Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state. Methods: We used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state. Results: SOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals. Conclusion: By directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.

Effect of early enteral nutrition on critical care outcomes in patients with acute ischemic stroke.

OBJECTIVE: Stroke-associated pneumonia (SAP) is a comorbidity of ischemic stroke related to clinical outcomes. Early enteral nutrition (EEN; within 48 hours) reduces the incidence of infection and length of intensive care unit (ICU)/hospital stay. The relationship between EEN and critical care outcomes, including SAP, in patients with ischemic stroke has been insufficiently studied. METHODS: We recruited 499 patients in this retrospective observational study. We evaluated SAP incidence within 14 days from admission. Patients were divided into an EEN group and a late EN group (LEN; start later than EEN). We compared groups regarding background and length of ICU/hospital stay. RESULTS: EN was started within 48 hours in 236 patients. SAP was diagnosed in 94 patients (18.8%), with most in the LEN group (28.1% vs. 8.5%). Median [interquartile range] lengths of hospitalization (22 [12-30] days vs. 35 [20-45] days) and ICU stay (4 [2-5] days vs. 6 [3-8] days) were longer in the LEN group. EEN reduced the incidence of SAP. By contrast, consciousness disturbance and worsening consciousness level increased the SAP incidence. Increased age and National Institutes of Health Stroke Scale score were associated with start of prolonged EN. CONCLUSIONS: We found that EEN may reduce SAP risk.

Cerebellitis in a human T-lymphotropic virus type 1 carrier: a case report.

Human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to HAM/TSP and ATL, HTLV-I-associated encephalopathy and cerebellar involvement have been reported. We report a case of an 87-year-old Japanese woman presenting with progressive dysarthria and gait disturbance. Neurological examination showed word-finding difficulty, scanning speech, saccadic eye movements, ocular dysmetria, gaze-evoked nystagmus and bilateral dysmetria. There was no motor weakness or spasticity. HTLV-I antibody was detected in both her serum and cerebrospinal fluid. Cerebrospinal fluid neopterin (57 pg/mL) and IgG index (3.27) were significantly elevated. MRI showed cerebellar swelling. She was finally diagnosed with HTLV-I associated cerebellitis. Two courses of high-dose intravenous methylpredonine therapy attenuated cerebellar ataxia and cerebellar swelling. It suggests that cerebellitis can result from HTLV-I infection, regardless of the existence of ATL or HAM/TSP.

Clinical perspectives on ischemic stroke.

Treatments for acute stroke have improved over the past years, but have largely been limited to revascularization strategies. The topic of neuroprotection, or strategies to limit brain tissue damage or even reverse it, has remained elusive. Thus, the clinical mainstays for stroke management have focused on prevention. The lack of clinical translation of neuroprotective therapies which have shown promise in the laboratory may, in part, be due to a historic inattention to comorbidities suffered by a majority of stroke patients. With the advent of more stroke models that include one or more relevant comorbidities, it may be possible to identify effective treatments that may translate into new treatments at the clinical level. In the meantime, we review comorbidities in stroke patients, modification of stroke risk factors and available acute stroke treatments in the clinic.

Effective Tools to Predict Depression in Acute and Subacute Phase of Ischemic Stroke.

OBJECTIVE: Despite the high frequency of depression in the first year following stroke, few studies have predicted risk of depression after the acute and subacute stroke periods. The aim of this study was to identify, in the acute and subacute periods, measures that would predict major depression during the first year after stroke. METHODS: Study subjects were inpatients with ischemic stroke aged 20-85 years within 6 weeks of onset. Patients were evaluated at baseline and at 3, 6, 9, and 12 months. Patients were diagnosed with major depression using the Structured Clinical Interview for DSM-IV. The severity of depressive symptoms was measured with the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Of the 152 potential patients who met inclusion criteria, 49 had follow-up evaluations; one patient with major depression in the acute and subacute periods was excluded from the analysis. Among the remaining 48 patients, the number of those with major depression during the first year of stroke onset was five (10.4%). Patients who developed major depression had significantly more depressive symptoms in the acute and subacute stroke phase as assessed by both the PHQ-9 and MADRS. Patients with PHQ-9 scores ≥9 in the acute and subacute stroke phases were significantly more likely to develop major depression in a chronic phase of stroke. CONCLUSIONS: The self-administered PHQ-9 can identify patients in the acute and subacute stroke periods who are at increased risk for developing major depression during the first year after stroke.

Effectiveness of Nonvitamin K Antagonist Oral Anticoagulants and Warfarin for Preventing Further Cerebral Microbleeds in Acute Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation and At Least One Microbleed: CMB-NOW Multisite Pilot Trial.

BACKGROUND: Nonvitamin K antagonist oral anticoagulants (NOACs) are considered superior, or at least noninferior, to warfarin in preventing stroke or systemic embolism in patients with nonvalvular atrial fibrillation. Here, we recruited acute ischemic stroke patients with nonvalvular atrial fibrillation and at least one cerebral microbleed (CMB), and evaluated the proportion of patients who had an increased number of CMBs (%) after receiving anticoagulant therapy with NOACs or with warfarin for 12 months. METHODS: This was a multicenter, prospective, observational cohort study at 20 centers, conducted between 2015 and 2017, in which we recruited 85 patients with at least one CMB detected by 1.5T magnetic resonance imaging (T2*WI) at baseline, who received NOACs or warfarin for at least 12 months. We compared the proportions of patients with increased numbers of CMBs in the NOACs and warfarin treatment groups. RESULTS: The proportions of patients with increased numbers of CMBs at month 12 of treatment were 28.6% and 66.7% in the NOACs and warfarin groups, respectively. The new CMBs showed no specific regional localization in either group. In the NOACs and warfarin groups, physicians prescribed lower-than-standard dosing in 13.3% and 50% of the cases, respectively. The administration of reduced doses at physicians' discretion did not appear to alter the incidence of new CMBs. DISCUSSION: This is the first evidence to suggest efficacy of NOACs for preventing further CMBs in patients with at least one CMB, although no statistical evaluation was carried out.

Microglial Calcium Release-Activated Calcium Channel Inhibition Improves Outcome from Experimental Traumatic Brain Injury and Microglia-Induced Neuronal Death.

Store-operated Ca2+ entry (SOCE) mediated by calcium release-activated calcium (CRAC) channels contributes to calcium signaling. The resulting intracellular calcium increases activate calcineurin, which in turn activates immune transcription factor nuclear factor of activated T cells (NFAT). Microglia contain CRAC channels, but little is known whether these channels play a role in acute brain insults. We studied a novel CRAC channel inhibitor to explore the therapeutic potential of this compound in microglia-mediated injury. Cultured microglial BV2 cells were activated by Toll-like receptor agonists or IFNγ. Some cultures were treated with a novel CRAC channel inhibitor (CM-EX-137). Western blots revealed the presence of CRAC channel proteins STIM1 and Orai1 in BV2 cells. CM-EX-137 decreased nitric oxide (NO) release and inducible nitric oxide synthase (iNOS) expression in activated microglia and reduced agonist-induced intracellular calcium accumulation in microglia, while suppressing inflammatory transcription factors nuclear factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Male C57/BL6 mice exposed to experimental brain trauma and treated with CM-EX-137 had decreased lesion size, brain hemorrhage, and improved neurological deficits with decreased microglial activation, iNOS and Orai1 and STIM1 levels. We suggest a novel anti-inflammatory approach for managing acute brain injury. Our observations also shed light on new calcium signaling pathways not described previously in brain injury models.

Cilostazol is Effective to Prevent Stroke-Associated Pneumonia in Patients Receiving Tube Feeding.

Stroke-associated pneumonia (SAP) is a frequent complication in acute ischemic stroke (IS) patients, especially those receiving tube feeding (TF). In this retrospective study, we investigated whether or not cilostazol, a pluripotent phosphodiesterase III-specific inhibitor with anti-platelet and vasculogenic effects, can prevent SAP in these patients and reduce their duration of stay in intensive care unit/hospitalization. We recruited 158 IS patients receiving TF. Patients' characteristics (including age, gender, past history), National Institute of Health Stroke Scale and serum albumin level on admission, concomitant medications associated with SAP prevention (including cilostazol), and stroke characteristics (bilateral subcortical white matter lesion, brainstem involvement, large infarction, and asymptomatic hemorrhagic infarction) were compared between the SAP(-) and SAP(+) groups. Cilostazol was more frequently used in the SAP(-) group (20.8% vs. 6.1%, p < 0.05). Duration of intensive care unit was longer in patients with SAP (9 ± 8 vs. 6 ± 6 days, p < 0.05). However, the length of stay in an intensive care unit and duration of hospitalization were not reduced due to the prevention of SAP by cilostazol treatment. Cilostazol administration was associated with reduced SAP incidence in acute IS patients receiving TF.

A case of recurrent Mikulicz's disease with mononeuritis multiplex.

We report an 82-year-old man with recurrence of Mikulicz's disease accompanied with mononeuritis multiplex. On admission, both upper eyelids, the salivary gland, the dorsum of the left hand and both legs were swollen. Neurological examination showed motor weakness of distal limbs (manual muscle testing 3/5) and decreased touch, pain and vibration sensation of the dorsum of the left hand and both legs. Deep tendon reflex in both legs was also decreased. We diagnosed Mikulicz's disease based on high serum immunoglobulin (Ig)G4 (630 mg/dl, 26.1% of total IgG) and lacrimal gland biopsy findings. Clinical symptoms and motor conduction study findings improved after steroid therapy. However, tapering of the steroid dose resulted in recurrence two years later. Steroid therapy is usually effective for IgG4-related neuropathy, and we found that an increase of steroid dose was effective to treat the recurrence. But, in general, a suitable maintenance dose of steroid in combination with an immunosuppressant may be necessary to prevent relapse.

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome) Complicated by Perforation of the Small Intestine and Cholecystitis.

We report a case of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) complicated by perforation of the small intestine and necrotizing cholecystitis. A 69-year-old man with a history of bronchial asthma was admitted with mononeuritis multiplex. The laboratory findings included remarkable eosinophilia. He was treated with corticosteroids and his laboratory indices showed improvement; however, his functional deficits remained. His neuropathy gradually improved after the addition of intravenous immunoglobulin (IVIG). He was subsequently treated with oral prednisolone (40 mg/day) as maintenance therapy. Within a month after finishing IVIG, he developed perforation of the small intestine and necrotizing cholecystitis. Intestinal perforation has often been reported as a gastrointestinal complication of EGPA. In contrast, cholecystitis is a rare complication. We report this case because the manifestation of more than one complication is extremely rare. Gastrointestinal symptoms may be a complication of EGPA itself and/or immunosuppressive treatment.

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke.

While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.

A Recurrent Case of Ischemic Stroke Caused by Vasospasm due to Giant Cell Arteritis.

A 73-year-old man was admitted with sudden right upper-limb weakness. He had a temporal headache on the left side and had a 4-month history of fever. Meandering of the left temporal artery (TA) with induration and high inflammatory responses (white blood cell count 22,500 per microliter, C-reactive protein 35.0 mg/dL, and elevated sedimentation rate [ESR] 80 mm/h) were observed. Glycometabolism and lipid metabolism were normal, and autoimmune antibodies were negative. Cultivation tests revealed no bacteria in either blood culture or cerebrospinal fluid. Brain magnetic resonance imaging (MRI) showed ischemic lesion in the left frontal lobe, while magnetic resonance angiography (MRA) and carotid ultrasonography showed unstable plaque lesions in the left extracranial internal carotid artery (ICA). According to reported criteria (age > 50 years, new onset of headache, abnormality of the TA, and raised ESR), we diagnosed giant cell arteritis (GCA) with acute ischemic stroke (IS) and gave the patient antithrombotic therapy (aspirin 100 mg, cilostazol 200 mg). After admission, hemiparesis progressed but fluctuated. Subsequent MRI showed new lesions in the left watershed area. MRA also showed vasospasm in the middle cerebral artery and C5 portion of the ICA. Considering the correlation with GCA pathophysiology, oral prednisolone therapy was administered. Steroid therapy has prevented stroke recurrence and improved the symptoms and vasospasm. We wish to emphasize that GCA can induce IS via vasospasm, and steroid therapy is recommended.

Paraneoplastic Anti-3-hydroxy-3-methylglutary-coenzyme A Reductase Antibody-positive Immune-mediated Necrotizing Myopathy in a Patient with Uterine Cancer.

We report the case of a 69-year-old woman with proximal limb muscle weakness, who received post-operative chemotherapy for uterine cancer. Her serum creatinine kinase level was high (10,779 mg/dL) and a muscle biopsy from her left biceps revealed various sizes of muscle fibers accompanied by necrotic and regenerating fibers. She was positive for anti-3 hydroxy-3-methylglutary-coenzyme A reductase (anti-HMGCR) antibodies, but negative for anti-signal recognition particle (anti-SRP) antibodies. She was diagnosed with immune-mediated necrotizing myopathy (IMNM) and treated with prednisolone. Our findings indicate that not only drug-induced myopathy but also paraneoplastic myopathy can be involved in the pathogenesis of IMNM.

Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm.

OBJECTIVE: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. METHODS: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy. RESULTS: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5-9] to 0 [0-5], p<0.01) and HIT-6 (from 55 [54-64] to 44 [36-52], p<0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95-629.39, p<0.001) and history of chronic headache (odds ratio 28.53: 2.96-275.10, p<0.001). CONCLUSIONS: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH.

Adult-onset Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke (MELAS)-like Encephalopathy Diagnosed Based on the Complete Sequencing of Mitochondrial DNA Extracted from Biopsied Muscle without any Myopathic Changes.

The clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are not uniform. We herein report a male patient with unusual MELAS-like encephalopathy who had been experiencing isolated recurrent stroke-like episodes since he was 33 years old without any particular family history. Despite an extensive investigation, he had no other signs suggestive of MELAS. Although the muscle pathology showed a normal appearance, a mitochondrial genome sequence analysis of the biopsied muscle revealed a heteroplasmic m.10158T>C mutation in the mitochondrial complex I subunit gene, MT-ND3. To prevented further deterioration of the higher brain function, the early diagnosis and treatment of mitochondrial stroke-like episodes is important.

Contrast-enhanced ultrasonography is useful for evaluating the intraplaque neovascularization in aortic complex plaque of ischemic stroke patients.

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A Case of Suspected Breast Cancer Metastasis to Brachial Plexus Detected by Magnetic Resonance Neurography.

Metastasis of breast cancer is often detected through a long-term course and difficult to diagnose. We report a case of brachial plexopathy suspected to be the initial lesion of breast cancer metastasis, which was only detected by magnetic resonance (MR) neurography. A 61-year-old woman was admitted to our hospital within 2 years after operation for breast cancer because of progressive dysesthesia and motor weakness initially in the upper limb on the affected side and subsequently on the contralateral side. Enhanced computed tomography, axillary lymph node echo, gallium scintigraphy, and short tau inversion recovery MR images showed no abnormalities. MR neurography revealed a swollen region in the left brachial plexus. We suspected neuralgic amyotrophy and initiated treatment with intravenous immunoglobulin therapy and steroid therapy. However, there was no improvement, and the progression of motor weakness in the bilateral lower limbs appeared over 4 years. Concomitant elevation of carbohydrate antigen 15-3 level (58.9 U/ml) led us to suspect breast cancer metastasis, which was associated with the worsening of neurological findings, although gallium scintigraphy and bone scintigraphy showed no inflammatory and metastatic lesions. Swelling of the cauda equina in enhanced lumbar MR imaging and abnormal accumulation at the brachial plexus and cervical spinal cord in positron-emission tomography were newly detected contrary to the normal findings on the gallium scintigraphy, which suggested cerebrospinal fluid seeding. We suspected breast cancer metastasis about the initial brachial plexopathy based on the clinical course. MR neurography may be a helpful tool to detect metastatic lesion, especially in nerve roots.

Characteristics of Cerebral White Matter Lesions on MRI in Juvenile Patients with Migraine.

OBJECTIVE: Cerebral white matter lesions (WMLs) have been frequently observed on MRI in patients with migraine. We investigated characteristics of WMLs in migraine and tried to determine the relationship between its causal mechanism and arteriosclerosis. METHODS: A head MRI was performed in juvenile migraine patients. The distributions of deep and periventricular WMLs were separately studied in the anterior and posterior circulation. Grading was conducted according to the Fazekas classification. Arteriosclerotic risk factors were identified, and their effects on WMLs were investigated. RESULTS: WMLs were observed in 85 (40.5%) of 210 patients in our hospital. This is significantly higher than the 10 (19.2%) of 63 patients in the control group (p < 0.01). WMLs were significantly observed on the anterior territory of the deep white matter (p < 0.01) and the posterior territory of the periventricular white matter (p < 0.05). Multivariable analysis revealed that the occurrence of WMLs was not related to arteriosclerotic risk factors, while migraine (p < 0.01) and aging (p < 0.05) were significant risk factors. CONCLUSION: While migraine was a risk factor of WMLs, its relationship with arteriosclerotic factors was weak. Accordingly, a mechanism other than arteriosclerosis may be involved.