Posts Tagged Clinical trial

[ARTICLE] Cell-Based Therapies for Stroke: Are We There Yet? – Full Text

Stroke is the second leading cause of death and physical disability, with a global lifetime incidence rate of 1 in 6. Currently, the only FDA approved treatment for ischemic stroke is the administration of tissue plasminogen activator (tPA). Stem cell clinical trials for stroke have been underway for close to two decades, with data suggesting that cell therapies are safe, feasible, and potentially efficacious. However, clinical trials for stroke account for <1% of all stem cell trials. Nevertheless, the resources devoted to clinical research to identify new treatments for stroke is still significant (53–64 million US$, Phase 1–4). Notably, a quarter of cell therapy clinical trials for stroke have been withdrawn (15.2%) or terminated (6.8%) to date. This review discusses the bottlenecks in delivering a successful cell therapy for stroke, and the cost-to-benefit ratio necessary to justify these expensive trials. Further, this review will critically assess the currently available data from completed stroke trials, the importance of standardization in outcome reporting, and the role of industry-led research in the development of cell therapies for stroke.

Introduction

Background

Stroke has a devastating effect on the society worldwide. In addition to its significant mortality rate of 50% as reported in 5-year survival studies (1), it affects as many as 1 in 6 people in their lifetimes, and is the leading cause of disability worldwide (2). A stroke results in a complex interplay of inflammation and repair with effects on neural, vascular, and connective tissue in and around the affected areas of the brain (3). Therefore, sequelae of stroke such as paralysis, chronic pain, and seizures can persist long term and prevent the patient from fully reintegrating into society. Stroke therefore remains the costliest healthcare burden as a whole (4). In 2012, the total cost of stroke in Australia was estimated to be about $5 billion with direct health care costs attributing to $881 million of the total (5).

Unfortunately, treatment options for stroke are still greatly limited. Intravenous recombinant tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT) are currently the only effective treatments available for acute stroke. However, there is only a brief window of opportunity where they can be successfully applied. EVT is performed until up to 24 h of stroke onset (6), while tPA is applied within 4.5 h of stroke onset. Notably, the recent WAKE-UP (NCT01525290) (7) and EXTEND (NCT01580839) trials have shown that this therapeutic window can be safely extended to 9 h from stroke onset. Furthermore, advancements in acute stroke care and neurorehabilitation have shown to be effective in improving neurological function (8). However, there are no treatments that offer restoration of function and as a result, many patients are left with residual deficits following a stroke. Cell-based therapies have shown promising results in animal models addressing the recovery phase following stroke (9). This is encouraging as currently, there are no approved treatment options addressing the reversal of neurological damages once a stroke has occurred (10).

The majority of data from animal studies and clinical trials demonstrate the therapeutic potential of stem cells in the restoration of central nervous system (CNS) function (1112), applicable to neurodegenerative diseases as well as traumatic brain injury. Transplanted stem cells were reportedly able to differentiate into neurons and glial cells, whilst supporting neural reconstruction and angiogenesis in the ischemic region of the brain (13). Previous work demonstrated the ability of mesenchymal stem cells (MSCs) to differentiate into neurons, astrocytes (14), endothelial cells (1516), and oligodendrocyte lineage cells (17) such as NG2-positive cells (18in vitro, and undergo neuronal or glial differentiation in vivo (19). Bone marrow-derived mesenchymal stem cells (BMSCs) have shown potential to differentiate into endothelial cells in vitro (20). Additionally, both BMSCs and adipose stem cells (ASCs) have been shown to demonstrate neural lineage differentiation potential in vitro (2123). Furthermore, stem cells are able to modulate multiple cell signaling pathways involved in endogenous neurogenesis, angiogenesis, immune modulation and neural plasticity, sometimes in addition to cell replacement (3). The delivery of stem cells from the brain, bone marrow, umbilical cord, and adipose tissue, have been reported to reduce infarct size and improve functional outcomes regardless of tissue source (9). While these were initially exciting reports, they raise the question as to the validity of the findings to date since these preclinical reports are almost uniformly positive. The absence of scientific skepticism and robust debate may in fact have negated progress in this field.

Cell-based therapies have been investigated as a clinical option since the 1990s. The first pilot stroke studies in 2005 investigated the safety of intracranial delivery of stem cells (including porcine neural stem cells) to patients with chronic basal ganglia infarcts or subcortical motor strokes (2425). However, since the publication of these reports, hundreds of preclinical studies have shown that a variety of cell types including those derived from non-neural tissues can enhance structural and functional recovery in stroke. Cell therapy trials, mainly targeted at small cohorts of patients with chronic stroke, completed in the 2000s, showed satisfactory safety profiles and suggestions of efficacy (10). Current treatments such as tPA and EVT only have a narrow therapeutic window, limited efficacy in severe stroke and may be accompanied by severe side effects. Specifically, the side effects of EVT include intracranial hemorrhage, vessel dissection, emboli to new vascular territories, and vasospasm (26). The benefit of tPA for patients with a severe stroke with a large artery occlusion can vary significantly (27). This is mainly due to the failure (<30%) of early recanalisation of the occlusion. Thus, despite the treatment options stroke is still a major cause of mortality and morbidity, and there is need for new and improved therapies.

Stem cells have been postulated to significantly extend the period of intervention and target subacute as well as the chronic phase of stroke. Numerous neurological disorders such as Parkinson’s disease (1228), Alzheimer’s disease (29), age-related macular degeneration (30), traumatic brain injury (31), and malignant gliomas (32) have been investigated for the applicability of stem cell therapy. These studies have partly influenced the investigation of stem cell therapies for stroke. A small fraction of stem cell research has been successfully translated to clinical trials. As detailed in Table 1, most currently active trials use neuronal stem cells (NSCs), MSCs or BMSCs (3537), including conditionally immortalized neural stem-cell line (CTX-DP) CTX0E03 (38), neural stem/progenitor cells (NSCs/NPSCs) (e.g., NCT03296618), umbilical cord blood (CoBis2, NCT03004976), adipose (NCT02813512), or amnion epithelial cells (hAECs, ACTRN 1261800076279) (39).

Table 1. Challenges and bottlenecks of stem cell therapy and clinical trials using stem cells (3334).

[…]

 

Continue —>  Frontiers | Cell-Based Therapies for Stroke: Are We There Yet? | Neurology

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[ARTICLE] Efficacy of physical therapy associated with botulinum toxin type A on functional performance in post-stroke spasticity: A randomized, double-blinded, placebo-controlled trial – Full Text

Abstract

The aim was to investigate if botulinum toxin type A (BTx-A) associated with physical therapy is superior to physical therapy alone in post stroke spasticity. A randomized, double-blinded controlled trial was performed in a rehabilitation unit on Northeastern, Brazil. Patients with post stroke spasticity were enrolled either to BTx-A injections and a pre-defined program of physical therapy or saline injections plus physical therapy. Primary endpoint was functional performance evaluated through time up and go test, six minutes walking test and Fugl-Meyer scale for upper limb. Secondary endpoint was spasticity improvement. Confidence interval was considered at 95%. Although there was a significant decrease in upper limbs flexor tonus (P<0.05) in the BTx-A group, there was no difference regarding functional performance after 9 months of treatment. When analyzing gait speed and performance, both groups showed a significant improvement in the third month of treatment, however it was not sustained over time. Although BTx-A shows superiority to improve muscle tone, physical therapy is the cornerstone to improve function in the upper limbs of post stroke patients.

Introduction

Stroke is the major cause of permanent and temporary functional incapacity worldwide among adults, affecting limb strength, motor control, balance and mobility.1 Spasticity is characterized by an increase in tonic stretch reflex movement velocity dependent and post-stroke spasticity is frequently associated with poor functional performance due to abnormal postural patterns, leading to retractions, atrophy, selective movement control loss, limb weakness, fibrosis and structured contractions.2 Moreover, impairment in activities of daily living (ADL) such as feeding, locomotion, proper hygiene and sleeping habits results in poor quality of life (QOL) and increased burden to relatives and caregivers.3

Several trials support the efficacy and safety of botulinum toxin type A (BTx-A) on spasticity treatment, reducing muscle permanent contraction and abnormal postural patterns, therefore, favoring rehabilitation process.4 Physical therapy has been described to be effective in post-stroke spastic patients through prevention of secondary incapacities and promoting behavioral reeducation, based on biomechanical and neurophysiological patterns. These techniques include physical exercises that focus on functional rehabilitation, reduction of limb spasticity, muscle strength improvement and sustained joint movement amplitude, besides proprioceptive and sensorial stimuli.5

Several trials with BTx-A show functional improvement in post-stroke spastic patients when compared to placebo, however, none have studied the impact of physical therapy alone.4

The aim of this trial was to investigate if BTx-A treatment associated with physical therapy is superior to physical therapy alone on functional performance in post-stroke spastic patients.[…]

 

Continue —> Efficacy of physical therapy associated with botulinum toxin type A on functional performance in post-stroke spasticity: A randomized, double-blinded, placebo-controlled trial

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[ARTICLE] Classification of Traumatic Brain Injury for Targeted Therapies – Full Text

Abstract

The heterogeneity of traumatic brain injury (TBI) is considered one of the most significant barriers to finding effective therapeutic interventions. In October, 2007, the National Institute of Neurological Disorders and Stroke, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to outline the steps needed to develop a reliable, efficient and valid classification system for TBI that could be used to link specific patterns of brain and neurovascular injury with appropriate therapeutic interventions. Currently, the Glasgow Coma Scale (GCS) is the primary selection criterion for inclusion in most TBI clinical trials. While the GCS is extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms which are responsible for neurological deficits and targeted by interventions. On the premise that brain injuries with similar pathoanatomic features are likely to share common pathophysiologic mechanisms, participants proposed that a new, multidimensional classification system should be developed for TBI clinical trials. It was agreed that preclinical models were vital in establishing pathophysiologic mechanisms relevant to specific pathoanatomic types of TBI and verifying that a given therapeutic approach improves outcome in these targeted TBI types. In a clinical trial, patients with the targeted pathoanatomic injury type would be selected using an initial diagnostic entry criterion, including their severity of injury. Coexisting brain injury types would be identified and multivariate prognostic modeling used for refinement of inclusion/exclusion criteria and patient stratification. Outcome assessment would utilize endpoints relevant to the targeted injury type. Advantages and disadvantages of currently available diagnostic, monitoring, and assessment tools were discussed. Recommendations were made for enhancing the utility of available or emerging tools in order to facilitate implementation of a pathoanatomic classification approach for clinical trials.

Introduction

Traumatic brain injury (TBI) remains a major cause of death and disability. Although much has been learned about the molecular and cellular mechanisms of TBI in the past 20 years, these advances have failed to translate into a successful clinical trial, and thus there has been no significant improvement in treatment. Among the numerous barriers to finding effective interventions to improve outcomes after TBI, the heterogeneity of the injury and identification and classification of patients most likely to benefit from the treatment are considered some of the most significant challenges (Doppenberg et al., 2004; Marshall, 2000; Narayan et al., 2002).

The type of classification one develops depends on the available data and the purpose of the classification system. An etiological classification describes the factors to change in order to prevent the condition. A symptom classificationdescribes the clinical manifestation of the problem to be solved. A prognostic classification describes the factors associated with outcome, and a pathoanatomic classification describes the abnormality to be targeted by the treatment. Most diseases were originally classified on the basis of the clinical picture using a symptom-based classification system. Beginning in the 18th century, autopsies became more routine, and an increasing number of disease conditions were classified by their pathoanatomic lesions. With improvement of diagnostic tools, modern disease classification in most fields of medicine uses a mixture of anatomically, physiologically, metabolically, immunologically, and genetically defined parameters.

Currently, the primary selection criterion for inclusion in a TBI clinical trial is the Glasgow Coma Scale (GCS), a clinical scale that assesses the level of consciousness after TBI. Patients are typically divided into the broad categories of mild, moderate, and severe injury. While the GCS has proved to be extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms responsible for the neurological deficits. This is clearly demonstrated in Figure 1, in which all six patients are classified as having a severe TBI. Given the heterogeneity of the pathoanatomic features depicted in these computed tomography (CT) scans, it is difficult to see how a therapy targeted simply for severe TBI could effectively treat all of these different types of injury. Many tools such as CT scans and magnetic resonance imaging (MRI) already exist to help differentiate the multiple types of brain injury and variety of host factors and other confounders that might influence the yield of clinical trials. In addition, newer advances in neuroimaging, biomarkers, and bioinformatics may increase the effectiveness of clinical trials by helping to classify patients into groups most likely to benefit from specific treatments.

 

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Heterogeneity of severe traumatic brain injury (TBI). Computed tomography (CT) scans of six different patients with severe TBI, defined as a Glasgow Coma Scale score of <8, highlighting the significant heterogeneity of pathological findings. CT scans represent patients with epidural hematomas (EDH), contusions and parenchymal hematomas (Contusion/Hematoma), diffuse axonal injury (DAI), subdural hematoma (SDH), subarachnoid hemorrhage and intraventricular hemorrhage (SAH/IVH), and diffuse brain swelling (Diffuse Swelling).

Continue —>  Classification of Traumatic Brain Injury for Targeted Therapies

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[ARTICLE] Classification of Traumatic Brain Injury for Targeted Therapies. Journal of Neurotrauma – Full Text

Abstract

The heterogeneity of traumatic brain injury (TBI) is considered one of the most significant barriers to finding effective therapeutic interventions. In October, 2007, the National Institute of Neurological Disorders and Stroke, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to outline the steps needed to develop a reliable, efficient and valid classification system for TBI that could be used to link specific patterns of brain and neurovascular injury with appropriate therapeutic interventions. Currently, the Glasgow Coma Scale (GCS) is the primary selection criterion for inclusion in most TBI clinical trials. While the GCS is extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms which are responsible for neurological deficits and targeted by interventions. On the premise that brain injuries with similar pathoanatomic features are likely to share common pathophysiologic mechanisms, participants proposed that a new, multidimensional classification system should be developed for TBI clinical trials. It was agreed that preclinical models were vital in establishing pathophysiologic mechanisms relevant to specific pathoanatomic types of TBI and verifying that a given therapeutic approach improves outcome in these targeted TBI types. In a clinical trial, patients with the targeted pathoanatomic injury type would be selected using an initial diagnostic entry criterion, including their severity of injury. Coexisting brain injury types would be identified and multivariate prognostic modeling used for refinement of inclusion/exclusion criteria and patient stratification. Outcome assessment would utilize endpoints relevant to the targeted injury type. Advantages and disadvantages of currently available diagnostic, monitoring, and assessment tools were discussed. Recommendations were made for enhancing the utility of available or emerging tools in order to facilitate implementation of a pathoanatomic classification approach for clinical trials.

Introduction

Traumatic brain injury (TBI) remains a major cause of death and disability. Although much has been learned about the molecular and cellular mechanisms of TBI in the past 20 years, these advances have failed to translate into a successful clinical trial, and thus there has been no significant improvement in treatment. Among the numerous barriers to finding effective interventions to improve outcomes after TBI, the heterogeneity of the injury and identification and classification of patients most likely to benefit from the treatment are considered some of the most significant challenges (Doppenberg et al., 2004; Marshall, 2000; Narayan et al., 2002).

The type of classification one develops depends on the available data and the purpose of the classification system. An etiological classification describes the factors to change in order to prevent the condition. A symptom classificationdescribes the clinical manifestation of the problem to be solved. A prognostic classification describes the factors associated with outcome, and a pathoanatomic classification describes the abnormality to be targeted by the treatment. Most diseases were originally classified on the basis of the clinical picture using a symptom-based classification system. Beginning in the 18th century, autopsies became more routine, and an increasing number of disease conditions were classified by their pathoanatomic lesions. With improvement of diagnostic tools, modern disease classification in most fields of medicine uses a mixture of anatomically, physiologically, metabolically, immunologically, and genetically defined parameters.

Currently, the primary selection criterion for inclusion in a TBI clinical trial is the Glasgow Coma Scale (GCS), a clinical scale that assesses the level of consciousness after TBI. Patients are typically divided into the broad categories of mild, moderate, and severe injury. While the GCS has proved to be extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms responsible for the neurological deficits. This is clearly demonstrated in Figure 1, in which all six patients are classified as having a severe TBI. Given the heterogeneity of the pathoanatomic features depicted in these computed tomography (CT) scans, it is difficult to see how a therapy targeted simply for severe TBI could effectively treat all of these different types of injury. Many tools such as CT scans and magnetic resonance imaging (MRI) already exist to help differentiate the multiple types of brain injury and variety of host factors and other confounders that might influence the yield of clinical trials. In addition, newer advances in neuroimaging, biomarkers, and bioinformatics may increase the effectiveness of clinical trials by helping to classify patients into groups most likely to benefit from specific treatments. […]

 

Continue —> Classification of Traumatic Brain Injury for Targeted Therapies

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[WEB SITE] Doctors appear to have reached unexpected consensus in prescribing pediatric anti-seizure medications

July 19, 2017

The number of available anti-seizure medications has exploded in the past two decades, going from just a handful of medicines available in the 1990s to more than 20 now. Once the Food and Drug Administration (FDA) approves each new medicine based on trials in adults, it’s available for clinicians to prescribe off-label to all age groups. However, says William D. Gaillard, M.D., division chief of Child Neurology and Epilepsy, Neurophysiology and Critical Care Neurology at Children’s National Health System, trials that lead to FDA approval for adults do not provide any information about which medications are best for children.

“With so many medications and so little data,” Dr. Gaillard says, “one might think doctors would choose a wider variety of medicines when they prescribe to children with epilepsy.”

However, the results from a recent study by Dr. Gaillard and colleagues, published online in Pediatric Neurology on June 27, 2017, show otherwise. The study indicates that doctors in the United States appear to have reached an unexpected consensus about which medication to prescribe for their pediatric patients.

The study is part of a broader effort to collect data on the youngest epilepsy patients — those younger than 3 years old, the age at which epilepsy most often becomes evident. As part of this endeavor, researchers from 17 U.S. pediatric epilepsy centers enrolled in the study 495 children younger than 36 months old who had been newly diagnosed with non-syndromic epilepsy (a condition not linked to any of the commonly recognized genetic epilepsy syndromes).

The researchers mined these patients’ electronic medical records for information about their demographics, disease and treatments. About half of the study participants were younger than 1 year old when they were diagnosed with epilepsy. About half had disease marked by focal features, meaning that their epilepsy appeared to originate from a particular place in the brain. Nearly all were treated with a single medication, as opposed to a cocktail of multiple medicines.

Of those treated with a single medication, nearly all were treated with one of five medicines: Levetiracetam, oxcarbazepine, phenobarbital, topiramate and zonisamide. However, the data showed a clear prescribing preference. About 63 percent of the patients were prescribed levetiracetam as a first choice. By contrast, oxcarbazepine and phenobarbital, the next most frequently prescribed medicines, were taken by patients as a first choice by a mere 14 percent and 13 percent respectively.

Even more striking, of the children who were not prescribed levetiracetam initially but required a second medication due to inadequate efficacy or unacceptable side effects, 62 percent also received this medication. That made levetiracetam the first or second choice for about 74 percent of all the children in the study, despite the availability of more than 20 anti-seizure medications.

It’s not clear why levetiracetam is such a frequent choice in the United States, says Dr. Gaillard. However, in its favor, the drug is available in a liquid formulation, causes no ill effects medically and can be started intravenously if necessary. Studies have shown that it appears to be effective in controlling seizures in about 40 percent of infants.

Yet, levetiracetam’s market dominance appears to be a North American phenomenon, the study authors write. A recent international survey that Dr. Gaillard also participated in suggests that outside of this continent, carbazepine and oxcarbazepine were the most frequently prescribed medications to treat focal seizures.

What’s really necessary, Dr. Gaillard says, is real data on efficacy for each of the medications commonly prescribed to pediatric epilepsy patients–a marked vacuum in research that prevents doctors from using evidence-based reasoning when making medication choices.

“This study identifies current practices, but whether those practices are correct is a separate question,” he explains. “Just because a medication is used commonly doesn’t mean it is the best medication we should be using.”

To answer that question, he says, researchers will need to perform a head-to-head clinical trial comparing the top available epilepsy medications in children. This study sets the stage for such a trial by identifying which medications should be included.

“Uncontrolled pediatric epilepsy can have serious consequences, from potential problems in development to a higher risk of death,” Dr. Gaillard says. “You want to use the optimal medicine to treat the disease.”

Source: Doctors appear to have reached unexpected consensus in prescribing pediatric anti-seizure medications

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[ARTICLE] Biomarkers of stroke recovery: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable – Full Text

In practical terms, biomarkers should improve our ability to predict long-term outcomes after stroke across multiple domains. This is beneficial for: (a) patients, caregivers and clinicians; (b) planning subsequent clinical pathways and goal setting; and (c) identifying whom and when to target, and in some instances at which dose, with interventions for promoting stroke recovery.2 This last point is particularly important as methods for accurate prediction of long-term outcome would allow clinical trials of restorative and rehabilitation interventions to be stratified based on the potential for neurobiological recovery in a way that is currently not possible when trials are performed in the absence of valid biomarkers. Unpredictable outcomes after stroke, particularly in those who present with the most severe impairment3 mean that clinical trials of rehabilitation interventions need hundreds of patients to be appropriately powered. Use of biomarkers would allow incorporation of accurate information about the underlying impairment, and thus the size of these intervention trials could be considerably reduced,4 with obvious benefits. These principles are no different in the context of stroke recovery as compared to general medical research.5

Interventions fall into two broad mechanistic categories: (1) behavioural interventions that take advantage of experience and learning-dependent plasticity (e.g. motor, sensory, cognitive, and speech and language therapy), and (2) treatments that enhance the potential for experience and learning-dependent plasticity to maximise the effects of behavioural interventions (e.g. pharmacotherapy or non-invasive brain stimulation).6 To identify in whom and when to intervene, we need biomarkers that reflect the underlying biological mechanisms being targeted therapeutically.

Our goal is to provide a consensus statement regarding the evidence for SRBs that are helpful in outcome prediction and therefore identifying subgroups for stratification to be used in trials.7 We focused on SRBs that can investigate the structure or function of the brain (Table 1). Four functional domains (motor, somatosensation, cognition, and language (Table 2)) were considered according to recovery phase post stroke (hyperacute: <24 h; acute: 1 to 7 days; early subacute: 1 week to 3 months; late subacute: 3 months to 6 months; chronic: > 6 months8). For each functional domain, we provide recommendations for biomarkers that either are: (1) ready to guide stratification of subgroups of patients for clinical trials and/or to predict outcome, or (2) are a developmental priority (Table 3). Finally, we provide an example of how inclusion of a clinical trial-ready biomarker might have benefitted a recent phase III trial. As there is generally limited evidence at this time for blood or genetic biomarkers, we do not discuss these, but recommend they are a developmental priority.912 We also recognize that many other functional domains exist, but focus here on the four that have the most developed science. […]

Continue —> Biomarkers of stroke recovery: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation RoundtableInternational Journal of Stroke – Lara A Boyd, Kathryn S Hayward, Nick S Ward, Cathy M Stinear, Charlotte Rosso, Rebecca J Fisher, Alexandre R Carter, Alex P Leff, David A Copland, Leeanne M Carey, Leonardo G Cohen, D Michele Basso, Jane M Maguire, Steven C Cramer, 2017

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[WEB SITE] Study shows continuous electrical stimulation suppresses seizures in patients with epilepsy.

When surgery and medication don’t help people with epilepsy, electrical stimulation of the brain has been a treatment of last resort. Unfortunately, typical approaches, such as vagal nerve stimulation or responsive nerve stimulation, rarely stop seizures altogether. But a new Mayo Clinic study in JAMA Neurology shows that seizures were suppressed in patients treated with continuous electrical stimulation.

Epilepsy is a central nervous system disorder in which nerve cell activity in the brain becomes disrupted. In the study, 13 patients with drug-resistant epilepsy were deemed unsuitable for resective surgery, which removes a portion of the brain — usually about the size of a golf ball — that was causing seizures. When patients are evaluated for surgery, a grid of electrical contacts is placed on the brain to record seizures and interictal epileptiform discharges (IEDs). IEDs are electrical discharges that occur intermittently during normal brain function, and have been used as markers to locate portions of brain affected by epilepsy.

In the study, the grid of electrical contacts was used for stimulation at levels the patient would not notice. If the stimulation provided clinical benefit to the patient, this temporary grid was replaced with more permanent contacts that could offer continuous stimulation.

Ten of the 13 patients, 77 percent, reported improvement for both epilepsy severity and life satisfaction. The majority of patients experienced more than 50 percent reduction in seizures, and 44 percent were free of disabling seizures. The reduction in IED rate occurred within minutes of initiating stimulation.

“This study suggests that subthreshold cortical stimulation is both effective clinically and reduces interictal epileptiform discharges,” says lead author Brian Lundstrom, M.D., Ph.D., a neurology epilepsy fellow at Mayo Clinic. “We think this approach not only provides an effective treatment for those with focal epilepsy but will allow us to develop ways of assessing seizure likelihood for all epilepsy patients. It would be of enormous clinical benefit if we could personalize treatment regimens for individual patients without waiting for seizures to happen.”

During seizures, abnormal electrical activity in the brain sometimes results in loss of consciousness. For people with epilepsy, seizures severely limit their ability to perform tasks where even a momentary loss of consciousness could prove disastrous — driving a car, swimming or holding an infant, for example. Approximately 50 million people worldwide have epilepsy, according to the World Health Organization.

Seizures sometimes have been compared to electrical storms in the brain. Seizure signs and symptoms may include:

•Temporary confusion
•A staring spell
•Uncontrollable jerking movements of the arms and legs
•Loss of consciousness or awareness

Treatment with medications or surgery can control seizures for about two-thirds of people with epilepsy. However, when drug-resistant focal epilepsy occurs in an area of the brain that controls speech, language, vision, sensation or movement, resective surgery is not an option.

“For people who have epilepsy that can’t be treated with surgery or medication, effective neurostimulation could be a wonderful treatment option,” Dr. Lundstrom says.

The risks of subthreshold cortical stimulation are relatively minimal and include typical infection and bleeding risks as well as the possibility that the stimulation would not be subthreshold and would be noticed by the patient, Dr. Lundstrom says. The authors note that further investigation is needed to quantify treatment effect and examine the effect mechanism. The authors plan to examine the efficacy of this approach in a prospective clinical trial.

This study represents ongoing efforts to restore normal function to epileptic brain tissue by using neurostimulation. Other efforts are aimed at understanding the physiologic changes that chronic stimulation produces in brain tissue.

Source: Study shows continuous electrical stimulation suppresses seizures in patients with epilepsy

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[WEB SITE] When Will a Clinical Trial for Traumatic Brain Injury Succeed? – AANS Neurosurgeon

 Uzma Samadani, MD, PhD, FAANS; Samuel R. Daly | Features
AANS Neurosurgeon: Volume 25, Number 3, 2016

TBI is the leading cause of death and disability in Americans under age 35 and the leading cause of premature death and disability worldwide (1). In 2009 alone, 2.4 million patients presented to an emergency department (ED) with a TBI and an additional 52,695 died from their injury (2). Currently, at least 5.3 million U.S. residents live with long-term disabilities related to a TBI (3). The economic toll of TBI has been reported as $75 billion for a single year (4). Between 2002 and 2010, the rate of TBI in the U.S. population increased by over 50 percent, (1) excluding the military and those that do not seek medical care (5).

Despite the colossal nature of the problem, little progress has been made in developing new therapeutics for TBI. A PubMed search reveals 30 failed clinical trials for TBI since 1993, 25 of which have been in the last 15 years and 13 of which have been in the last five years (6-35). These 30 trials failed to find a significant effect for treatments that were supported by extensive preclinical studies and Phase I and II trials. They included hypothermia and temperature control (11 studies), hypertonic saline (three studies), progesterone (two studies), prostacyclin (two studies), surgical intervention (one study), intracranial pressure monitoring (one study) and a number of other pharmacological interventions (10 studies). The estimated total cost of these trials is $1.1 billion (36).

All 30 of these trials were prospective, randomized, controlled studies based on well-executed preliminary studies. Ninety-three percent indicated blinded assessment, and 70 percent were done at multiple centers. Patient retention was unprecedented. For example, the SYNAPSE trial tested the effect of progesterone in a double-blind, randomized manner with more than 1,000 participants and 96 percent, six-month retention. Thus, rather than blaming standard methodological limitations for these failed trials, one must look deeper into how TBI trials recruit and assess the outcome of the patients.

Table 1: Major Inclusion Criteria
Inclusion Criteria Number of Studies
GCS 18
GCS + CT 8
GCS + Pupil Reactivity 2
GCS + ICP 1
ICP 1

The Glasgow Coma Scale (GCS) was used as a major inclusion criterion in 29 of the 30 studies (97 percent) and was the only major inclusion criteria in 18 studies (Table 1). This measure, which has been in use for 40 years, conveys the clinically-relevant acute exam of the verbal, motor and eye movement response of a patient. Using GCS to select patients for clinical trials may be suboptimal because it does not account for diverse pathophysiology at any level of brain injury severity. For example, a patient with severe TBI (GCS 3-8) can be minimally or non-responsive due to a wide diversity of underlying pathophysiology with different outcomes such as a non-significant impact while intoxicated, a treatable subdural or epidural hematoma or a diffuse axonal or anoxic injury, the latter of which may be associated with very poor outcomes. Recognition of the limitations of the mild/moderate/severe paradigm was the impetus for the 3,000-patient, 13-center TRACK-TBI study (37) and the European CENTER TBI project (38).

Imaging was only used as a major inclusion or exclusion criteria in eight of the 30 failed trials; however, conventional acute imaging performed for trauma may not fully differentiate complex pathophysiology, such as diffuse axonal injury (DAI) or anoxic injury.

Table 2: Outcome Measures Utilized
Outcome Measure Number of Studies
GOS(-E) 6
GOS(-E) as Primary Outcome 15
GOS(-E) as Secondary Outcome 4
PCPC 2
Neuropsych Battery 1
Length of Stay 1
Seizures 1

The 5-point Glasgow Outcome Scale (GOS), or its extended 8-point version (GOS-E) was used as the primary outcome measure in 21 of the 30 studies (70 percent), and was the only outcome measure used in six of those studies (Table 2). Four of the remaining studies used the GOS as a secondary outcome measure, and two used an outcome assessment that is structured similarly to the GOS in the pediatric populations (Pediatric Cerebral Performance Category). Three studies used other means of measuring outcome. While GOS or GOS-E accurately captures global phenomena, it may fail to assess subtle differences in outcomes over a wide range of functioning. We speculate that clinical trials for brain injury will have a better probability of success when there are means of detecting and classifying brain injury appropriately, according to its pathophysiology as patients enter a trial and more sensitive outcome measures to assess recovery as patients leave a trial are utilized.

Multimodal algorithmic assessment to obtain an accurate pathophysiologic diagnosis is routine with virtually every other body system. For example, when a patient presents to the emergency room with chest pain, the workup includes imaging of the heart and lungs (echocardiogram, angiogram, chest x-ray and/or CT scan), an assessment of the electrical activity of the heart (electrocardiogram) and blood tests to analyze the concentration of various proteins that indicate cardiac or other pathology, such as troponin or D-dimers. No one would ever conceive of conducting a clinical trial for “chest pain” based on only a physical examination and a single imaging study to assess the impact of a single universal intervention with an 8-point outcome measure. On the contrary, initiatives for precision medicine seek to define even baseline patient characteristics prior to accurate diagnosis. The complexity of the central nervous system even before an injury befuddles simple functional assessment. TBI should warrant a similar multimodal assessment that enables a more clear understanding of the underlying pathophysiology of the type of brain injury before enrollment in a trial.

Among the many possible assessment tools being investigated for better classification of brain injury are serum biomarkers, eye tracking and magnetic resonance imaging (MRI). Our laboratory is among many engaged in research to enable better classification of brain injury. We will prospectively enroll more than 1,000 trauma patients at Hennepin County Medical Center (HCMC) in Minneapolis and will follow these individuals for a year after their injury. This study aims to develop a multi-modal classification scheme for brain injury that will be able to accurately diagnose acute pathophysiology in brain-injured subjects with eye tracking, the analysis of protein markers in patient blood samples and radiographic imaging.

Abnormal eye movements are found in up to 90 percent of patients with so-called “mild” TBI or concussion (39-44). The eye tracking employed in this study will be non-spatially calibrated and used to detect subtle abnormalities in motility and sustained vergence; the ability of the eyes to focus on a single point in space over time (45). Eye tracking fundamentally detects palsies in cranial nerves III and VI (46), and eye tracking metrics correlate with the severity of concussion symptoms and the improvement of those symptoms over time in both an adult emergency department population (47) and in a pediatric concussion center population (48). Disruption of eye tracking metrics clinically correlates with convergence dysfunction and abnormal near point of convergence in children (48). Eye tracking detects concussion as defined by its symptoms with a high sensitivity and specificity (49).

Protein biomarkers in the serum of TBI patients have been extensively researched in the last 20 years and represent potentially promising indicators of the nature of the brain injury, including the exact type of cellular injury that has occurred in the brain (neuronal, glial or axonal).

Preliminary models have already been proposed providing evidence that can aid in determining acute treatment plans, but these models are limited by statistical power and their nature as uni-variate models of blood-based biomarkers (50-53). Combining eye-tracking data with data from biomarkers in blood samples and other clinical data (i.e. brain imaging and the physical exam) and correlating it with detailed outcome measures at a high level of statistical power into a multivariate model has great potential for improving classification of brain injuries.

A model for classification and treatment of brain injury will be beneficial not only for patient prognostication and limiting the economic toll of TBI but also in gaining a more clear understanding of the underlying mechanisms of various brain injuries. With such understanding, we will increase the probability of successful clinical trials for the treatment of TBI.

Disclosures
Uzma Samadani, MD, PhD, has submitted several patents describing the eye tracking technology mentioned in this article. These patents are owned by NYU, HCMC and the VA and licensed to Oculogica Inc., a company co-founded by Dr. Samadani and in which she has an equity interest.  The U.S. also has a grant from Abbott Diagnostic Laboratories to investigate serum biomarkers for brain injury.

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  • Source: AANS Neurosurgeon When Will a Clinical Trial for Traumatic Brain Injury Succeed? – AANS Neurosurgeon

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    [ARTICLE] Stroke Treatment Associated with Rehabilitation Therapy and Transcranial DC Stimulation (START-tDCS): a study protocol for a randomized controlled trial – Full Text HTML/PDF

    Abstract

    Background

    Traditional treatment for motor impairment after stroke includes medication and physical rehabilitation. The transcranial direct current stimulation associated with a standard physical therapy program may be an effective therapeutic alternative for these patients.

    Methods

    This study is a sham-controlled, double-blind, randomized clinical trial aiming to evaluate the efficacy of transcranial direct current stimulation in activities of daily living and motor function post subacute stroke. In total there will be 40 patients enrolled, diagnosed with subacute, ischemic, unilateral, non-recurring stroke. Participants will be randomized to two groups, one with active stimulation and the other with a placebo current. Patients and investigators will be blinded. Everyone will receive systematic physical therapy, based on constraint-induced movement therapy. The intervention will be applied for 10 consecutive days. Patients will undergo three functional assessments: at baseline, week 2, and week 4. Neuropsychological tests will be performed at baseline and week 4. Adverse effects will be computed at each session. On completion of the baseline measures, randomization will be conducted using random permuted blocks. The randomization will be concealed until group allocation.

    Discussion

    This study will investigate the combined effects of transcranial direct current stimulation and physical therapy on functional improvement after stroke. We tested whether the combination of these treatments is more effective than physical therapy alone when administered in the early stages after stroke.

    Background

    A stroke is defined as an acute neurological dysfunction of vascular origin, with sudden development of clinical signs of brain function disorders, lasting more than 24 h [1].

    In this sense, new therapeutic modalities have been developed for monitoring patients after a stroke [2]. Simis et al. [3] conducted a placebo-controlled clinical trial and found that transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can cause increased hand motor function compared to placebo stimulation. TMS has been used to minimize the limitations post stroke, such as functional independence and motor recovery [4], [5], but it is not portable/mobile and is expensive. In contrast, tDCS offers some advantages compared to TMS, being portable, more economical, and easy to operate. The effects are polarity-dependent, leading to an increase or a decrease in cortical excitability [6]. Although some studies have shown that increasing the current intensity is related to more robust effects [7], this is also true for adverse effects such as headache and discomfort under the electrode [8]. Therefore, the maximum current intensity used is generally 2 mA, and the cortex density varies between 0.029 and 0.08 mA/cm 2[9]. Animal studies with a higher current density of 25 mA/cm 2 did not induce lesions in the brain tissue, meaning that limits well above those applied in humans did not result in potential adverse effects [10], thereby demonstrating that it is a safe technique.

    There is evidence that repeated sessions of tDCS may be associated with a longer duration of the behavioral effects [11]. Monte-Silva et al. [12] demonstrated that the interval between the sessions can be critical to performance. The authors found that when an extra session of tDCS is applied for 1 hour after the first session, the effects last for a longer time (120 minutes) compared to the effect of only one or two consecutive sessions, while an extra session of tDCS applied beyond that period (that is, 3 hours) did not influence the effect of the first session. These findings show that studies with the aim of achieving lasting effects should consider the timing-dependent plasticity stimulation regulation in the human motor cortex [13].

    Regarding physical therapy, different approaches can be found for motor recovery, such as mirror therapy [14], repetitive task practice [15], and robotic training [16]. However, the type of training that is combined with stimulation determines how generalizable the benefits would be. Improvements are specific for tasks that are strategically paired with stimulation [17].

    In this perspective, efforts are currently being made to standardize the application of the methods that can be combined with tDCS for the treatment of stroke. Bolognini et al. [18] developed a placebo-controlled trial to investigate the neuropsychological and behavioral effects of bihemispheric tDCS (cathodic stimulation in the unaffected hemisphere and anode in the affected cortex) combined with a standard physical therapy program called constraint-induced movement therapy (CIMT) [19]. The data show that CIMT applied alone only seems to be effective in modulating cortical excitability, but is not able to restore the balance of transcallosal inhibition. According to the authors, bihemispheric tDCS can already achieve this goal and promote greater functional recovery. Studies show that CIMT is associated with functional improvement in acute and subacute stages of stroke [20]–[23]. Although most studies in neurostimulation therapy involve post-stroke patient monitoring for short periods [24], [25], longitudinal studies would clarify the action mechanisms and the effective duration of this association (tDCS plus CIMT) from the early stages of stroke.

    The effectiveness of stroke interventions is often described by measures of disability, or functional assessment. Evaluations that deal with activities of daily living (ADLs) generally include the Functional Independence Measure, the Katz index and the Barthel index (BI), the latter being a prevalent measure for the clinical evaluation of stroke patients, with substantial supporting research [26]–[28]. However, there are few studies involving the ADLs as the primary outcome for a marker of functional recovery after neurostimulation. For example, in a systematic review where the efficacy of tDCS in ADLs and motor function after stroke were analyzed, the authors found that the results are inaccurate and the effect was not sustained when studies of high methodological quality were included. There were 15 studies involving a total of 455 participants included, with only randomized controlled trials and randomized controlled cross-over trials evaluated. Of the total, the analysis of five studies involving 286 participants to examine the effects of tDCS on our primary outcome (ADLs evaluated by BI) has shown that no effect was observed on the performance at the end of the intervention. In three studies from this systematic review involving 99 participants to evaluate the effects of tDCS in BI scores at the end of follow-up, evidence suggested an effect on the ADL performance, but the confidence intervals were wide, and the effect was not sustained when they only included studies with low risk of bias. Thus, the authors point to the need for future research in this area to improve the generalization of the results [29].

    Although clinical trials can be found that measure the efficacy of tDCS in ADLs pointing to positive effects [30],

    [31] among other factors, in general they only include participants in the chronic stage with brain injuries in different areas and varying levels of functional incapacity.

    Therefore, central questions remain: For a daily protocol of 10 days, does the active tDCS applied under a 2 mA current and associated with CIMT have a superior response to the simulated (placebo) current applied with CIMT, and if so, what is the size of the effect? What adverse effects are associated with the therapy? Does functional improvement in the ADLs persist over time?

    In light of this, a clinical trial phase II/III will be developed to evaluate the therapeutic effects of tDCS in patients in the subacute stage after stroke. The purposes are two: 1) discuss topics related to safety, adverse effects, feasibility, and effectiveness of tDCS in the treatment of stroke patients; 2) present the work protocol prior to clinical trial results, ensuring adherence to protocol. Our hypothesis is that the active stimulation in the affected hemisphere is more effective than a simulated (placebo) current in activities of daily living in subacute stroke. Secondly, we are interested in knowing whether tDCS is effective in the recovery of the following motor variables: spasticity, use of the affected limb, balance, posture, fall risk, muscle strength, and upper and lower limb function. Also, we aim to analyze if a possible functional improvement produces a change in the patients’ perception of their quality of life. We hope that the study will contribute to the discussion of the methodological procedures of clinical trials phase II/III involving neuromodulation for the treatment of patients after stroke.

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    Continue (HTML) —>  Trials | Full text | Stroke Treatment Associated with Rehabilitation Therapy and Transcranial DC Stimulation (START-tDCS): a study protocol for a randomized controlled trial

    Fig. 1. CONSORT (Consolidated Standards of Reporting Trials) flowchart of the clinical trial. BI: Barthel index; CIMT: constraint-induced movement therapy; MMSE, Mini Mental State Examination; MoCA: Montreal Cognitive Assessment; MRC: Medical Research Council (scale); NIHSS, National Institutes of Health Stroke Scale; PASS: Postural Assessment Scale for Stroke; SF-36: Medical Outcomes Study 36-item Short-Form Health Survey; SPPB: Short Physical Performance Battery; tDCS, transcranial direct current stimulation; WMFT: Wolf Motor Function Test

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