Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Magnetic resonance imaging findings of the lower limb muscles in anti-mitochondrial M2 antibody-positive myositis.

Anti-mitochondrial M2 antibody (AMA-M2)-positive myositis is an idiopathic inflammatory myopathy (IIM). Of all patients with myositis, 2.5-19.5% have AMA-M2 antibodies. However, the detailed distribution of muscles affected in AMA-positive myositis is unknown. Therefore, we examined lower muscle magnetic resonance imaging (MRI) findings of patients with AMA-positive myositis. Among the 63 patients with IIM at our institute, 5 (7.9%) were positive for AMA-M2 antibodies. However, one was also positive for anti-Jo1 antibodies; therefore, four patients were finally participated in this study. All patients had high-intensity MRI signals in the proximal muscles, including the gluteus maximus and iliopsoas muscles, and in the thigh muscles, including the vastus lateralis, vastus medialis, adductor magnus, and semimembranosus muscles. Lower leg muscles were relatively spared. Fascial edema was observed in all patients and was also present in the lower leg muscles. Subcutaneous edema was observed, particularly in the proximal portion of the lower limbs. In AMA-positive myositis, proximal muscles, including the gluteus maximus, vastus lateralis, adductor magnus, and the semimembranosus, were markedly affected, while the lower leg muscles were relatively preserved. Additionally, fascial edema was evident even in lower leg muscles. Therefore, muscle MRI can be a useful diagnostic aid for AMA-positive myositis.

Persistent Severe Cerebral Edema with Neutrophil Infiltration Following Listeria Meningitis.

A 51-year-old man was admitted to the hospital with a diagnosis of Listeria monocytogenes meningitis. Diffuse cerebral edema appeared after improvement of meningitis with appropriate treatment and worsened for two months. Due to brain herniation, brain tissue leaked through the incision made during the drain insertion in a hydrocephalus surgery. We found pathological evidence of significant neutrophil infiltration with a few lymphocytes without bacterial detection in the degraded brain tissue. The present case indicates that fatal cerebral edema with significant neutrophil infiltration may develop even after appropriate treatment for L. monocytogenes meningitis.

Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment.

Vitamin B12 deficiency is associated with cognitive impairment, hyperhomocysteinemia, and hippocampal atrophy. However, the recovery of cognition with vitamin B12 supplementation remains controversial. Of the 1716 patients who visited our outpatient clinic for dementia, 83 had vitamin B12 deficiency. Among these, 39 patients (mean age, 80.1 ± 8.2 years) had undergone Mini-Mental State Examination (MMSE) and laboratory tests for vitamin B12, homocysteine (Hcy), and folic acid levels. The hippocampal volume was estimated using the z-score of the MRI-voxel-based specific regional analysis system for Alzheimer's disease. This is multi-center, open-label, single-arm study. All the 39 patients were administered vitamin B12 and underwent reassessment to measure the retested for MMSE and Hcy after 21−133 days (median = 56 days, interquartile range (IQR) = 43−79 days). After vitamin B12 supplementation, the mean MMSE score improved significantly from 20.5 ± 6.4 to 22.9 ± 5.5 (p < 0.001). Hcy level decreased significantly from 22.9 ± 16.9 nmol/mL to 11.5 ± 3.9 nmol/mL (p < 0.001). Significant correlation was detected between the extent of change in MMSE scores and baseline Hcy values. The degree of MMSE score was not correlated with hippocampal atrophy assessed by the z-score. While several other factors should be considered, vitamin B12 supplementation resulted in improved cognitive function, at least in the short term, in patients with vitamin B12 deficiency.

Center of pressure velocities in patients with body lateropulsion: three case report series of Wallenberg's syndrome.

PURPOSE: In patients with Wallenberg's syndrome who present with body lateropulsion (BL), whether the center of pressure (COP) position and velocity characterize postural dysregulation is unknown. We measured time-course changes in COP parameters in three BL patients. METHODS: Three patients with acute Wallenberg's syndrome presented with BL. COP was measured for time-course changes during first standing and every week thereafter. COP positions, which indicate the deviation in the center of gravity, were calculated. COP velocities associated with dynamic movements of the center of gravity were analyzed separately for the BL and non-BL sides. RESULTS: All patients showed that COP position shifted to the BL side in first standing and changed to the center over time. COP velocities to the BL side were fast in first standing. Two of the three patients had significantly faster COP velocities to the BL side than to the non-BL side (p < .05), and one did not. In all three cases, the faster COP velocities to the BL side decreased significantly after 2 weeks compared to the initial standing position (p < .001). The change seemed to be related to the time when independent walking became possible. CONCLUSIONS: Fast COP velocity to the BL side might reflect postural dysregulation in patients with BL. These findings might be useful information for devising effective rehabilitation in patients with BL.

Effectiveness of a self-reporting yes/no survey for dementia screening-trial in Fukui, Japan.

Background: Early intervention for dementia patients is extremely important for the prevention of dementia. However, so far, it is not clear as to what kind of screening will be useful for the early detection of dementia. Objective: We aimed to investigate the relationship between the results of a short self-reporting yes/no survey selected in Kihon Checklist, developed by the Japanese Ministry of Health, Labor and Welfare to identify older adults who are at risk of requiring support/care, and other original items developed by Dementia Prevention Team, Fukui, Japan, and Mini-Mental State Examination (MMSE) scores, and determine the diagnostic efficacy of the self-reporting yes/no survey. Methods: Self-reporting yes/no surveys were conducted for 87,687 individuals aged ≥65 years, living in Fukui, Japan, and did not have Long-Term Care Insurance, Japan. According to the survey results, selected individuals were advised to visit a local hospital to be assessed with MMSE. Results: Individuals who could not make a call by looking up phone numbers and manage their own deposits and savings at the bank or automatic teller machine (ATM) had an increased risk of low MMSE score (≤23; odds ratio: 2.74 [1.89-3.97]; 95% confidence interval: 2.12 [1.46-3.07]). Conclusions: Self-reporting yes/no survey could effectively screen for dementia. Not being able to make a call by looking up phone numbers and not being able to manage their own deposits and savings at the bank or ATM are signs of dementia.

Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein.

The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs), which are composed of amyloid ß protein (Aß), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 µM CQ had no effect on cell viability; however, 100 µM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment.

Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.

A case of longitudinally extensive transverse myelitis with an isolated pontine lesion following epidural and spinal anesthesia for cesarean section.

Severe neurologic complications following epidural and spinal anesthesia rarely occur. Transverse myelitis has been reported as a rare complication of epidural or spinal anesthesia. We report a case of longitudinally extensive transverse myelitis and an isolated pontine lesion, which responded to immunotherapy. The patient was a 31-year-old pregnant woman who underwent elective cesarean section under epidural and spinal anesthesia. Though the insertions of the epidural and spinal catheters were smooth, she experienced back pain and transient hearing loss during epidural anesthesia. Postoperatively, she exhibited severe motor weakness in both lower extremities, neuralgia below the level of Th10 dermatome, and urinary retention. Magnetic resonance imaging showed longitudinally extensive transverse myelitis from T6 to T10 with a ring-shaped enhanced lesion and an isolated pontine lesion. These findings on magnetic resonance imaging were suggestive of autoimmune diseases such as neuromyelitis optica. The patient was diagnosed with an immunoreactive disease triggered by epidural or spinal anesthesia and was administered high-dose methylprednisolone, which led to the improvement in clinical symptoms. Clinicians should be aware of the possibility of the development of longitudinally extensive transverse myelitis and isolated pontine lesions after cesarean section under epidural and spinal anesthesia.

[Spinal dural arteriovenous fistula presented with rapidly progressive myelopathy, longitudinally extensive spinal cord lesion, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid glucose levels: a case report].

A 75-year-old woman developed low back pain, weakness of the lower extremities, and urinary retention. On day 7 after the onset of symptoms, she was brought to the emergency department of our hospital by an ambulance because of progressive weakness of both lower extremities. Spine MRI showed longitudinally extensive spinal cord lesion (LESCL) at the Th8-Th11 spinal cord level and flow voids around the lesions. Lumbar puncture revealed a normal opening pressure, yellowish appearance, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid (CSF) glucose levels. Based on the rapidly progressing myelopathy, LESCL, and CSF findings, we initially diagnosed the patient with myelitis and administered acyclovir and high-dose intravenous immunoglobulin on day 7. Spine MRI with gadolinium-enhancement showed longitudinally extending flow voids of the thoracic cord, and digital subtraction arteriogram (DSA) revealed arteriovenous shunt on the dura with dilated and tortuous intradural veins. We finally diagnosed her with spinal dural arteriovenous fistula (SDAVF). Cases of SDAVF might be initially misdiagnosed as myelitis because of showing rapid progressive myelopathy, pleocytosis with polymorphonuclear predominance, and decreased CSF glucose levels. Lumbar puncture and steroid administration for the cases of SDAVF could aggravate the patient's neurological symptoms. Therefore, lumbar puncture and initiation of immunotherapy should be avoided until SDAVF is completely excluded in patients with suspected myelitis on spine MRI without gadolinium-enhancement, even if their neurological symptoms progress rapidly.

Pioglitazone prevents tau oligomerization.

Tau aggregation and amyloid ß protein (Aß) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aß production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3ß, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.

[The investigation of understanding and comfort of patients taking Divigel(®) 1 mg].

Hormone replacement therapy (HRT) given by injection or administered orally or topically can improve the QOL of patients with menopausal symptoms. Because patient comfort is influenced largely by the dosage form, pharmacists should understand the properties of each dosage form and provide appropriate information to individual patients. In this study, we investigated the understanding of medicines and diseases of patients receiving HRT and discuss the approaches pharmacists can take to improve patients' adherence. Thirty-seven patients (mean age 51.7±3.6 years) taking estradiol gel (Divigel(®) 1 mg) completed a questionnaire asked by their pharmacist. Responses indicated 70% of patients failed to use the gel as prescribed, and they had poor knowledge of both the sites where the gel shouldn't be applied and appropriate measures to take if having forgotten to apply the gel (43% and 11% correct understanding, respectively). Since the duration of HRT treatment for menopausal symptom is 2-5 years, patients should be administered the minimum effective dose in the shortest amount of time. Hence it is important to maintain patients' adherence particularly in this limited administration period. HRT guidelines define HRT outcome as not only improvement of menopausal symptoms but also suppression of bone resorption, improvement of glucose and lipid metabolism, and reduced prevalence of Alzheimer's disease. Accordingly, pharmacists should facilitate proper adherence to HRT to improve and maintain women's QOL in the perimenopausal period, necessitating they actively provide pharmaceutical care such as preparing useful instructions patients can repeatedly use and periodically checking patients' understanding of their HRT medications.

[An autopsied case of zygomycosis invasing in the central nervous system and vessels, which is difficult in the differential diagnosis from aspergillosis].

A 59-year-old man with a long history of under-treated diabetes mellitus presented with severe inflammation that had spread from the sinus to the left orbital cavity. The bilateral internal carotid arteries were severely stenotic, causing multiple infarctions in the brain parenchyma. There was no ß-D-glucan detected in the cerebrospinal fluid. Based on the presence of central nervous system (CNS) inflammation and vascular involvements that spread from the sinusitis, we tentatively diagnosed this patient as having invasive fungal CNS infection, i.e. zygomycosis or aspergillosis. Although the patient was treated with anti-fungal drugs such as liposomal amphotericin B and voriconazole, he died of respiratory failure. Pathological examination of the autopsied tissues demonstrated zygomycosis in the brain and heart. The prevalence of zygomycosis is generally very low (-5% of CNS infections) compared with that of other fungal infections. The lack of an appropriate diagnostic marker may lead to the under- or mis-diagnosis of zygomycosis. Moreover, it is hard to differentiate zygomycosis from aspergillosis because the two diseases share common clinical features such as the association of sinusitis and vascular involvement. The clinically diagnostic points that discriminate zygomycosis from aspergillosis are as followed; i) ß-D-glucan is negative in zygomycosis but positive in aspergillosis; ii) diabetes is more frequent in patients with zygomycosis to those with aspergillosis; iii) the infectious lesion in aspergillosis shows an iso-low-intensity on T(2) weighted MRI image but shows a high intensity lesion in zygomycosis. The mortality rate of CNS zygomycosis is so high that an early diagnosis of it is warranted and the start appropriate anti-fungal treatments or surgical drainage in the early stage of the disease.

[Effects of voriconazole and vascular lesions in invasion of aspergillosis into the central nerve system].

We report 2 patients showing invasion of aspergillosis into the central nerve system (CNS). Patient 1, an 81-year-old woman, underwent surgery for sphenoidal sinusitis. She developed cerebral infarction with unconsciousness on 12th postoperative day. CSF examination demonstrated pleocytosis with increased protein and aspergillus antigen. She was diagnosed as having invasion of aspergillosis into the CNS, and was treated with voriconazole. Her clinical manifestations and CSF findings markedly improved. However, the effects of voriconazole gradually attenuated and she demonstrated recurrence of the cerebral infarction. After 2 months, she died of systemic aspergillosis and sepsis. Autopsy studies. Severe atherosclerotic changes with calcification were demonstrated in the bilateral carotid and basilar arteries, and many aspergillus were clustered in the vessel walls. Granulomatous inflammatory lesions with aspergillus were also demonstrated in the area surrounding the chiasm. There were no massive infarcts or bleeding in the brain, but multiple small infarcts were present. Patinet 2, a 64-year-old man, showing bilateral visual loss, was receiving treatment with corticosteroids under a diagnosis of optic neuritis. Two weeks later, he developed cerebral infarction. CSF examination showed pleocytosis with increased protein and aspergillus antigen. He was diagnosed as having invasive aspergillosis from the sphenoidal sinusitis into the CNS. He was treated with voriconazole, and unconsciousness and CSF findings improved transiently. However, he developed a recurrence of the brain infarction and pneumonia and finally died 6 months later. Treatment by voriconazole was definitely effective in both patients, but both patients died of recurrent cerebral infarction, possibly due to resistance for voriconazole, or developing multicellular filamentous biofilms. Voriconazole is recommended as the first choice of antifungal agents for aspergillosis. Aspergillus infection is strongly invasive into arterial vessels. It is important to consider the possible occurrence of cerebrovascular disease when treating invasion of aspergillosis into the CNS.