Frontiers Of Neurology And Neuroscience[JOURNAL]
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200 papers
Vessel and Vessel Wall Imaging.
Jung SC, Kang DW, Turan TN
Front Neurol Neurosci · 2016 · PMID 27960184 · Publisher ↗
Angiography is a useful, important, common imaging method, with digital subtraction angiography (DSA) remaining the gold standard for luminal imaging. Computed tomography angiography (CTA) is minimally invasive and quite...
Angiography is a useful, important, common imaging method, with digital subtraction angiography (DSA) remaining the gold standard for luminal imaging. Computed tomography angiography (CTA) is minimally invasive and quite accurate in the evaluation of stenosis. Magnetic resonance angiography (MRA) is a good screening tool with the least invasiveness. Angiography mostly represents intracranial artery disease as luminal stenosis, which is often not sufficient to evaluate intracranial vascular pathology. The modalities provide indirect information about vascular pathology because luminal change, such as stenosis, results from the changes of vessel walls. Vessel wall imaging using high-resolution magnetic resonance imaging (HR-MRI) has been recently introduced for direct evaluation of vessel walls beyond just luminal information such as the severity of stenosis. HR-MRI for vessel walls can present the characteristic radiological findings for each intracranial artery disease such as atherosclerosis, dissection, moyamoya disease, and vasculitis. The radiological features are useful to differentiate among intracranial artery disease. This chapter discusses the role and radiological features of angiography and HR-MRI for vessel walls.
Antithrombotic Therapy.
Kwon SU, Kim JS
Front Neurol Neurosci · 2016 · PMID 27960183 · Publisher ↗
Symptomatic cerebral atherosclerosis including intracranial atherosclerosis (ICAS) is associated with a high risk of recurrent stroke. Antithrombotic agents are the mainstay of therapy in these patients. Several studies...
Symptomatic cerebral atherosclerosis including intracranial atherosclerosis (ICAS) is associated with a high risk of recurrent stroke. Antithrombotic agents are the mainstay of therapy in these patients. Several studies have found anticoagulation (warfarin) to increase the risk of bleeding events and have an efficacy no better than that of aspirin. Therefore, anticoagulants are not widely used unless patients develop recurrent ischemic symptoms despite receiving antiplatelet therapy. Because ICAS progression is not uncommon and the risk of stroke recurrence is high when aspirin monotherapy is used, dual antiplatelet agents may be needed at least in the early disease stage. The Trial of Cilostazol in Symptomatic Intracranial Stenosis (TOSS) found that aspirin plus cilostazol was significantly better than aspirin monotherapy in preventing progression (6.7 vs. 28.8%, p = 0.008). The TOSS II trial that compared aspirin plus cilostazol with aspirin plus clopidogrel found no significant difference in the progression rate (9.3% vs. 15.5%, p = 0.092). However, the overall changes in stenosis were more favorable (i.e., less progression and more regression) in the cilostazol group (p = 0.049). TOSS studies have limitations in that the end points were changes in magnetic resonance angiography results rather than clinical outcomes. Based on the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial results, and the fair outcome found in patients enrolled in the SAMMPRIS (Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis) trial, aspirin plus clopidogrel has been recommended in the early stage of symptomatic ICAS. However, the combination of aspirin and clopidogrel did not show superiority over aspirin monotherapy in ICAS patients in a recent CHANCE substudy. Considering that ICAS is the major pathology leading to stroke worldwide, further studies are needed to identify the best medication strategy in ICAS patients. Until then, physicians may choose appropriate antiplatelet agents after careful consideration of the characteristics of both the patients (i.e., degree of stenosis, stroke mechanism, risk of stroke, and risk of bleeding) and the antiplatelet agent (e.g., side effect, cost).
Stroke Mechanisms.
Wong KS, Caplan LR, Kim JS
Front Neurol Neurosci · 2016 · PMID 27960181 · Publisher ↗
Recent advances in neuroimaging technologies, such as diffusion weighted magnetic resonance imaging (MRI), perfusion weighted computed tomography (CT)/MRI, MR/CT angiography and Doppler ultrasonography allow us to determ...
Recent advances in neuroimaging technologies, such as diffusion weighted magnetic resonance imaging (MRI), perfusion weighted computed tomography (CT)/MRI, MR/CT angiography and Doppler ultrasonography allow us to determine the mechanisms of stroke and transient ischemic attack. In addition, high-resolution vessel wall MRI is nowadays increasingly used to understand the stroke mechanism in patients with intracranial atherosclerosis. Artery to artery embolism, hypoperfusion and the combination of the two are the important stroke mechanisms in patients with extracranial atherosclerosis. In addition to the above two, branch occlusion and in-situ thrombotic occlusion are important stroke mechanisms in patients with intracranial atherosclerosis. Branch occlusion leads to subcortical or brainstem infarcts indistinguishable from infarcts caused by small artery disease. In-situ thrombotic occlusion leads to larger territorial infarcts. However, whole territory infarcts are uncommon due to relatively well developed collateral circulation in these patients. The treatment strategy should be based on the correct understanding of the stroke mechanism in individual patients.
Angioplasty and Stenting.
Leung TW, Wabnitz AM, Miao Z … +1 more , Chimowitz MI
Front Neurol Neurosci · 2016 · PMID 27960179 · Publisher ↗
The high rate of recurrent strokes in patients with intracranial atherosclerotic disease (ICAS) despite medical therapy prompted intracranial angioplasty and/or stenting an adjunctive treatment option. The minute caliber...
The high rate of recurrent strokes in patients with intracranial atherosclerotic disease (ICAS) despite medical therapy prompted intracranial angioplasty and/or stenting an adjunctive treatment option. The minute calibers of cerebral arteries, the relative paucity of supporting medial and adventitia layers, the presence of end-anastomosing perforator branches, and the vascular tortuosity from groin to head all demand specialized operative skills and dedicated tools. Since the stroke mechanism of ICAS is diverse, patient selection for endovascular treatment requires a sound understanding of the underlying pathophysiology. Patients with territorial cerebral hypo-perfusion associated with a high-grade steno-occlusive lesion may benefit most from endovascular revascularization. On the other hand, patients with atheromatous branch disease may stand a higher risk of perforator stroke from 'snow plowing' effect if angioplasty or stenting is inadvertently performed. A joint evaluation on the indication, procedural risks and benefits, and an individualized peri-operative care plan by a stroke neurologist and a neuro-interventionist is crucial prior to a procedure. Currently, the U.S. Food and Drug Administration approved Wingspan for patients who have developed two or more strokes despite aggressive medical management. The treatment indication will likely evolve in parallel with the advancement of endovascular techniques and our understanding of ICAS.
Moyamoya Disease.
Fujimura M, Bang OY, Kim JS
Front Neurol Neurosci · 2016 · PMID 27960175 · Publisher ↗
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease characterized by progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain...
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease characterized by progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is unknown, recent genetic studies have identified RNF213 in the 17q25-ter region as an important susceptibility gene of MMD among East Asian populations. A c.14576G>A polymorphism in RNF213 was identified in 95% of MMD patients with a family history and in 79% of sporadic cases, and patients carrying this polymorphism exhibited significantly earlier disease onset and a more-severe form of MMD. Due possibly to genetic differences, the prevalence of MMD is higher in East Asia (e.g., Korea and Japan) than in Western countries. The MMD prevalence peaks at two ages with different clinical presentations: around 10 years and at 30-45 years. Ischemic symptoms, including transient ischemic attacks, are the most important clinical manifestation in both children and adults. Intracranial hemorrhages are more frequent in adults than in children. Catheter angiography is a diagnostic method of choice. Magnetic resonance angiography and computed tomography angiography are noninvasive diagnostic methods. High-resolution vessel-wall magnetic resonance imaging also helps in diagnosing MMD by revealing concentric vessel-wall narrowing with basal collaterals. Surgical revascularization such as extracranial-intracranial bypass is the preferred procedure for MMD patients presenting with ischemic stroke. Surgical therapy may also be effective in patients with hemorrhages, based on recent observations in the Japan Adult Moyamoya trial. Procedure-related cerebral infarction and hyperperfusion syndrome are potential complications that can lead to neurological deterioration.
Non-Atherosclerotic Intracranial Arterial Diseases.
Kim JS, Caplan LR
Front Neurol Neurosci · 2016 · PMID 27960174 · Publisher ↗
Atherosclerosis is not the only cause of intracranial arterial disease. Arterial dissection, moyamoya disease, vascular inflammatory disease, vasospasm and immunologic disorders are important non-atherosclerotic intracra...
Atherosclerosis is not the only cause of intracranial arterial disease. Arterial dissection, moyamoya disease, vascular inflammatory disease, vasospasm and immunologic disorders are important non-atherosclerotic intracranial arterial diseases. Identification of the correct etiology is important in establishing treatment strategies and assessing prognosis. Careful history taking and appropriate laboratory testing are essential. Although catheter angiography is the most important diagnostic tool to examine various intracranial arterial diseases, other diagnostic modalities such as CT angiography and MR angiography are nowadays widely used. High resolution vessel wall MRI also can assist in making the correct diagnosis as this can yield information regarding vessel wall pathology. Certain diseases such as infectious vasculopathies and moyamoya disease are more prevalent in certain parts of the world, and physicians practicing in these regions should be mindful of these disorders. In this chapter, these non-atherosclerotic intracranial arterial diseases are discussed. Moyamoya disease will be described in another chapter.
Intracranial Arteries - Anatomy and Collaterals.
Liebeskind DS, Caplan LR
Front Neurol Neurosci · 2016 · PMID 27960167 · Publisher ↗
Anatomy, physiology, and pathophysiology are inextricably linked in patients with intracranial atherosclerosis. Knowledge of abnormal or pathological conditions such as intracranial atherosclerosis stems from detailed re...
Anatomy, physiology, and pathophysiology are inextricably linked in patients with intracranial atherosclerosis. Knowledge of abnormal or pathological conditions such as intracranial atherosclerosis stems from detailed recognition of the normal pattern of vascular anatomy. The vascular anatomy of the intracranial arteries, both at the level of the vessel wall and as a larger structure or conduit, is a reflection of physiology over time, from in utero stages through adult life. The unique characteristics of arteries at the base of the brain may help our understanding of atherosclerotic lesions that tend to afflict specific arterial segments. Although much of the knowledge regarding intracranial arteries originates from pathology and angiography series over several centuries, evolving noninvasive techniques have rapidly expanded our perspective. As each imaging modality provides a depiction that combines anatomy and flow physiology, it is important to interpret each image with a solid understanding of typical arterial anatomy and corresponding collateral routes. Compensatory collateral perfusion and downstream flow status have recently emerged as pivotal variables in the clinical management of patients with atherosclerosis. Ongoing studies that illustrate the anatomy and pathophysiology of these proximal arterial segments across modalities will help refine our knowledge of the interplay between vascular anatomy and cerebral blood flow. Future studies may help elucidate pivotal arterial factors far beyond the degree of stenosis, examining downstream influences on cerebral perfusion, artery-to-artery thromboembolic potential, amenability to endovascular therapies and stent conformation, and the propensity for restenosis due to biophysical factors.
Clinical Stroke Syndromes.
Kim JS, Caplan LR
Front Neurol Neurosci · 2016 · PMID 27960164 · Publisher ↗
The main mechanism of stroke in patients who have extracranial atherosclerosis is artery to artery embolism, occasionally associated with hemodynamic disturbances. Although these mechanisms are also important in patients...
The main mechanism of stroke in patients who have extracranial atherosclerosis is artery to artery embolism, occasionally associated with hemodynamic disturbances. Although these mechanisms are also important in patients with intracranial atherosclerosis, branch occlusion and in-situ thrombotic occlusion play a relatively more important role in these patients. Accordingly, clinical stroke syndromes differ between extracranial atherosclerosis and intracranial atherosclerosis. In anterior circulation, middle cerebral artery atherosclerosis frequently produces subcortical infarction by way of branch occlusion. The clinical syndromes are similar to lacunar syndromes classically associated with small perforator artery diseases, although a larger size infarction can be accompanied by cortical dysfunction such as aphasia or neglect. In-situ thrombotic occlusion of the large intracranial anterior circulation arteries leads to larger infarction that results in cortical symptoms - however, parts of the cortex are usually spared due to relatively well developed collateral circulation associated with prolonged perfusion impairment. In the posterior circulation, intracranial atherosclerosis is common in the distal vertebral artery and basilar artery that often causes medullary and pontine infarction syndromes, mostly by way of branch occlusion. Posterior cerebral artery atherosclerosis produces pure midbrain or thalamic infarction through branch occlusion. Artery to artery embolisms from posterior fossa intracranial atherosclerosis lead to cortical infarction - cerebellar or temporo-occipital lobe infarction, producing ataxic syndromes, and visual field defects and associated neurobehavioral syndromes, respectively.
Biomarkers, Natural Course and Prognosis.
Arenillas JF, López-Cancio E, Wong KS
Front Neurol Neurosci · 2016 · PMID 27960160 · Publisher ↗
Increasing our knowledge about intracranial atherosclerosis (ICAS) natural history and prognostic factors is essential to improve its preventive therapy and thus reduce the dramatic clinical consequences caused by this e...
Increasing our knowledge about intracranial atherosclerosis (ICAS) natural history and prognostic factors is essential to improve its preventive therapy and thus reduce the dramatic clinical consequences caused by this entity. ICAS is characterized by a chronic and progressive course until it becomes symptomatic, mostly through complication of an unstable intracranial atherosclerotic plaque. Population-based studies in healthy subjects have shown that the prevalence of asymptomatic ICAS is higher in Asian than in Caucasian populations. In both settings, asymptomatic ICAS is associated with classical vascular risk factors and with the metabolic syndrome, and it is burdened with an increasing risk of having incident stroke and cognitive impairment. When it reaches its symptomatic stage, ICAS is a dynamic and aggressive condition, and affected patients are at high risk of having recurrent stroke and other major vascular events. The Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial has recently shown a robust impact of intensive medical therapy reducing the risk of clinical recurrence of symptomatic ICAS. However, even under best medical therapy and degree of risk factor control, symptomatic ICAS-related recurrence risk continues to be the highest among all stroke etiologic subtypes. The second part of the chapter reviews the current understanding of prognostic factors that may help discriminate the high-risk ICAS patients, divided into local factors (vulnerable ICAS plaque) and systemic factors (vulnerable ICAS patient). Regarding research on local factors, high-resolution magnetic resonance imaging (HRMRI) is an emerging technique that allows in vivo evaluation of intracranial arterial wall, which is displacing our research focus from intracranial stenosis degree towards intracranial atherosclerotic plaque composition and activity. Characterization of the vulnerable ICAS patient may be improved with biomarker research. The latest contributions in this field help support the hypothesis that inflammation determines the risk of progression and complication of this disease, as it occurs in atherosclerosis affecting extracranial arterial beds.
Risk Factors.
Uehara T, Bang OY, Kim JS … +2 more , Minematsu K, Sacco R
Front Neurol Neurosci · 2016 · PMID 27960158 · Publisher ↗
Studies investigating risk factors for intracranial atherosclerosis (ICAS) have been infrequent. However, due to recent availability of non-invasive vascular imaging techniques that can assess intracranial cerebral arter...
Studies investigating risk factors for intracranial atherosclerosis (ICAS) have been infrequent. However, due to recent availability of non-invasive vascular imaging techniques that can assess intracranial cerebral arteries, there are a growing number of studies on risk factors for ICAS. Conventional vascular risk factors such as hypertension, diabetes, hypercholesterolemia and cigarette smoking are risk factors for ICAS. However, it remains uncertain whether there is a difference in risk factors between ICAS and extracranial atherosclerosis (ECAS). It also remains unclear why ICAS is more common in Asians and Blacks than in Caucasians. Although we reviewed available evidences on these differences, the review was limited because studies were heterogeneous in the definition of risk factors, diagnostic method, and characteristics of study subjects (hospitalized vs. community) or cerebral vessels (symptomatic vs. asymptomatic). Nevertheless, it seems that hypercholesterolemia is more closely associated with ECAS than ICAS. The difference in hypercholesterolemia prevalence is one of the main reasons for racial differences in the location of cerebral atherosclerosis. Intracranial arteries contain higher antioxidant level than extracranial arteries and may be more vulnerable to risk factors that deplete antioxidants (e.g., metabolic syndrome and diabetes mellitus). Intracranial arteries may be more vulnerable to factors associated with hemodynamic stress (e.g., advanced, salt-retaining hypertension and arterial tortuosity) because of a smaller diameter, thinner media and adventitia, and fewer elastic medial fibers than extracranial arteries. Additionally, non-atherosclerotic arterial diseases (e.g., moyamoya disease) that commonly occur in the intracranial arteries of East Asians may contaminate the reports of ICAS cases. Various genes, including RNF 213, might also explain racial differences in atherosclerotic location. Prospective, well-designed risk factor and genetic studies should be performed in a homogeneous group of patients with diverse ethnicities. These efforts are essential in the prevention of atherosclerotic diseases based on adequate knowledge of the risk factors and pathogenesis.
Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.
Tortelli R, Seripa D, Panza F … +2 more , Solfrizzi V, Logroscino G
Front Neurol Neurosci · 2016 · PMID 27464072 · Publisher ↗
BACKGROUND: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor...
BACKGROUND: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. SUMMARY: Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. KEY MESSAGES: The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification.
Cerebrospinal Fluid Biomarkers for Target Engagement and Efficacy in Clinical Trials for Alzheimer's and Parkinson's Diseases.
Parnetti L, Eusebi P, Lleó A
Front Neurol Neurosci · 2016 · PMID 27463974 · Publisher ↗
BACKGROUND: Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Aβ42, total tau, and phos...
BACKGROUND: Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Aβ42, total tau, and phosphorylated tau) are used in clinical practice to support the diagnosis in the prodromal stages of the disease. In Parkinson's disease (PD), the investigation is following the pathway of AD research and some promising markers have been identified, with the main aim to favor an early diagnosis, i.e. in the premotor phase. Some of these CSF markers have also been incorporated in AD and PD clinical trials to demonstrate target engagement of the drug and/or to enrich the patient populations. In this chapter, we will review the main CSF biomarkers for AD and PD and their potential application to clinical trials. SUMMARY: In clinical trials assessing the efficacy of disease-modifying agents for AD, CSF biomarkers are currently used both as a diagnostic criterion for inclusion and for monitoring the biochemical impact of the drug on the upstream neurodegenerative mechanisms. Accordingly, recent trials devoted to PD are following such a procedure, although in this neurodegenerative disorder CSF biomarkers are not ready yet for routine clinical use. KEY MESSAGES: AD and PD are neurodegenerative disorders that share a long asymptomatic/prodromal phase in which neurodegenerative phenomena already take place in the brain. Clinical trials assessing the efficacy of disease-modifying agents should include the CSF measurement of related biomarkers as biochemical proof of the underlying pathology as well as of the impact of the drug on these pathogenic mechanisms.
Current Issues in Randomized Clinical Trials of Neurodegenerative Disorders at Enrolment and Reporting: Diagnosis, Recruitment, Representativeness of Patients, Ethnicity, and Quality of Reporting.
Logroscino G, Capozzo R, Tortelli R … +1 more , Marin B
Front Neurol Neurosci · 2016 · PMID 27463823 · Publisher ↗
BACKGROUND: The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challenging for RCTs in neurodegenerative disorders (NDD). SUMMAR...
BACKGROUND: The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challenging for RCTs in neurodegenerative disorders (NDD). SUMMARY: At the time of inclusion in the study, an early and accurate diagnosis is mandatory. Variability of diagnostic criteria, mostly based on clinical grounds, lag time between onset and enrolment, and phenotypic heterogeneity are the main drivers of diagnostic complexity. High-quality data in terms of diagnostic reliability, phenotypic description, follow-up, and evaluation of outcomes are key determinants and are highly conditioned by the expertise of the investigators and center recruitment rate. Representativeness of NDD patients is mandatory to postulate the generalizability of the results of RCTs. There is, however, a systematic selection bias in terms of age (more likely to be younger), sex (more likely to be male), ethnicity (more likely to be of European/Caucasian origin), and other prognostic factors (more likely to be favorable). In the publication phase, researchers need to report properly all of the main features of the RCT. Consolidated Standards of Reporting Trials (CONSORT) facilitates the report and interpretation of RCTs, but adherence to these guidelines needs to be improved. KEY MESSAGES: Several issues discussed in this review may alter the internal and external validity of an RCT. To date, the impact on phenotype at study entry has often been overlooked. A differential effect of the selection of subjects and of specific clinical and nonclinical features needs to be systematically explored in the RCT planning phase.
Biomarkers in Randomized Clinical Trials: Positron Emission Tomography and Nuclear Medicine Techniques.
Singhal T, Stern E
Front Neurol Neurosci · 2016 · PMID 27463807 · Publisher ↗
BACKGROUND: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are nuclear medicine techniques that utilize the tracer principle to image biological processes using radiolabeled mol...
BACKGROUND: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are nuclear medicine techniques that utilize the tracer principle to image biological processes using radiolabeled molecules. Numerous PET and SPECT radiopharmaceuticals have been developed over the years that qualify as biomarkers for neurological disorders. SUMMARY: This chapter reviews the use of PET and SPECT in neurological clinical trials, and emphasizes the concepts and lessons learned from these experiences. KEY MESSAGES: Key considerations for successful use of PET or SPECT imaging as biomarkers in neurological randomized trials include: (1) in vivo behavior of the radiotracer and the PET or SPECT imaging parameter studied should reflect an essential aspect of the underlying pathology and/or pathophysiology of the disease under question, (2) the underlying biological target and radiotracer distribution should have the potential to vary with treatment under study conditions, and adjustments must be made for any other known changes (e.g. physiological) that may occur over time, (3) image reconstruction techniques and quantitative or semiquantitative image analysis approaches should be robust and standardized across trial sites, and (4) newer molecular targets should be explored based on insights obtained from basic science research and translational observations. Successful implementation of PET and SPECT in clinical trials and practice has a highly significant potential to contribute towards improving outcomes and clinical care for patients with neurological disorders.
Peculiarities of Neurological Disorders and Study Designs.
Beghi E, Pupillo E, Giussani G
Front Neurol Neurosci · 2016 · PMID 27463686 · Publisher ↗
BACKGROUND: Neurological disorders are heterogeneous clinical conditions with variable course and outcome. SUMMARY: The basic aspects of the commonest neurological disorders are addressed along with the proposed structur...
BACKGROUND: Neurological disorders are heterogeneous clinical conditions with variable course and outcome. SUMMARY: The basic aspects of the commonest neurological disorders are addressed along with the proposed structure of randomized clinical trials (RCTs). Dementing disorders, including Alzheimer's disease (AD), are clinical conditions in which altered cognitive functions are associated with behavioral and personality changes. Parkinson's disease (PD) is a multisystem disorder characterized by motor dysfunction associated with dysautonomia, sleep and olfactory disturbances, cognitive changes, and depression. Amyotrophic lateral sclerosis (ALS) is an invariably fatal clinical condition involving motor neurons. The available treatments are purely symptomatic for PD but virtually ineffective for AD and ALS. Headache disorders, multiple sclerosis, and epilepsy, three diseases characterized by recurrent symptoms and chronic or episodic course, can be fairly easily controlled by current treatments, but cannot be prevented nor cured. The objectives of treatments of neurodegenerative disorders include primary prevention, slowing or arrest of disease progression, and control of symptoms. Stroke is an acute clinical condition causing frequent disability and death, with only one approved treatment. There are many challenges to acute stroke clinical trials; among them, the very short therapeutic window and the issue of stroke heterogeneity. In this chapter, only the core elements of the study designs are outlined. KEY MESSAGES: The design of an RCT must be adapted to the basic characteristics of each clinical condition.
Biomarkers in Randomized Clinical Trials: Magnetic Resonance Imaging.
Whitwell JL
Front Neurol Neurosci · 2016 · PMID 27463684 · Publisher ↗
BACKGROUND: It is essential that randomized clinical trials (RCTs) incorporate biomarkers of disease progression that would be sensitive to the effects of disease-modifying treatments. Magnetic resonance imaging (MRI) ca...
BACKGROUND: It is essential that randomized clinical trials (RCTs) incorporate biomarkers of disease progression that would be sensitive to the effects of disease-modifying treatments. Magnetic resonance imaging (MRI) can be safely repeated over time, and is routinely performed in clinical centers, making it an ideal modality to be incorporated into RCTs. SUMMARY: This chapter discusses potential structural MRI biomarkers that have been proposed for a number of different neurodegenerative disorders, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy syndrome (PSPS), and Parkinson's disease (PD). All of these disorders represent targets for ongoing and future RCTs. Rates of hippocampal atrophy and ventricular expansion provide excellent biomarkers of disease progression in AD, and may also provide biomarkers in prodromal and preclinical phases of the disease, as well as in DLB. Rates of ventricular expansion also perform well in FTD, although regional frontal and temporal measurements could also be useful. Rates of midbrain atrophy provide the most feasible MRI biomarker in PSPS. In contrast, PD is not associated with specific patterns of cerebral atrophy and further work is needed in order to define useful MRI biomarkers. Sample size calculations using these MRI biomarkers are presented and discussed. KEY MESSAGES: Rates of cerebral atrophy provide valuable potential biomarkers of disease progression in neurodegenerative disorders, and have already begun to be utilized as outcome measures in RCTs. Measurements from other structural and functional MRI modalities require more longitudinal validation, but may prove to be useful in the future.
The Basic Structure of a Randomized Clinical Trial.
Beghi E
Front Neurol Neurosci · 2016 · PMID 27463525 · Publisher ↗
BACKGROUND: According to the Directive 2001/20/EC of the European Union, a clinical trial is any investigation in human subjects intended to (1) discover or verify the clinical, pharmacological, and/or other pharmacodyna...
BACKGROUND: According to the Directive 2001/20/EC of the European Union, a clinical trial is any investigation in human subjects intended to (1) discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more investigational medicinal product(s), (2) identify any adverse reactions to one or more investigational medicinal product(s), (3) and/or study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. SUMMARY: The major steps in the planning and conduction of a randomized clinical trial (RCT) include the definition of the study population, the random assignment of treatments, the choice of the measures of treatment effects, the duration of the experiment, the assessment of the tolerability and safety of the treatment, and the choice of alternative design models. In doing this, a constant reference will be made to the peculiarities (and diversities) of neurological disorders. KEY MESSAGES: An RCT is the best model to test the efficacy, tolerability, and safety of a drug, and reflects the need to disentangle the effects of the treatment from the effects of other prognostic variables. This requires a number of restrictions that are, at the same time, limitations for the application of the study results to the individuals who will receive the treatment in clinical practice.
Assessing Functional Decline in Neurological Diseases Clinical Trials: Duration of Follow-Up - The Case of Multiple Sclerosis.
Martinelli Boneschi F, Comi G
Front Neurol Neurosci · 2016 · PMID 27463522 · Publisher ↗
BACKGROUND: The main objective in the treatment of multiple sclerosis is to prevent or postpone the long-term disability caused by the disease, which in most cases occurs over years. However, most randomized clinical tri...
BACKGROUND: The main objective in the treatment of multiple sclerosis is to prevent or postpone the long-term disability caused by the disease, which in most cases occurs over years. However, most randomized clinical trials (RCTs) assessing the efficacy and safety of disease-modifying drugs have been designed to measure the short-term efficacy of disease-modifying drugs (up to 2-4 years) in reducing relapse rate and disease activity at magnetic resonance imaging (MRI). SUMMARY: In this chapter we will discuss how drug efficacy in reducing short-term relapse rate and MRI activity impact on delaying the accumulation of long-term disability, and we will summarize the available literature on the long-term efficacy of the drugs as assessed by the few long-term observational and long-term extension RCTs on available drugs, focusing on interferon-β treatment as the one with a more extensive literature. KEY MESSAGES: Additional long-term observational studies and long-term extension of follow-up periods for patients included in RCTs are needed to explore the long-term efficacy of available drugs which are known to be effective at the short-term level.
Disease Course, Outcome Measures, and Prognostic Predictors in Epilepsy: Opportunities for Improving Outcome of Drug Trials.
Schmidt D
Front Neurol Neurosci · 2016 · PMID 27463375 · Publisher ↗
BACKGROUND: A major concern over the development of new antiepileptic drugs (AEDs) is that the new AEDs have not added substantial clinical benefit over available antiseizure treatment. Additionally, current AEDs have ne...
BACKGROUND: A major concern over the development of new antiepileptic drugs (AEDs) is that the new AEDs have not added substantial clinical benefit over available antiseizure treatment. Additionally, current AEDs have neither improved the health of epilepsy patients nor been shown to prevent epilepsy or to improve the disease. SUMMARY: This chapter reviews new data on patterns of epilepsy with remission and relapse, prognostic factors for seizure outcome, and innovative patient-related outcome measures. Applying this knowledge presents opportunities to improve the drug treatment of epilepsy. KEY MESSAGES: Patient-relevant outcome measures and trial designs may be optimized to provide both evidence for efficacy and safety of AEDs and, in addition, for added clinical benefit over existing treatment. Added benefit of a new AED may be shown by evidence of higher antiseizure efficacy, better health, shorter disease duration, fewer side effects, and improved quality of life compared to available standard treatment. Moving from largely patient-irrelevant outcome measures such as 50% seizure reduction or use of placebo controls to innovative comparison of new AEDs versus standard treatment will revitalize the clinical development of new antiseizure treatments. Hopefully this will usher in a new era of much-needed antiepileptogenic agents that prevent or improve the patterns of epilepsy.
Age, Comorbidity, Frailty in Observational and Analytic Studies of Neurological Diseases.
Novy J, Sander JW
Front Neurol Neurosci · 2016 · PMID 27463228 · Publisher ↗
BACKGROUND: Comorbidities are rarely taken into account in studies of neurological conditions although they may be a confounder of the outcome and treatment. The relationship between comorbidities and neurological condit...
BACKGROUND: Comorbidities are rarely taken into account in studies of neurological conditions although they may be a confounder of the outcome and treatment. The relationship between comorbidities and neurological conditions is also problematic as comorbidities may be symptoms of the underlying cause of the neurologic condition or long-term adverse effects of the treatment. SUMMARY: There is evidence that several common neurological conditions have an increased burden of somatic and psychiatric comorbidities compared with matched samples from the general population. Depression is probably the most common comorbidity. Both psychiatric and somatic comorbidities have been shown to account for some of the premature mortality encountered in these neurological conditions. Comorbidities and age can also be important factors in the response and tolerance to treatment, and can alter the general outcome of a disease. KEY MESSAGES: Age and comorbidities should not be overlooked in the observation and assessment of neurological conditions and their treatment.
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