NUS1 and Epilepsy-myoclonus-ataxia Syndrome: An Under-recognized Entity?

Background: Variants of the NUS1 gene have recently been linked to a spectrum of phenotypes including epilepsy, cerebellar ataxia, cortical myoclonus and intellectual disability (ID), and primary congenital defects of glycosylation. Case Report: We report a case of myoclonus epilepsy, mild cerebellar ataxia, and ID due to a new de-novo NUS1 missense variant (c.868C>T, p.R290C), and review the current literature of NUS1-associated clinical phenotypes. Discussion: Pathogenic variants of NUS1 are found in a rapidly growing number of cases diagnosed with myoclonus epilepsy and/or myoclonus-ataxia syndrome. NUS1 should be included in the genetic screening of undiagnosed forms of myoclonus, myoclonus-ataxia, and progressive myoclonus epilepsies.

Training in Neurology: Diagnostic Accuracy Among Neurology Residents: The "Close the Loop" Project.

OBJECTIVE: To describe cases presented by junior neurology residents and to evaluate resident diagnostic patterns to help address individual and systemic educational needs. METHODS: For 6 academic years, details of all morning report cases assessed and presented by junior neurology residents were logged, including the resident's independent initial diagnostic impression. Cases were later revisited at subsequent morning reports to "close the loop" on a final diagnosis. We conducted retrospective review to quantify case demographics and to determine resident diagnostic accuracy based on prespecified localization pathways. RESULTS: Demographic analysis included 1,472 cases; of these, 1,301 qualified for accuracy analysis due to diagnostic uncertainty at time of morning report. Non-neurologic etiologies represented 26.0% of cases. CNS etiologies were the majority (86.0%) of neurologic cases. The most frequent diagnoses were ischemic stroke and seizure. Overall resident diagnostic accuracy was 64.0%. Accuracy was similar between central and peripheral etiologies. Of 1,301 cases, 15.3% were overcalled as neurologic, while neurologic disease was rarely mistaken as non-neurologic (5.1%). Most diagnostic errors (49.1%) occurred when determining whether a case was neurologic. Where in the localization pathway errors occurred varied between etiologies. CONCLUSION: Overall diagnostic accuracy for neurology junior residents in our cohort was similar to prior work conducted in smaller samples. Analysis of errors, particularly at the critical "neurologic or non-neurologic" decision point, warrants further investigation. Close the loop methodology is simple to employ and can guide educational and quality initiatives to improve neurology resident clinical acumen.

Medical, Surgical, and Genetic Treatment of Huntington Disease.

Huntington disease, a neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, is caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Current treatments target symptom management because there are no disease-modifying therapies at this time. Investigation of RNA-based and DNA-based treatment strategies are emerging and hold promise of possible future disease-modifying therapy.

An Update on Myoclonus Management.

INTRODUCTION: Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, lightning-like involuntary jerks. There are many possible causes of myoclonus and both the etiology and characteristics of the myoclonus are important in securing the diagnosis and treatment. Myoclonus may be challenging to treat, as it frequently requires multiple medications for acceptable results. Few randomized controlled trials investigating the optimal treatment for myoclonus are available, and expert experience and case series guide treatment. Areas Covered: In this article, the authors review the basics of myoclonus and its classification. The authors discuss the current management of myoclonus and then focus on recent updates in the literature, including both pharmacologic and surgical options. Expert opinion: Myoclonus remains a challenge to manage, and there is a paucity of rigorous clinical trials guiding treatment paradigms. Furthermore, due to the etiological heterogeneity of myoclonus, defining the appropriate scope for high-quality clinical trials is challenging. In order to advance the field, the myoclonus study group needs to be revived in the US and abroad so that interested investigators can collaborate on multicenter clinical trials for myoclonus treatments.

Sporadic Creutzfeldt-Jakob Disease With Unilateral Symptoms in the Setting of Metastatic Renal Cell Carcinoma.

INTRODUCTION: Although it is not rare for magnetic resonance imaging findings in Creutzfeldt-Jakob disease to be asymmetric, unilateral clinical syndromes are uncommonly reported and may confound diagnosis. In addition, neurological paraneoplastic syndromes are not common in renal cell carcinoma, though there are cases reported, often without an offending antibody isolated. CASE REPORT: A 66-year-old man was admitted with 1 month of left-sided numbness and "loss of control" of the left arm. Examination revealed action-induced irregular jerking movements of the left arm. Mental status testing was normal. Magnetic resonance imaging brain revealed patchy areas of restricted diffusion along the cerebral cortices. Screening computed tomographic scans revealed innumerable lung nodules compatible with metastases, as well as a renal mass consistent with renal cell carcinoma. Lumbar puncture was performed and cerebrospinal fluid was sent for paraneoplastic autoantibody evaluation and protein 14-3-3. Over the next week the patient developed dystonic posturing of the left arm, left leg jerking movements, a right arm action tremor, and cognitive impairment. Paraneoplastic autoantibodies were negative. Protein 14-3-3 was elevated and brain biopsy revealed spongiform encephalopathy with positive immunoblotting. The patient died about 2 months from symptom onset. CONCLUSIONS: Creutzfeldt-Jakob disease can present with entirely unilateral myoclonus and numbness, without specific complaints of cognitive impairment. Not every difficult or unclear neurological syndrome in a patient with metastatic cancer is a paraneoplastic syndrome.

Focal task specific dystonia: a review and update.

In this review, we summarize recent advances in understanding the etiology, risk factors and pathophysiology of focal task specific dystonia (FTSD), movement disorders characterized by abnormal motor activation during the performance of specific, repetitive actions. We focus on two common FTSD, musician's dystonia and writer's cramp. FTSD may pose a threat to the patient's livelihood, and improved therapeutic treatments are needed.

Epidemiological survey-based formulae to approximate incidence and prevalence of neurological disorders in the United States: a meta-analysis.

BACKGROUND: This study aims to create a convenient reference for both clinicians and researchers so that vis-à-vis comparisons between brain disorders can be made quickly and accurately. We report here the incidence and prevalence of the major adult-onset brain disorders in the United States using a meta-analysis approach. MATERIAL AND METHODS: Epidemiological figures were collected from the most recent, reliable data available in the research literature. Population statistics were based on the most recent census from the US Census Bureau. Extrapolations were made only when necessary. The most current epidemiological studies for each disorder were chosen. All effort was made to use studies based on national cohorts. Studies reviewed were conducted between 1950 and 2009. The data of the leading studies for several neurological studies was compiled in order to obtain the most accurate extrapolations. Results were compared to commonly accepted values in order to evaluate validity. RESULTS: It was found that 6.75% of the American adult population is afflicted with brain disorders. This number was eclipsed by the 8.02% of Floridians with brain disorders, which is due to the large aged population residing in the state. CONCLUSIONS: There was a noticeable lack of epidemiological data concerning adult-onset brain disorders. Since approximately 1 out of every 7 households is affected by brain disorders, increased research into this arena is warranted.

Reproductive health choices for young adults with sickle cell disease or trait: randomized controlled trial immediate posttest effects.

BACKGROUND: People with sickle cell disease (SCD) or sickle cell trait (SCT) may not have information about genetic inheritance needed for making informed reproductive health decisions. CHOICES is a Web-based, multimedia educational intervention that provides information about reproductive options and consequences to help those with SCD or SCT identify and implement an informed parenting plan. Efficacy of CHOICES compared with usual care must be evaluated. OBJECTIVE: The purpose was to compare immediate posttest effects of CHOICES versus an attention-control usual care intervention (e-Book) on SCD-/SCT-related reproductive health knowledge, intention, and behavior. METHODS: In a randomized controlled study, we recruited subjects with SCD/SCT from clinics, community settings, and online networks with data collected at sites convenient to the 234 subjects with SCD (n = 136) or SCT (n = 98). Their ages ranged from 18 to 35 years; 65% were women, and 94% were African American. Subjects completed a measure of sickle cell reproductive knowledge, intention, and behavior before and immediately after the intervention. RESULTS: Compared with the e-Book group, the CHOICES group had significantly higher average knowledge scores and probability of reporting a parenting plan to avoid SCD or SCD and SCT when pretest scores were controlled. Effects on intention and planned behavior were not significant. The CHOICES group showed significant change in their intention and planned behavior, whereas the e-Book group did not show significant change in their intention, but their planned behavior differed significantly. DISCUSSION: Initial efficacy findings are encouraging but warrant planned booster sessions and outcome follow-ups to determine sustained intervention efficacy on reproductive health knowledge, intention, and actual behavior of persons with SCD/SCT.

Stroke in the eye of the beholder.

The pathophysiological changes that occur during ischemic stroke can have a profound effect on the surrounding nerve tissue. To this end, we advance the hypothesis that retinal damage can occur as a consequence of ischemic stroke in animal models. We discuss the preclinical evidence over the last 3 decades supporting this hypothesis of retinal damage following ischemic stroke. In our evaluation of the hypothesis, we highlight the animal models providing evidence of pathological and mechanistic link between ischemic stroke and retinal damage. That retinal damage is closely associated with ischemic stroke, yet remains neglected in stroke treatment regimen, provides the impetus for recognizing the treatment of retinal damage as a critical component of stroke therapy.

Nestin overexpression precedes caspase-3 upregulation in rats exposed to controlled cortical impact traumatic brain injury.

Our understanding of biological mechanisms and treatment options for traumatic brain injury (TBI) is limited. Here, we employed quantitative real-time PCR (QRT-PCR) and immunohistochemical analyses to determine the dynamic expression of cell proliferation and apoptosis in an effort to provide insights into the therapeutic window for developing regenerative strategies for TBI. For this purpose, young adult Sprague-Dawley rats were subjected to experimental TBI using a controlled cortical impactor, then euthanized 1-48 hours after TBI for QRT-PCR and immunohistochemistry. QRT-PCR revealed that brains from TBI exposed rats initially displayed nestin mRNA expression that modestly increased as early as 1-hour post-TBI, then significantly peaked at 8 hours, but thereafter reverted to pre-TBI levels. On the other hand, caspase-3 mRNA expression was slightly elevated at 8 hours post-TBI, which did not become significantly upregulated until 48 hours. Immunofluorescent microscopy revealed a significant surge in nestin immunoreactive cells in the cortex, corpus callosum, and subventricular zone at 24 hours post-TBI, whereas a significant increase in the number of active caspase-3 immunoreactive cells was only found in the cortex and not until 48 hours. These results suggest that the injured brain attempts to repair itself via cell proliferation immediately after TBI, but that this endogenous regenerative mechanism is not sufficient to abrogate the secondary apoptotic cell death. Treatment strategies designed to amplify cell proliferation and to prevent apoptosis are likely to exert maximal benefits when initiated at the acute phase of TBI.

Cyclosporine-A as a neuroprotective agent against stroke: its translation from laboratory research to clinical application.

Stoke remains a leading cause of death and disability with limited treatment options. Extensive research has been aimed at studying cell death events that accompany stroke and how to use these same cell death pathways as potential therapeutic targets for treating the disease. The mitochondrial permeability transition pore (MPTP) has been implicated as a major factor associated with stroke-induced neuronal cell death. MPTP activation and increased permeability has been shown to contribute to the events that lead to cell death. Cyclosporine A (CsA), a widely used immunosuppressant in transplantation and rheumatic medicine, has been recently shown to possess neuroprotective properties through its ability to block the MPTP, which in turn inhibits neuronal damage. This newfound CsA-mediated neuroprotection pathway prompted research on its use to prevent cell death in stroke and other neurological conditions. Preclinical studies are being conducted in hopes of establishing the safety and efficacy guidelines for CsA use in human trials as a potential neuroprotective agent against stroke. In this review, we provide an overview of the current laboratory and clinical status of CsA neuroprotection.

Intravenous infusion of GDNF gene-modified human umbilical cord blood CD34+ cells protects against cerebral ischemic injury in spontaneously hypertensive rats.

This study assessed the potential of intravenous transplantation of human umbilical cord blood (HUCB) CD34+ cells transfected with glial cell line-derived neurotrophic factor (GDNF) gene to exert therapeutic benefits in spontaneous hypertensive rats (SHR) exposed to transient middle cerebral artery occlusion (MCAO). SHR with MCAO were randomly assigned to receive intravenously transplantation of vehicle, the plasmid containing the enhanced green fluorescent protein (pEGFP)-CD34+ cells or pEGFP-GDNF-CD34+ cells at 6h after stroke. The CD34+ cells transfected with GDNF gene expressed higher levels of GDNF mRNA and protein than nontransfected HUCB CD34+ cells in vitro. At 28 days after transplantation of GDNF gene modified CD34+ cells, significantly more GFP positive cells, neurons, and astrocytes, likely derived from the grafted cells, populated the peri-infarct area compared to those injected with pEGFP-CD34+ cells or vehicle. Furthermore, the stroke animals transplanted with GDNF gene modified CD34+ cells showed a significant increase in GDNF level in the infarcted hemisphere, reduced brain infarction volume, and enhanced functional recovery compared with those that received pEGFP-CD34+ cells. This study supports the use of a combined gene and stem cell therapy for treating stroke.

In vitro non-viral lipofectamine delivery of the gene for glial cell line-derived neurotrophic factor to human umbilical cord blood CD34+ cells.

Using a lipofection technique, we explored a non-viral delivery of plasmid DNA encoding a rat pGDNF (glial cell line-derived neurotrophic factor) to CD34+ cells derived from human umbilical cord blood (HUCB) cells in order to obtain cells stably expressing the GDNF gene. The target gene GDNF was amplified from cortex cells of newborn Sprague-Dawley rats by reverse transcriptase polymerase chain reaction (RT-PCR) and inserted into vector pEGFP-N1 to construct the eukaryotic expression vector pEGFP/GDNF. The positive clones were identified by sequencing and endonuclease digestion. The expression of pEGFP/GDNF-transfected HUCB cells CD34+ was examined by ELISA. Single fragment of 640 bp was obtained after the rat GDNF cDNA was amplified by RT-PCR. Two fragments of about 4.3 kb and 640 pb were obtained after digestion of recombinant plasmid pEGFP/GDNF with XhoI/KpnI. The nucleic acid fragment of 640 bp was confirmed to agree well with the sequence of GDNF gene published by GenBank. The expression of GDNF mRNA and the level of GDNF from pEGFP/GDNF-transfected CD34+ cells were increased substantially, compared with pEGFP control plasmid transfected CD34+ cells (P<0.05). Moreover, co-culture of primary rat cells with the pEGFP/GDNF-transfected CD34+ cells promoted enhanced neuroprotection against oxygen-glucose deprivation induced cell dysfunctions. The present results support the use of the non-viral plasmid liposome for therapeutic gene expression for stem cell therapy.

Severity of controlled cortical impact traumatic brain injury in rats and mice dictates degree of behavioral deficits.

The clinical presentation of traumatic brain injury (TBI) involves either mild, moderate, or severe injury to the head resulting in long-term and even permanent disability. The recapitulation of this clinical scenario in animal models should allow examination of the pathophysiology of the trauma and its treatment. To date, only a few studies have demonstrated TBI animal models encompassing the three levels of trauma severity. Thus, in the present study we characterized in mice and rats both brain histopathologic and behavioral alterations across a range of injury magnitudes arising from mild, moderate, and severe TBI produced by controlled cortical impact injury technique. Here, we replicated the previously observed TBI severity-dependent brain damage as revealed by 2,3,5-triphenyltetrazolium chloride staining (severe > moderate > mild) in rats, but also extended this pattern of histopathologic changes in mice. Moreover, we showed severity-dependent abnormalities in locomotor and cognitive behaviors in TBI-exposed rats and mice. Taken together, these results support the use of rodent models of TBI as a sensitive platform for investigations of the injury-induced neurostructural and behavioral deficits, which should serve as key outcome parameters for testing experimental therapeutics.

Quantitative analyses of matrix metalloproteinase activity after traumatic brain injury in adult rats.

Recent laboratory evidence implicates matrix metalloproteinases (MMPs) as playing a pivotal role in ischemic and traumatic brain injuries (TBI). Here, quantitative real-time PCR analyses revealed that brains from TBI rats displayed significantly elevated MMP-9 expression at 24 h post-TBI, which remained upregulated at least until 48 h after injury. Immunohistochemical analyses similarly revealed significantly increased MMP-9 immunoreactivity at 24 and 48 h post-TBI. These results demonstrate that alterations in MMPs (i.e., MMP-9) commenced immediately after TBI, suggesting that treatment strategies designed to maintain MMP integrity should be initiated in the acute phase of injury.

Systemic delivery of umbilical cord blood cells for stroke therapy: a review.

PURPOSE: This review paper summarizes relevant studies, discusses potential mechanisms of transplanted cell-mediated neuroprotection, and builds a case for the need to establish outcome parameters that are critical for transplantation success. In particular, we outline the advantages and disadvantages of systemic delivery of human umbilical cord blood (HUCB) cells in the field of cellular transplantation for treating ischemic stroke. METHODS: A MEDLINE/PubMed systematic search of published articles in peer-reviewed journals over the last 25 years was performed focusing on the theme of HUCB as donor graft source for transplantation therapy in neurological disorders with emphasis on stroke. RESULTS: Ischemic stroke remains a leading cause of human death and disability. Although stroke survivors may gain spontaneous partial functional recovery, they often suffer from sensory-motor dysfunction, behavioral/neurological alterations, and various degrees of paralysis. Currently, limited clinical intervention is available to prevent ischemic damage and restore lost function in stroke victims. Stem cells from fetal tissues, bone marrow, and HUCB has emerged in the last few years as a potential cell transplant cell source for ischemic stroke, because of their capability to differentiate into multiple cell types and the possibility that they may provide trophic support for cell survival, tissue repair, and functional recovery. CONCLUSION: A growing number of studies highlight the potential of systemic delivery of HUCB cells as a novel therapeutic approach for stroke. However, additional preclinical studies are warranted to reveal the optimal HUCB transplant regimen that is safe and efficacious prior to proceeding to large-scale clinical application of these cells for stroke therapy.

Transplantation of human umbilical cord blood cells for the repair of myocardial infarction.

Cell therapy for myocardial disease is a rapidly evolving medical field. A vast and growing body of evidence indicates that cell-based strategies have promising therapeutic potential. Recent clinical and pre-clinical studies demonstrate a varying degree of improvement in cardiac function using different sources of adult stem cell types such as bone marrow-derived progenitor cells and skeletal myoblasts. However, the currently available regimens for cell transplantation into the infarcted myocardium have limitations from practical points of view, in particular the logistics in harvesting donor cells. Accordingly, there is an urgent need for a new source of adult stem cells. Human umbilical cord blood (HUCB) is a good candidate and appears to have several key advantages. HUCB is a viable and practical source of progenitor cells. Compared to bone marrow, HUCB contains a higher number of immature stem/progenitor cells. The aim of our review is to provide an update on the preclinical experiments with emphasis on the possible mechanisms underlying the therapeutic benefits of HUCB cell transplantation for myocardial infarction.

No pain, no gain--exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra.

BACKGROUND: We describe a rare case of severe rhabdomyolysis provoked by ingestion of a performance-enhancer herbal supplement containing ephedra. CASE REPORT: A healthy 21-year-old Army soldier complained of "complete muscle failure" after collapsing at the end of Army Physical Fitness Test. The patient was found to be tachycardic and hypotensive, but his vital signs quickly stabilized after receiving sodium chloride in the ambulance. Physical examination of the patient, including a thorough neuromuscular exam, was unremarkable. Urine tested positive for myoglobin. Initial creatinine kinase was 426 U/L, which increased to a maximum creatinine kinase of 241,418 ti/IL by hospital day 6. The patient also developed acute renal failure secondary to pigment-induced actute tubular necrosis. He was treated with bicarbonate-containing fluid. The patient's creatinine kinase and renal function had normalized at one month follow-up. A muscle biopsy was negative for underlying neuromuscular disease. His past medical history was only notable for the patient having taken 2 tablets of an herbal supplement containing ephedra every day for a month leading to his physical fitness test. CONCLUSIONS: Rhabdomvolvsis and myoglobinuric renal failure associated with ephedra use are a very uncommion occurrence, but a significant clinical event that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements.

Gene therapy, cell transplantation and stroke.

The use of neuroteratocarcinoma cells for transplantation therapy in stroke has emerged as a strategy for cell replacement therapy that has begun its transition from basic science laboratories to a clinical setting. Procurement logistics and novel neuroprotective functions associated with these cells allow neuroteratocarcinoma cells to serve as efficacious alternatives to using fetal cells as donor cell grafts for stroke therapy, although the optimal transplantation regimen must still be determined. In particular, the limitations of current stroke treatments and management reveal an urgent need to examine the efficacy of experimental treatments, such as neural transplantation, in order to develop better treatment therapies. This chapter will discuss the characteristics of NT2N cells, the role of the host brain microenvironment and NT2N cell grafts, laboratory research and clinical trials for the intracerebral transplantation of NT2N cells in stroke, the mechanisms underlying the grafts' effects, and NT2N cell grafts and the need for immunosuppression. This chapter will also highlight some of the most recent findings regarding NT2N cells.

Viral vector strategy for glial cell line-derived neurotrophic factor therapy for stroke.

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily. Over the last decade, GDNF has been shown to promote regenerative and restorative effects on dopaminergic neurons. Accumulating evidence also demonstrates that administration of GDNF to areas of ischemic brain injury limits cerebral infarction and reduces damage to motor functions in animal models of stroke. Neurotrophic factor and anti-apoptotic mechanisms, among others, have been proposed to underlie the therapeutic effects of GDNF. A major obstacle for GDNF therapy is the protein delivery to the brain, as well as its sustained bioavailability over time. Gene therapy and the use of viral vectors offer a technique for longevity of GDNF expression within the brain. In this review, we consider the risks and benefits of GDNF gene therapy as it relates to the treatment of stroke.