Nicoline Schiess

Hashimoto's encephalopathy

Hashimotos encephalopathy (HE) is a controversial neurological disorder that comprises a heterogenous group of neurological symptoms that manifest in patients with high titers of antithyroid antibodies. Clinical manifestations of HE may include encephalopathic features such as seizures, behavioral and psychiatric manifestations, movement disorders, and coma. Although it has been linked to cases of Hashimotos thyroiditis or thyroid dysfunction, the most common immunological feature of HE is the presence of high titers of antithyroglobulin or anti‐TPO (antimicrosomal) antibodies. At present, it is unclear whether antithyroid antibodies represent an immune epiphenomenon in a subset of patients with encephalopathic processes or they are really associated with pathogenic mechanisms of the disorder. The significance of classifying encephalopathies under the term HE will be determined in the future once the relevance of the role of antithyroid antibodies is demonstrated or dismissed by more detailed experimental and immunopathological studies. The responsiveness of HE to steroids or other therapies such as plasmapheresis supports the hypothesis that this is a disorder that involves immune pathogenic mechanisms. Further controlled studies of the use of steroids, plasmapheresis, or immunosuppressant medications are needed in the future to prove the concept of the pathogenic role of antithyroid antibodies in HE.

Evolution of HIV dementia with HIV infection

Dementia remains one of the most fearsome complications of HIV infection. It also poses a significant challenge for the clinician both in terms of diagnosis and treatment. The use of antiretroviral agents has led to a decrease in the incidence of HIV dementia but the prevalence of milder forms of neurocognitive impairment has increased. Occasionally, the immune reconstitution caused by these agents may target the brain leading to a syndrome characterized by a severe, progressive and often fatal dementia. The progression of HIV dementia may also be determined by host and viral genetic factors, and the existence of co-morbid factors such as drug abuse, hepatitis C infection and aging. Oxidative stress markers appear to be predictive of active dementia. However, currently there is no specific treatment available for HIV dementia.

Natalizumab : Bound to rebound?

Since it first came to trial, natalizumab (Tysabri) has kept the multiple sclerosis (MS) world in a constant state of flux. Shortly after its initial launch, the appearance of three cases of progressive multifocal leukoencephalopathy (PML), a devastating infection of the CNS caused by the JC virus, resulted in the drug’s withdrawal from the market. Reintroduced in 2006, it is currently in use as monotherapy in thousands of patients worldwide, but four additional cases of PML were recently reported in patients on natalizumab monotherapy for less than 18 months. While these cases strongly support a mechanistic association between the drug and JC virus reactivation/infection,1 the short-term risk of PML still appears to be quite low (4 confirmed cases out of ∼10,000 patients treated for 18 months). Nonetheless, these new cases are concerning and some patients and physicians will choose to discontinue therapy. Several groups have raised the possibility of a rebound effect in cohorts of patients discontinuing natalizumab.2,3 This has led to the concern that stopping natalizumab might lead to …Neurology 2009;72:392–393 Since it first came to trial, natalizumab (Tysabri) has kept the multiple sclerosis (MS) world in a constant state of flux. Shortly after its initial launch, the appearance of three cases of progressive multifocal leukoencephalopathy (PML), a devastating infection of the CNS caused by the JC virus, resulted in the drug’s withdrawal from the market. Reintroduced in 2006, it is currently in use as monotherapy in thousands of patients worldwide, but four additional cases of PML were recently reported in patients on natalizumab monotherapy for less than 18 months. While these cases strongly support a mechanistic association between the drug and JC virus reactivation/infection,1 the short-term risk of PML still appears to be quite low (4 confirmed cases out of 10,000 patients treated for 18 months). Nonetheless, these new cases are concerning and some patients and physicians will choose to discontinue therapy. Several groups have raised the possibility of a rebound effect in cohorts of patients discontinuing natalizumab.2,3 This has led to the concern that stopping natalizumab might lead to a sudden worsening of MS disease. However, rebound was not seen during a 6-month washout period following a phase II placebo-controlled trial with natalizumab.4 Natalizumab is a monoclonal antibody that binds the 4 integrin chain of the very late activation antigen (VLA)-4 adhesion molecule and blocks mononuclear cell migration and perhaps costimulatory activating signals. The question has been raised as to whether immune cells that are blocked from trafficking build up in the blood persistently during natalizumab therapy, or whether these cells eventually die by attrition and thereby avert the potential for a catastrophic flood of immune cells into the CNS. In this issue of Neurology, Stüve et al.5 explore the idea of a rebound phenomenon by investigating clinical activity, MRI changes, and immunologic peripheral blood/CSF markers in 23 patients with MS who received natalizumab as part of the AFFIRM and SENTINEL trials. Samples were taken at the time of drug cessation and 14 months later. Reassuringly, most of the patients in this cohort remained clinically and radiographically stable. Immune cell counts in the periphery and CSF still showed natalizumab-mediated effects at 6 months, but returned to normal levels, without any rebound, after 14 months, and no infectious complications occurred. This is encouraging to clinicians treating patients with natalizumab who are concerned about the possibility of a rebound phenomenon upon cessation of the drug. The limitations, however, include a small sample size in which only 21 patients had relapse rates evaluated, 17 had Expanded Disability Status Scale scores, 16 had MRIs, and an even smaller subset had immunologic measurements. Nonetheless, this was a reasonable sample size for such extensive immunologic studies. How can these data be reconciled with the reports of clinical or MRI rebound by Tubridy and Vellinga? The most likely explanation is that short-term treatment with natalizumab, as was characteristic of these two studies, does indeed result in trapping and accumulation of viable activated lymphocytes in the periphery that retain their capacity to cause CNS disease. The Tubridy study only used two doses of natalizumab and in the Vellinga study the effect was driven by patients with short exposures to natalizumab (median of two infusions). In contrast, more prolonged treatment with natalizumab, as was done in the study by Miller et al.4 (6 months) and the phase III trials (120 weeks), probably results in death of the peripheral activated T cells. Thereby, not only is there no rebound, but there may be disease quiescence even upon discontinuing the drug, while new pathogenic immune cells are generated and expanded in the peripheral blood. The persistent leukocytosis seen in the periphery may occur not only through blockade of cell migration, but also due to enhanced egress from the bone marrow. These lymphocytes may not only be less activated through blockade of the costimulatory properties of VLA-4 signaling, but

Impaired toll-like receptor 8 signaling in multiple sclerosis

BackgroundThe etiology and immunopathology of multiple sclerosis (MS) is not well understood. It is recognized that although autoreactive T cells are the main early mediators of disease, other cell types, including cells of the innate immune system contribute to MS pathogenesis. The objective of this study was to determine if Toll-like receptor (TLR) signaling is functionally altered in patients with MS.FindingsPeripheral blood mononuclear cells from healthy donors and patients with relapsing remitting MS were stimulated with specific agonists of TLRs 3, 7, 8 and 9. Using quantitative polymerase chain reaction transcript levels of tumor necrosis factor-α, interferon-α and interleukin (IL)-12β were quantified from patients with MS and healthy donors. TLR8-induced production of IL12B transcripts and protein was functionally impaired in patients with MS as compared to healthy controls (P <0.05 and P <0.005, respectively). Patients with MS also expressed lower baseline levels of TLR8 as compared to healthy controls (P <0.05).ConclusionsTLR8 expression and signaling is impaired in peripheral blood mononuclear cells from patients with MS. This finding suggests that loss of TLR8 signaling may be contributing to autoimmune processes in MS.

Management of Brain Abscess

Despite recent advances in neuroimaging techniques, brain abscesses can be difficult to diagnose and may often require surgical intervention. The primary sources of infection are often difficult to locate; hence, even if an abscess is suspected, the organisms may remain unknown. In other patients, the location of the lesion may be in a site of the brain where surgical intervention may not be possible. The types of brain abscesses, their pathophysiology including predisposing conditions, and their characteristic radiologic features are discussed in this review, with particular emphasis on the indications and modes of medical management of brain abscesses. It discusses the use of antimicrobial agents that have the best central nervous system penetration and outlines a strategy for treatment of organisms likely to infect the brain with the different types of predisposing conditions. Also discussed are the indications for empirical therapy, and antimicrobial regimens for this purpose are suggested.

How global MS prevalence is changing: A retrospective chart review in the United Arab Emirates

BACKGROUND Multiple Sclerosis (MS) is an autoimmune disorder leading to central nervous system inflammation. Traditionally, reported MS prevalence rates in the Middle East are low. Few studies include age/sex standardization giving an unreliable estimate of regional prevalence. OBJECTIVE to determine the prevalence, incidence and characteristics of MS in Abu Dhabi, United Arab Emirates. METHODS A retrospective chart review was conducted at the four largest hospitals in Abu Dhabi Emirate between 2010 and 2014. Data collected included MS type, age and symptoms at onset, expanded disability status scale, treatment, laboratory findings and family history. RESULTS 510 patients were identified consisting of 318 (62.2%) Emiratis and 192 (37.6%) expatriates. Total crude prevalence rate was 18/100,000 (95% CI: 10-30/100,000). Crude prevalence rate in Emiratis was 57.09 (95% CI:50 to 63/100,000) but increased to 64.44 (95% CI: 57 to 72/100,000) when age standardized. Age-standardized incidence rate in Emiratis was 6.0 MS cases per 100,000 person-years (95% CI: 5.5 to 6.5 cases per 100,000 person-years). CONCLUSION At 64.44/100,000, the Abu Dhabi Emirati population has one of the highest, most reliable prevalence rate on the Arab peninsula. Age/sex standardized prevalence rates, uncommonly reported in the Middle East, should be standard for all prevalence studies.

Novel PNKP mutation in siblings with ataxia-oculomotor apraxia type 4

Abstract The phenotypic and genetic spectrum of ataxia with oculomotor apraxia (AOA) disorders is rapidly evolving and new technologies such as genetic mapping using whole exome sequencing reveal subtle distinctions among the various subtypes. We report a novel PNKP mutation in two siblings with progressive ataxia, abnormal saccades, sensorimotor neuropathy and dystonia consistent with the AOA type 4 phenotype. Laboratory evaluation revealed hypoalbuminemia, hypercholesterolemia with elevated LDL, elevated IgE levels and normal α fetoprotein levels. Eye movement examination demonstrated a marked saccade initiation defect with profound hypometric horizontal saccades. Vertical saccades were also affected but less so. Also present were conspicuous thrusting head movements when attempting to change gaze, but rather than an apraxia these were an adaptive strategy to take advantage of an intact vestibulo-ocular reflex to carry the eyes to a new target of interest. This is demonstrated in accompanying videos.

Western Lessons/Eastern Perspectives: Combining Neurology and Psychiatry in Preclinical Medical Student Education in Malaysia

Designated the “Decade of the Brain,” the 1990s was a time of increased public and political awareness of neuroscience and brought a renewed vigor and inspection to the interplay between the brain and themind. Coming after several decades of abundant research in the field, the end of the twentieth century marked significant changes in the understanding of the pathology and etiology of many psychological and neurologic diseases. In light of increasing public awareness, new technologies, and changing perceptions of psychiatric disease etiology, a growing number of practitioners within the fields have identified a need for more collaboration and interaction between psychiatrists and neurologists and a redesigning of the way medical students are taught about the brain and the mind. Notable neuroscientists, educators, and physicians argue that “the education of future psychiatrists and neurologists should be redesigned” [1].

Emerging Therapies for Multiple Sclerosis: Update on Current Clinical Trials

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that can result in severe morbidity and mortality. The past 15 years have seen a dramatic improvement in the available treatment options for MS patients. Before the 1990s, steroids administered during acute attacks were the only effective medications for the disease. Since then, seven drugs have been approved by the US Food and Drug Administration for use in MS, and many trials investigating new treatments are in progress. The experimental agents range from vaccines to monoclonal antibodies to drugs with novel mechanisms of action. In addition, the importance of vitamin D and its interaction with the immune system has become increasingly apparent. This selective review of current clinical trials provides a concise summary of promising new MS therapies on the horizon.

Global Neurology: Navigating Career Possibilities

Abstract Neurology has not typically been associated with international relief work; however, with the growth of chronic cardiovascular disease and stroke associated with unhealthy eating and sedentary ways, the appearance of “new” neurologic diseases, such as the Zika and West Nile viruses, and the high numbers of seizure disorders resulting from neuroinfectious diseases, more opportunities are arising for international and globally oriented neurologists. Multiple opportunities exist for developing a global clinician‐educator career pathway, including private institutions, nongovernmental organizations, government‐funded opportunities such as Medical Education Partnership Initiative, Fogarty and Fulbright Scholarships, and the American Academy of Neurologys Global Health Section. Furthermore, increasing research capacity in developing countries and increased funding opportunities for global health research have led to new opportunities for neurologists to establish global health research careers. These opportunities could not have come at a better time, as many faculty members have noted a particularly strong interest in global neurology from medical students and residents. Career categories and opportunities for neurologists desiring to work globally are discussed along with the emerging “global neurologist” academic pathway.