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Parental lineage has been shown to increase the risk of Alzheimer’s disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55–80 years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. The X chromosome-attributable relative risk was estimated by calculating the following odds ratio (OR): (women with paternal lineage:women with maternal lineage)/(men with paternal lineage:men with maternal lineage). The proportion of genetic risk borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1 years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1–10.1; p = 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12–90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.

The aim of this study was to assess the neurological complications of SARS-CoV-2 infection and compare phenotypes and outcomes in infected patients with and without selected neurological manifestations.The data source was a registry established by the European Academy of Neurology during the first wave of the COVID-19 pandemic. Neurologists collected data on patients with COVID-19 seen as in- and outpatients and in emergency rooms in 23 European and seven non-European countries. Prospective and retrospective data included patient demographics, lifestyle habits, comorbidities, main COVID-19 complications, hospital and intensive care unit admissions, diagnostic tests, and outcome. Acute/subacute selected neurological manifestations in patients with COVID-19 were analysed, comparing individuals with and without each condition for several risk factors.By July 31, 2021, 1523 patients (758 men, 756 women, and nine intersex/unknown, aged 16-101 years) were registered. Neurological manifestations were diagnosed in 1213 infected patients (79.6%). At study entry, 978 patients (64.2%) had one or more chronic general or neurological comorbidities. Predominant acute/subacute neurological manifestations were cognitive dysfunction (N = 449, 29.5%), stroke (N = 392, 25.7%), sleep-wake disturbances (N = 250, 16.4%), dysautonomia (N = 224, 14.7%), peripheral neuropathy (N = 145, 9.5%), movement disorders (N = 142, 9.3%), ataxia (N = 134, 8.8%), and seizures (N = 126, 8.3%). These manifestations tended to differ with regard to age, general and neurological comorbidities, infection severity and non-neurological manifestations, extent of association with other acute/subacute neurological manifestations, and outcome.Patients with COVID-19 and neurological manifestations present with distinct phenotypes. Differences in age, general and neurological comorbidities, and infection severity characterize the various neurological manifestations of COVID-19.

Background: In 2013 the Israel Ministry of Health identified the care and treatment of acute cerebral ischemic stroke as failing to achieve expected standards. The Ministry decided to raise standards by defining and instituting, nationwide, a battery of linked care quality indicators to be applied across all relevant facilities and contexts. Five indicators were selected for five key junctures in the AIS care process. Methods: This paper presents and analyses the effects of the implementation of these new care quality indicators on the post-discharge quality of life outcomes of Israeli stroke sufferers. The patient sample comprises patients from Israel’s Central region, where stroke care provision and access is relatively high, and from the peripheral North region, where provision and access are limited. Results: Those who were not treated with thrombolytic treatment and/or cerebral blood vessel catheterization, those who suffered severer strokes, women, the older age groups, non-Jews and North region residents display significantly worse physical functioning outcomes and worse quality of life outcomes on all indicators. Conclusions: Stroke care access and provision disparities translate into significantly higher rates of post-discharge disability, impaired physical and social functioning, and a lower quality of life. The effectiveness of healthcare improvement by the deployment of care indicators is closely associated with the lifestyle, socio-demographic and socioeconomic status of different population groups. The effective implementation of quality care indicators also relies heavily on closing the access and provision gaps between the populations living in central and peripheral areas. Two obvious directions for action are to expand and improve the rehabilitation care network and to combat the age discrimination in hospital stroke treatment.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review butyrate and its different chemical forms (butyrates). Butyrates have plausible mechanisms for slowing ALS progression and positive pre-clinical studies. One trial suggests that sodium phenylbutyrate (NaPB) in combination with Tauroursodeoxycholic acid (TUDCA) can slow ALS progression and prolong survival, but the specific contribution of NaPB toward this effect is unclear. Butyrates appear reasonably safe for use in humans. Based on the above information, we support a trial of a butyrate in PALS, but we cannot yet recommend one as a treatment.

Despite the increasing number of reports on the spectrum of neurological manifestations of COVID-19 (neuro-COVID), few studies have assessed short- and long-term outcome of the disease.This is a cohort study enrolling adult patients with neuro-COVID seen in neurological consultation. Data were collected prospectively or retrospectively in the European Academy of Neurology NEuro-covid ReGistrY ((ENERGY). The outcome at discharge was measured using the modified Rankin Scale and defined as 'stable/improved' if the modified Rankin Scale score was equal to or lower than the pre-morbid score, 'worse' if the score was higher than the pre-morbid score. Status at 6 months was also recorded. Demographic and clinical variables were assessed as predictors of outcome at discharge and 6 months.From July 2020 to March 2021, 971 patients from 19 countries were included. 810 (83.4%) were hospitalized. 432 (53.3%) were discharged with worse functional status. Older age, stupor/coma, stroke and intensive care unit (ICU) admission were predictors of worse outcome at discharge. 132 (16.3%) died in hospital. Older age, cancer, cardiovascular complications, refractory shock, stupor/coma and ICU admission were associated with death. 262 were followed for 6 months. Acute stroke or ataxia, ICU admission and degree of functional impairment at discharge were predictors of worse outcome. 65/221 hospitalized patients (29.4%) and 10/32 non-hospitalized patients (24.4%) experienced persisting neurological symptoms/signs. 10/262 patients (3.8%) developed new neurological complaints during the 6 months of follow-up.Neuro-COVID is a severe disease associated with worse functional status at discharge, particularly in older subjects and those with comorbidities and acute complications of infection.

Parental lineage has been shown to increase the risk of Alzheimer's disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55-80 years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. The X chromosome-attributable relative risk was estimated by calculating the following odds ratio (OR): (women with paternal lineage:women with maternal lineage)/(men with paternal lineage:men with maternal lineage). The proportion of genetic risk borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1 years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1-10.1; p = 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12-90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.

Background Observational studies of thrombolysis outcomes in wake-up acute ischemic stroke patients selected based on non-contrast brain CT criteria suggested that treated patients did as well as or better than those not treated, after adjustment for baseline characteristics. We began offering thrombolytic treatment (IVTPA) to patients presenting with wake-up strokes and normal non-contrast brain CTs, who could be treated within 4.5 h of being found. Design/methods A retrospective chart review was performed in patients presenting with AIS between November 2014 and December 2017 who received IVTPA. A planned subgroup analysis compared patients with wake-up strokes and normal non-contrast brain CTs to patients with witnessed stroke treated within 4.5 h of being found, or of witnessed onset, respectively. Results Three hundred and six patients were treated, 279 with witnessed-onset and 27 with wake-up strokes. The latter were not candidates for endovascular intervention. Efficacy and safety were similar in both groups. Discharges home, respectively, were 143(53%) and 13(48%); facility discharges were 112(40.1%) and 11(40.7%) and in-hospital mortality was 19 (6.8%) and 3 (11%). Treatment-related symptomatic bleeds were: 5(1.8%) and 1 (3.7%), respectively. Conclusions The findings affirm, in a new clinical series reflecting routine practice, that it is safe to treat with IVTPA patients with wake-up strokes and a normal brain CT scan, who are not candidates for endovascular intervention. We hypothesize, that when the non-contrast brain CT scan is normal, it may be safe to extend beyond 4.5 h the IVTPA treatment eligibility window in similar patients with witnessed-onset stroke., Highlights • A new patient series reflecting routine stroke care at a university hospital • IVTPA treatment if

OBJECTIVE: To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). METHODS: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale–Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. RESULTS: Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. CONCLUSIONS: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. CLINICALTRIALS.GOV IDENTIFIER: NCT02405182.

Introduction We previously reported on 40 patients with Guillain-Barre syndrome (GBS) identified 1999–2005 at our center, and showed that a higher proportion had an axonal pattern, compared to Europe and North America. Methods Retrospective chart review of 100 adult patients with GBS between 2006 and 2018 at Shamir Medical Center. Results 46.8% of those with an abnormal EMG had an axonal pattern. Of the 60 patients who presented with mild disease (defined as Hughes score 1–2), walking deteriorated in 35 (58%, considering any worsening of Hughes score). 20 patients (33%) lost the ability to walk independently (Hughes score 3), 8 reached a point they could not walk (Hughes 4), and 2 needed mechanical ventilation. Ninety-four of 100 patients (94%) were treated with intravenous immunoglobulins (IVIg). Using ECG monitoring and DVT prophylaxis, IVIg-related adverse reactions were rare. Conclusions This study demonstrated a higher proportion of axonal GBS patients in Israel, compared to European and North American patients, replicating the findings in the 1999–2005 patients. Due to the progressive nature of the disease, with more than half of patients presenting with mild disease deteriorating and needing inpatient rehabilitation - we advocate initiation of treatment once a clinical diagnosis of GBS is made.

The goal of this study was to analyze the reasons for delayed diagnosis of Guillain-Barre syndrome (GBS).We retrospectively reviewed the records of all adult patients with GBS treated at Shamir Medical Center (SMC) from 2006 to 2018. We divided the patients into two groups: those with early initiation of treatment (within 24 h of arrival to ED), and those with later initiation of treatment (24 h after arrival). We extracted epidemiological and clinical data regarding those groups, and compared them.100 patients with GBS were treated between 2006 and 2018 at SMC. 50 patients were treated within 24 h of arrival, and in 50 - treatment was initiated later. Of those with delayed treatment, 9 had mild disease, but did receive a working diagnosis of GBS. 41 patients were not diagnosed initially as a clear-cut GBS, and alternative diagnoses were considered, the most common were orthopedic (11/41), vascular (7/41) or nutritional deficiency (6\41). Findings that increased the likelihood for alternative diagnoses to be considered first were severe limb or back pain (26/41); intact or brisk reflexes (17/41); and an atypical pattern of weakness (7\41).GBS is a challenging diagnosis. Acknowledging the heterogeneity of its presentation and knowing its pitfalls is crucial for the prompt and accurate diagnosis of the disease.

Background Establishing mechanisms of disease causation in neurodegenerative diseases has long seemed to be beyond the pale of traditional epidemiological tools. Establishing a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared a particularly elusive goal. This review shows that a likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference. Key points Advances in characterizing the biology of ALS suggest that most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network. Evidence-based methods identified the most credible exogenous risk factor – smoking. AB Hill's nine viewpoints to inferring causation from association were invoked. The most likely mechanism consistent with smoking being a risk factor for ALS was inferred: cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis. Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS. The plausibility of this mechanism was affirmed by its coherence/consistency with other observations in sporadic, familial and western Pacific ALS. Conclusion Application of traditional epidemiological reasoning suggests that cumulative DNA damage may contribute to disease onset in ALS.

Amyotrophic lateral sclerosis (ALS) incidence is lower in African Americans (AAs) and Hispanics than in Caucasians (CAUs). Initially, this observation was ascribed to reduced case-finding or underreferral of minorities to ALS clinics. However, this observation has been confirmed in population-based studies1,2; in the First Gulf War veterans study,3 where case finding was proactive and access to care universal; and in the National Mortality Study.4 A second observation has been that AAs with ALS survive longer. Data from New Jersey2 showed an AA ALS age-adjusted incidence of 0.88 per 100,000 per year compared to 1.80 for CAUs (50% lower), and an AA ALS age-adjusted point prevalence of 2.93 compared to 4.62 for CAUs (35% lower), with no overlap of the 95% confidence intervals. This implied an approximately 25% longer mean duration of disease from onset. A follow-up study5 in the incident cohort showed that median survival from diagnosis of AA patients was 41 months compared to 20 months for CAU patients. A multivariate analysis showed that age accounted for some of the difference; after adjusting for age, the protective effect of AA ethnicity on mortality was evident in the point estimate of the hazard ratio for dying (0.69), but the 95% confidence interval spanned unity (0.41–1.17). In contrast, a study from Arkansas in a clinic referral population6 showed lower incidence of ALS in AAs compared to CAUs, based on a clinic referral population and death certificate data, younger age at onset, and similar survival from onset.

Background: Identifying mechanisms of neurodegenerative disease causation has for long seemed to be beyond the pale of traditional epidemiological tools. Elucidating a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared particularly elusive (1). The impression, that environmental risk factors for ALS were not providing consistent direction, meant there was no sturdy epidemiologically-based "handle" to grasp when trying to envisage a biological mechanism for triggering sporadic ALS (2). There have been challenges with interpreting the data. At times, generic concerns over potential limitations of traditional epidemiological studies have appeared to overshadow the findings in circumstances where these limitations had been overcome largely. At other times, studies with different degrees of methodological limitations have been lumped together, thereby obscuring the results of the studies with less limitations. On occasion, methodological limitations have been downplayed or ignored entirely.Emergence of Mendelian Randomization (MR) methods has offered the promise of overcoming some of the potential limitations of epidemiological studies that used traditional methods. MR methods apply concepts developed in the field of economics to infer causality in the presence of unmeasured confounding (3). The principal idea is: 1) a genetic pattern is identified that predicts a suspected risk factor - a laboratory value in patients' blood, or a particular behavior; 2) that pattern is sought in patients and controls; 3) excess presence of the pattern in patients suggests that the risk factor plays a causal role in producing the disease.However, application of MR methods requires that several underlying assumptions, specific to these methods, have been satisfied (3). Moreover, epidemiological analyses using MR methods need to adhere to core epidemiological and statistical principles. Finally, findings from MR studies need to be interpreted critically, with close attention to the context from which they arise, and with utilization of internal and external comparators (4,5).This presentation will discuss the assumptions that need to be met to apply MR methods in general and how they relate to studies in patients with ALS, drawing on recently published reports.

Use of TPA to treat patients with acute ischemic stroke was introduced in Assaf Harofeh Medical Center (AHMC) in Israel in November 2007 initially with strict adherence to the inclusion/exclusion criteria of the pivotal NINDS TPA studies published in 1995. The treatment window was expanded in 2010 to 4.5h following the results of ECASS-III. Application of the 2013 AHA/ASA Guidelines resulted in further expanded inclusion and relaxed exclusion criteria.A retrospective chart review was conducted of patients who received TPA at AHMC to evaluate the additional impact of applying the 2013 guidelines. Number of patients treated, outcomes at discharge, and safety were compared between two periods: May 2011-January 2013 (the 21months preceding the 2013 Guidelines); and February 2013-October 2014 (the 21months after publication of the 2013 Guidelines). Statistical analysis was done using z-tests for differences between proportions, and t-tests to compare means.63 patients were treated during the immediate pre-2013 Guideline period (36/year, or approximately 5% of patients with ischemic stroke), and 105 during the post-2013 Guidelines period (60/year, approximately 8.3% of patients with ischemic stroke) (p0.001). During the two periods, respectively: discharges home were 22(34%) and 55(52%) (p0.05); facility discharges were 29(46%) and 33(31%); and inter-hospital transfers were 6(9%), and 11(10% of treated patients). Most transfers were for endovascular treatment. Total treatment-related symptomatic bleeds in the two periods, respectively, was: 4(6%) and 4(4%), and the number of in-hospital deaths was 6 (9%) and 6 (6%) (unchanged).Application of the 2013 AHA/ASA Guidelines resulted in a 64% increase in the number of acute ischemic stroke patients treated with TPA at AHMC with no worsening of aggregate outcomes and no increase in bleeds or deaths.

Amyotrophic lateral sclerosis (ALS) is a multilevel disease of the motor neuron system. The mechanisms triggering disease onset should be considered separately from those facilitating its spread and motor neuron death. In 2005, I brought together clinical and epidemiological evidence to support the hypothesis that acquired nucleic acid changes may trigger sporadic ALS. Since 2005, the conceptual foundations for this hypothesis have been strengthened. The journal Amyotrophic Lateral Sclerosis was renamed Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. The focal onset, with simultaneous initial maximal upper and lower motor neuron involvement in the region of onset, and patterns of spread, were characterized further. Clues from the epidemiology of sporadic ALS were affirmed by quantitative analysis, including the increase in disease incidence with age, suggesting accrual of time-dependent changes, and the confirmation of smoking as an established risk factor. Additional observations support the conclusion that accrued somatic mutations trigger onset of ALS. Muscle Nerve 53: 842-849, 2016.

Thymectomy is a reliable surgical method for treating patients with myasthenia gravis (MG) and benign tumors of the thymus. Despite the advantages of minimally invasive surgical approaches for resection of thymic neoplasms, there are still controversies regarding the superiority of one type of surgery over another.To report the results of our initial Israeli experience with robotic thymectomy in 22 patients with MG and suspected benign thymic tumors.We retrospectively analyzed 22 patients (10 men, 12 women) who underwent robotic thymectomy by a left-sided (16) or right-sided approach (6) using the da Vinci robotic system at Assaf Harofeh Medical Center. Seven patients were diagnosed with MG before surgery and 14 had suspected benign thymic neoplasms.Average operative time was 90 minutes. There were no deaths or intraoperative complications. Postoperative complications occurred in two patients (dyspnea and pleural effusion). Median blood loss was 12.3 cc (range 5-35 cc), median hospital stay 2.9 days (range 2-5 days), and mean weight of resected thymus 32.1 grams. Seven patients had thymic hyperplasia, six a lipothymoma, one a thymic cyst. Seven each had thymomas in different stages and one had a cavernous hemangioma.Robotic thymectomy is a safe, technically effective surgical method for resection of thymic neoplasms. The advantages of this technique are safety, short hospitalization period, little blood loss, and low complications. We have included this surgical procedure in our thoracic surgery residency program and recommend a learning curve program of 10 to 12 procedures during residency.

Amyotrophic lateral sclerosis is the most common degenerative disease of the motor neuron network. Due to its inevitably fatal outcome, numerous attempts have been made to ameliorate its course. The emergence of every new technology has spurred research to see if it might benefit patients with ALS (PALS). This paper suggests a detailed road map to be followed when performing clinical research in PALS to satisfy the ethics requirements of the Declaration of Helsinki, expressed using the terminology of Beauchamp and Childress. The ethics principles that need to be satisfied are arranged in a hierarchical manner, each having to be satisfied before the next is approached: Justice; Beneficence, Nonmaleficence, Professional-Patient Relationship, and Respect for Autonomy. Study participants' autonomy can be respected only when all other principles have been addressed before PALS are approached to participate. Five 'red flags' are identified, which, if present, might indicate a risk that PALS may be exploited. PALS who are contemplating new treatments or clinical trials and their families will be assured that their best interests are the only ones that matter whenever adherence to established ethics principles and avoidance of known pitfalls are made explicit.

BACKGROUND: Observational studies of thrombolysis outcomes in wake-up acute ischemic stroke (AIS) patients selected based on non-contrast brain CT criteria suggested that treated patients did as well as or better than those not treated, after adjustment for baseline characteristics. We began offering thrombolytic treatment (IVTPA) to patients presenting with wake-up strokes and normal non-contrast brain CTs, who could be treated within 4.5 hours of being found.DESIGN/METHODS: A retrospective chart review was performed in patients presenting with AIS between November 2014 and December 2017 who received IVTPA. A planned subgroup analysis compared patients with wake-up strokes and normal non-contrast brain CTs to patients with witnessed stroke treated within 4.5 hours of being found, or of witnessed onset, respectively.RESULTS: Three hundred and six patients were treated, 279 with witnessed and 27 with wake-up strokes. Efficacy and safety were similar in both groups. Discharges home, respectively, were 143(53%) and 13(48%); facility discharges were 112(40.1%) and 11(40.7%) and in-hospital mortality was 19 (6.8%) and 3 (11%). Treatment-related symptomatic bleeds were: 5(1.8%) and 1 (3.7%), respectively.CONCLUSIONS: The findings show that it is safe to treat patients with wake-up strokes and a normal brain CT scan with IV TPA. Demonstrating safe utilization of absence of early ischemic tissue changes on CT to expand thrombolytic treatment eligibility in patients with wake-up stroke suggests that it may be safe to extend beyond 4.5 hours the treatment eligibility window in patients with witnessed stroke onset, when the non-contrast brain CT scan is normal.

Amyotrophic lateral sclerosis (ALS) is the neurodegenerative disease caused by systematic unraveling of the motor network, resulting in progressive loss of upper and lower motor neurons, leading to muscle wasting and weakness, culminating in ventilatory failure and death.1 There are no treatments that prevent the inexorable course. Stem cells have been promoted as potential therapy for ALS based on their ability to self-renew and differentiate into multiple cell types with the ultimate goal of repairing or replacing injured cells. However, replacing injured cells does not have a high likelihood of successfully treating ALS. Even if stem cells differentiated into motor neurons, it would be difficult to imagine the new motor neurons reproducing the extensive connections lost among cortical neurons, or between specific cortical neurons and their spinal counterparts, or among spinal neurons, or between spinal neurons and their target muscles. Moreover, new motor neurons, if integrated into a diseased network, might be subject to the same pathologic processes that brought about the demise of the original motor neurons. A more attainable goal for stem cells in ALS is that they help extend the lives of spinal motor neurons. The presumptive rationale for transplanting neural progenitor cells (NPCs) in patients with ALS is based on the in vitro demonstration that such cells secrete protective growth factors and, in vivo, can differentiate into neurons and glia that can repair injured cells.2 Transplantation of NPCs derived from a single 8-week human fetal spinal cord extended lifespan by 17 days when injected into the spinal cords of G93A SOD rats, a common model of ALS. In these studies, the grafts underwent extensive neuronal and to a lesser extent astrocytic differentiation, presumably mediated by graft intrinsic factors and the host microenvironment.3, 4

Objective: To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predicts adverse surgical outcomes. Methods: A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified according to the evidence-based methodology of the American Academy of Neurology. Objective outcomes of postoperative onset of paraparesis, paraplegia, and quadriplegia were used because no randomized or masked studies were available. Results and Recommendations: Four Class I and 8 Class II studies met inclusion criteria for analysis. The 4 Class I studies and 7 of the 8 Class II studies reached significance in showing that paraparesis, paraplegia, and quadriplegia occurred in the IOM patients with EP changes compared with the IOM group without EP changes. All studies were consistent in showing all occurrences of paraparesis, paraplegia, and quadriplegia in the IOM patients with EP changes, with no occurrences of paraparesis, paraplegia, and quadriplegia in patients without EP changes. In the Class I studies, 16%–40% of the IOM patients with EP changes developed postoperative-onset paraparesis, paraplegia, or quadriplegia. IOM is established as effective to predict an increased risk of the adverse outcomes of paraparesis, paraplegia, and quadriplegia in spinal surgery (4 Class I and 7 Class II studies). Surgeons and other members of the operating team should be alerted to the increased risk of severe adverse neurologic outcomes in patients with important IOM changes (Level A). Neurology ® 2012;78:585–589

Amyotrophic lateral sclerosis (ALS) affects approximately 1 in 400 adults of western European ancestry, making it the most common degenerative disease of the motor neuron network. ALS has a mean age at onset of 65 and 85%–90% of cases occur sporadically. Ten to fifteen percent of cases have a recognized genetic contribution, usually in known ALS gene-carrying families.1 In populations of European extraction, the commonest cause of familial ALS, accounting for up to 40% of familial cases, is the C9orf72 hexanucleotide repeat expansion.2 C9orf72 has a broader associated phenotype including frontotemporal dementia and a more rapid clinical progression. Men with spinal-onset disease have a lower median age at onset and drive the more rapid clinical progression.2 Other gene variants also associate with earlier age at onset and more rapid progression; for example, the A4V variant mutated SOD1 gene.3

Objectives: A 2003 evidence-based review of exogenous risk factors for sporadic amyotrophic lateral sclerosis (ALS) identified smoking as the only risk factor that attained “probable” (more likely than not) status, based on 2 class II studies. The purpose of the current, evidence-based, update was to see if the conclusion of the previous review needed to be modified, based on studies published since. Methods: A Medline literature search was conducted for the period between 2003 and April 2009 using the search terms smoking and (ALS or “amyotrophic lateral sclerosis” or MND or “motor neuron disease”). The references of primary articles and reviews were checked to assure completeness of the search. Primary articles published since the previous review were classified as before. Results: Twenty-eight titles were identified, but only 7 articles met inclusion criteria. Of these, 1 provided class II evidence, and 1 class III evidence: both showed increased risk of ALS with smoking. The class II study showed a dose-response effect, and risk decreasing with number of years since quitting smoking. Five articles provided class IV or V evidence, which may not be relied upon to draw conclusions. Conclusions: Smoking may be considered an established risk factor for sporadic amyotrophic lateral sclerosis (ALS) (level A rating; 3 class II studies, 1 class III study). Evidence-based analysis of epidemiologic data shows concordance among results of better-designed studies linking smoking to ALS, and lets those results drive the conclusions.

An evidence-based review was undertaken of the literature published between 2002 and 2006 about sports, trauma and ALS in order to see if there were new data to modify the conclusions of a previous review (2003). The new data support the previous conclusions that physical activity and trauma are probably ("more likely than not") not risk factors for ALS (Level II conclusions). This review concludes also that the reports of an apparent excess of ALS in Italian soccer players likely reflect incorrect analysis of the data. The appearance of excess relies on accepting as valid estimation methods resulting in improbably low numbers of expected cases. A different method is proposed: it generates more plausible numbers of expected cases, compared to which there is no excess of total cases (Level C conclusion). A theoretical framework is developed to analyze the possible influence of a "healthy worker effect" on incidence of neurodegenerative diseases in cohorts of employed or formerly employed individuals. In lieu of theoretical speculations, data are needed to measure this effect, while controlling for known lifestyle factors and accounting for the effect of loss of competing causes of mortality.

Background and purpose: Recurrent ischemic stroke in patients with CS and PFO has been proposed as a marker of increased risk for paradoxical embolism. It is unclear, whether the excess risk is driven by specific features of the PFO (right-to-left shunt (RLS) size, RLS at rest, associated atrial septum aneurysm (ASA)) or the presence of vascular risk factors (vRF). We compare the prevalence of vRF, TEE features, and baseline medications in PFO patients with first-ever versus multiple CS. Methods: From September 2008 to March 2013, the International PFO Consortium enrolled 993 patients with ischemic stroke or transient ischemic attack (TIA) and newly diagnosed PFO. In this analysis of baseline data, we included 386 patients with first-ever CS and no radiological evidence of prior cerebral ischemia (first-ever CS group, mean age, 52y) as well as 71 patients with recurrent CS and multiple ischemic lesions on CT and/or MRI (multiple CS group, mean age, 59y). Patients with TIA as index event, those with first-ever CS but additional “silent” ischemic lesions on imaging as well as those with recurrent CS without radiological findings of prior cerebral ischemia were excluded. We used nonparametric tests for independent samples and the Bonferroni correction for multiple comparisons. Results: Age > 55y (63% vs. 44%, P=0.001), hypertension (52% vs. 30%, P=0.001), hyperlipidemia (64% vs. 44%, P=0.003), and coronary artery disease (15% vs. 3%, P=0.001) were significantly more frequent in the multiple CS than in the first-ever CS group. The frequencies of male gender, current smoking, diabetes, migraine with or without aura, associated ASA, RLS size, and RLS at rest did not differ between groups. At baseline, patients with multiple CS were more likely to be on antiplatelets (50% vs. 18%), antihypertensive (51% vs. 22%) or lipid lowering drugs (44% vs. 10%, P=0.001 for each comparison) than patients with first-ever CS. The frequency of anticoagulant treatment did not differ between groups. Conclusions: In patients with CS, vRF but not specific PFO features were associated with recurrent cerebral ischemic events. The ongoing prospective part of the International PFO Consortium will likely shed light upon the role of vRF control for secondary stroke prevention in patients with PFO.

An evidence-based medicine approach was applied to evaluate analytic studies of exogenous risk factors for amyotrophic lateral sclerosis (ALS) published since 1991. Classification systems for evaluating the literature and for drawing conclusions based on the class of available evidence were developed, modeled on those used by national societies. Considerations regarding the impact on the general public of confirming a role for putative risk factors were made explicit. There was evidence in support of smoking being a probable (‘more likely than not’) risk factor for ALS. Smoking has broad public health impact, no redeeming features, and is a modifiable risk factor. Evidence supported the conclusion that the following were probably not risk factors for ALS: trauma, physical activity, residence in rural areas and alcohol consumption. Evidence-based medicine methodology does not permit calculation of the magnitude of type I or type II errors in drawing these conclusions. New evidence may change these conclusions. Recommendations for future research include: draw on clinical trial methodology in designing future, confirmatory, case-control studies; consider utilizing cohort studies, recognizing the longer timelines for these to come to fruition; accord priority to investigating putative risk factors with greatest public health impact. Advances in study methodology may lead to development of finite research cycles for individual putative risk factors for sporadic ALS.

Objective: To review the risk of MS exacerbations after infectious episodes potentially preventable by vaccination, and the risks and benefits of immunizing patients with MS. Methods: The authors searched MEDLINE (1966 to January 2001; U.S. National Library of Medicine, Bethesda, MD), HealthSTAR, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) database (Cinahl Information Systems, Glendale, CA) for English-language articles. Each study was summarized and rated for quality of evidence. Then feasible data were pooled and analyzed in meta-analysis. Results: The risk of contracting common infectious diseases in patients with MS is not well established. There is strong evidence for an increased risk of MS exacerbations during weeks around an infectious episode. There is strong evidence against an increased risk of MS exacerbation after influenza immunization. There is no evidence that hepatitis B, varicella, tetanus, or Bacille Calmette–Guerin vaccines increase the risk of MS exacerbations. Insufficient evidence was found for other vaccines. Conclusions: Evidence supports 1) strategies to minimize the risk of acquiring infectious diseases that may trigger exacerbations of MS; and 2) the safety of using influenza, hepatitis B, varicella, tetanus, and Bacille Calmette–Guerin (BCG) vaccines in patients with MS.

Review of the literature on prevention of post-lumbar puncture headaches (PLPHAs) since the publication of the original assessment in 2000 yielded one study comparing use of cutting to atraumatic needles in diagnostic lumbar punctures, providing Class I evidence in favor of the atraumatic needle. Taken in conjunction with data from most studies in the anesthesiology literature, the Therapeutics and Technology Assessment Subcommittee concluded that use of an atraumatic spinal needle in adult patient populations reduces the frequency of PLPHA (Level A recommendation). It affirmed a previous conclusion that smaller needle size is associated with reduced frequency of PLPHA (Level A recommendation).

SummaryAlzheimer’s disease is a known risk factor for seizures, and age older than 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. The authors suspect that there may be a causal relationship between dementia pathology and the development an

We have examined, as predictors of survival in patients with amyotrophic lateral sclerosis (ALS), linear estimates of rates of disease progression (LEP), based on motor unit number estimates (MUNE). Motor unit number estimates of thenar, hypothenar, and extensor digitorum brevis muscles (according to the manual method of McComas), isometric grip and foot dorsiflexion (FD) strength, and forced vital capacity (FVC) were available in 34 patients. Linear estimates of rates of disease progression were derived. Probability of survival was calculated using the Kaplan-Meier method. Motor unit number estimates, LEP based on MUNE, and demographic characteristics were tested as risk factors within the Cox Proportional Hazards Model, using regression techniques. Individually, all MUNE-based LEP were highly significant (P < 0.00005); bulbar onset attained modest significance (P = 0.044). Secondary analysis showed MUNE-based LEP were more significant than regionally concordant function-based LEP. Linear estimates of rates of disease progression based on MUNE may thus predict survival of patients with ALS better than LEP based on function.