CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health-sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. METHODS: All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. RESULTS: Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5-29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%-64%) complete and 2 of 20 (10%; 95% confidence interval, 1%-32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%-82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%-49) patients had a modified Rankin scale of 0 to 1. CONCLUSIONS: Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

Ophthalmoplegia with migraine in adults: is it ophthalmoplegic migraine?

OBJECTIVE: Ophthalmoplegic migraine (OM) is a rare disorder characterized by recurrent oculomotor nerve palsy in children, following migraine headaches. We report 62 adults, seen consecutively, who developed acute ophthalmoplegia with severe attacks of migraine over a 10-year (1996-2005) period. An overwhelming majority of these patients had an antecedent worsening in severity of migraine headaches, before the ophthalmoplegic attack. METHODS: Sixty-two patients, aged 15-68 years, with an acute attack of OM underwent detailed clinical, biochemical, and neuroradiological evaluation. RESULTS: There were 62 patients with 86 attacks of OM. Whereas 48 patients had a single attack, 14 had 2 or more attacks, fulfilling the International Headache Society criteria for probable and definite OM, respectively. At presentation, isolated abducens, oculomotor, and trochlear nerve involvements were seen in 35 (56.5%), 21 (33.9%), and 5 (8.1%) patients, respectively. One patient had simultaneous involvement of 3rd and 6th nerves. Fifty-one (82.3%) patients exhibited an antecedent worsening in severity of migraine, before developing ophthalmoplegia during (59/95.2%) or within 24 hours (3/4.8%) of a severe migraine attack, respectively. Detailed biochemistry and cranial neuroimaging were normal. No case had any nerve enhancement. Use of steroids hastened recovery (P < .05). CONCLUSION: We conclude: (1) OM in adults is characterized by single attacks of ophthalmoplegia in a great majority of patients; and (2) 6th nerve involvement occurs commonly. Our results indicate that moving OM to the chapter on cranial neuralgias in the second edition of the International Headache Classification may be premature, since nerve palsy occurred during a severe migraine attack in all patients.

Seizure type, antiepileptic drugs, and reproductive endocrine dysfunction in Indian women with epilepsy: a cross-sectional study.

BACKGROUND: There is paucity of data regarding occurrence of reproductive endocrine disorders in Asian women with epilepsy (WWE) on antiepileptic drug (AED) therapy. PURPOSE: To determine the occurrence of reproductive endocrine disorders in Indian WWE, by seizure type and the AED use. METHODS: Consecutive 427 reproductive age WWE receiving various AEDs were screened for the occurrence of menstrual abnormalities, weight change, and hirsutism. Of these, 53 WWE with menstrual disturbances and/or hirsutism were further evaluated for ovarian morphology and reproductive hormonal profile. RESULTS: Menstrual abnormalities and/or hirsutism were observed in 83 of 427 (19.4%) WWE irrespective of epileptic seizure type; of these, 50 (60.2%) received valproate, 21 (25.3%) received carbamazepine, 11 (13.3%) received phenytoin, and one (1.2%) received phenobarbitone as the primary AED. Almost half of valproate-treated women had significant weight gain and obesity. Among 53 of 83 women evaluated further, 23.5% and 63.6% of valproate-treated women, 25% and 58.3% of carbamazepine-treated women, and none and 20% of phenytoin-treated women had polycystic ovaries (PCO) and hyperandrogenemia (HA), respectively. Valproate-treated women had significantly higher frequency of polycystic ovarian syndrome (PCOS) (11.8% vs. 2.5%, p < 0.0001) and mean serum testrosterone levels (1.78 vs. 1.36 ng/ml, p = 0.03), compared with women treated with other AEDs. LIMITATIONS: Limitations include small number of women in antiepileptic subgroups and a high drop out rate in women who underwent ultrasound and endocrinological investigations. CONCLUSION: Menstrual abnormalities, weight gain, obesity, and PCOS are frequent and significantly higher in WWE receiving valproate, independent of seizure type.

Acute splenic responses in patients with ischemic stroke and intracerebral hemorrhage.

Animal models provide evidence of spleen mediated post-stroke activation of the peripheral immune system. Translation of these findings to stroke patients requires estimation of pre-stroke spleen volume along with quantification of its day-to-day variation. We enrolled a cohort of 158 healthy volunteers and measured their spleen volume over the course of five consecutive days. We also enrolled a concurrent cohort of 158 stroke patients, measured initial spleen volume within 24 h of stroke symptom onset followed by daily assessments. Blood samples for cytokine analysis were collected from a subset of patients. Using data from healthy volunteers, we fit longitudinal quantile regression models to construct gender and body surface area based normograms of spleen volume. We quantified day-to-day variation and defined splenic contraction. Based on our criteria, approximately 40% of stroke patients experienced substantial post-stroke reduction in splenic volume. African Americans, older patients, and patients with past history of stroke have significantly higher odds of post-stroke splenic contraction. All measured cytokine levels were elevated in patients with splenic contraction, with significant differences for interferon gamma, interleukin 6, 10, 12, and 13. Our work provides reference standards for further work, validation of pre-clinical findings, and characterization of patients with post-stroke splenic contraction.

Transcranial magnetic stimulation: role in the evaluation of disability in multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis (MS), transcranial magnetic stimulation (TMS) has shown significant prolongation of central motor conduction time (CMCT). Abnormal CMCT may reflect sub-clinical involvement of motor pathways and correlate with clinical motor disability. OBJECTIVE: To determine the diagnostic yield of TMS in MS and the possible correlation of TMS abnormalities with clinical disability. MATERIALS AND METHODS: Thirty patients with clinically definite MS presenting in acute relapse or with progressive disease course and 30 healthy controls were evaluated. TMS parameters evaluated included threshold intensity, motor evoked potentials (MEP) amplitudes and latencies and CMCT. Reassessment studies were done after three months. STATISTICAL ANALYSIS: Student t-test, Mann-Whitney U test and Spearman's rank correlation test were used to assess the relationships. RESULTS: Patients with MS had significantly higher threshold intensities, prolonged CMCT and reduced MEP amplitudes as compared to controls. Abnormalities in at least one parameter were observed in 86.7% of patients. When inter-side asymmetries in MEP latency and/or in CMCT were considered, the diagnostic yield increased to 96.7%. The diagnostic yield was 74.7% for visual evoked potentials, 13.3% for brainstem auditory evoked response and 10% for cerebrospinal fluid oligoclonal band. One MS patient without pyramidal or cerebellar dysfunction had prolonged CMCT. CMCT abnormalities correlated significantly with the degree of pyramidal signs, limb ataxia, intention tremor, dysdiadokokinesia and overall cerebellar score. In patients who had clinical improvement, follow-up studies showed improvement in CMCT parameters. CONCLUSION: TMS is a highly sensitive technique to evaluate cortico-spinal conduction abnormalities in MS that may have no clinical correlate and in monitoring the course of the disease. The effects of cerebellar dysfunction on TMS results need further evaluation.

CTP infarct core may predict poor outcome in stroke patients treated with IV t-PA.

BACKGROUND: Computerized tomography perfusion (CTP) has been widely studied in assessing physiological brain tissue parameters in patients with acute ischemic stroke (AIS). The utility of CTP to predict clinical outcome in patients with AIS treated with intravenous tissue plasminogen activator (IV t-PA) is controversial. We reviewed CTP data in AIS patients treated with IV t-PA to uncover potential predictors of clinical outcome. METHODS: We retrospectively identified AIS patients from our stroke registry (7/07 to 2/10) who underwent CTP on arrival and then received IV t-PA. A neuroradiologist blinded to outcome performed all CTP parameter measurements on a commercially available Siemens Neuro PCT workstation. Tissue at risk (TAR) was defined as the area of infarct territory with a relative time to peak (rTTP) greater than 4s. Non-viable tissue (NVT) was defined as the area of infarct territory with absolute cerebral blood volume (CBV) less than 2 ml/100g and cerebral blood flow (CBF) less than 12.7 ml/100g/min. Penumbra was defined as the area of (TAR) minus the area of (NVT). Excellent clinical outcome was defined as mRS (0-1), good clinical outcome was defined as mRS (0-2), and poor clinical outcome was defined as mRS (4-6), all measured at hospital discharge and 90 days if available. Recanalization data was obtained when available by comparing pre-thrombolytic CTA data and post-treatment MRA/CTA images by a single blinded radiologist. RESULTS: We identified 61 patients that met our inclusion criteria with a mean age of 68 (29-94), median NIHSS on admission of 13 (1-40), and median discharge mRS of 4 (0-6). Using multivariate logistic regression and ordinal logistic regression controlling for age and admission NIHSS, none of the CTP parameters were statistically associated with excellent or good clinical outcome (mRS<2). Using multivariate analysis controlling for age and admission NIHSS, NVT area>30 cm(2) (OR=5.12, CI: 0.95-27, p=0.05) was statistically associated with poor clinical outcome at discharge. NVT area ≥ 30 cm(2) was a potential predictor of poor outcome at discharge even when controlling for age and NIHSS. CONCLUSION: CTP parameters derived from commercially available software and published thresholds yield little predictive value for good clinical outcomes for AIS patients treated with IV t-PA but may be useful in predicting poor clinical outcome especially if the area of non-viable tissue is greater than 30 cm(2).

Changes in spleen size in patients with acute ischemic stroke: a pilot observational study.

BACKGROUND: In animal models, the spleen contracts after acute ischemic stroke, followed by release of inflammatory cells leading to secondary brain injury. AIMS: We aim to characterize splenic responses in patients with acute ischemic stroke. METHODS: In this prospective observational study, we measured daily spleen sizes with abdominal ultrasound in 30 patients with suspected acute ischemic stroke. Splenic ultrasounds were also performed in 20 healthy individuals. RESULTS: A generalized estimating equation, longitudinal regression model for adjusted spleen measurements showed the difference between baseline spleen volume (within six-hours of stroke onset) and the volume at the last measured time point (up to seven-days) to be statistically significant (volume difference of 51·9 cm(3) , P = 0·04). Healthy controls had significantly smaller day-to-day variations; the maximum observed difference in mean spleen volume between any two time points was 9·5 cm(3) , with the average change over the period of observation being 1·24 cm(3) . A statistically significant negative association was also observed between the pattern of change of total white blood cell count and spleen volume (P = 0·01). An analysis of individual cases demonstrated possible associations between daily spleen volume changes and clinical course. CONCLUSIONS: We hypothesize that the spleen may initially contract after ischemic stroke followed by a re-expansion and that it contributes to ischemic brain injury mediated via cellular components. Characterization of the splenic response after stroke and its contribution to cerebral ischemic injury has the potential to provide new opportunities for the development of novel stroke therapies.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Investigational therapies for ischemic stroke: neuroprotection and neurorecovery.

Stroke is one of the leading causes of death and disability worldwide. Current treatment strategies for ischemic stroke primarily focus on reducing the size of ischemic damage and rescuing dying cells early after occurrence. To date, intravenous recombinant tissue plasminogen activator is the only United States Food and Drug Administration approved therapy for acute ischemic stroke, but its use is limited by a narrow therapeutic window. The pathophysiology of stroke is complex and it involves excitotoxicity mechanisms, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis, angiogenesis, neuroprotection, and neurorestoration. Regeneration of the brain after damage is still active days and even weeks after a stroke occurs, which might provide a second window for treatment. A huge number of neuroprotective agents have been designed to interrupt the ischemic cascade, but therapeutic trials of these agents have yet to show consistent benefit, despite successful preceding animal studies. Several agents of great promise are currently in the middle to late stages of the clinical trial setting and may emerge in routine practice in the near future. In this review, we highlight select pharmacologic and cell-based therapies that are currently in the clinical trial stage for stroke.

Sodium valproate, hyperandrogenism and altered ovarian function in Indian women with epilepsy: a prospective study.

PURPOSE: To assess the association of long-term sodium valproate therapy with reproductive endocrine disorders in Indian women with generalized epilepsy. METHODS: Clinical parameters, ovarian morphology, and serum reproductive hormone concentrations were evaluated in 30 clinically normal and eumenorrheic reproductive age women with generalized epilepsy who were newly initiated on valproate. Longitudinal evaluations were done in 25 of these women after 1 year, and in some of them after 2 and 3 years of therapy. RESULTS: Of the 25 women who completed 1 year follow-up, we observed clinically relevant weight gain in 40%, hirsutism in 20%, menstrual abnormalities in 24%, polycystic ovaries (PCO) in 16%, polycystic ovarian syndrome (PCOS) in 20%, and a significant increase in mean serum testosterone (p=0.046). A significant positive correlation existed between weight gain and the development of menstrual abnormalities (r=0.66, p<0.0001), hirsutism (r=0.53, p=0.006) and PCO (r=0.51, p=0.012). No correlation existed between weight change and serum reproductive hormonal changes. Yearly follow-up for next 2 years in some of these women revealed persistence of menstrual abnormalities, hirsutism and PCO, a significant linear increase in mean body weight, body mass index, and serum testosterone concentrations, and an increase in serum LH levels from second year onwards. LIMITATIONS: Limitations include small sample size and a high dropout rate on follow-up. CONCLUSIONS: Long-term valproate therapy in Indian women with generalized epilepsy is associated with development of hirsutism, significant weight gain, stable or progressive alterations in reproductive hormonal function, and ultimately a higher occurrence of PCOS.

Polyneuropathy in Osteosclerotic Myeloma Coexisting With Hyaline Vascular Castleman's Disease.

Peripheral neuropathy is usually the presenting feature of POEMS syndrome. Approximately 50% of patients with POEMS syndrome are associated with osteosclerotic myeloma, a rare variant of multiple myeloma, and some with Castleman's disease, an unusual lymphoproliferative disorder. The multicentric plasma cell variant of Castleman's disease is usually associated with systemic disorders rather than its localized form of mediastinal lymphoid hyperplasia characterized by hyalinization of follicles and interfollicular vascular proliferation. We report a 48-year-old woman who presented with progressive sensorimotor demyelinating polyradiculoneuropathy, bilateral optic disc edema, hepatosplenomegaly, generalized lymphadenopathy, and skin changes. There was associated thrombocytosis, hypothyroidism, hypoparathyroidism, mixed osteolytic and osteosclerotic bone lesions, monoclonal gammopathy of IgG lambda type, and hyaline vascular type of Castleman's disease. This combination of POEMS syndrome, osteosclerotic myeloma with a hyaline vascular type of Castleman's disease is uncommon.