Showing papers in "Expert Review of Neurotherapeutics in 2019"

Intracerebral hemorrhage: an update on diagnosis and treatment.

Abstract: Introduction: Spontaneous non-traumatic intracerebral hemorrhage (ICH) is most often caused by small vessel diseases: deep perforator arteriopathy (hypertensive arteriopathy) or cerebral amyloid angiopathy (CAA). Although ICH accounts for only 10-15% of all strokes it causes a high proportion of stroke mortality and morbidity, with few proven effective acute or preventive treatments. Areas covered: We conducted a literature search on etiology, diagnosis, treatment, management and current clinical trials in ICH. In this review, We describe the causes, diagnosis (including new brain imaging biomarkers), classification, pathophysiological understanding, treatment (medical and surgical), and secondary prevention of ICH. Expert opinion: In recent years, significant advances have been made in deciphering causes, understanding pathophysiology, and improving acute treatment and prevention of ICH. However, the clinical outcome remains poor and many challenges remain. Acute interventions delivered rapidly (including medical therapies - targeting hematoma expansion, hemoglobin toxicity, inflammation, edema, anticoagulant reversal - and minimally invasive surgery) are likely to improve acute outcomes. Improved classification of the underlying arteriopathies (from neuroimaging and genetic studies) and prognosis should allow tailored prevention strategies (including sustained blood pressure control and optimized antithrombotic therapy) to further improve longer-term outcome in this devastating disease.

Microbiota-gut brain axis involvement in neuropsychiatric disorders

Abstract: Introduction: The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has rev...

An update on ketamine and its two enantiomers as rapid-acting antidepressants.

Abstract: Introduction: Depression is one of the most disabling diseases worldwide. Approximately one-third of depressed patients are treatment-resistant to the currently available antidepressants and there is a significant therapeutic time lag of weeks to months. There is a clear unmet need for rapid-acting and more efficacious treatments. (R,S)-ketamine, an old anesthetic drug, appears now to be going through a renaissance. Areas covered: This paper reviews recent literature describing the antidepressant effects of ketamine and its enantiomer (S)-ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). Furthermore, the authors discuss the therapeutic potential of (R)-ketamine, another enantiomer of (R,S)-ketamine, and (S)-norketamine. Expert commentary: A number of clinical studies have demonstrated that (R,S)-ketamine has rapid-acting and sustained antidepressant activity in treatment-resistant patients with MDD, BD, and other psychiatric disorders. Off-label use of ketamine for mood disorders is proving popular in the United States. Meanwhile, preclinical data suggests that (R)-ketamine can exert longer-lasting antidepressant effects than (S)-ketamine in animal models of depression, and (R)-ketamine may have less detrimental side effects than (R,S)-ketamine and (S)-ketamine. Additionally, (S)-norketamine exhibits rapid and sustained antidepressant effects, with a potency similar to that of (S)-ketamine. Unlike (S)-ketamine, (S)-norketamine does not cause behavioral and biochemical abnormalities and could be a safer than (S)-ketamine too.

Esketamine for treatment resistant depression

Abstract: Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2-3 trials are reviewed. Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine's approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.

Biomarkers for bipolar disorder: current status and challenges ahead.

Abstract: Introduction: Bipolar disorder (BD) is a chronic psychiatric disorder marked by clinical and pathophysiological heterogeneity. There is a high expectation that personalized approaches can improve t...

Edaravone for the treatment of amyotrophic lateral sclerosis

Abstract: Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2–4 years from onset. To date, the anti-glutamat...

Multidisciplinary care for people with Parkinson's disease: the new kids on the block!

Abstract: Introduction: Parkinson’s disease (PD) is a chronic multisystem disorder that causes a wide variety of motor and non-motor symptoms. Over time, the progressive nature of the disease increases the r...

Novel uses of retinal imaging with optical coherence tomography in multiple sclerosis.

Abstract: Introduction: Multiple Sclerosis (MS) is the most common chronic autoimmune neuroinflammatory condition in young adults. It is often accompanied by optic neuritis (ON) and retinal neuro-axonal damage causing visual disturbances. Optical coherence tomography (OCT) is a sensitive non-invasive method for quantifying intraretinal layer volumes. Recently, OCT not only showed to be a reliable marker for ON-associated damage, but also proved its high prognostic value for functional outcome and disability accrual in patients with MS. Consequently, OCT is discussed as a potential marker for monitoring disease severity and therapeutic response in individual patients. Areas covered: This article summarizes our current understanding of structural retinal changes in MS and describes the future potential of OCT for differential diagnosis, monitoring of the disease course and for clinical trials. Expert commentary: Today, OCT is used in clinical practice in specialized MS centers. Standardized parameters across devices are urgently needed for supporting clinical utility. Novel parameters are desirable to increase sensitivity and specificity in terms of MS.

Traditional Ayurvedic and herbal remedies for Alzheimer’s disease: from bench to bedside

Abstract: Introduction: Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder prevalent worldwide among elderly populations. Owing to limited efficacy, side effects, and poor patient complian...

An update on NMDA antagonists in depression

Abstract: Introduction: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One ...

Risk factors for intracranial hemorrhage after mechanical thrombectomy: a systematic review and meta-analysis.

Abstract: Background: Intracerebral hemorrhage (ICH) is the most feared complication of mechanical thrombectomy (MT). This study aims to provide a comprehensive overview of ICH risk factors. Methods: The authors systematically searched Pubmed and Embase (from inception to November 2018) for studies evaluating independent predictors for symptomatic ICH (sICH), parenchymal hematoma (PH), hemorrhagic infarction (HI), and any ICH after MT. Results: This analysis included a total of 42 studies involving 10,001 patients. The combined rate was 8% (7-10%) for sICH, 13% (10-15%) for PH, 25% (20-29%) for HI, and 35% (31-39%) for any ICH. Meta-analysis identified the following predictors of sICH: female sex (OR 2.98, 95%CI 1.23-7.25, I2 = 26.3%), treatment interval (OR 1.01, 95%CI 1-1.03, I2 = 69.20%), tirofiban use (OR 3.16, 95%CI 2.11-4.73, I2 = 0%), and ASPECTS score on admission (OR 0.63, 95%CI 0.54-0.74, I2 = 0%). Predictors of any ICH were diabetes mellitus (OR 1.95, 95%CI 1.29-2.94, I2 = 35.7%), deep white matter on diffusion-weighted imaging (OR 3.11, 95%CI 1.56-6.20, I2 = 0%), and intravenous recombinant tissue plasminogen activator (rt-PA) (OR 2.57, 95%CI 1.28-5.17, I2 = 0%). Conclusion: Many predictors of ICH were identified, however, given the lack of robust evidence, larger cohort studies should be prioritized to confirm these predictors.

Anxiety, depression and sleep disorders in patients with diabetic neuropathic pain: a systematic review.

Abstract: Introduction: Diabetic neuropathic pain (DNP) is a disabling complication suffered by patients with diabetic neuropathy. DNP coexists with different conditions, especially mental and sleep disorder...

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.

Abstract: Introduction: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in ...

Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease

Abstract: The amyloid-β (Aβ) cascade hypothesis of the Alzheimer’s disease (AD) assumes that the brain accumulation of this 40–42 amino acid peptide represents the initial event of the pathological process a...

Evidence-based treatment of Tourette’s disorder and chronic tic disorders.

Abstract: Introduction: Chronic Tic Disorders and Tourette's Disorder (collectively referred to as TD) are characterized by sudden, rapid, and repetitive motor movements or vocalizations called tics. Children, adolescents, and adults with TD often experience co-occurring psychiatric symptoms and impairments in multiple domains. As a result of tics and other symptoms, patients with TD can develop negative self-views, require considerable accommodations, and experience a poor quality of life. Therefore, the efficient and effective management of TD bears considerable importance. Areas covered: This expert review evaluated the empirical support for behavioral and pharmacological interventions based on the results of randomized controlled trials (RCTs). Behavioral interventions evaluated include habit reversal training (HRT), comprehensive behavioral intervention for tics (CBIT), and exposure response prevention (ERP). Reviewed pharmacological interventions included alpha-2 agonists, antipsychotics, and anticonvulsants. Expert opinion: This review identified several efficacious behavioral and pharmacological interventions for TD. However, several gaps in the management of TD include: (1) the access/availability of behavioral interventions, (2) novel and more efficacious treatment approaches, and (3) the development of more comprehensive interventions to manage TD. In order to advance the treatment of TD, additional research is necessary to efficiently, effectively, and comprehensively develop and evaluate new treatments for patients with TD.

Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures.

Abstract: Introduction: Tuberous sclerosis complex (TSC) is a rare genetic disorder resulting in benign tumors in various organs. It is caused by mutations in TSC1 or TSC2 genes causing hyperactivation of the mammalian target of rapamycin (mTOR) pathway. The majority of patients with TSC develop epilepsy, and approximately two-thirds become refractory to antiepileptic drugs (AEDs). Recently, the mTOR inhibitor everolimus was approved as adjunctive therapy for TSC-associated partial seizures. Areas covered: This article covers different characteristics of everolimus, including major clinical trials leading to its approval in TSC-associated partial seizures, safety concerns, drug pharmacokinetics/pharmacodynamics, and an overview of potential competitors and other agents used to treat TSC-associated seizures. Expert opinion: Unlike many other therapies for treating TSC-associated seizures, everolimus addresses the underlying pathophysiology of TSC, and since it has also been shown to improve other TSC manifestations such as subependymal giant cell astrocytomas and renal angiomyolipomas, everolimus provides a potential multisystemic therapy for TSC. An important avenue for future research is exploring the possible use of everolimus as a preventative treatment for seizures as there is the potential to prevent negative developmental outcomes associated with TSC.

Cortico-limbic connectivity as a possible biomarker for bipolar disorder: where are we now?

Abstract: Introduction: The fronto-limbic network has been suggested as a key circuitry in the pathophysiology and maintenance of bipolar disorder. In the past decade, a disrupted connectivity within prefron...

Neuropsychological, electrophysiological, and neuroimaging biomarkers for REM behavior disorder.

Abstract: Introduction: Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by dream enacting behaviors allowed by the loss of physiological atonia during REM sleep. This disorder is recognized as a prodromal stage of neurodegenerative disease, in particular Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). Therefore, a timely identification of biomarkers able to predict an early conversion into neurodegeneration is of utmost importance. Areas covered: In this review, the authors provide updated evidence regarding the presence of neuropsychological, electrophysiological and neuroimaging markers in isolated RBD (iRBD) patients when the neurodegeneration is yet to come. Expert opinion: Cognitive profile of iRBD patients is characterized by the presence of impairment in visuospatial abilities and executive function that is observed in α-synucleinopathies. However, longitudinal studies showed that impaired executive functions, rather than visuospatial abilities, augmented conversion risk. Cortical slowdown during wake and REM sleep suggest the presence of an ongoing neurodegenerative process paralleled by cognitive decline. Neuroimaging findings showed that impairment nigrostriatal dopaminergic system might be a good marker to identify those patients at higher risk of short-term conversion. Although a growing body of evidence the identification of biomarkers still represents a critical issue in iRBD.

Neuromodulation - Science and Practice in Epilepsy: Vagus Nerve Stimulation, Thalamic Deep Brain Stimulation, and Responsive NeuroStimulation

Abstract: Introduction: Neuromodulation devices can be safe and effective for the treatment of drug-resistant epilepsy. A body of scientific work supports peripheral, subcortical and cortical targets, each with different fundamental methods of action. Areas covered: High-quality evidence is available for vagal nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Mechanistic research in animals and human studies are reviewed, along with key data from VNS, DBS, and RNS clinical trials. Specifically, the authors review some of the science behind the most frequently used medical devices for neuromodulation, the evidence that lead to their adoption, a delineation of the populations that often benefit from these devices, and perspectives on clinical practice to optimize benefit in treatment of seizures. Expert Commentary: Neuromodulation is increasingly used to complement medical management of refractory epilepsy. Device preference will be made on the basis of patient preference, physician familiarity and other individualized factors. Right now, the field is very new and decision-making will improve with experience.

Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential?

Abstract: Taurine is a β-amino acid present in high concentrations in different areas of the mammalian central nervous system (CNS). It participates in different physiological processes such as osmoregulatio...

Gut microbiota in ALS: possible role in pathogenesis?

Abstract: Introduction: The gut microbiota has important roles in maintaining human health. The microbiota and its metabolic byproducts could play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Areas covered: The authors evaluate the methods of assessing the gut microbiota, and also review how the gut microbiota affects the various physiological functions of the gut. The authors then consider how gut dysbiosis could theoretically affect the pathogenesis of ALS. They present the current evidence regarding the composition of the gut microbiota in ALS and in rodent models of ALS. Finally, the authors review therapies that could improve gut dysbiosis in the context of ALS. Expert opinion: Currently reported studies suggest some instances of gut dysbiosis in ALS patients and mouse models; however, these studies are limited, and more information with well-controlled larger datasets is required to make a definitive judgment about the role of the gut microbiota in ALS pathogenesis. Overall this is an emerging field that is worthy of further investigation. The authors advocate for larger studies using modern metagenomic techniques to address the current knowledge gaps.

Metabolism and inflammation: implications for traumatic brain injury therapeutics.

Abstract: Introduction: Traumatic Brain Injury (TBI) is a leading cause of death and disability in young people, affecting 69 million people annually, worldwide. The initial trauma disrupts brain homeostasis...

Identifying risk factors for cognitive issues in multiple sclerosis.

Abstract: Introduction: Cognitive impairment (CI) in Multiple Sclerosis (MS) has progressively regained clinical and research interest and is currently recognized as a debilitating and burdensome pro...

Patient selection for migraine preventive treatment with anti-CGRP(r) monoclonal antibodies.

Abstract: Introduction: Migraine is the most common neurological disorder and represents the first cause of disability in under 50s in both genders. Available preventive drugs were primarily developed for indications other than migraine and with an unclear mechanism of action in migraine pathophysiology. Areas covered: This article reviews current preventive treatments and their shortcomings and the road that, through the understanding of calcitonin gene-related peptide (CGRP) role in migraine pathophysiology, carried to the approval of the 3 first-in-class monoclonal antibodies (mAbs) acting on the CGRP pathway. Data from phase 2 and phase 3 clinical trials of erenumab, galcanezumab and fremanezumab, both for episodic and chronic migraine prevention, are consistent for safety and efficacy. Expert opinion: Anti-calcitonin gene-related peptide mAbs have potential advantages over conventional treatments such as ease of use, quick onset of action, persistent efficacy, placebo-like safety profile and absence of pharmacological interactions. Pharmacoeconomic studies should evaluate the economic impact of these drugs taking into account the overall direct and indirect costs related to untreated migraine and to migraine treated with the other available preventive therapies. Given the high cost of these therapies, it is essential to implement all possible strategies to optimize their effectiveness by optimization of patients' selection.

Vascular aspects of multiple sclerosis: emphasis on perfusion and cardiovascular comorbidities.

Abstract: Introduction: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. Over the last two decades, more favorable MS long-term o...

An update on thymectomy in myasthenia gravis

Abstract: Introduction: Myasthenia gravis (MG) is one of the best treatable autoimmune diseases. However, in most patients, treatment is necessarily long-term and related side effects are a serious burden. Thymectomy has a special place in the disease management as a non-pharmacological disease-modifying therapy. For several decades, its role has only been supported by observational studies. Despite the recently achieved class I evidence, many questions remain unaddressed. Areas covered: This review discusses the pathogenic role of the thymus and evidence and controversies concerning therapeutic thymectomy. It also describes minimally invasive techniques that have largely replaced open surgery and the available evidence in MG patients. Expert opinion: Thymectomy plays a primary role in MG management, though its use is still controversial in some disease subtypes. Patient selection for surgery and adequate pre-operative MG control are critical. Thymectomy must ensure the exeresis of the whole thymus together with peri-thymic fat tissue. Minimally invasive techniques have many advantages over open approaches, provided they are as extensive as trans-sternal thymectomy. The investigation of thymectomy-related biomarkers will contribute to enhance the knowledge of its impact on the specific immune response.

Motor speech and non-motor language endophenotypes of Parkinson's disease.

Abstract: Introduction: Idiopathic Parkinson's Disease (PD) results in a range of motor and non-motor impairments. Clinical diagnosis commonly occurs after substantial neurophysiological damage limiting the opportunity for neuroprotective treatments. Uncovering sensitive objective markers with the capacity to detect pre-symptomatic disease and track disease progression is therefore a priority. Speech may provide an ideal proxy marker for PD; a quantifiable biometric that displays salient changes in early disease and appears to evolve with disease progression.Areas covered: This review describes the endophenotype of speech, voice, cognition and language modalities in PD and investigates the speech as a 'proxy marker' of PD disease state.Expert opinion: Detailed characterization at different disease stages are needed and must incorporate longitudinal assessment to capture small but significant changes in speech, voice, cognition and language modalities within patient changes over time. Advances in technology are leading to new opportunities for acquiring data remotely and more frequently, offering more ecologically valid testing environments. Combined with automated signal processing and analysis, symptoms may also be tracked in-home readily. Features extracted may provide a 'proxy marker' for early identification of PD and objective monitoring of disease progression.

The future role of robots in neuro-rehabilitation.

Abstract: The World Health Organization estimates that about 15% of the world’s population has some form of disability [1]. Rehabilitation has a key role in decreasing the level of disability. Application of advanced technologies in rehabilitation is a promising opportunity to attain this goal. The development of rehabilitation robots started in the late 1980s. The following decade was a pioneering phase. After the year 2000, the first representatives of commercially available robots appeared. These devices can assist in practicing upper or lower limb movements and motor relearning, and in developing proprioception, cognitive functions, and attention. There is equipment that patients can use to practice the same movements as with the robots, but it does not provide mechanical assistance; so patients have to rely on their own strength. The emphasis is on high repetition, interactive and personalised therapy. The aim is to attain a higher level of function in a shorter time frame. The philosophy of the application of robots in rehabilitation is not to replace the therapist, but to widen treatment options [2]. The two main goals of therapy with rehabilitation robots are to develop upper limb function and to support gait re-education. Rehabilitation robots are used mainly following central nervous system damage, primarily after stroke. Multiple clinical trials and meta-analyses have been conducted regarding these robots. Concerning the efficacy of electromechanical arm training, Mehrholz et al. [3] analysed 45 randomized controlled trials with 1619 participants. They found that this kind of therapy promotes improvement in arm function and muscle strength, as well as execution of activities of daily living. Nevertheless, the methodologies of the studies were quite different, and 24 different devices were used. Robot-mediated training on a treadmill is a widely used method for gait re-education. Mehrholz et al. [4] selected 36 trials with 1472 subjects in a Cochrane review and found that poststroke patients who received such training in addition to traditional physiotherapy were more likely to achieve independent walking, than subjects who received traditional therapy alone. These results suggest that robot-mediated therapy gives certain advantages for patients, at least in motor relearning; but several unanswered questions remain: Which kind of exercises are most beneficial, in which phase, how often, and for how long in order to yield optimal results? To compare routinely used types of upper limb therapy, Pollock et al. evaluated 40 reviews covering 18 different interventions (including robotics) in a Cochrane review [5] and stated that the available evidence is insufficient to determine the most effective therapy for improving upper limb function. The authors urged researchers to conduct large randomized controlled trials to find the best practice. Although thousands of patients took part in research trials, it is difficult to compare the results. As yet, no unifiedmethodology or generally used outcome measures for the trials exist; this makes evaluation uncertain [6]. However, some initiatives have been proposed for harmonizing methodologies. The European Network for Robotics in Neurorehabilitation (in the scope of the European Cooperation in Science and Technology – EU COST Action) has published recommendations on protocols for assessment in clinical practice and research in rehabilitation robotics [7]. There is another reason that can make the evaluation more difficult: there are non-robotic devices which provide similar exercises but without robotic assistance. In several studies such devices are used and mentioned as ‘robots’. Studies conducted on the basis of harmonized methodologies could result in a higher level of evidence, which could help create clinical guidelines for application of rehabilitation robotics. According to the present American guidelines for rehabilitation for adults post-stroke, the application of robotic devices for improving mobility ‘may be considered’; and in improving upper limb function, it is ‘reasonable to consider’ [8]. The British guidelines accredited by the National Institute of Health and Care Excellence (NICE) recommend the consideration of electromechanically assisted gait training for those who cannot walk independently after stroke, but also recommend offering robot-assisted arm training to patients only in the context of a research study [9]. The reason for these quite cautious guidelines could be that only weak evidence can be established based on the diverse, hardly comparable trials. It seems that low treatment dose and duration can negatively affect the results. Nevertheless, robot-mediated therapy is considered also because it has very few side effects [10]. Most of the devices make it possible to exercise in a virtual environment [11]. Very few robots provide practice using real objects in a real environment; one of them is the Reharob system [12]. Application of virtual reality is easier to solve technically than practicing in a real environment, but does it

Ocrelizumab for the treatment of multiple sclerosis.

Abstract: Introduction: In the past decade, the role of B cells in the pathogenesis of multiple sclerosis (MS) is coming to the forefront. Depletion of B cells by anti-CD20 monoclonal antibodies (mAbs) has p...

Therapeutic strategies for social anxiety disorder: where are we now?

Abstract: Introduction: Classical well-established treatments of social anxiety disorder (SAD) are now complemented by more recent therapeutic strategies. This review aims to summarize available therapies for SAD and discuss recent evidence-based findings on the management of this disorder.Areas covered: Recent guidelines recommend psychotherapy, particularly cognitive-behavioral therapy (CBT), and pharmacotherapy, as first-line treatments of patients with SAD, without a clear superiority of one option over the other. CBT includes classical approaches such as in vivo exposure to social situations and cognitive therapy, but new modalities and techniques have been recently developed: third-wave approaches, internet-delivered therapy, virtual reality exposure, and cognitive bias modification. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors have been also extensively studied and shown to be effective in SAD. Two alternative strategies have been developed to treat SAD with disappointing results: cognitive bias modification, and pharmacological augmentation of psychotherapy using D-cycloserine during exposure sessions.Expert opinion: Personalized treatments for SAD patients are now available. Innovative strategies such as online psychotherapy and virtual reality exposure are useful alternatives to CBT and SSRIs. Future developments and optimization of attention bias modification and of pharmacological augmentation of psychotherapy can be promising.