Outcome measures in immune-mediated neuropathies: the need to standardize their use and to understand the clinimetric essentials

Abstract   Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy-related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.     

Update on neuropathies associated with monoclonal gammopathy of undetermined significance (2008-2010)

Studies on paraproteinemic neuropathies have appeared in the last 2 years improving the diagnosis of these neuropathies, clarifying their pathogenesis, and informing practice by randomized clinical trial publications. Two recent randomized controlled trials with rituximab failed to provide evidence of efficacy in primary outcome measures, despite the fact that anti-myelin-associated glycoprotein (MAG) antibodies were reduced in most treated patients. This discrepancy, besides inducing the search for more effective therapy for this neuropathy, indicates that some aspects on the pathogenesis of this neuropathy probably need further clarification.     

Revue de la littérature récente sur les neuropathies périphériques : actualités thérapeutiques

Improvement of therapeutic strategies for peripheral neuropathies requires multicentric clinical trials. For chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a randomized controlled multicentric study compared IgIV to pulses of methylprednisolone (MP) given for 6 months. The primary endpoint was treatment discontinuation due to inefficacy or intolerance; 45 patients were enrolled: more patients had interrupted MP than IVIg, usually because of inefficacy. A multicentric randomized clinical trial (PREDICT) evaluated long-term remission of CIDP after short-term corticosteroid therapy (pulses of dexamethasone or prednisolone); 39 patients were enrolled: 26% achieved cure or remission, a relapse occurred in 50% after a delay of 11 to 17 months. Differential diagnosis was identified in 58% of patients who had not responded to any therapy. For refractory CIDP, a retrospective study showed the possibility of functional improvement in 24% of cases after adjunction of animmunomodulatory agent; cyclosporine was associated with the highest rate of adverse events or side effects. In familial amyloidotic polyneuropathy, a multicentric controlled study against placebo with tafamidis, an akinetic stabilizer of transthyretin (TTR) 20 mg/d, in early stage of Val30MetTTR showed efficiency in the evaluable group and led to marketing authorization by the EMA in stage 1 to slow the progression of the neuropathy. A Cochrane database system review showed that there are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome, for neuropathies with anti-MAG antibodies, or multifocal motor neuropathy on which to base practice. This review underlines the usefulness of multicentric randomized trials to assess treatments in peripheral neuropathies.     

Animal Models of Peripheral Neuropathies

Peripheral neuropathies are common neurological diseases, and various animal models have been developed to study disease pathogenesis and test potential therapeutic drugs. Three commonly studied disease models with huge public health impact are diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, and human immunodeficiency virus-associated sensory neuropathies. A common theme in these animal models is the comprehensive use of pathological, electrophysiological, and behavioral outcome measures that mimic the human disease. In recent years, the focus has shifted to the use of outcome measures that are also available in clinical use and can be done in a blinded and quantitative manner. One such evaluation tool is the evaluation of epidermal innervation with a simple skin biopsy. Future clinical trials will be needed to validate the translational usefulness of this outcome measure and validation against accepted outcome measures that rely on clinical symptoms or examination findings in patients.     

Intensive care management [corrected] of patients with intracerebral hemorrhage

Approximately 10-15% of acute strokes are caused by non-aneurysmatic intracerebral hemorrhage (ICH) and incidences are expected to increase due to an aging population. Studies from the 1990s estimated mortality of ICH to be as high as 50%. However, these figures may partly be attributed to the fact that patients suffering from ICH frequently received only supportive therapy and the poor prognosis may therefore be more a self-fulfilling prophecy. Recently it has been shown that treatment in a specialized neurological intensive care unit alone was associated with better outcomes after ICH. In recent years considerable efforts have been undertaken in order to develop new therapies for ICH and to assess them in randomized controlled trials. Apart from admission status, hemorrhage volume is considered to be the main prognostic factor and impeding the spread of the hematoma is thus a basic therapeutic principle. The use of activated factor VIIa (aFVIIa) to stop hematoma enlargement has been assessed in two large randomized controlled trials, however the promising results of the dose-finding study could not be confirmed in a phase III trial. Although hemostatic therapy with aFVIIa reduced growth of the hematoma it failed to improve clinical outcome. Similar results were found in a randomized controlled trial on blood pressure management in acute ICH. The link between reduction of hematoma growth and improved outcome is therefore still lacking. Likewise the value of surgical hematoma evacuation remains uncertain. In the largest randomized controlled trial on surgical treatment in ICH so far, only a small subgroup of patients with superficial hemorrhages seemed to benefit from hematoma evacuation. Whether improved intensive care can contribute to improved outcome after ICH will be shown by data obtained in the coming years.     

The natural history of multiple sclerosis: implications for trial design.

The understanding of the natural history of multiple sclerosis has many implications for the design and interpretation of randomized controlled trials. Selection criteria, patient stratification, outcome measurements, and definitions of treatment failure can influence randomized controlled trial results and limit comparisons among trials. The focus of future studies should shift from short-term determinations of efficacy to definitive evaluations of long-term effectiveness. This will require novel investigative strategies such as the use of historic controls derived from natural history studies.     

Reflexiones sobre el uso de la hipotermia moderada en el tratamiento del paciente con un traumatismo craneoencefálico grave

Traumatic brain injury initiates several metabolic processes that can increase the primary injury. It is well established that in severe head injuries, posttraumatic secondary insults, such as brain hypoxia, hypotension or anemia, exacerbate neuronal injury and lead to a poorer outcome. Experimental and clinical evidence suggests that moderate hypothermia (32–34°C), may limit some of these deleterious secondary metabolic responses. Recent laboratory studies and prospective controlled clinical trials of induced moderate hypothermia for relatively short periods (24–48 h) in patients with severe head injury, have demonstrated good intracranial pressure control and better outcome when compared with patients maintained in normothermia and given conventional treatment. Despite its proven clinical role in neuroprotection, hypothermia research has been inconstantly followed for various reasons. In this paper we review the mechanisms of neuroprotection in hypothermia, the different preclinical and clinical studies that favor its use as a neuroprotector in severe head injury or in patients in whom high intracranial pressure is refractory to first tier measures. The evidence that favors hypothermia is discussed. We also discuss the negative results of the still unpublished multicentre trial on prophylactic moderate hypothermia developed in the USA. The main problem with moderate hypothermia is the lack of a systematic methodology to induce and maintain it. Also, optimal duration of its use and the methodology and timing for rewarming have not been determined. Consequently, the results of different trials are difficult to analyze and compare. However, most evidence suggests that hypothermia provides remarkable protection against the adverse effects of neuronal damage that is exacerbated by secondary injury. Further prospective controlled trials with clearly defined methodology are needed before this method is implemented in daily clinical practice. The most important task for the years to come may be to focus on refining this procedure, defining the optimal time of cooling and rewarming and to optimize the methods of rapidly inducing and maintaining Iow temperature. It is also essential to define the most appropriate method and velocity of the rewarming phase, in which many successfully controlled patients deteriorate and die.     

Improving adherence to antidepressants: a systematic review of interventions

BACKGROUND: Effectiveness of antidepressant medication is reduced by patients' nonadherence. Several interventions to improve adherence in patients diagnosed with unipolar depression have been tested. OBJECTIVE: To systematically review the effectiveness of interventions that aimed to improve adherence to antidepressant medication in patients with unipolar depression. METHOD: Systematic review of English-language articles of randomized controlled trials obtained by a computerized literature search of MEDLINE (1966-January 2002) using the terms patient compliance, patient dropout, treatment refusal, patient education, adherence, clinical trial, randomized controlled trial, controlled trial, depressive disorder, and depression; PSYCINFO (1984-January 2002) using the terms random, clinical, control, trial, adherence, compliance, noncompliance, dropouts, patient education, depression, major depression, affective disorders, and dysthymic disorder; EMBASE (1980-January 2002) using the terms patient compliance, patient dropouts, illness behavior, treatment refusal, patient education, clinical trial, controlled study, randomized controlled trial, and depression; and the Cochrane Controlled Trials Register (no restrictions) using the terms random*, complian*, adheren*, pharmacotherapy, regimen*, educat*, medicat*, depression, and depressive disorder. RESULTS: Educational interventions to enhance adherence failed to demonstrate a clear benefit on adherence and depression outcome. However, collaborative care interventions tested in primary care demonstrated significant improvements in adherence during the acute and continuation phase of treatment and were associated with clinical benefit, especially in patients suffering from major depression who were prescribed adequate dosages of antidepressant medication. CONCLUSION: We found evidence to support the introduction of interventions to enhance adherence with antidepressant medication in primary care, not only because of better adherence but also because of better treatment results. Because collaborative care interventions require additional resources, a better understanding of the mode of action of different programs is needed to reduce avoidable costs. The effectiveness of educational interventions needs more evidence.     

Routine Management of Volume Status After Aneurysmal Subarachnoid Hemorrhage

Prophylactic use of hypervolemia and hypertension is believed to present an option to decrease the incidence of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage and improve neurologic outcome. A Medline literature search was conducted to review available evidence regarding volume management after subarachnoid hemorrhage. Quality of selected studies was evaluated, using the standardized GRADE system. Eleven studies focused on prophylactic hypervolemic therapy after aneurysmal subarachnoid hemorrhage were identified, including four randomized controlled trials. Available studies showed a large heterogeneity in physiologic treatment goals and interventions applied. The oldest and smallest randomized controlled trial suggested a positive effect, but had severe limitations in trial design. Neither of the other randomized controlled studies showed outcome benefit with hypervolemic therapy. Results from observational studies were not found to support the use of prophylactic hypervolemia and hypertension. Complication frequency was repeatedly reported to be higher with the application of prophylactic hypervolemia. In summary, prophylactic hyperdynamic therapy after subarachnoid hemorrhage has not been adequately shown to effectively raise cerebral blood flow or improve neurological outcome. In contrast, there is evidence for harm using overly aggressive hydration.     

脑出血后血压与脑灌注和继续出血及预后的关系

脑出血后如何控制血压、改善预后一直存在着争论。过低的血压可能引起脑灌注不足,导致进一步的脑损伤,而过高的血压则可能导致继续出血。本文针对最近的部分临床研究结果,对适当降压能减少继续出血的发生、改善预后做一简单综述。由于目前暂无成熟的血压控制方案,尚需大规模的随机对照临床研究为脑出血后血压控制提供有力的依据。     

Treatment of neuropathic pain

Neuropathic pain is a common symptom associated with peripheral neuropathy and can be as or more disabling than the effects of nerve damage from the neuropathy. Though treatment of the underlying pathophysiology causing neuropathies may not be possible, treatment of neuropathic pain is. The author reviews the major medications used, dosing schedules, and data from randomized controlled trials.     

Current treatments of chronic immune‐mediated demyelinating polyneuropathies

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy are three demyelinating acquired neuropathies, with distinct responses to immunotherapy. In placebo‐controlled, double‐blind, randomized trials, intravenous immunoglobulin (IVIg) has been effective for CIDP and MMN, and plasmapheresis has been effective for CIDP. Corticosteroids have been beneficial in controlled trials for CIDP. Other agents, including cyclophosphamide, rituximab, azathioprine, cyclosporine, interferons, fludarabine, mycophenolate mofetil, and etanercept, have been reported to benefit some patients with inflammatory demyelinating neuropathies in case series and case reports. This review examines the use and toxicity associated with these immunotherapy medications in treating patients with chronic immune‐mediated demyelinating neuropathies. Muscle Nerve, 2009     

Sequential designs for clinical trials in amyotrophic lateral sclerosis.

BACKGROUND: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied. METHODS: As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs. RESULTS: In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed. CONCLUSIONS: We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation.     

Alcoholics in acute medical settings have increased risk for other drug, mood, and personality disorders

OBJECTIVE: Brief medical management and alcohol pharmacotherapy are effective treatments for alcoholic participants enrolled in randomized controlled trials, and this suggests that alcoholism treatment may be delivered successfully in medical settings. However, medical patients may differ from clinical trial participants in ways that suggest a need for more intensive alcoholism treatment. To explore this possibility, this study evaluated the prevalence of mental health disorders in the U.S. population stratified by alcoholism and recent hospitalization or emergency room use. METHODS: Data from the National Epidemiological Survey on Alcohol and Related Conditions were analyzed. Subjects with information on alcohol use disorders, emergency room use, hospitalization, and several mental health diagnoses were included (n = 41,961). Methods appropriate for complex survey data were used to determine the relative risk for mental health diagnoses as a function of a current alcohol use disorder and receipt of acute medical care (hospitalization or emergency room visits) within the past year. RESULTS: Results showed that, relative to alcoholic adults who did not have an emergency room visit or hospitalization, alcoholic adults with use of these services had an increased prevalence of personality disorders, depression, and other drug use disorders. CONCLUSION: Research is needed to evaluate if these and other differences will lead to poorer treatment outcomes for this group relative to the more selected populations included in medical management efficacy trials.     

The psychosocial treatment of schizophrenia: an update

OBJECTIVE: The authors sought to update the randomized controlled trial literature of psychosocial treatments for schizophrenia. METHOD: Computerized literature searches were conducted to identify randomized controlled trials of various psychosocial interventions, with emphasis on studies published since a previous review of psychosocial treatments for schizophrenia in 1996. RESULTS: Family therapy and assertive community treatment have clear effects on the prevention of psychotic relapse and rehospitalization. However, these treatments have no consistent effects on other outcome measures (e.g., pervasive positive and negative symptoms, overall social functioning, and ability to obtain competitive employment). Social skills training improves social skills but has no clear effects on relapse prevention, psychopathology, or employment status. Supportive employment programs that use the place-and-train vocational model have important effects on obtaining competitive employment. Some studies have shown improvements in delusions and hallucinations following cognitive behavior therapy. Preliminary research indicates that personal therapy may improve social functioning. CONCLUSIONS: Relatively simple, long-term psychoeducational family therapy should be available to the majority of persons suffering from schizophrenia. Assertive community training programs ought to be offered to patients with frequent relapses and hospitalizations, especially if they have limited family support. Patients with schizophrenia can clearly improve their social competence with social skills training, which may translate into a more adaptive functioning in the community. For patients interested in working, rapid placement with ongoing support offers the best opportunity for maintaining a regular job in the community. Cognitive behavior therapy may benefit the large number of patients who continue to experience disabling psychotic symptoms despite optimal pharmacological treatment.     

Charcot–Marie–Tooth neuropathies: Current gene therapy advances and the route toward translation

Charcot–Marie–Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene- and disease- and even mutation-specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular-genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non-human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale-up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.     

Low-molecular-weight heparins and heparinoids and their use in acute or progressing ischemic stroke.

Thrombotic or thromboembolic occlusion of a cerebral artery is the most common pathophysiologic mechanism of acute ischemic stroke. An antithrombotic agent would therefore appear to be an ideal medication for treatment of this condition. Heparin is an effective anticoagulant, but it has poor bioavailability and effects on thrombin and platelets that predispose it to life-threatening complications such as hemorrhage and thrombocytopenia. Low-molecular-weight (LMW) heparins have better bioavailability, a higher anti-Xa:anti-IIa ratio, and less effect on platelets than heparin; yet their heterogeneity has hampered their proper investigation in clinical trials and it has not yet been proven that they exhibit less tendency toward hemorrhage and thrombocytopenia than conventional heparin. The LMW heparinoid, Org 10172, is superior to standard heparin in terms of its bioavailability, anti-Xa:anti-IIa ratio, and lack of effect on platelets. It is less likely than heparin and many LMW heparins to induce thrombocytopenia. Like the various heparins, Org 10172 exhibits dose-dependent hemorrhagic tendencies, yet preliminary studies have found doses that are safe for use in patients with acute ischemic stroke. These studies also suggest that Org 10172 may improve outcome and lessen mortality in this population. A prospective, randomized, double-blind, controlled trial is needed to establish the potential efficacy of Org 10172 in patients who suffer acute or progressing ischemic stroke.     

Antidepressants for bipolar depression: a systematic review of randomized, controlled trials

OBJECTIVE: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression. METHOD: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportion of patients who clinically responded to treatment and the rate of switching to mania. RESULTS: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo. Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%. CONCLUSIONS: Antidepressants are effective in the short-term treatment of bipolar depression. The trial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition and follow-up of emerging mania and partial remission.     

Small fibre neuropathies

PURPOSE OF REVIEW: To summarize the recent advances in aetiology, diagnostic assessment, and treatment of small fibre neuropathies. RECENT FINDINGS: New causes of small fibre neuropathy have been recognized and advances in neurophysiologic and neuropathologic techniques for investigating small fibres have been made, increasing the interest in this field. In particular, skin biopsy proved to be a sensitive method to diagnose small fibre neuropathy. It allows the detection of subclinical abnormalities of peripheral nerve function in patients with diabetes and tongue denervation in patients with burning mouth syndrome. This technique has also been used to demonstrate the neuroprotective effect of erythropoietin in experimental models of neuropathy. Among nonconventional neurophysiologic techniques for investigating small fibres, laser-evoked potential and contact heat-evoked potential stimulators have been developed and deserve particular interest. Several trials on neuropathic pain that is a typical feature of small fibre neuropathies have been performed and guidelines have recently been published. SUMMARY: Detection of small fibre impairment allows earlier diagnosis of neuropathy and could be used as an outcome measure in future regenerative neuropathy trials. Standardization of skin biopsy can have an important impact on clinical practice and research. Further studies are needed to assess the reliability of current neurophysiologic techniques for testing small fibre function in peripheral neuropathies and the correlation with well established neuropathologic examination.