Prolonged Transient Global Amnesia: Part of the Clinical Spectrum or a Separate Disease Entity?

Background: Transient global amnesia (TGA) is the prototypical neurologic disease for acute-onset reversible amnesia. It is currently defined by resolution of symptoms within 24-hours. In this case report we describe an atypical case of prolonged TGA, emphasizing our current lack of knowledge surrounding this disease entity and its pathophysiology. Results: A 66-year old female presented acutely with profound anterograde amnesia and variable retrograde amnesia with no inciting event. A thorough workup to exclude alternative causes of amnesia (including computed tomography angiogram and electroencephalogram) was normal. Her magnetic resonance imaging was consistent with TGA, with punctate diffusion restriction changes bilaterally in the hippocampi. She was also mildly hypoxemic with no discernible cause. She was ultimately diagnosed with TGA although her diagnosis remains controversial as her symptoms persisted for 72-hours. Conclusion: Our patients clinical and imaging features (apart from her protracted time-course and hypoxemia) were in keeping with a diagnosis of TGA. The association of hypoxemia, COVID-19, obstructive sleep apnea, and the development of TGA remains to be elucidated. Although the underlying pathophysiology for TGA is unknown several mechanisms have been postulated including cortical spreading depression and reversible hypoxic-ischemic injury. The time course for symptom resolution, could be an important clue in discerning the pathophysiology of TGA on an individual basis. Importantly, a clinician should not be deterred by amnestic symptoms lasting >24-hours, if the patients clinical/radiologic presentation is consistent with TGA.

A Clinical Approach to Existing and Emerging Therapeutics in Neuromyelitis Optica Spectrum Disorder.

PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorder (NMOSD) is a rare but highly disabling disease of the central nervous system. Unlike multiple sclerosis, disability in NMOSD occurs secondary to relapses that, not uncommonly, lead to blindness, paralysis, and death. Recently, newer, targeted immunotherapies have been trialed and are now in the treatment arsenal. We have endeavoured to evaluate the current state of NMOSD therapeutics. RECENT FINDINGS: This review provides a pragmatic evaluation of recent clinical trials and post-marketing data for rituximab, inebilizumab, satralizumab, eculizumab, and ravalizumab, contrasted to older agents. We also review contemporary issues such as treatment in the context of SARS-CoV2 infection and pregnancy. There has been a dramatic shift in NMOSD morbidity and mortality with earlier and improved disease recognition, diagnostic accuracy, and the advent of more effective, targeted therapies. Choosing a maintenance therapy remains nuanced depending on patient factors and accessibility. With over 100 putative agents in trials, disease-free survival is now a realistic goal for NMOSD patients.

Gastrointestinal Dysfunction in Stroke.

Gastrointestinal (GI) complications are seen in over 50% of ischemic stroke survivors; the most common complications are dysphagia, constipation, and GI bleeding. The bidirectional relationship of the gut-brain axis and stroke has recently gained traction, wherein stroke contributes to gut dysbiosis (alterations in the normal host intestinal microbiome) and gut dysbiosis perpetuates poor functional neurologic outcomes in stroke. It is postulated that the propagation of proinflammatory cells and gut metabolites (including trimethylamine N-oxide and short-chain fatty acids) from the GI tract to the central nervous system play a central role in gut-brain axis dysfunction. In this review, we discuss the known GI complications in acute ischemic stroke, our current knowledge from experimental stroke models for gut-brain axis dysfunction in stroke, and emerging therapeutics that target the gut-brain axis.

Diagnosing viral encephalitis and emerging concepts.

PURPOSE OF REVIEW: This review offers a contemporary clinical approach to the diagnosis of viral encephalitis and discusses recent advances in the field. The neurologic effects of coronaviruses, including COVID-19, as well as management of encephalitis are not covered in this review. RECENT FINDINGS: The diagnostic tools for evaluating patients with viral encephalitis are evolving quickly. Multiplex PCR panels are now in widespread use and allow for rapid pathogen detection and potentially reduce empiric antimicrobial exposure in certain patients, while metagenomic next-generation sequencing holds great promise in diagnosing challenging and rarer causes of viral encephalitis. We also review topical and emerging infections pertinent to neuroinfectious disease practice, including emerging arboviruses, monkeypox virus (mpox), and measles. SUMMARY: Although etiological diagnosis remains challenging in viral encephalitis, recent advances may soon provide the clinician with additional tools. Environmental changes, host factors (such as ubiquitous use of immunosuppression), and societal trends (re-emergence of vaccine preventable diseases) are likely to change the landscape of neurologic infections that are considered and treated in clinical practice.

Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis.

In contrast to the multiple disease-modifying therapies that are available for relapsing-remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing-remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton's tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use.

The benefits of neuroinflammation for the repair of the injured central nervous system.

Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer's disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.

Drug exposure and the risk of multiple sclerosis: A systematic review.

BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81-2.20; adj.HR = 1.30;95%CI:0.44-3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21-1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3-0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10-1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29-1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1-23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69-2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47-10.42 and 3.48;95%CI:1.45-8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45-0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1-0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4-1.6). CONCLUSIONS: The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

Evaluating Soluble EMMPRIN as a Marker of Disease Activity in Multiple Sclerosis: Studies of Serum and Cerebrospinal Fluid.

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is an inducer of matrix metalloproteinases and has roles in leukocyte activation and migration. We reported previously that in MS and its animal model, experimental autoimmune encephalomyelitis, cell surface-associated EMMPRIN was significantly elevated in leukocytes around inflammatory perivascular cuffs in the CNS. In this study we report that activated T-cells can secrete soluble form of EMMPRIN (sEMMPRIN) upon activation. As sEMMPRIN is also present in biological fluids, we determined whether sEMMPRIN is altered in the CSF and sera of MS subjects. Sera from individuals without neurological conditions served as controls, while CSFs collected from subjects undergoing discectomy, and without evidence of CNS pathology, were used as a comparator group. We found that serum levels of sEMMPRIN from clinically stable MS patients or other inflammatory conditions did not differ from control subjects. Paired serum and CSF samples demonstrated poor correlation of sEMMPRIN. Interestingly, sEMMPRIN levels were approximately 60% higher in CSFs compared to sera. sEMMPRIN CSF levels were significantly higher in secondary progressive compared to primary progressive subjects. Thus we conclude that measurement of sEMMPRIN in serum is not informative for disease activity in MS. The differential expression of sEMMPRIN in the CSF of primary and secondary progressive MS invites hypotheses of the still undefined roles of EMMPRIN in the CNS.

Changes in tissue directionality reflect differences in myelin content after demyelination in mice spinal cords.

Changes in myelin integrity are key manifestations of many neurological diseases including multiple sclerosis but precise measurement of myelin in vivo is challenging. The goal of this study was to evaluate myelin content in histological images obtained from a lysolecithin mouse model of demyelination, using a new quantitative method named structure tensor analysis. Injury was targeted at the dorsal column of mice spinal cords. We obtained 16 histological images stained with luxol fast blue for myelin from 9 mice: 9 images from lesion epicenter and 7 from a distant area 500-µm away from the epicenter. In each image, we categorized 3 tissue types: healthy, completely demyelinated, and partially demyelinated. Structure tensor analysis was applied to quantify the coherency (anisotropy), energy (trace of dominant directions), and angular entropy (degree of disorder) of each tissue. We found that completely demyelinated lesions had significantly lower coherency and energy but higher angular entropy than partially demyelinated and healthy tissues at both the epicenter and distant areas of the injury. In addition, the coherency of healthy tissue was greater than partially demyelinated tissue at each site. Within tissue category, we did not find differences in any measure between spinal cord locations. Our findings suggest that greater myelin integrity is associated with better tissue anisotropy, independent of injury location. Structure tensor analysis may serve as a new tool for quantitative measurement of myelin content in white matter, and this may help understand disease mechanisms and development in MS and other demyelinating disorders.