Aline Herlopian

Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study☆

We explore the safety, and therapeutic benefit of intrathecal injection of ex-vivo expanded autologous bone marrow derived mesenchymal stem cells (BM-MSCs) in 10 patients with advanced multiple sclerosis (MS). Patients were assessed at 3, 6 and 12 months. Assessment at 3-6 months revealed Expanded Disability Scale Score (EDSS) improvement in 5/7, stabilization in 1/7, and worsening in 1/7 patients. MRI at 3 months revealed new or enlarging lesions in 5/7 and Gadolinium (Gd+) enhancing lesions in 3/7 patients. Vision and low contrast sensitivity testing at 3 months showed improvement in 5/6 and worsening in 1/6 patients. Early results show hints of clinical but not radiological efficacy and evidence of safety with no serious adverse events.

Extracranial venous stenosis is an unlikely cause of multiple sclerosis.

Background: Extracranial venous stenosis (EVS) has recently been implicated as the primary cause of multiple sclerosis (MS). Objective: The aim of this study was to determine the presence of EVS in MS patients. Methods: We performed selective extracranial venography on 42 patients with early MS (EMS): clinically isolated syndrome (CIS) or relapsing—remitting MS (RRMS) of less than 5 years duration, and late MS (LMS): RRMS of more than 10 years duration. Magnetic resonance imaging (MRI) and clinical relapse data were reviewed for all patients with EVS. Results: EVS was present in 7/29 patients with EMS and 12/13 patients with LMS, a highly significant statistical difference (p< 0.001). Only 3/42 patients (all in the LMS group) had two vessel stenoses, while the rest had only one vessel involved. EVS was seen in 1/11 patients with CIS compared with 6/18 RRMS patients of less than 5 years duration. Disease duration was greater in patients with EVS overall (p < 0.005). LMS remained an independent predictor of EVS following multivariate adjustment for gender, age at disease onset and Expanded Disability Status Scale (EDSS) (Adjusted Odds Ratio = 29 (3—298); p = 0.005]. Within the EMS group, patients with (n = 7) and without (n = 22) EVS had similar EDSS and disease duration, suggesting similar disease severity. No clear correlation could be found between site of EVS and anatomic localization of either clinical relapses or MRI gadolinium-enhancing lesions. Conclusions: We conclude that EVS is an unlikely cause of MS since it is not present in most patients early in the disease and rarely involves more than one extracranial vein. It is likely to be a late secondary phenomenon.

Ipilimumab-induced necrotic myelopathy in a patient with metastatic melanoma: A case report and review of literature

Ipilimumab is a novel humanized monoclonal antibody directed against cytotoxic T lymphocyte antigen 4, a T-cell surface molecule involved in down-regulation and suppression of the T cell response to stimuli. Patients treated with ipilimumab are at risk for immune-related adverse events involving the skin, digestive tract, liver and endocrine organs. Few case reports of immune-related adverse effects involving central or peripheral nervous system due to ipilimumab are published. These include inflammatory myopathy, aseptic meningitis, severe meningo-radiculo-neuritis, temporal arteritis, Guillain-Barre syndrome, and posterior reversible encephalopathy syndrome. We report the first case of ipilimumab-induced progressive necrotic myelopathy.

Extreme delta brush evolving into status epilepticus in a patient with anti-NMDA encephalitis

Extreme delta brush (EDB) is an EEG pattern unique to anti-NMDA encephalitis. It is correlated with seizures and status epilepticus in patients who have a prolonged course of illness. The etiology of the underlying association between EDB and seizures is not understood. We present a patient with anti-NMDA encephalitis who developed status epilepticus evolving from the high frequency activity of the extreme delta brush. This case demonstrates that EDB is not only a marker for a greater propensity for seizures but also directly implicated in seizure generation.

Epilepsy surgery in a developing country (Lebanon): ten years experience and predictors of outcome

We present our 10-year experience and preoperative predictors of outcome in 93 adults and children who underwent epilepsy surgery at the American University of Beirut. Presurgical evaluation included video-EEG monitoring, MRI, neuropsychological assessment with invasive monitoring, and other tests (PET, SPECT, Wada). Surgeries included temporal (54%), extratemporal (22%), and multilobar resections (13%), hemispherectomy (4%), vagal nerve stimulation (6%), and corpus callosotomy (1%). Mesial temporal sclerosiswas the mostcommonaetiology (37%). After resective surgery, 70% had Engel class I, 9% class II, 14% class III, and 7% class IV. The number of antiepileptic drugs before surgery was the only preoperative factor associated with Engel class I (p=0.005). Despite the presence of financial and philanthropic aid, many patients could not be operated on for financial reasons. We conclude that advanced epilepsy presurgical workups, surgical procedures, and favourable outcomes, comparable to those of developed countries, are achievable in developing countries, but that issues of financial coverage remain to be addressed.

Predictive Value of Electrocorticography in Patients With Mesial Temporal Lobe Epilepsy Undergoing Selective Amygdalohippocampectomy

Purpose: The utility of intraoperative electrocorticography has been reported in predicting seizure outcome in patients with mesial temporal lobe epilepsy due to mesial temporal sclerosis (MTS) undergoing standard temporal lobectomy. Three studies reported the predictive outcome in patients with MTS undergoing selective amygdalohippocampectomy (sAHE). We evaluate the predictive value of the intraoperative electrocorticography in postoperative outcome in patients with mesial temporal lobe epilepsy secondary to MTS undergoing sAHE. Methods: Retrospective analysis of 36 consecutive patients with mesial temporal lobe epilepsy undergoing sAHE between 2001 and 2012. A single neurosurgeon performed the sAHE. Preresection and postresection spikes were recorded in all patients and interpreted by two epileptologists. Long-term postoperative seizure freedom was correlated with intraoperative electrocorticography findings. Results: Ten patients had normal brain MRI (G1), whereas 26 had MTS (G2). All patients had MTS on histopathology. Mean duration of postoperative follow-up was 21.3 and 24.4 months for G1 and G2, respectively. In G1, 4/10 (40%) had resolution of spikes after sAHE, with 2/4 (50%) seizure free at last follow-up. Spikes were persistent in 6/10 (60%), with 5/6 (83%) seizure free at last follow-up (P value = 0.5). In G2, 7/26 (27%) had postresection resolution of spikes, with 5/7 (71%) seizure free at last follow-up. Spikes were persistent in 19/26 (73%), with 13/19 (68%) seizure free at last follow-up (P value = 0.62). The difference between the two arms of G1 and G2 was statistically insignificant. Conclusions: Postresection intraoperative electrocorticography has limited value in predicting postoperative seizure freedom in patients with mesial temporal lobe epilepsy secondary to MTS undergoing sAHE.

S82. Paroxysmal sympathetic hyperactivity evident as cyclical pattern on quantitative EEG analysis

Introduction Episodic fluctuations in sympathetic activity following traumatic brain injury (TBI) have been described for decades, with paroxysmal sympathetic hyperactivity (PSH) being the currently accepted term for this entity. While early reports postulated an epileptic mechanism, our understanding of the pathophysiology of PSH has evolved. Current hypotheses center around deregulation of central descending inhibitory inputs from the insula and cingulate cortex, resulting in increased sympathetic output from the hypothalamus, diencephalon and brainstem. We present a case of PSH with evidence of disrupted sympathetic arousal networks. Methods A 41-year-old woman suffered a TBI with multifocal supratentorial hemorrhages and intraparenchymal contusions. Eight days post-MVA she developed episodes of tachycardia, hypertension, diaphoresis, back-arching and extensor posturing of the upper extremities upon stimulus. These events were assumed to be epileptic and treated with lorazepam (up to 16 mg/24 h) and phenobarbital (up to 345 mg/24 h) to no avail. Episodes improved with dexmedetomidine and clonidine. Continuous video-EEG was ordered for event characterization. Results EEG background was characterized by reactive generalized theta activity without interictal discharges. Multiple stimulus-induced stereotypical events were captured on the first EEG, prior to initiation of anti-epileptic drugs and dexmedetomidine. These were time-locked with static generalized rhythmic delta activity, often sharply contoured (GRDA + S). Quantitative EEG cycled between GRDA+S and polymorphic theta; transitions were often associated with stimulation or arousal. Thus, the events were shown to be stimulus/arousal-induced PSH time-locked with GRDA+S. The second EEG on lorazepam (2 mg q6h) and dexmedetomidine (26 mcg/kg/h) demonstrated less GRDA and no PSH. The third EEG on phenobarbital (130 mg qhs) and less dexmedetomidine (1.5 mcg/kg/h) demonstrated polymorphic delta slowing during episodes of PSH. Therefore, PSH was seen prior to initiation of dexmedetomidine and while on a low dose, but not while on a higher dose. Phenobarbital did not improve PSH. Conclusion Episodes of PSH were non-epileptic and concordant with cyclical stimulus or arousal-induced GRDA. This pattern is thought to represent cortical-subcortical dysfunction rather than hyperexcitability, as shown in a recent retrospective analysis of critical care continuous EEG in which no association was found between GRDA and seizures. The cyclical pattern on scalp and quantitative EEG reflected increased generalized rhythmicity with arousal and episodes of PSH; akin to stimulus/arousal-induced rhythmic or periodic or ictal discharges (SIRPIDs) seen in critically ill patients. The pattern seen on the cEEG reflects network disruption during PSH rather than a hyperirritable cortex; we believe that treatment of PSH should target sympathetic arousal networks rather than cortical hyperexcitability.

Epilepsy surgery in a developing country (Lebanon)

We present our 10-year experience and preoperative predictors of outcome in 93 adults and children who underwent epilepsy surgery at the American University of Beirut. Presurgical evaluation included video-EEG monitoring, MRI, neuropsychological assessment with invasive monitoring, and other tests (PET, SPECT, Wada). Surgeries included temporal (54%), extratemporal (22%), and multilobar resections (13%), hemispherectomy (4%), vagal nerve stimulation (6%), and corpus callosotomy (1%). Mesial temporal sclerosiswas the mostcommonaetiology (37%). After resective surgery, 70% had Engel class I, 9% class II, 14% class III, and 7% class IV. The number of antiepileptic drugs before surgery was the only preoperative factor associated with Engel class I (p=0.005). Despite the presence of financial and philanthropic aid, many patients could not be operated on for financial reasons. We conclude that advanced epilepsy presurgical workups, surgical procedures, and favourable outcomes, comparable to those of developed countries, are achievable in developing countries, but that issues of financial coverage remain to be addressed.

Authors’ reply to ‘Report of extracranial venous stenosis in relapsing–remitting multiple sclerosis patients’

Walker states that clinically isolated syndrome (CIS) is not multiple sclerosis (MS) according to McDonald’s Criteria, which is true. Follow-up studies, however, have shown that CIS patients, as defined in our paper, are at more than 80% risk of developing MS as per McDonald’s criteria over the next 5 years. This has lead to the widely accepted recommendation to treat CIS patients early on with disease-modifying drugs. We clearly state in the ‘Materials and methods’ section that the early MS (EMS) group comprises patients with remitting–relapsing MS (RRMS) as per McDonald’s criteria as well as patients with CIS according to our definition. The EMS group, therefore, does not follow McDonald’s criteria (since the latter do not address CIS diagnosis) but was rather set up to assess the disease at its earliest stages in order to define the temporal relation between extracranial venous stenosis (EVS) and MS. A similar approach has been used by other groups to asses this temporal relation. It is of note that the groups that tried to confirm the theory of Professor Zamboni, and are mentioned in Walker’s letter, have relied mostly on Doppler studies. As mentioned in our paper, there are no standardized internationally accepted criteria for normal Doppler venous flow parameters, which can explain, at least in part, the discrepancies in the results. On the other hand, our study is the first to assess the presence of EVS in MS patients by selective venous angiography which is still the gold standard for diagnosis. Walker states that MS patients are indifferent if their venous restrictions are a cause or a later product of MS. We disagree with this statement since the absence of EVS at the earliest stages of MS makes it an unlikely cause of the disease. The vast majority of patients are seeking unproved and potentially risky therapies for their EVS based on the belief that it is the underlying cause of the disease and not a late-occurring secondary phenomenon. The more important question that needs to be addressed is the following: does EVS contribute to disability progression in the later stages of the disease, or is it just a marker of disease progression just like brain atrophy? What we think is unequivocal at this time, is that objective data based on the ‘gold standard’ venous angiography indicates that EVS is not a prerequisite to MS and, therefore, is unlikely to provide a potential cure pathway.