A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Reversible cerebral vasoconstriction syndrome: a thunderclap headache-associated condition.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by a sudden, severe headache at onset, vascular narrowing involving the circle of Willis and its immediate branches, and angiographic evidence of vasoconstriction reversibility within minutes to weeks of onset. RCVS is underrecognized and often misdiagnosed; it can defy clinical detection because it can mimic common conditions such as migraine and ischemic stroke. A lack of shared nosology has hampered awareness and understanding of the syndrome. Clinicians must consider primary angiitis of the central nervous system because of its high rates of morbidity and mortality if left untreated. RCVS has a number of primary and secondary associations (cerebral hemorrhage, vasoactive substances, the peripartum period, bathing, and physical exertion) but also occurs in isolation. RCVS can present in conjunction with hypertensive encephalopathy, preeclampsia, and reversible posterior leukoencephalopathy. This review provides an up-to-date account of RCVS.

Reversible cerebral vasoconstriction syndrome or primary angiitis of the central nervous system?

BACKGROUND: Reversible Cerebral Vasoconstriction Syndrome (RCVS) may present as thunderclap headache (TCH), accompanied by reversible cerebral vasospasm and focal neurological deficits, often without a clear precipitant. RCVS may be mistaken for Primary Angiitis of the Central Nervous System (PACNS) due to the presence of similar angiographic features of segmental narrowing of cerebral arteries. We discuss the clinical features of a young female migraine patient who developed TCH and was found to have RCVS following initial treatment with corticosteroids for PACNS, in the context of a systematic review of the available medical literature. METHODS: A Medline search was performed to identify all case reports since 1966 describing RCVS and PACNS that provide sufficient clinical detail to permit diagnostic classification according to published criteria. RCVS included case studies in which there was angiographic or transcranial Doppler ultrasound evidence of near-to-complete resolution of cerebral vasoconstriction in the absence of a well-recognized secondary cause. PACNS included reports of histologically confirmed PACNS either through biopsy or necropsy. RESULTS: Reversible Cerebral Vasoconstriction Syndrome occurs primarily in females and is characterized by sudden, severe headache at onset, normal CSF analysis, vasoconstriction involving the Circle of Willis and its immediate branches, and angiographic or TCD ultrasound evidence of near-to-complete vasospastic resolution within 1-4 weeks. It occurs typically in the context of vasoconstrictive drug use, the peripartum period, bathing, and physical exertion. CONCLUSION: Initial and follow-up (within 4 weeks) non-invasive angiographic studies are indicated in patients who present with TCH or who have clinical presentations that could be consistent with RCVS or PACNS in the absence of a well-recognized secondary cause, such as subarachnoid haemorrhage. Early reversibility of cerebral vasospasm is the key neuroradiological feature that supports the clinical diagnosis of RCVS.

Progress in clinical neurosciences: Migraine-stroke: a causal relationship, but which direction?

A significant association between migraine and ischemic stroke has been demonstrated in population and case-control studies. The risk of ischemic stroke appears to be higher in migraine with aura (MWA) than migraine without aura (MwoA). Migraine-stroke comprises a number of distinct entities, including migrainous infarction, in which ischemic stroke occurs during an attack of MWA and migraine-related stroke, in which the causal link is less clear. Migrainous infarction accounts for only one-third of migraine-stroke, strokes may occur during attacks of MwoA, and a number of cerebrovascular disorders may present as MWA or MwoA. Migraine may occur as a consequence of conditions that are known to cause stroke; therefore it remains to be determined whether migraine predisposes to stroke in the absence of any known disease associations, if it is an epiphenomenon of an underlying stroke diathesis, or if it requires the presence of another stroke risk factor to produce cerebral ischemia. Furthermore, it is unclear if ischemia results in migraine more often than migraine results in ischemia. Careful clinical studies that evaluate this bidirectional relationship are needed to determine why migraine patients are subject to a higher risk of ischemic stroke.

Disease adaptation may have decreased quality-of-life responsiveness in patients with chronic progressive neurological disorders.

OBJECTIVE: We hypothesized that disease adaptation could be measured in chronic progressive neurological disorders (CPND) through paired longitudinal comparisons of quality of life (QOL) and health status (HS) and of the mental health (MH) and physical health (PH) domains of QOL instruments. STUDY DESIGN AND SETTING: We identified 193 quantitative studies of QOL and HS in a systematic review of episodic (END) and chronic progressive (CPND) neurological disorders. Effect size or other responsiveness measures were analyzed in 31 studies that included paired longitudinal comparisons of QOL-HS, MH-PH, or both. Responsiveness means were compared using the paired-sample t-test or sign test. RESULTS: In 12 paired comparisons, QOL responsiveness was significantly lower than HS (P=.05, sign test). In 53 paired MH-PH effect-size comparisons, MH responsiveness was lower than PH (P=.02, t=2.48, paired sample). Significantly lower MH responsiveness was observed in 28 paired CPND comparisons (P < .01, t=3.86, paired sample) but not in 25 paired END comparisons (P=.50, t=0.68, paired sample). CONCLUSION: Lower responsiveness of QOL in CPND may be related to disease adaptation. Further prospective studies are needed to confirm our findings and to investigate the importance of disease adaptation in the evaluation of neurological disease and in health resource allocation.

Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis.

BACKGROUND: There is controversy as to whether migraine is associated with white matter abnormalities (WMAs) on magnetic resonance images. These abnormalities may be important as a risk factor for future stroke. Further, it is controversial whether any increased risk of WMAs is attributable to comorbidities such as vascular disease. METHODS: A meta-analysis of published case-control studies was undertaken to address the relationship between migraine and magnetic resonance imaging WMAs. Seven studies were identified. Data from studies reporting the incidence of magnetic resonance imaging WMAs in those with migraine and appropriate control populations were used to calculate odds ratios for WMAs in migraine for each study. A stratified meta-analysis was performed using studies that did and did not exclude subjects with disease comorbidities. RESULTS: The summary odds ratio shows that those with migraine are at increased risk for WMAs (odds ratio, 3.9 [95% confidence interval, 2.26-6.72]). The risk does not differ between studies that included subjects with comorbidities and those that did not. CONCLUSION: This meta-analysis demonstrates that subjects with migraine are at higher risk of having WMAs on magnetic resonance images than those without migraine. This increased risk is present even in younger individuals who do not have co-occurring cerebrovascular disease risk factors. Prospective studies are needed to determine whether the increased risk of stroke in migraine is mediated or foreshadowed by the presence of WMAs.

West Nile virus infection in the intensive care unit: a case series and literature review.

BACKGROUND: West Nile virus (WNV) is a rapidly spreading infectious disease in North America. Critical care issues related to WNV are not well described. OBJECTIVES: Three cases of severe WNV meningoencephalitis with flaccid paralysis are reported and relevant critical care issues are highlighted. METHODS: Case series and a review of the literature. RESULTS: Three patients with WNV meningoencephalitis and flaccid paralysis were admitted to the authors' academic, tertiary-care intensive care unit (ICU) in the late summer of 2002. All three patients were middle-aged or elderly and presented with a febrile illness that preceded or coincided with their neurological symptoms. Confirmation of WNV infection was problematic because each patient had at least one initial negative serum serology test. Radiological testing yielded nonspecific results. Serial electroencephalograms were consistent with severe toxic metabolic encephalopathy in all cases. All patients had a severe, diffuse axonal polyneuropathy demonstrated by nerve conduction studies and electromyography. Prolonged mechanical ventilation resulted in ICU lengths of stay of 44 to 118 days. At one point, 21% of the ICU beds were dedicated for these patients. All three patients died in hospital - two following the withdrawal of life support. One patient demonstrated resolving encephalitis and was discharged from the ICU after a 118-day ICU stay, but later died in a step-down unit. CONCLUSIONS: The management of WNV-related critical illness creates challenges in making a timely and accurate diagnosis, and predicting patient morbidity and mortality. As a consequence, end-of-life discussions with families are especially difficult. The prolonged ICU length of stay and growing incidence of this disease may challenge limited critical care resources.

Neurological manifestations of West Nile virus infection.

BACKGROUND: Over the past four years, West Nile virus (WNV) has become a significant health issue in North America. In 2002, WNV infection made its first appearance in the human population in Canada. METHODS: Patients who presented to the University Health Network and Mount Sinai Hospital in Toronto with neurological disease attributed to WNV infection were identified and followed by the neurology service. Clinical features and results of laboratory, electrodiagnostic, radiological and pathological studies are presented. RESULTS: In August and September 2002, 26 patients were admitted with WNV infection; 14 presented with neurological illness. Encephalitis was the most common presentation (11 patients). Eleven patients developed neuromuscular disease; two at presentation and nine after encephalitis. While the majority had a motor process that localized to the anterior horn cell and/or motor neuron, two patients had evidence of a demyelinating neuropathy and one a sensorimotor axonal neuropathy. Less common manifestations included rhombencephalitis, ataxia, myelopathy and parkinsonism. Death occurred in four patients; two > 75 years of age, and two who were immunocompromised. CONCLUSIONS: The most common neurological manifestation of WNV infection was encephalitis with subsequent neuromuscular involvement. The diversity of clinical and pathological findings, however, suggests widespread involvement of the central and peripheral nervous system. A poorer prognosis for neurological recovery and overall survival was seen in older and immunocompromised patients.

The electrodiagnosis of ulnar nerve entrapment at the elbow.

Entrapment of the ulnar nerve at the elbow is the second most common focal peripheral neuropathy. Recent advances have facilitated the electrodiagnosis of this common nerve entrapment. The goals of electrodiagnosis are to localize ulnar nerve dysfunction, confirm that the disturbance is confined to the ulnar nerve, and assess the severity of ulnar nerve dysfunction. The goal of this review is to highlight the important advances in anatomy, neurophysiology and methodology that impact upon the electrodiagnosis of entrapment of the ulnar nerve at the elbow, illustrate the limits of electrodiagnosis, and discuss methodological issues that may be the subject of further study. Careful attention to elbow position, temperature, and conservative estimates of conduction block should be part of common practice. Awareness of anatomical variations in structural anatomy, anomalous innervation and fascicular arrangement of ulnar nerve fibers are required to interpret electrodiagnostic studies accurately. The most reliable finding is slowing of the ulnar across-elbow motor nerve conduction velocity to less than 50 m/sec while recording from the abductor digiti minimi muscle, and should be carefully interpreted in the presence of a polyneuropathy or other neurogenic process. Alternative techniques such as relative ulnar slowing in different ulnar nerve segments, use of alternative muscles, sensory and mixed nerve techniques provide complementary information, and like all nerve conduction studies are highly operator-dependent and should be used on a case by case basis. Recent studies have focused the electromyographer's attention on the use of shorter across-elbow segments (2-5 cm). This may offer a reasonable trade-off between sensitivity and measurement error and may result in improved electrodiagnosis.