Varicella-Zoster Meningitis and Myelitis After Herpes Zoster Dermatitis Treatment With Amenamevir: A Case Series and Literature Review.

Varicella-zoster virus (VZV), known for causing chickenpox, establishes latent infections in neural tissues. Reactivation of VZV can lead to herpes zoster (HZ) and various neurological complications. In this report, we present four cases of VZV meningitis and myelitis following amenamevir treatment for HZ dermatitis with positive VZV DNA in cerebrospinal fluid (CSF) revealed by polymerase chain reaction (PCR). Three of them were considered immunocompromised hosts given the fact that two of these patients were taking immunosuppressive drugs for rheumatoid arthritis, and one patient had a history of sigmoid colon cancer (four months after resection). After HZ onset, amenamevir, which has poor CSF transfer, was prescribed for all the patients, and all of them developed central nervous complications by VZV (meningitis in three cases and myelitis in one case) confirmed by PCR. All the patients were treated with acyclovir, which has a higher CSF transfer, and fully recovered. We speculate that amenamevir might have failed to prevent VZV infection in the central nervous system (CNS) and think that consideration should be given to administering acyclovir in preference to amenamevir for ΗΖ patients at high risk of CNS VZV infection, such as immunocompromised hosts.

[Immune checkpoint inhibitor-induced anti-striational antibodies in myasthenia gravis and myositis: a case report].

A 78-year-old man was treated with ipilimumab and nivolumab for advanced renal cell carcinoma with liver and lymph node metastasis. He developed diplopia, ptosis, dysphagia, and weakness of the limbs and neck, 1 month after treatment. Serum creatine kinase (CK) levels were elevated, and neck MRI revealed inflammation of the deep trunk muscles. Although anti-acetylcholine receptor antibody was negative, the edrophonium test was positive. Anti-striational antibodies such as the anti-titin and the anti-muscular voltage-gated potassium channel (Kv 1.4) antibodies (which serve as biomarkers of immune checkpoint inhibitors associated with myasthenia gravis and myositis) were positive (anti-titin antibody titer 11.51, normal <1 index; anti-Kv 1.4 antibody titer 15.13, normal <1 index). Intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days), plasmapheresis, and oral prednisolone (PSL) (20 mg/day) administration improved the patient's neurological function and normalized the serum CK levels. The PSL dosage was tapered without any worsening of clinical signs. The antibody titers decreased but remained positive (anti-titin antibody 5.00, anti-Kv 1.4 antibody 3.83) one year after the initial evaluation. Therefore, low-dose PSL (5 mg/day) administration was continued, and the patient was in remission.

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response.

A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

P-Wave Terminal Force in Lead V1 Predicts Paroxysmal Atrial Fibrillation in Acute Ischemic Stroke.

BACKGROUND: Detection of paroxysmal atrial fibrillation (PAF) in cryptogenic stroke is critical to selecting an antithrombotic therapy for preventing recurrent stroke. However, the predictor of PAF in patients with acute ischemic stroke is not well elucidated. P-wave terminal force in lead V1 (PTFV1) is a standard electrocardiogram marker of left atrial abnormality. In this study, we aimed to investigate the utility of PTFV1 for the prediction of PAF in patients with acute ischemic stroke. METHODS: The study included 295 consecutive patients who had acute ischemic stroke and were admitted to the hospital between September 2014 and August 2016. Patients with a known history of PAF, persistent atrial fibrillation, or cardiac pacemaker were excluded from the study. The clinical characteristics of patients with or without PAF were compared, and multiple logistic regression analysis was performed to assess the independent contribution of each variable. RESULTS: Among 226 patients eligible for our analysis, 16 (7.1%) were diagnosed with PAF after admission. PTFV1 was significantly higher in patients with PAF than those without PAF (.051 versus .027 mm⋅s; P < .001). Multivariate analysis showed that PTFV1 per .01 mm⋅s increase was strongly associated with PAF (odds ratio, 1.61; 95% confidence interval, 1.24-2.09; P < .001). The optimal cutoff value of PTFV1 for the prediction of PAF was .04 mm⋅s. CONCLUSIONS: PTFV1 is a strong predictor of PAF detection in acute ischemic stroke.

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.

Chronic Elevation of Tumor Necrosis Factor-α Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice.

BACKGROUND AND PURPOSE: Leptomeningeal collateral growth is a key factor that defines the severity of ischemic stroke. Patients with stroke generally have vascular risk factors, such as diabetes mellitus; however, consensus is lacking on how diabetes mellitus affects leptomeningeal arteriogenesis. We investigate the influence of diabetes mellitus on the leptomeningeal arteriogenesis. METHODS: We measured the vessel diameter of the leptomeningeal anastomoses 14 days after the common carotid artery occlusion in db/db, db/+, and streptozotocin-induced hyperglycemic mice. In another set of these mice, we measured the infarct volume attributed to subsequent middle cerebral artery occlusion 14 days after the common carotid artery occlusion. Mac-2-positive cells on the dorsal brain surface and the mRNA expression of several macrophage-related factors in the cerebral cortex were examined. Finally, we tested whether the leptomeningeal arteriogenesis could be restored by pharmaceutical intervention in the db/db mice. RESULTS: Cerebral hypoperfusion led to significant ipsilateral leptomeningeal collateral growth in db/+ mice and streptozotocin-induced hyperglycemic mice. The collateral growth contributed to reduced infarct volume. In contrast, leptomeningeal arteriogenesis was impaired in the db/db mice. The number of Mac-2-positive cells was increased and tumor necrosis factor-α mRNA expression was induced after common carotid artery occlusion in the db/+ mice. However, these responses were not observed in the db/db mice. Administration of the tumor necrosis factor-α inhibitor etanercept before common carotid artery occlusion restored the hypoperfusion-induced leptomeningeal collateral growth in db/db mice. CONCLUSIONS: These results indicate that leptomeningeal arteriogenesis is impaired in db/db mice and that suppression of the tumor necrosis factor-α response to hypoperfusion is the major contributing factor.

Granulocyte colony-stimulating factor fails to enhance leptomeningeal collateral growth in spontaneously hypertensive rats.

The promotion of collateral artery growth is an attractive approach for the treatment of chronic brain hypoperfusion due to occlusive artery disease. We previously reported that hypertension impaired the collateral artery growth of leptomeningeal anastomoses after brain hypoperfusion. Granulocyte colony-stimulating factor (G-CSF) enhances arteriogenesis in a mouse model via a mechanism involving monocyte/macrophage mobilization. However, the arteriogenic effect of G-CSF in hypertension remains unknown. In the present study, we tested whether G-CSF affected collateral artery growth in both normotensive and hypertensive model rat. Left common carotid artery (CCA) occlusion was performed to induce hypoperfusion in the brains of Wistar rats and spontaneously hypertensive rats (SHR). G-CSF was administered subcutaneously for 5 consecutive days. The superficial angioarchitecture of the leptomeningeal anastomoses and the circle of Willis after CCA occlusion and G-CSF treatment were visualized by latex perfusion. Circulating blood monocytes and CD68-positive cells, which represented the macrophages on the dorsal surface of the brain, were counted. G-CSF enhanced leptomeningeal collateral growth in Wistar rats, but not in SHR. G-CSF increased circulating blood monocytes in both Wistar rats and SHR. The number of CD68-positive cells on the dorsal surface of the brain was increased by G-CSF in Wistar rats, but not in SHR. The increase in macrophage accumulation correlated with the observed arteriogenic effects. In conclusion, G-CSF promotes collateral artery growth in the normotensive model rat, but not in the hypertensive model rat.

Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery. Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR). METHODS: Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser(1177)-phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N(5)-(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia. RESULTS: In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N(5)-(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin. CONCLUSIONS: These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR.

SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB.

The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.

Granulocyte colony-stimulating factor enhances arteriogenesis and ameliorates cerebral damage in a mouse model of ischemic stroke.

BACKGROUND AND PURPOSE: Enhancing collateral artery growth is a potent therapeutic approach to treat cardiovascular ischemic disease from occlusive artery. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has gained attention for its ability to promote arteriogenesis, ameliorating brain damage, by the mechanisms involving monocyte upregulation. However, the recent clinical study testing its efficacy in myocardial ischemia has raised the question about its safety. We tested alternative colony-stimulating factors for their effects on collateral artery growth and brain protection. METHODS: Brain hypoperfusion was produced by occluding the left common carotid artery in C57/BL6 mice. After the surgery, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, or GM-CSF (100 µg/kg/day) was administered daily for 5 days. The angioarchitecture for leptomeningeal anastomoses and the circle of Willis were visualized after the colony-stimulating factor treatment. Circulating blood monocytes and Mac-2-positive cells in the dorsal surface of the brain were determined. A set of animals underwent subsequent ipsilateral middle cerebral artery occlusion and infarct volume was assessed. RESULTS: Granulocyte colony-stimulating factor as well as GM-CSF promoted leptomeningeal collateral growth after common carotid artery occlusion. Both granulocyte colony-stimulating factor and GM-CSF increased circulating blood monocytes and Mac-2-positive cells in the dorsal brain surface, suggesting the mechanisms coupled to monocyte upregulation might be shared. Infarct volume after middle cerebral artery occlusion was reduced by granulocyte colony-stimulating factor, similarly to GM-CSF. Macrophage colony-stimulating factor showed none of theses effects. CONCLUSIONS: Granulocyte colony-stimulating factor enhances collateral artery growth and reduces infarct volume in a mouse model of brain ischemia, similarly to GM-CSF.

Hypertension impairs leptomeningeal collateral growth after common carotid artery occlusion: restoration by antihypertensive treatment.

Chronic mild hypoperfusion has been shown to enlarge pial collateral vessels in normal mouse brains. The purpose of this study was to clarify the effect of hypertension on pial collateral vessel development after chronic hypoperfusion using spontaneously hypertensive rats (SHR). In normotensive rats, unilateral common carotid artery (CCA) occlusion enlarged leptomeningeal collateral vessels. CCA occlusion also preserved residual cerebral blood flow (CBF) and attenuated infarct size after middle cerebral artery (MCA) occlusion 14 days later. In contrast, in SHR, CCA occlusion neither enlarged the leptomeningeal anastomosis nor showed protective effects after MCA occlusion. However, decreasing blood pressure using an angiotensin II AT1 receptor blocker restored the beneficial effect of CCA occlusion on collateral growth as well as on residual CBF and infarct size after MCA occlusion. Adaptive responses in CBF autoregulation curves observed 14 days after CCA occlusion in normotensive rats were impaired in untreated SHR, but were restored after antihypertensive treatment. In conclusion, SHR have impaired leptomeningeal collateral growth after CCA occlusion, but antihypertensive treatment restores the beneficial effect of CCA occlusion on collateral circulation.

An angiotensin II type 1 receptor blocker can preserve endothelial function and attenuate brain ischemic damage in spontaneously hypertensive rats.

Hypertension reduces endothelial nitric oxide synthase (eNOS) expression and leads to endothelial dysfunction. However, few studies have demonstrated the influences of hypertension on eNOS function in the cerebral cortex. The present study investigates the influences of hypertension on endothelial function in the cerebral cortex and the protective effects of antihypertensive agents against brain ischemia through the preservation of endothelial function. Five- and ten-week-old male Wistar rats and spontaneously hypertensive rats (SHR) were used for experiments. Five-week-old SHR received olmesartan, hydralazine, or vehicle for 5 weeks in drinking water. eNOS activation in the cerebral cortex was evaluated by analyzing levels of total and Ser(1177)-phosphorylated eNOS protein by Western blot. Blood pressure of 10-week-old SHR without treatment was clearly high, and the ratio of phospho-eNOS/total eNOS protein was significantly low. Five-week treatment with olmesartan or hydralazine suppressed the elevation of blood pressure and the reduction of phosphorylated eNOS-Ser(1177) in SHR, and olmesartan was more effective in maintaining phosphorylation of eNOS-Ser(1177) than hydralazine. To assess the contribution of eNOS to maintaining cerebral blood flow (CBF), we monitored CBF by laser-Doppler flowmetry after L-N(5)-(1-iminoethyl)ornithine (L-NIO) infusion. CBF response to L-NIO was preserved in olmesartan-treated SHR but not in hydralazine-treated SHR. Furthermore, infarct volume 48 hr after transient focal brain ischemia in olmesartan-treated SHR was significantly reduced compared with vehicle-treated SHR. These findings indicate that chronic prehypertensive treatment with olmesartan could attenuate brain ischemic injury through the maintenance of endothelial function in the cerebral cortex in SHR.

Activation of NR2A receptors induces ischemic tolerance through CREB signaling.

Previous exposure to a nonlethal ischemic insult protects the brain against subsequent harmful ischemia. N-methyl-D-aspartate (NMDA) receptors are a highly studied target of neuroprotection after ischemia. Recently, NMDA receptor subtypes were implicated in neuronal survival and death. We focused on the contribution of NR2A and cyclic-AMP response element (CRE)-binding protein (CREB) signaling to ischemic tolerance using primary cortical neurons. Ischemia in vitro was modeled by oxygen-glucose deprivation (OGD). Ischemic tolerance was induced by applying 45-mins OGD 24 h before 180-mins OGD. Sublethal OGD also induced cross-tolerance against lethal glutamate and hydrogen peroxide. After sublethal OGD, expression of phosphorylated CREB and CRE transcriptional activity were significantly increased. When CRE activity was inhibited by CREB-S133A, a mutant CREB, ischemic tolerance was abolished. Inhibiting NR2A using NVP-AAM077 attenuated preconditioning-induced neuroprotection and correlated with decreased CRE activity levels. Activating NR2A using bicuculline and 4-aminopiridine induced resistance to lethal ischemia accompanied by elevated CRE activity levels, and this effect was abolished by NVP-AAM077. Elevated brain-derived neurotrophic factor (BDNF) transcriptional activities were observed after sublethal OGD and administration of bicuculline and 4-aminopiridine. NR2A-containing NMDA receptors and CREB signaling have important functions in the induction of ischemic tolerance. This may provide potential novel therapeutic strategies to treat ischemic stroke.

[Ineffective thrombolytic therapy for calcified cerebral emboli originated from calcified internal carotid artery stenosis].

We report a 71-year-old man who presented with acute right hemiparesis and aphasia The admission CT and CT angiogram showed multiple small calcified emboli in branches of the left middle cerebral artery. The patient had shown no sign of improvement after intravenous thrombolytic therapy. Follow-up CT indicated acute multiple infarctions in the left middle cerebral artery area coincident with the calcified emboli. Carotid duplex sonography and cervical CT angiogram showed calcified plaque with ulceration at the origin of left internal carotid artery, which is the origin of those emboli Since calcified cerebral emboli (CCE) are rare, it should be further investigated if intravenous thrombolysis is effective in CCE.

Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats.

Lowering the blood pressure (BP) during the acute period following ischemic stroke is still a controversial treatment. In this study, we investigated the effect of postischemic treatment using the angiotensin II type 1 receptor blocker, candesartan, on brain damage in focal cerebral ischemia. Spontaneously hypertensive rats underwent transient occlusion of the middle cerebral artery for 1 h. Candesartan (0.1, 1 and 10 mg kg(-1)) or vehicle was administered orally 3 and 24 h after ischemia. Blood pressure and neurological function were monitored, and infarct volume was evaluated 48 h after occlusion. Cerebral blood flow was measured using laser Doppler flowmetry before and after treatment with candesartan. Activation of Rho-kinase in cerebral microvessels was evaluated by immunohistochemistry. Systolic blood pressure was markedly lowered with both moderate and high doses, but it did not fall with a low dose of candesartan. The infarct volume was reduced in rats treated with the low dose of candesartan but not in those treated with the moderate or high doses. Cerebral blood flow decreased in parallel with the reduction in BP 3 h after treatment using the moderate dose, but it did not change after treatment with the low dose of candesartan, compared with vehicle. Rho-kinase was activated in the brain vessels of the ischemic cortex, but treatment with candesartan suppressed it. Our results show that oral administration of candesartan after transient focal ischemia reduced infarct volume at doses that showed little effect on BP. The neurovascular protective effects of candesartan may be caused by the inhibition of Rho-kinase in brain microvessels.

[Incongruous homonymous quadrantanopia due to suprasellar calcificated lesions].

A 53 year-old woman with a history of tuberculous meningitis at 3 years of age incidentally found a right incongruous homonymous quadrantanopia in ophthalmologic check-up. On magnetic resonance imaging and helical computed tomography, the left optic tract was obscured by suprasellar calcified lesions. The left internal carotid artery was diffusely narrowed and occluded at its terminal portion as demonstrated by cerebral angiography. The calcificated lesions were diagnosed to derive from old tuberculous meningitis on the basis of her history, their location and the association of vascular occlusive changes. Incongruous homonymous hemianopsia due to optic tract damage is usually caused by tumor or aneurysm. Its occurrence by calcified inflammatory lesions has never been reported previously. The present case is considered of value in this respect.