Marc Gotkine

Emergent Stenting to Treat Patients With Carotid Artery Dissection Clinically and Radiologically Directed Therapeutic Decision Making

Background and Purpose— Carotid artery dissection (CAD) is a common cause of stroke in young patients. Clots formed at the low-flow zone in the false arterial lumen may give rise to distal emboli, and the mural hematoma may eventually occlude the artery. Anticoagulation is currently the accepted treatment, but it is unknown which patients will improve spontaneously, which will respond to anticoagulation, and which will have an exacerbation of ischemic symptoms despite therapy. Endovascular treatment of CAD may be an attractive alternative to anticoagulation, and methods of identifying patients who stand to benefit from such therapy need to be established. Methods— We present here 3 cases of spontaneous symptomatic CAD in which endovascular stenting procedures were performed on the basis of a paradigm aimed at identifying potentially salvageable but at-risk brain tissue by combining clinical with MRI (diffusion and perfusion) and angiographic data. Results— Diffusion-perfusion MRI mismatches and/or evidence of cerebral ischemia on angiographic parenchymography were identified in all patients. They did not respond to anticoagulation, were therefore treated with endovascular stents, and had excellent outcomes. Conclusions— Endovascular stent placement may be an immediate, effective, and safe method of restoring vessel lumen integrity. It may be considered for selected patients who are clinically symptomatic despite anticoagulant treatment and in whom neuroimaging methods suggest that the neurological signs originate from a viable, hypoperfused, ischemic penumbra.

Recanalization after intravenous thrombolysis: Does a recanalization time window exist?

Background: To evaluate the time course of major vessel recanalization under IV thrombolysis in relation to functional outcome in acute ischemic stroke. Methods: A total of 99 patients with an acute anterior circulation vessel occlusion who underwent IV thrombolysis were included. All patients had a standardized admission and follow-up procedure. Color-coded duplex sonography was performed on admission, 30 minutes after thrombolysis, and at 6 and 24 hours after onset of symptoms. Recanalization was classified as complete, partial, and absent. Functional outcome was rated with the modified Rankin Scale on day 30. Results: Complete recanalization occurred significantly more frequently in patients with multiple branch occlusions compared to those with mainstem occlusion (OR 5.33; 95% CI, 2.18 to 13.05; p < 0.0001) and was associated with lower NIH Stroke Scale (NIHSS) scores (p < 0.001). Not the specific time point of recanalization at 6 or 24 hours after stroke onset, but recanalization per se within 24 hours (OR 7.8; 95% CI 2.2 to 28.2; p = 0.002) was significantly associated with a favorable outcome. Multivariate analysis revealed recanalization at any time within 24 hours and NIHSS scores on days 1 and 7 together explaining 75% of the functional outcome variance 30 days after stroke. Conclusions: Complete recanalization up to 24 hours after stroke onset is significantly associated with the short-term clinical course and functional outcome 30 days after acute stroke.

Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials

IMPORTANCE Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases. OBJECTIVE To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells. INTERVENTIONS Patients were administered a single dose of MSC-NTF cells. MAIN OUTCOMES AND MEASURES The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale-Revised score and the respiratory function. RESULTS Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale-Revised score in the IT (or IT+IM)-treated patients was reduced (from -5.1% to -1.2%/month percentage predicted forced vital capacity, P < .04 and from -1.2 to 0.6 ALS Functional Rating Scale-Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale-Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression. CONCLUSIONS AND RELEVANCE The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT01051882 and NCT01777646.

Acute Disseminating Encephalomyelitis in Neuromyelitis Optica: Closing the Floodgates

OBJECTIVE To report the clinical and radiological features of 2 patients with neuromyelitis optica (NMO) associated with severe acute disseminating encephalomyelitis. The first patient had anti-aquaporin 4 antibodies (NMO-IgG) but no lesion enhancement, in contrast to the second patient who was seronegative for NMO-IgG but had clear lesion enhancement on magnetic resonance imaging. DESIGN Clinical, laboratory, and radiological analysis of 10 patients presenting with features compatible with an NMO-spectrum disorder, 2 of whom developed acute disseminating encephalomyelitis. SETTING Inpatient ward at the Department of Neurology, Hadassah University. PATIENTS Patients admitted during a 1-year period with features compatible with an NMO-spectrum disorder. INTERVENTIONS Medical histories and imaging data were reviewed and serum samples were analyzed for the presence of NMO-IgG. MAIN OUTCOME MEASURES Clinical and paraclinical evidence of brain involvement. RESULTS Of 10 patients tested, 5 were positive for NMO-IgG. One seropositive and 1 seronegative patient had an acute disseminating encephalomyelitis-like episode. In both cases, the clinical, laboratory, and electroencephalographic findings supported a diagnosis of acute disseminating encephalomyelitis. Magnetic resonance imaging demonstrated extensive bilateral white matter lesions in both patients. Lesions in the seropositive patient were notably lacking in enhancement following gadolinium injection, whereas robust lesion enhancement was observed in the seronegative patient. CONCLUSIONS Acute disseminating encephalomyelitis without lesion enhancement on magnetic resonance imaging may represent a childhood manifestation of seropositive NMO. The lack of enhancement suggests an intact blood-brain barrier and supports a unique mechanism of edema induction due to dysfunction of water channels.

Myasthenia gravis-associated neuromyelitis optica-like disease: an immunological link between the central nervous system and muscle?

BACKGROUND Although overt involvement of the central nervous system (CNS) in myasthenia gravis (MG) is considered rare, hyperreflexia is a common and yet unexplained finding. Aquaporin 4 (AQP4), the target autoantigen in neuromyelitis optica, is expressed both in the CNS and in the neuromuscular junction. OBJECTIVES To evaluate the prevalence of even mild CNS involvement in patients with MG and to identify features indicative of neuromyelitis optica-like disease. DESIGN Cohort study. SETTING Outpatient clinic. PATIENTS A cohort of 164 patients with MG. METHODS In 24 patients with MG, signs of CNS involvement were detected; 15 of these patients had at least 1 additional paraclinical indication of neuromyelitis optica-like disease (presence of antibodies against AQP4, pathological visual evoked potentials, or white matter lesions detected on brain and/or spinal magnetic resonance imaging scans) and fulfilled the inclusion and exclusion criteria for our study. RESULTS Of the 15 patients who had at least 1 additional paraclinical indication of neuromyelitis optica-like disease, 14 had abnormal visual evoked potentials, and in 6 of 9 patients in whom magnetic resonance imaging was performed, there was evidence of lesions in the white matter of the brain and/or spinal cord. Anti-AQP4 antibodies were detected in 7 patients (out of the 14 tested). Thymic enlargement (hyperplasia or thymoma) was more frequent in patients with MG who had signs of CNS involvement than in patients with MG who did not. CONCLUSIONS The incidence of CNS involvement in MG is higher than previously reported and is expressed predominantly as a pyramidal syndrome accompanied by optical tract involvement (frequently subclinical). These features bear some resemblance to neuromyelitis optica spectrum disease, supported also by the presence of anti-AQP4 antibodies in 7 of the 14 patients tested. This association may represent a new nosological entity or may indicate that an autoimmune process targeting AQP4 is an integral part of the immunopathogenetic mechanisms in MG.

Lack of hemispheric localizing value of the palmomental reflex

I read the article by Gotkine et al.1 with great interest. They concluded there was no significant association between the side of the reflex and the side of hemispheric lesion in patients with unilateral reflexes and the unilateral lesions. We are interested in palmomental reflex (PMR) in various neurological disorders and are routinely performing this test. In my experience, there is no significant correlation between the side of positive reflex and the pathognomonic site. I would like to ask the authors to clarify a few points. If 89% of …

Increased severity over generations of Charcot-Marie-Tooth disease type 1A

BackgroundCharcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance.ObjectivesWe set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations.MethodsThirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS).ResultsIn 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001).Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test).ConclusionsOur findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

Rare combination of myasthenia and motor neuronopathy, responsive to Msc-Ntf stem cell therapy

A 75-year-old man was referred to the Hadassah Medical Center with a 6-month history of progressive limb weakness, dysarthria, and cognitive deterioration. His past medical history included prostate hyperplasia, hypothyroidism, diabetes mellitus, cardiac arrhythmias controlled by pacemaker implantation (1997), and hypertension. Autoimmune myasthenia gravis (MG) had been diagnosed 2 years earlier, based on symptoms of fluctuating fatigue, dysarthric speech, eyelid ptosis, and seropositivity for muscle acetylcholine receptor (AChR) binding antibody. MRI did not reveal thymic enlargement, and malignancy markers (and whole-body computed tomography) were negative. Moderate improvement followed treatment, initially with intravenous immune globulin and later with low dose corticosteroids, pyridostigmine, and azathioprine. The patient was evaluated previously at the Mayo Clinic (Rochester, Minnesota) and had been diagnosed with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The diagnosis was based on the cognitive exam and clinical features of progressive diffuse upper and lower motor neuron dysfunction with electromyographic findings (low motor amplitudes, no focal slowing or conduction blocks, no postexercise facilitation, presence of diffuse fibrillation and fasciculation potentials, and large complex motor unit potentials in all limbs) fulfilling the El-Escorial criteria for ALS. MRI and positron emission tomography scans of the brain showed moderate atrophy predominantly affecting the frontal and temporal lobes. Spinal fluid was acellular with slightly elevated total protein (50 mg%). Autoimmune serology revealed antibodies specific for muscle (AChR binding 9.47 nmol/L [normal 0.00–0.02]; AChR modulating 100% loss [normal 0–20%]; striational 15,360 [normal <60]) and thyroglobulin, and antinuclear antibody. On admission, the patient had memory impairment and signs of frontotemporal functional deficits, typical of FTD. Dysarthria rendered speech totally incomprehensible. He had mild eyelid ptosis bilaterally (without extraocular muscle weakness or diplopia) and was markedly quadriparetic (confined to wheelchair) with bilateral foot drop. Distal hand and foot muscles were moderately atrophic, and fasciculations were prominent in all limbs. Deep tendon reflexes were brisk in arms and legs (except hypoactive Achilles reflexes), and an extensor plantar response was evoked bilaterally. Superficial sensation was normal, and vibration sense was reduced slightly distally in the legs. Due to the diagnosis of MG, the patient did not meet inclusion criteria for the Hadassah clinical trial in ALS with autologous enhanced mesenchymal stem cells (MSCNTF, BrainstormVR , Petach Tikva; NCT01051882). The Hadassah Ethics Committee issued a special license for treatment on a compassionate basis. MSC-NTF (prepared from the patient’s bone marrow) were injected intrathecally (1.5 3 10 per kilogram of body weight) and at 24 sites along the biceps and triceps muscles of the right arm (1.5 3 10 per site). The intrathecal and intramuscular administration of the cells were chosen based on previous animal and clinical studies from our groups, which showed good migration of the intrathecally injected cells to the CNS and amelioration of the “dying-back” phenomenon by intramuscularly injected MSC in early stages of ALS in the SOD mouse model (unpublished data and Dadon-Nachum et al.). For the next 2 days the patient had a low-grade fever, headache, and was more confused, but at discharge, these problems had completely subsided. Treatment with azathioprine (125 mg/day) was discontinued 1 month before the injection and readministered 30 days after the treatment. Pyridostigmine (60 mg 3 times daily) and low dose oral prednisolone (10 mg/day) were continued. At 1 month after transplantation, the patient and his family reported significant improvement in cognition, speech, and muscle power. He was able to walk at least 20 meters without any support. The dysarthria improved to the extent he was able to clearly deliver a speech to an audience. ALS Functional Score Scale-Revised (ALSFRS-R, performed at all time points by the same evaluator and confirmed by a second senior examiner) score rose from 36 to 44, and respiratory forced vital capacity (FVC) and cognitive function also improved significantly (Supplementary Table 1, which is available online, and Fig. 1). VC 2013 Wiley Periodicals, Inc.

Triathletes are over-represented in a population of patients with ALS.

Abstract The nature of the association between vigorous physical activity and ALS is unknown, although a possible link to head and neck trauma has been suggested. Observation of a prize-winning triathlete who developed ALS prompted us to analyse our ALS clinic data. We undertook a retrospective cross-sectional clinic-based observational study, analysing self-reported patient data from 185 patients with ALS enrolled in our ALS clinic. We identified patients reporting regular participation in triathlons (ALS-T) and compared clinical and demographic data to other patients with ALS. Data from the Israeli Triathlon Association were used to estimate the frequency of triathlon participation in the general population. Of 185 patients with ALS, five (2.7%) reported triathlon participation compared to the estimated exposure rate of 0.17% in the general population, giving an odds ratio of 16.15 (95% CI 5.85–36.38, p < 0.0001); this highly significant odds ratio remained even after adjustments were made to address potential sources of bias. ALS-T were younger and had a higher frequency of bulbar onset compared to other patients with ALS. In conclusion, our observed excess of triathletes in ALS patients justifies a cohort study focusing on triathletes and suggests that vigorous exercise itself may be related to a predominance of bulbar-onset patients, irrespective of head and neck trauma.

Effect of neck flexion on somatosensory and motor evoked potentials in Hirayama disease

UNLABELLED Hirayama disease (HD) is a rare motor disorder mainly affecting young men, characterized by atrophy and weakness of forearm and hand muscles corresponding to a C7-T1 myotome distribution. The weakness is usually unilateral or asymmetric and progression usually stops within several years. The etiology of HD is not well understood. One hypothesis, mainly based on MRI findings, is that the weakness is a consequence of cervical flexion myelopathy. The aim of this study was to explore the function of corticospinal and ascending somatosensory pathways during neck flexion using evoked responses. MATERIALS AND METHODS 15 men with HD and 7 age-matched control male subjects underwent somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP) studies with the neck in neutral position and fully flexed. SSEP studies included electrical stimulation of median and ulnar nerves at the wrist, and tibial nerve at the ankle with recording over the ipsilateral Erbs point, cervical spine, and contralateral sensory cortex. MEP recordings were obtained by magnetic stimulation of the motor cortex and the cervical lower spinal roots; the evoked responses were recorded from the contralateral thenar and abductor hallucis muscles. RESULTS MEP recordings demonstrated significant lower amplitudes, and slightly prolonged latencies in HD patients on cervical stimulation, compared to control subjects. During neck flexion, MEP studies also demonstrated a statistically significant drop in mean upper limb amplitude on cervical stimulation in HD patients, as well as in control subjects, although to a lesser degree. In contrast, no significant differences were found in SSEP studies in HD patients compared to control subjects, or between neutral and flexed position in these groups. CONCLUSION The study shows a negative effect of cervical flexion on MEP amplitudes in HD patients as well as in control subjects, requiring more studies to investigate its significance. Neck flexion did not have an influence on any SSEP parameters in patients or controls.