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Study objectives Obstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion. Methods We used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring. Results We found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals. Conclusions Our findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke.

STUDY OBJECTIVES: The role of obstructive sleep apnea (OSA) in the overall outcome of ruptured intracranial aneurysms (RIAs) is unknown. We have investigated the role of OSA in overall outcome of RIAs. METHODS: Data from 159 consecutive patients were retrospectively reviewed. A chi-square test and regression analysis were performed to determine the significant difference. A value of P < .05 was considered significant. RESULTS: The prevalence of OSA in RIAs was fivefold higher in the nonaneurysm patient group, P = .002. The number of patients with hypertension (P < .0001), body mass index ≥ 30 (P < .0001), hyperlipidemia (P = .018), chronic heart disease (P = .002) or prior ischemic stroke (P = .001) was significantly higher in the OSA group. Similarly, the number of wide-neck aneurysms (P < .0001) and aneurysm > 7 mm (P = .004), poor Hunt and Hess grade IV-V (P = .005), vasospasms, (P = .03), and patients with poor Modified Rankin Scale scores (3–6) was significantly higher in the OSA group (P < .0001). Interestingly, for the first time in univariate (P = .01) and multivariate (P = .003) regression analysis, OSA was identified as an individual predictor of unfavorable outcome of RIAs. In addition, hypertension (P = .04), smoking (P = .049), chronic heart disease (P = .01), and Hunt and Hess grade IV-V (P = .04) were revealed as predictors of poor outcome of RIAs. CONCLUSIONS: This is a novel study to determine the association between OSA and ruptured cerebral aneurysm in terms of comorbidities, size of aneurysm, severity of symptoms, and outcomes after treatment. In addition, for the first time, OSA is identified as a positive predictor of unfavorable outcome of RIAs. CITATION: Chernyshev OY, Bir SC, Maiti TK, Patra DP, Sun H, Guthikonda B, Kelley RE, Cuellar H, Minagar A, Nanda A. The relationship between obstructive sleep apnea and ruptured intracranial aneurysms. J Clin Sleep Med. 2019;15(12):1839–1848.

The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a type of post-translational modification which is important for numerous cellular processes, including mRNA splicing, DNA repair, signal transduction, protein interaction, and transport. PRMTs have been extensively associated with various pathologies, including cancer, inflammation, and immunity response. However, the role of PRMTs has not been well described in vascular and neurological function. Aberrant expression of PRMTs can alter its metabolic products, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). Increased ADMA levels are recognized as an independent risk factor for cardiovascular disease and mortality. Recent studies have provided considerable advances in the development of small-molecule inhibitors of PRMTs to study their function under normal and pathological states. In this review, we aim to elucidate the particular roles of PRMTs in vascular and neuronal function as a potential target for cardiovascular and neurological diseases.

Background: Alzheimer’s disease (AD) animal models have revealed neuroprotective actions of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate for attenuating AD-associated neural, vascular, and cognitive disturbances. Objective: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations were prepared. Methods: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice). Results: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated Bryostatin-1 formulation (1, 2.5, or 5 μg/mouse) three times the week before testing and then daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment. Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform, indicating retention of spatial memory. Conclusion: These data suggest that cognitive deficits associated with AD could be treated using highly potent nanoparticle-encapsulated formulations of Bryostatin-1.

Usually, demyelinating diseases of human central nervous system manifest as chronic illnesses with episodic exacerbations followed by remissions, which may be spontaneous or follow treatment with corticosteroids or other immunosuppressive agents. Yet, occasionally inflammatory demyelinating diseases manifest acutely with a rapidly progressive course that may even cause life-threatening complications, thus demanding drastic treatment decisions. Such potentially disabling and lethal complications stem from extensive brain, brainstem, and spinal cord involvement in a number of pathologic processes, such as edema with mass effect, herniation syndrome, progressive weakness with its adverse impact on respiratory function, and other medical complications. The present chapter reviews a wide range of acute inflammatory demyelinating diseases, including acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, and transverse myelitis. Imitators of these acute demyelinating events are also discussed. Diagnostic procedures and optimal treatment options are presented.

OBJECTIVEObstructive sleep apnea (OSA) is associated with the progression of abdominal and thoracic aortic aneurysms. However, the role of OSA in the overall outcome of intracranial aneurysms (IAs) has not yet been established. Authors of this report investigated the role of OSA in the overall outcome of IAs.METHODSRadiological and clinical data on patients (from 2010 through 2015) with confirmed IA were retrospectively reviewed. Significant differences between the OSA and non-OSA groups were determined using a chi-square test. Logistic regression analysis was performed to identify the predictors of an unfavorable IA outcome.RESULTSAmong the 283 patients with confirmed IAs, 45 patients (16%) were positively screened for OSA, a proportion that was significantly higher than the prevalence of OSA in nonaneurysmal neurosurgical patients (4%, p = 0.008). The percentage of patients with hypertension (p = 0.018), a body mass index ≥ 30 kg/m2 (p < 0.0001), hyperlipidemia (p = 0.034), diabetes mellitus (p = 0.005), chronic heart disease (CHD; p = 0.024), or prior stroke (p = 0.03) was significantly higher in the OSA group than in the non-OSA group. Similarly, the percentage of wide-necked aneurysms (p = 0.00001) and patients with a poor Hunt and Hess Grade IV–V (p = 0.01) was significantly higher in the OSA group than in the non-OSA group. In addition, the percentage of ruptured aneurysms (p = 0.03) and vasospasms (p = 0.03) was significantly higher in the OSA group. The percentage of patients with poor modified Rankin Scale (mRS) scores (3–6) was significantly higher in the OSA group (p = 0.03). A separate cohort of patients with ruptured IAs showed similar results. In both univariate (p = 0.01) and multivariate (p = 0.04) regression analyses, OSA was identified as an individual predictor of an unfavorable outcome. In addition, hypertension and prior stroke were revealed as predictors of a poor IA outcome.CONCLUSIONSComplications of IA such as rupture and vasospasm are often the consequence of uncontrolled OSA. Overall outcome (mRS) of IAs is also affected by the co-occurrence of OSA. Therefore, the coexistence of OSA with IA affects the outcome of IAs. Obstructive sleep apnea is a risk factor for a poor outcome in IA patients.

While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler's murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection.

Optimal treatment of intracranial aneurysms (IAs) in elderly patients has not yet been well established. We have investigated the clinical and radiological outcomes and predictors of unfavorable outcome of IAs in elderly patients. Radiological and clinical data of 85 elderly patients from 2010 through 2015 were retrospectively reviewed. Significant differences between the groups were determined by a chi-square test. Regression analysis was performed to identify the predictors of unfavorable outcome. Among the 85 patients with IAs, the number of patients with >7 mm size aneurysm (p = 0.01), diabetes mellitus (DM) (p = 0.02), smoking (0.009) and Hunt and Hess grade 4–5 (p = 0.003) was significantly higher in the ruptured group compared to the unruptured group. Similarly, the number of patients who underwent clipping was higher in the ruptured aneurysm group (p = 0.01). The overall clinical outcome was comparatively better in the unruptured group (p = 0.03); however, microsurgical clipping of aneurysms provides a significantly higher rate of complete aneurysmal occlusion (p = 0.008). Overall, there was no significant difference in outcome in respect to treatment approach. In regression analysis, hypertension (HTN), obstructive sleep apnea (OSA), prior stroke, ruptured aneurysms and partial occlusion of aneurysms were identified as predictors of unfavorable outcome of IAs. Intracranial aneurysms in elderly patients reveals that endovascular treatment provides better clinical outcome; however, microsurgical clipping yields higher complete occlusion. Retreatment of residual aneurysms was comparatively more in the coiling group. Practice pattern has shifted from clipping to coiling for aneurysms in posterior circulation but not for aneurysms in anterior circulation.

Cervicogenic headache affects a significant portion of the entire population. This type of headache especially with atypical presentation is often hard to diagnose and manage since its etiopathophysiology is not been yet well understood. We have investigated the prevalence of cervicogenic headache with atypical presentation and discussed the etiology of it, and the outcome of surgical intervention on this type of headache in patients with cervical degenerative disease.Radiological and clinical data of 160 patients (from 2001 through 2016) were retrospectively reviewed. Significant differences between the groups were determined by chi-square test. Logistic regression analysis was performed to identify the predictors of unfavorable outcome.In this study, 10% of the patients had atypical presentation of cervicogenic headache. In overall cohort, after surgical intervention, there was significant improvement in symptoms and pain control, whether the presentation is typical or atypical. Sixty-one percent of the patients had no complaints, and 90% of the patients were headache-free (p0.0001). Sixty-nine percent of the patients were free of neck, shoulder and extremity pain, and visual analogue scale pain score was reduced by 7 points (pre-op, 8.4 vs. last follow-up, 1.5, p0.0001). However, number of patients with reduced headache was significantly higher in the group with typical presentation of headache (90.1%) compared to group with atypical (80%) presentation, p=0.04. In this study, female gender, smoking, obesity and depression were identified as predictors of overall unfavourable outcome. In addition, in a separate analysis, smoking and depression were revealed as risk factors for persistent headache.A notable portion of patients with cervicogenic headache can have an atypical presentation mimicking a primary type headache. However, cervicogenic headaches with atypical presentation can be difficult to diagnose and manage at the initial visit of the patients. Etiopathophysiology of this type of headache could be explained by the theories including discogenic, convergence and sensitization-desensitization theories. When cervicogenic headache is accompanied with CDD, performing ACDF or laminectomy would be the treatment of choice. Surgical intervention can also relieve the accompanying neck, shoulder and extremity pain with minimal complications. Lastly, outcomes of surgical intervention depend on the patients' morbidities including obesity, smoking and depression.

The lymphatic system maintains tissue homeostasis by transporting interstitial fluid, lipids and debris from tissues to the main circulation, and delivers antigen and antigen presenting cells to local lymph nodes where they elicit immune responses. During inflammation, lymph flow increases to limit edema and prevents tissue antigen-presenting cell transport. Lymphatics also adjust their contractile activity to increase fluid transfer during acute inflammation. Conversely, chronic inflammation can provoke lymphostasis, which might limit pathogen spread within the circulation; however, decreased lymph flow leads to the persistence of immune cells and mediators in tissues to intensifying injury. Here, we review lymphatic structure function within the gut, heart and central nervous system, discussing potential roles of these lymphatics in the etiology of inflammatory bowel disease, myocarditis and neurovascular disease, and as novel targets for therapeutic management of several disease states.

Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular ‘trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in ‘liquid biopsy' approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer's disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases.

Aims Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. Main methods Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. Key findings Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. Significance Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.

Background Besides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined. Methods We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke ‘transient middle cerebral artery occusion (MCAO)/reperfusion’ mice model. Findings We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner. Interpretation Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid “translation” of these cells into clinical trials in the near-term.

Background: Multiple sclerosis (MS) is one of the most common chronic immune-mediated diseases of the human central nervous system and an important cause of non-traumatic neurologic disability among young population in several countries. Recent reports from East Asia, South East Asia and South Asia have proposed a low to moderate prevalence of MS in these countries. Methods: A literature review search was carried out in December 2014 in Medline, Embase, Scopus and Cochrane library to recover original population-based studies on MS epidemiology in East Asia, South East Asia and South Asia countries published between January 1, 1950 and December 30, 2014. We intended search strategies using the key words: multiple sclerosis, prevalence, incidence and epidemiology. Based on our inclusion criteria, 68 epidemiologic studies were included in this systematic review. Results: The most extensively used diagnostic criteria in the studies were McDonald's criteria. Most studies were performed in a multi-center hospital setting. The female to male ratio varied and ranged from 0.7 in India to 9.0 in China. The mean age at disease onset ranged from the lowest age of 25.3 in Iran to the highest age of 46.4 in China. MS prevalence ranged from 0.77 in 100,000 populations in Hong Kong (1999) to 85.80 in 100,000 in Iran (2013). Conclusions: Advances in MS registries around the globe allow nationwide population-based studies and will allow worldly comparisons between the prevalence and incidence in different regions that are provided to monitor estimation.

Sickle cell disease (SCD) is one of the most common inherited blood disorder among African Americans affecting 70,000–100,000 individuals in the United States. It is characterized by abnormal hemoglobin (HbS) which develops into severe hemolytic anemia and vaso-occlusive crisis. Therefore, patients with SCD suffer from a chronic state of inflammation, which is responsible for multiple organ damage, ischemic attacks, and premature death. Another major hallmark of SCD patients is the abnormally low levels of omega-3 fatty acids, especially docosahexaenoic acid (DHA) in their red blood cell membranes. Treatment with DHA can reduce red blood cell adhesion and enhance cerebral blood flow, thus, our main goal is to investigate the effect of SC411, which is a novel, highly purified DHA ethyl ester formulation with a proprietary delivery platform in SCD. Utilizing a transgenic mouse model of SCD (HbSS-Townes) and recurrent hypoxic challenges (10%O2, 0.5% CO2 and balance N2 for 3 h) to mimic ischemic-like conditions, our data suggest that SC411 can elevate blood DHA and eicosapentaenoic acid (EPA) levels after 8 weeks of treatment. SC411 can also decrease arachidonic acid (AA) and sickling of red blood cells. In addition, SC411-treated SCD mice showed presented with cerebral blood flow, alleviated neuroinflammation, and revived working memory which ultimately enhanced overall survival. In summary, this study suggests that treatment with SC411 improves cellular and functional outcomes in SCD mice. This finding may provide novel therapeutic opportunities in the treatment against ischemic injury elicited by SCD.

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies against stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia.

Traditionally, multiple sclerosis (MS) was considered to be a CD4 T cell-mediated CNS autoimmunity, compatible with experimental autoimmune encephalitis model, which can be characterized by focal lesions in the white matter. However, studies of recent decades revealed several missing pieces of MS puzzle and showed that MS pathogenesis is more complex than the traditional view and may include the following: a primary degenerative process (e.g. oligodendroglial pathology), generalized abnormality of normal-appearing brain tissue, pronounced gray matter pathology, involvement of innate immunity, and CD8 T cells and B cells. Here, we review these findings and discuss their implications in MS pathogenesis.

Background: Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA. Results: ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory. Conclusions: We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that usually affects young adults. The disease affects about 2.5 million people worldwide and is more frequently seen in females. The prevalence of MS appears to be different in various parts of the world, ranging from less than 5/100,000 in some African countries to more than 200/100,000 in Western Europe and North America (Kingwell et al., 2013). MS was first described by the French neurologist Jean-Martin Charcot who, in 1868, assimilated these findings into a single syndrome he called “sclerose en plaques,” and characterized it as a distinct neurological disease whilst clarifying some clinical and pathological features of the disease. The etiology of this potentially debilitating disease is still unknown but both environmental and genetic factors interact in disease development and progression. Many environmental factors such as vitamin D deficiency, viral infections such as Epstein Barr Virus (EBV), and smoking have been mentioned as triggering factors in genetically susceptible people. To date no single gene or locus has been found to be the gene for MS but several class II major histocompatibility complex (MHC) genes such as HLA DRB1*1501-DQA1*0102-DQB1*0602 alleles have been demonstrated to be associated with MS susceptibility. Over recent decades MS has been presented with its two different aspects of inflammation and degeneration. Although there are several approved and nonapproved medications to overcome or at least control the inflammatory aspect of the disease, at present there is no accepted therapy for controlling the degenerative phase, which may start even at the early stages of the disease. This chapter covers the clinical manifestations, pathophysiology, diagnosis, and treatment strategies in MS. There are several new disease-modifying therapies that have been approved recently, and there are several options in the pipeline that will be added to the currently approved ones. Recent approved drugs have been associated with rare but serious adverse events that need close monitoring and proper clinical or radiological vigilance in order to reduce catastrophic complications from these drugs.

Macrophages/microglia and astrocytes are two major resident cells within the human central nervous system, and play significant roles in pathogenesis of multiple sclerosis (MS). As immune cells, macrophage/microglia are involved in destruction of the myelin sheath, and lipid-laden macrophages are the hallmark of inflammatory demyelination. The astrocytes, as a main component of the blood-brain barrier (BBB), are significantly involved in preservation of the BBB, inflammatory demyelination, neuronal degeneration, and repair mechanisms of MS. Meticulous analysis of the existing knowledge of their roles in pathogenesis will guide us towards a better understanding of the fundamental pathogenic mechanisms of inflammatory demyelination and remyelination.

Multiple sclerosis (MS) is presumably an immune mediated disease of the human central nervous system with two salient pathophysiologic components: inflammatory demyelination and neurodegeneration. Both arms of MS pathophysiology cause loss of myelin sheath and myelin-producing cells, oligodendrocytes. Existing therapies for MS are based heavily on suppression of the peripheral immune system, with no significant impact on neurodegeneration and repair of lost myelin. The remyelination process is expected to restore normal neuronal activity and repair some of the existing injury to the CNS. However, the remyelination process is often overwhelmed by the demyelinating process, and in that condition, the outcome will be neuronal and axonal loss, along with accumulating disability for the MS patient.

Sarcoidosis is an immune-mediated, multisystem, inflammatory disorder of unknown etiology, which primarily affects pulmonary and lymphatic systems as well as skin. The pathologic hallmark of sarcoidosis is noncaseating epithelioid granulomas, which develop in the affected organs. Uncommonly, both central and peripheral nervous systems are affected by sarcoidosis, and patients with neurosarcoidosis present with a wide spectrum of neurologic manifestations due to the widespread nature of the underlying illness. While nervous system involvement in sarcoidosis is uncommon, in a certain number of patients, neurologic symptoms can be the initial and exclusive manifestation of sarcoidosis. Neurosarcoidosis is a great imitator of other pathologies and high clinical vigilance is required to diagnose it correctly. A discussion of the clinical features, underlying pathophysiology, and present management options for neurosarcoidosis is presented.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the human central nervous system disease that typically strikes young adults, particularly females. Current knowledge of pathophysiology and diagnosis of MS has been rapidly evolving and so are the treatment options. In this chapter, we review the seven emerging disease modifying therapies at different stages of development, their proposed mechanism of action, route of administration, and potential adverse events noted during the clinical trials. The most recent findings are presented here.

Toll-like receptors (TLRs) constitute a family of proteins that play significant roles in the human innate immune system and are expressed by a number of sentinel cells such as macrophages and dendritic cells. Alzheimer’s disease and multiple sclerosis both represent incurable and progressive neurologic diseases with potent neuroinflammatory and neurodegenerative components in their pathophysiology. In this chapter, the potential roles of TLRs in their pathophysiology are presented.

Background Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as ‘microparticles' into the circulation. Objective To investigate the relationships between these endothelial biomarkers and MS. Methods We examined the relative abundance of CD31 + /PECAM-1, CD51 + CD61 + (αV–β3) and CD54 + (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing–remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different microparticle species in MS with conventional MRI (T2- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. Results Differences in circulating microparticle levels were found among MS groups, and several microparticle species (CD31 + /CD51 + /CD61 + /CD54 + ) were found to correlate with conventional MRI and SWI features of MS. Conclusion These results indicate that circulating microparticles' profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses.

The human cerebellum is composed of 2 hemispheres and a narrow medial section (vermis). Three pairs of dense fiber bundles (peduncles) connect the cerebellum to the brain. The cerebellum possesses widespread outgoing connections. Insult can result in neurologic deficits, including ataxia, hypotonia, dysarthria, and ocular motility problems. It is particularly susceptible to toxic effects of metabolic and medicinal insults. The cerebellum is potentially sensitive to alcohol, drug exposure, illicit drugs, and environmental poisons (mercury, lead, manganese, and toluene/benzene derivatives). The astute clinician must be aware of the multiple potential factors that can adversely affect cerebellar function.

In many cases, acute ataxia presents a neurologic emergency that must be assessed and treated effectively in order to save a patient's life and protect the patient from potential permanent complications and disabilities. A thorough knowledge of cerebellar anatomy and physiology and familiarity with common causes of acute ataxia, enable the clinician to develop a rapid and effective diagnostic approach and effective management approach.

The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning.

Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

The risks and benefits of arteriovenous malformation (AVM) treatment should be considered cautiously in each patient since management strategy of it depends on various factors including age of the patient, location and volume of AVM and presence of other vascular abnormalities. Current management options of AVM include observation, endovascular embolization, radiosurgery and microsurgical resection or in combination of any two of the above procedures. Here, we have discussed a case of intracranial AVM with radiation induced early cyst formation, and performed a literature review to determine the optimum treatment of complex intracranial AVM. Standard search strategies were performed in PubMed/Medline using appropriate terms such as “intracranial arteriovenous malformation” radiosurgery, embolization and microsurgical resection as well as medical subject headings. The particular case in this study was retrospectively reviewed. Literature review revealed that the mean marginal radiation dose used by the different authors was 19 Gy, cysts were developed in 3.6% patients, the average time to form cyst was 6.6 years, average volume of cyst was 6.7 ml and maximum cysts were removed by resection. In our case, the cyst was developed 2.5 years after radiosurgery. Radiation induced cyst formation is a delayed complication of AVM management. However, cyst formation in this case was comparatively earlier in our case. Therefore, continuous follow-up after radiosurgery is required for early detection of cyst formation. In addition, the review revealed that embolization before radiosurgery was a poor strategy.

Purpose of review Neurologists often encounter patients with acute and chronic liver disease and must be aware of how these diseases can affect the nervous system. This is particularly true when evaluating patients with alterations in cognition and level of consciousness. Wilson disease, while uncommon, is a treatable condition with many neurologic and psychiatric symptoms. Neurologic disorders associated with liver disease may affect not only the brain, but also the spinal cord and peripheral nervous system. This article reviews the association of liver disease and the nervous system and provides new information regarding diagnostic and therapeutic approaches to evaluating patients with liver diseases. Recent findings Early recognition of hepatic encephalopathy may be possible using a combination of clinical suspicion and various neuropsychological studies. Management of severe hepatic encephalopathy from acute liver failure is important to neurologists involved in neurocritical care. Next-generation genetic testing may aid in the diagnosis of patients suspected of having Wilson disease. The relationship of numerous neurologic findings from hepatocerebral degeneration and from viral hepatitis is more widely recognized. Summary It is important for neurologists to recognize the neurologic symptoms that may occur in patients with acute and chronic liver failure, Wilson disease, and viral hepatitis to inform prompt diagnostic and management decisions.

Introduction: Obstructive sleep apnea (OSA) is associated with the progression of abdominal and thoracic aortic aneurysms. However, the role of OSA in the overall outcome of intracranial aneurysms (IAs) has not yet been established. We have investigated the role of OSA in the progression and outcome of intracranial aneurysms. Methods: Radiological and clinical data of 283 patients (from 2010 through 2015) were retrospectively reviewed. Significant differences between the OSA and non-OSA groups were determined by a chi-square test. Logistic regression analysis was performed to identify the predictors of unfavorable outcome. Results: Among the 283 patients with IAs, 45 (16%) patients were positively screened for OSA, a proportion that was significantly higher than the prevalence of OSA in the general population (4%), p=0.008. Number of patients with hypertension (p=0.018), BMI ≥ 30 (p Conclusions: The complications of IAs such as rupture and vasospasms are influenced by presence of OSA. Overall outcome (mRS) of IAs is also affected by the concurrence of OSA. Therefore, coexistence of OSA in patients with IAs affects progression as well as outcome of IAs. Lastly, OSA serves as an individual risk factor for poor outcome in these patients.

Infection with the human immunodeficiency virus (HIV) causes widespread annihilation of T lymphocytes along with massive decline and impairment of the cell-mediated immunity, which in turn translates into development of a wide gamut of opportunistic infections as well as malignancies. While acquired immunodeficiency syndrome (AIDS) is a systemic infection adversely affecting many organs, it particularly affects and involves the human nervous system. Shortly after seroconversion, HIV enters the nervous system and the infective and degenerative process of neuroAIDS initiates. In the past two decades, with invention and utilization of combination antiretroviral therapy, AIDS has transformed from a lethal disease to a more chronic illness, and more AIDS patients survive than ever before. The neurologic complications of AIDS involve both central and peripheral nervous systems and to a significant degree depend on the extent of ablation of the immune system by AIDS. One particular group of neuropsychiatric impairments due to HIV infection is recognized as HIV-associated neurocognitive disorder, which addresses abnormalities of memory, concentration, mental focus, and motor skills in HIV-infected individuals. Neurologic complications of HIV infection as well as their clinical manifestations and available treatments are discussed.