Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible Leucine-rich glioma-inactivated 1 (Lgi1)-mutant rats.

Leucine-rich glioma-inactivated 1 (LGI1) was identified as a causative gene of autosomal dominant lateral temporal lobe epilepsy. We previously reported that Lgi1-mutant rats carrying a missense mutation (L385R) showed audiogenic seizure-susceptibility. To explore the pathophysiological mechanisms underlying Lgi1-related epilepsy, we evaluated changes in glutamate and GABA release in Lgi1-mutant rats. Acoustic priming (AP) for audiogenic seizure-susceptibility was performed by applying intense sound stimulation (130 dB, 10 kHz, 5 min) on postnatal day 16. Extracellular glutamate and GABA levels in the hippocampus CA1 region were evaluated at 8 weeks of age, using in vivo microdialysis techniques. Under naïve conditions without AP, glutamate and GABA release evoked by high-K+ depolarization was more prominent in Lgi1-mutant than in wild-type (WT) rats. The AP treatment on day 16 significantly increased basal glutamate levels and depolarization-induced glutamate release both in Lgi1-mutant and WT rats, yielding greater depolarization-induced glutamate release in Lgi1-mutant rats. On the other hand, the AP treatment enhanced depolarization-induced GABA release only in WT rats, and not in Lgi1-mutant rats, illustrating reduced GABAergic neurotransmission in primed Lgi1-mutant rats. The present results suggest that enhanced glutamatergic and reduced GABAergic neurotransmission are involved in the audiogenic seizure-susceptibility associated with Lgi1-mutation.

[A case of Creutzfeldt-Jakob disease presenting with nonconvulsive status epilepticus in the early stages].

A 64-year-old Japanese woman presented with 1 week of recurrent convulsive seizures. At the time of admission, she was in a coma and did not present with convulsions. Intravenous diazepam administration improved her consciousness, although severe psychomotor excitement developed. Brain MRI demonstrated diffusion restriction in the cerebral cortex of the right hemisphere. Electroencephalography (EEG) showed periodic discharges centered around the parietal regions with right-sided dominance. Nonconvulsive status epilepticus (NCSE) was suspected, and the patient was actively treated with anti-epileptic drugs. She developed akinetic mutism and generalized myoclonus 1 month after admission. Follow-up EEG studies disclosed periodic synchronous discharges. Abnormal prion protein in the cerebral fluid was detected using a real-time quaking-induced conversion assay. The clinical diagnosis in the present case was sporadic Creutzfeldt-Jakob disease (CJD). Seizures as an initial symptom in patients with CJD are relatively rare. Our case suggests that CJD should be considered as a differential diagnosis when a patient presents with refractory NCSE.

Predictors of Stroke Outcome Extracted from Multivariate Linear Discriminant Analysis or Neural Network Analysis.

AIM: The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome. METHODS: Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission. RESULTS: Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02-1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome. CONCLUSION: Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.

Effects of vascular compression on the rostral ventrolateral medulla for blood pressure variability in stroke patients.

BACKGROUNDS: Vascular compression of the rostral ventrolateral medulla (RVLM) has been associated with hypertension or blood pressure (BP) variability. For acute ischemic stroke patients, increased BP variability may cause poor functional outcomes. We tested the hypothesis that RVLM compression was associated with increased BP variability or stroke outcome in acute ischemic stroke patients. METHODS: Acute ischemic stroke patients (n = 622) with 24-h ambulatory BP monitoring during the subacute phase of stroke (median 9 days from onset) were retrospectively studied. Variability in BP was evaluated with the SD and coefficient of variation of SBP and DBP. The morning surge was also evaluated. The presence of RVLM compression was evaluated using time-of-flight three-dimensional MRI. A poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. RESULTS: Patients with RVLM compression (n = 213) had significantly higher 24-h SBP mean, 24-h SBP SD, 24-h SBP coefficient of variation, 24-h DBP mean, 24-h DBP SD, and 24-h DBP coefficient of variation values and a higher prevalence of morning surge than those without (n = 409). Multiple regression analysis revealed that RVLM compression was associated with increased SBP variability, DBP variability, and morning surge. Despite the significant association between RVLM compression and BP variability, RVLM compression was not associated with poor stroke outcome. CONCLUSION: Although RVLM compression was closely associated with BP variability in the subacute ischemic stroke phase, an effect of RVLM compression on stroke outcome was not observed.

Increased blood pressure variability during the subacute phase in patients with ischemic stroke presenting with a low ankle-brachial index.

AIM: This study aimed to evaluate the associations of blood pressure (BP) variability in patients with ischemic stroke during the subacute phase using ambulatory blood pressure monitoring and the ankle-brachial index (ABI). METHODS: We retrospectively examined 831 consecutive patients (women 44.8%, mean age 76 ± 12 years) with acute ischemic stroke who underwent 24-h ambulatory blood pressure monitoring during the subacute phase of stroke (median 9 days from onset) and an ABI examination. BP variability was evaluated by assessing the standard deviation and coefficient of variation of systolic BP and diastolic BP. A low ABI was defined as an ABI <0.9. RESULTS: Of the 831 patients, 201 (24.2%) had a low ABI. Older age, lower body mass index, diabetes mellitus, chronic kidney disease, atrial fibrillation and a higher National Institutes of Health Stroke Scale score at admission were independently associated with a low ABI. The patients with a low ABI had a higher mean 24-h diastolic BP, higher standard deviation of both BP measurements (systolic BP and diastolic BP) and a higher coefficient of variation in both BP measurements than those with a higher ABI. According to the multivariable linear regression analysis, a low ABI was independently associated with increased BP variability (a high standard deviation or coefficient of variation of both BP measurements) after adjusting for baseline confounders. CONCLUSIONS: A low ABI was associated with increased BP variability during the subacute ischemic phase. Geriatr Gerontol Int 2020; 20: 448-454.

Increased blood pressure variability during the subacute phase of ischemic stroke is associated with poor functional outcomes at 3 months.

Thus far, it is well known that increased blood pressure variability may exacerbate stroke outcomes. Blood pressure in the acute phase would be influenced by both reactive hypertension to stroke and intrinsic blood pressure reactivity. Thus, we aimed to evaluate the association between blood pressure variability and outcomes at 3 months using ambulatory blood pressure monitoring in ischemic stroke patients in the subacute phase after reactive hypertension subsided. We retrospectively examined 626 consecutive patients with acute ischemic stroke who underwent 24-hour ambulatory blood pressure monitoring during the subacute phase of stroke (median, 9 days from onset). The variability in blood pressure was evaluated by assessing the standard deviation and coefficient of variation of systolic and diastolic blood pressure. The primary outcome was functional status at 3 months. A poor outcome was defined as a modified Rankin scale score of 3 or more and a good outcome as 2 or less. We assessed the functional outcome at 3 months in 497 patients (79.4%). The mean systolic and diastolic blood pressure levels were not associated with functional outcome. The multivariable analysis revealed that increases in the standard deviations of systolic and diastolic blood pressure, coefficient of variation of diastolic blood pressure, and morning blood pressure surge were associated with poor outcome. Blood pressure variability during the subacute phase of ischemic stroke can be a useful prognostic indicator of poor functional outcome at 3 months in patients with acute ischemic stroke.

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis.

Astrocytes regulate potassium and glutamate homeostasis via inwardly rectifying potassium (Kir) 4.1 channels in synapses, maintaining normal neural excitability. Numerous studies have shown that dysfunction of astrocytic Kir4.1 channels is involved in epileptogenesis in humans and animal models of epilepsy. Specifically, Kir4.1 channel inhibition by KCNJ10 gene mutation or expressional down-regulation increases the extracellular levels of potassium ions and glutamate in synapses and causes hyperexcitation of neurons. Moreover, recent investigations demonstrated that inhibition of Kir4.1 channels facilitates the expression of brain-derived neurotrophic factor (BDNF), an important modulator of epileptogenesis, in astrocytes. In this review, we summarize the current understanding on the role of astrocytic Kir4.1 channels in epileptogenesis, with a focus on functional and expressional changes in Kir4.1 channels and their regulation of BDNF secretion. We also discuss the potential of Kir4.1 channels as a therapeutic target for the prevention of epilepsy.

[Association between aseptic meningitis and jolt accentuation of headache in adults].

BACKGROUND AND PURPOSE: The purpose of this study was to elucidate the association between aseptic meningitis and jolt accentuation of headache (JAH) in adults. SUBJECTS AND METHOD: 87 patients with meningeal irritation (age; 35.6 ± 13.3 years old, 45 males) who were admitted to our hospital from 1st August 2013 to 31st August 2018 were included. The diagnosis was determined according to the following criteria:, aseptic meningitis was defined as cerebrospinal fluids (CSF) pleocytosis with no evidence of bacterial infection, fungal infection or carcinomatous findings; meningism was defined as the absence of CSF pleocytosis. None of these patients had consciousness disturbance and focal neurological abnormalities. The blood and CSF data were reviewed for analysis. RESULTS: 61 patients were in aseptic meningitis group, 26 patients were in meningism group. Multiple logistic regression analysis showed older age (OR 1.059, 95% Confidence interval (CI) 1.012-1.108, P = 0.013), lower CRP (OR 0.803, 95%CI 0.697-0.925, P = 0.002) and absence of JAH (OR 0.048, 95%CI 0.004-0.554, P = 0.015) were significantly associated with aseptic meningitis. The sensitivity and specificity of JAH in aseptic meningitis were 68.9%, 3.8%.

[An elderly case of Guillain-Barré syndrome with anti-GT1b antibodies].

An 85-year-old Japanese female was admitted with sudden onset of quadriparesis with areflexia. Preceding infection was not present. IgG anti-GT1b antibodies were prominently positive in serum. Nerve conduction study results suggested Guillain-Barré syndrome (GBS) classified as acute motor sensory axonal neuropathy (AMSAN). While intravenous immunoglobulin (IVIg) was started, bulbar palsy and respiratory failure progressed and the condition deteriorated. Although mechanical ventilation was required, second IVIg course led to gradual improvement of quadriparesis and bulbar palsy. In the present case with elderly-onset disease, the levels of anti-GT1b antibodies were elevated, which is relatively rare in GBS. It was suggested that anti-GT1b antibodies may be related to the development of axonal GBS with bulbar palsy.

[A rare case of Streptococcus agalactiae meningitis in previously healthy adult].

A 39-year-old previously healthy man was referred to our hospital because of acute onset of fever and consciousness disturbance. Neurological examinations revealed deteriorated consciousness, nuchal rigidity and Kernig's sign. A lumbar puncture yielded clouded fluid with a WBC 1,012/µl (polynuclear cell 96%), 147.3 mg/dl of protein, 44 mg/dl of glucose and Gram positive cocci. At first, he was treated with ceftriaxon and ampicillin. At Day 2, meropenem was added. Streptococcus agalactiae was isolated from blood and cerebrospinal fluid. He responded promptly to antimicrobial therapy, and within 2 days, he became lucid and afebrile. S. agalactiae was sensitive to ceftriaxone, ampicillin and meropenem. After Day 3, he was treated with meropenem only. We diagnosed his condition as S. agalactiae meningitis and was discharged from our hospital at Day 18. Many cases of S. agalactiae meningitis are known to occur in neonates, pregnant women, elderly, and persons with underlying disease such as diabetes, malignant disorders, liver dysfunction. But cases occurring in a previously healthy adult are rare. Neurologists should be aware that S. agalactiae may be cause bacterial meningitis in a previously healthy adults.

[A rare case of Streptococcus salivarius meningitis in elderly].

An 80-year-old man who had chronic heart failure and atrial fibrillation was refered to our hospital because of acute onset of fever and consciousness disturbance. Neurological examinations revealed deteriorated consciousness, nuchal rigidity and Kernig's sign. A lumber puncture yielded clouded fluid with a WBC 11,200/µl (polynuclear cell 94%), 758 mg/dl of protein, 1 mg/dl of glucose, 0.007 of cerebrospinal fluid-blood glucose ratio and Gram positive cocci. Diffusion-weighted images on brain MRI showed no signal intensity in bilateral ventricles at admission. He was treated with ceftriaxon, vancomycin and ampicillin. Streptococcus salivarius (S. salivarius) was isolated from blood and cerebrospinal fluid. He responded promptly to antibiotics therapy, and within 5 days, he became lucid and afebrile. S. salivarius was sensitive for ceftriaxone, vancomycin and ampicillin. After Day 6, he was treated with ceftriaxone only. We diagnosed his condition as S. salivarius meningitis. He discharged from our hospital at Day 22. Many cases of S. salivarius meningitis were occurred in second and fifth decade. But elderly case was rare. Neurologist should consider that elderly case with bacterial meningitis was caused by S. salivarius.

Increased seizure sensitivity, emotional defects and cognitive impairment in PHD finger protein 24 (Phf24)-null rats.

Phf24 is known as Gαi-interacting protein (GINIP) and is associated with the GABAB receptor. To study the function of Phf24 protein in the central nervous system (CNS), we have newly developed Phf24-null rats and investigated their behavioral phenotypes, especially changes in seizure sensitivity, emotional responses and cognitive functions. Phf24-null rats did not exhibit any spontaneous seizures. However, they showed a higher sensitivity to pentylenetetrazol (PTZ)- or pilocarpine-induced convulsive seizures. Phf24-null rats also showed an elevated susceptibility to kindling development with repeated PTZ treatments, suggesting that Phf24 acts as an inhibitory modulator in epileptogenesis. Although young Phf24-null rats showed normal gross behaviors, elevated spontaneous locomotor activity, especially in terms of the circadian dark period, emotional hyper-reactivity, reduced anxiety behaviors in the elevated plus-maze (EPM) test, and cognitive deficits in the Morris water maze test were explicitly observed at older age (20-week-old). The present results suggest that Phf24 is essential for proper functioning of the CNS, especially in preventing epileptogenesis and controlling emotional and cognitive functions.

Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats.

The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, which is a model of autosomal dominant lateral temporal lobe epilepsy in humans, to clarify the role of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis. Priming acoustic stimulation (at postnatal day 16) conferred seizure susceptibility on Lgi1 mutant rats, which evoked audiogenic seizures with test stimulation at eight weeks. In the seizure-susceptible Lgi1 mutant rats (before test stimulation), astrocytic Kir4.1 expression was down-regulated region-specifically in the cerebral cortex, hippocampus, and amygdala. In addition, prophylactic treatments of Lgi1 mutant rats with valproic acid (VPA, 30 mg/kg and 200 mg/kg) for two weeks prevented both the development of seizure susceptibility and the down-regulation of Kir4.1 expression in astrocytes. The present study demonstrated for the first time that the astrocytic Kir4.1 expression was reduced in the Lgi1-related seizure model, suggesting that the down-regulation of Kir4.1 channels in astrocytes is involved in audiogenic epileptogenesis caused by Lgi1 mutation. In addition, VPA seemed to have a prophylactic effect on Lgi1-related seizures.

Inwardly Rectifying Potassium Channel Kir4.1 as a Novel Modulator of BDNF Expression in Astrocytes.

Brain-derived neurotrophic factor (BDNF) is a key molecule essential for neural plasticity and development, and is implicated in the pathophysiology of various central nervous system (CNS) disorders. It is now documented that BDNF is synthesized not only in neurons, but also in astrocytes which actively regulate neuronal activities by forming tripartite synapses. Inwardly rectifying potassium (Kir) channel subunit Kir4.1, which is specifically expressed in astrocytes, constructs Kir4.1 and Kir4.1/5.1 channels, and mediates the spatial potassium (K⁺) buffering action of astrocytes. Recent evidence illustrates that Kir4.1 channels play important roles in bringing about the actions of antidepressant drugs and modulating BDNF expression in astrocytes. Although the precise mechanisms remain to be clarified, it seems likely that inhibition (down-regulation or blockade) of astrocytic Kir4.1 channels attenuates K⁺ buffering, increases neuronal excitability by elevating extracellular K⁺ and glutamate, and facilitates BDNF expression. Conversely, activation (up-regulation or opening) of Kir4.1 channels reduces neuronal excitability by lowering extracellular K⁺ and glutamate, and attenuates BDNF expression. Particularly, the former pathophysiological alterations seem to be important in epileptogenesis and pain sensitization, and the latter in the pathogenesis of depressive disorders. In this article, we review the functions of Kir4.1 channels, with a focus on their regulation of spatial K⁺ buffering and BDNF expression in astrocytes, and discuss the role of the astrocytic Kir4.1-BDNF system in modulating CNS disorders.

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region.

Inwardly rectifying potassium (Kir) channel subunits Kir4.1 are specifically expressed in astrocytes and regulate neuronal excitability by mediating spatial potassium buffering. In addition, it is now known that astrocytic Kir4.1 channels are closely involved in the pathogenesis of epilepsy. Here, to explore the role of Kir4.1 channels in the treatment of epilepsy, we evaluated the effects of the antiepileptic drugs, valproate, phenytoin, phenobarbital and ethosuximide, on Kir4.1 expression in astrocytes using immunohistochemical techniques. Repeated treatment of rats with valproate (30-300 mg/kg, i.p., for 1-10 days) significantly elevated the Kir4.1 expression levels in the cerebral cortex, amygdala and hippocampus. Up-regulation of Kir4.1 expression by valproate occurred in a dose- and treatment period-related manner, and did not accompany an increase in the number of astrocytes probed by glial fibrillary acidic protein (GFAP). In addition, repeated treatment with phenytoin (30 mg/kg, i.p., for 10 days) or phenobarbital (30 mg/kg, i.p., for 10 days) also elevated Kir4.1 expression region-specifically in the amygdala. However, ethosuximide (100 mg/kg, i.p., for 10 days), which can alleviate absence but not convulsive seizures, showed no effects on the astrocytic Kir4.1 expression. The present results demonstrated for the first time that the antiepileptic drugs effective for convulsive seizures (valproate, phenytoin, and phenobarbital) commonly elevate the astrocytic Kir4.1 channel expression in the limbic regions, which may be related to their antiepileptic actions.

Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons.

Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of epileptic disorders; however, the mechanisms of nACh receptors in seizure generation remain unknown. Here, we performed behavioral and immunohistochemical studies in mice and rats to clarify the mechanisms underlying nicotine-induced seizures. Treatment of animals with nicotine (1-4 mg/kg, i.p.) produced motor excitement in a dose-dependent manner and elicited convulsive seizures at 3 and 4 mg/kg. The nicotine-induced seizures were abolished by a subtype non-selective nACh antagonist, mecamylamine (MEC). An α7 nACh antagonist, methyllycaconitine, also significantly inhibited nicotine-induced seizures whereas an α4ß2 nACh antagonist, dihydro-ß-erythroidine, affected only weakly. Topographical analysis of Fos protein expression, a biological marker of neural excitation, revealed that a convulsive dose (4 mg/kg) of nicotine region-specifically activated neurons in the piriform cortex, amygdala, medial habenula, paratenial thalamus, anterior hypothalamus and solitary nucleus among 48 brain regions examined, and this was also suppressed by MEC. In addition, electric lesioning of the amygdala, but not the piriform cortex, medial habenula and thalamus, specifically inhibited nicotine-induced seizures. Furthermore, microinjection of nicotine (100 and 300 µg/side) into the amygdala elicited convulsive seizures in a dose-related manner. The present results suggest that nicotine elicits convulsive seizures by activating amygdalar neurons mainly via α7 nACh receptors.

Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes.

Inwardly rectifying potassium (Kir) 4.1 channels in astrocytes regulate neuronal excitability by mediating spatial potassium buffering. Although dysfunction of astrocytic Kir4.1 channels is implicated in the development of epileptic seizures, the functional mechanisms of Kir4.1 channels in modulating epileptogenesis remain unknown. We herein evaluated the effects of Kir4.1 inhibition (blockade and knockdown) on expression of brain-derived neurotrophic factor (BDNF), a key modulator of epileptogenesis, in the primary cultures of mouse astrocytes. For blockade of Kir4.1 channels, we tested several antidepressant agents which reportedly bound to and blocked Kir4.1 channels in a subunit-specific manner. Treatment of astrocytes with fluoxetine enhanced BDNF mRNA expression in a concentration-dependent manner and increased the BDNF protein level. Other antidepressants (e.g., sertraline and imipramine) also increased the expression of BDNF mRNA with relative potencies similar to those for inhibition of Kir4.1 channels. In addition, suppression of Kir4.1 expression by the transfection of small interfering RNA (siRNA) targeting Kir4.1 significantly increased the mRNA and protein levels of BDNF. The BDNF induction by Kir4.1 siRNA transfection was suppressed by the MEK1/2 inhibitor U0126, but not by the p38 MAPK inhibitor SB202190 or the JNK inhibitor SP600125. The present results demonstrated that inhibition of Kir4.1 channels facilitates BDNF expression in astrocytes primarily by activating the Ras/Raf/MEK/ERK pathway, which may be linked to the development of epilepsy and other neuropsychiatric disorders.

Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetylcholine receptors.

Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5-2mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific α7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the α4ß2 nACh antagonist dihydro-ß-erythroidine (DHßE) or the peripheral α3ß4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1mg/kg) of nicotine region-specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHßE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via α7 nACh receptors.

[A case of myasthenia gravis presenting solely with bulbar palsy unassociated with easy fatigability].

A 69-year-old Japanese female was admitted because of progressive nasal voice and dysphagia. Neurological examination revealed paresis of the soft palate with marked dysphagia and rhinolalia. Otherwise there was no weakness or easy fatigability in extraocular muscles and extremities. On laboratory test, anti-acetylcholine receptor antibody (anti-AChR Ab) was positive, while anti-muscle-specific tyrosine kinase antibody (anti-MuSK Ab) was negative. Edrophonium test was positive, resulting in clear improvement in phonation and swallowing. Harvey-Masland test of ocular and extremity muscles did not show any waning. With the diagnosis of bulbar myasthenia gravis, the patient was treated with methylprednisolone and pyridostigmine, resulting in clear improvement of the symptoms. The present case shows that it is important to consider MG even in cases presenting solely with progressive bulbar palsy without easy fatigability. So far, cases of bulbar myasthenia gravis with positive anti-MuSK Ab have often been reported. As shown in the present case, bulbar myasthenia gravis can also be associated with positive anti-ACh-R Ab but negative anti-MuSK Ab.