematoma is a rare cause of parkinsonism. We present the case of a 78-year-old man with right-side dominant parkinsonism about 3 months after a minor head injury. MRI reveals a chronic subdural hematoma on the left side with mildly displaced midline structures. The parkinsonian features were almost completely disappeared after neurosurgical evacuation of the hematoma without any anti-parkinson drug.