Immunoglobulin use in neurology: a practical approach.

Human immunoglobulin, delivered either intravenously (IVIg) or subcutaneously, is used to treat a range of immune-mediated neurological disorders. It has a role in acute or subacute inflammatory disease control and as a maintenance therapy in chronic disease management. This review considers mechanisms of IVIg action and the evidence for IVIg in neurological conditions. We use Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as frameworks to demonstrate an approach to IVIg use in acute and chronic dysimmune neurological conditions across two different healthcare systems: the UK and Australia. We highlight the benefits and limitations of IVIg and focus on practical considerations such as informed consent, managing risks and adverse effects, optimal dosing and monitoring response. We use these basic clinical practice principles to discuss the judicious use of an expensive and scarce blood product with international relevance.

Reframing the clinical phenotype and management of cryptococcal meningitis.

Cryptococcal meningitis is an important global health problem, resulting from infection with the yeast Cryptococcus, especially Cryptococcus neoformans and Cryptococcus gattii, which cause a spectrum of disease ranging from pulmonary and skin lesions to life-threatening central nervous system involvement. The diagnosis and management of cryptococcal meningitis have substantially changed in recent years. Cryptococcal meningitis often occurs in people living with advanced HIV infection, though in high-income countries with robust HIV detection and treatment programmes, it increasingly occurs in other groups, notably solid-organ transplant recipients, other immunosuppressed patients and even immunocompetent hosts. This review outlines the clinical presentation, management and prognosis of cryptococcal meningitis, including its salient differences in people living with HIV compared with HIV-negative patients. We discuss the importance of managing raised intracranial pressure and highlight the advantages of improved multidisciplinary team working involving neurologists, infectious disease specialists and neurosurgeons.

Paraproteinaemic neuropathy: MGUS and beyond.

Paraproteinaemic neuropathies comprise a heterogeneous group of neuro-haematological conditions with some distinct neurological, haematological and systemic phenotypes. The spectrum of disease varies from mild to severe, indolent to rapidly progressive and from small fibre sensory involvement to dramatic sensorimotor deficits. The haematological association may be overlooked, resulting in delayed treatment, disability, impaired quality of life and increased mortality. However, the presence of an irrelevant benign paraprotein can sometimes lead to inappropriate treatment. In this review, we outline our practical approach to paraproteinaemic disorders, discuss the utility and limitations of diagnostic tests and the distinctive clinical phenotypes and touch on the complex multidisciplinary management approaches.

Frequent central nervous system, pachymeningeal and plexus MRI changes in POEMS syndrome.

OBJECTIVE: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare multisystem disease associated with a plasma-cell dyscrasia. Although pachymeningeal involvement has occasionally been described, MRI of the central nervous system (CNS) has not yet been extensively investigated. METHODS: We retrospectively evaluated CNS MRI in Europe's largest single-center cohort of POEMS syndrome. Of 77 patients who have been formally diagnosed with POEMS, 41 had MRI brain and 29 had MRI spine. A control group of 33 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) was used as this is the major differential diagnosis. Of these CIDP patients, 12 underwent both MRI brain and spine, 7 had solely MRI brain and 14 had MRI spine. RESULTS: In 41 POEMS patients with MRI brain, we identified frequent smooth, diffuse meningeal thickening of the cerebral convexities and falx (n = 29, 71%), of which 4 had meningeal collections. 17 (41%) had vascular abnormalities including white-matter disease, of which 4 had established infarcts. Of 29 patients with MRI spine, 17 (59%) had thickening of the brachial and lumbosacral plexus. Conversely in 19 CIDP patients with MRI brain, none had meningeal thickening (p < 0.0001); however, 8 (42%) had vascular abnormalities (p = 0.85). Of 26 patients with MRI spine, 9 (35%) had brachial or lumbosacral plexus thickening (p = 0.06). CONCLUSIONS: In contrast to CIDP, POEMS patients frequently have pachymeningeal thickening. Vascular abnormalities and plexus thickening were also common but not statistically different to CIDP.

Diagnosis of amyloid neuropathy.

Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.

POEMS neuropathy: optimising diagnosis and management.

POEMS syndrome is a rare and disabling autoinflammatory condition characterised by a typical peripheral neuropathy and the presence of a monoclonal plasma cell disorder. The acronym 'POEMS' represents the complex and multisystem features of the disease, including polyneuropathy, organomegaly, endocrinopathy, a monoclonal plasma cell disorder and skin disease. The diagnosis of POEMS is a significant challenge because of the heterogeneity of clinical presentations and variation of POEMS features. Patients are often misdiagnosed with another cause of inflammatory neuropathy and receive one or more ineffective immunomodulatory medications, resulting in delayed diagnosis and further clinical deterioration before a diagnosis is made. University College London Hospitals sees one of the largest reported POEMS cohorts in Europe, and runs a multispecialist clinic to assist with diagnosis, treatment and ongoing support. This review draws upon our experience to present the typical features of POEMS syndrome and highlight diagnostic conundrums commonly experienced, supplemented with clinical cases. We provide an investigative guide for clinicians when considering POEMS as the diagnosis, and propose a treatment algorithm that centres on the site and degree of monoclonal cell proliferation.

The predictive value of T-tau and AB1-42 levels in idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) has no reliable biomarker to assist in the selection of patients who could benefit from ventriculo-peritoneal (VP) shunt insertion. The neurodegenerative markers T-tau and Aß1-42 have been found to successfully differentiate between Alzheimer's disease (AD) and INPH and therefore are candidate biomarkers for prognosis and shunt response in INPH. The aim of this study was to test the predictive value of cerebrospinal fluid (CSF) T-tau and Aß1-42 for shunt responsiveness. In particular, we pay attention to the subset of INPH patients with raised T-tau, who are often expected to be poor surgical candidates. METHODS: Single-centre retrospective analysis of probable INPH patients with CSF samples collected from 2006 to 2016. INDEX TEST: CSF levels of T-tau and Aß1-42. Reference standard: postoperative outcome. ROC analysis assessed the predictive value. RESULTS: A total of 144 CSF samples from INPH patients were analysed. Lumbar T-tau was a good predictor of post-operative mobility (AUROC 0.80). The majority of patients with a co-existing neurodegenerative disease responded well, including those with high T-tau levels. CONCLUSION: INPH patients tended to exhibit low levels of CSF T-tau, and this can be a good predictor outcome. However levels are highly variable between individuals. Raised T-tau and being shunt-responsive are not mutually exclusive, and such patients ought not necessarily be excluded from having a VP shunt. A combined panel of markers may be a more specific method for aiding selection of patients for VP shunt insertion. This is the most comprehensive presentation of CSF samples from INPH patients to date, thus providing further reference values to the current literature.

Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.

We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.

Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.

This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.

The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar [Right/Left hands]: ICC 0.997/0.96; Vigori: ICC 0.95/0.98). Meaningful changes were comparable between the two instruments, being higher in GBS compared to CIDP patients. In MGUSP/MMN poor responsiveness was seen. Significant more patients preferred the Vigorimeter. In conclusion, validity, reliability, and responsiveness aspects were comparable between the Jamar dynamometer and Vigorimeter. However, based on patients' preference, the Vigorimeter is recommended in future studies in immune-mediated neuropathies.

Zonisamide for neuropathic pain in adults.

BACKGROUND: Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. The efficacy of zonisamide for the relief of neuropathic pain has not previously been reviewed. OBJECTIVES: To assess the analgesic efficacy and associated adverse events of zonisamide for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (via CRSO), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organisation Clinical Trials Registry Platform) to 1 August 2014, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing zonisamide with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only full journal publication articles and clinical trial summaries. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We considered the evidence using three tiers. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier evidence derived from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence derived from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.We planned to calculate risk ratio (RR) and numbers needed to treat (NNT) and harm (NNH) for one additional event using standard methods expected by The Cochrane Collaboration. MAIN RESULTS: We included a single study treating 25 participants (13 zonisamide, 12 placebo) with painful diabetic neuropathy over 12 weeks. No first or second tier evidence was available for any outcome. The small size of the study and potential major bias due to a high proportion of early study withdrawals with zonisamide precluded any conclusions being drawn. There were two serious adverse events (one death) in zonisamide-treated participants, which were apparently not related to treatment. AUTHORS' CONCLUSIONS: The review found a lack of evidence suggesting that zonisamide provides pain relief in any neuropathic pain condition. Effective medicines with much greater supportive evidence are available.

Quinine for muscle cramps.

BACKGROUND: Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014. OBJECTIVES: To assess the efficacy and safety of quinine-based agents in treating muscle cramps. SEARCH METHODS: On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014. SELECTION CRITERIA: Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events. AUTHORS' CONCLUSIONS: There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

Neuropsychiatric systemic lupus erythematosus: a diagnostic challenge.

A 58-year-old woman presented to neuropsychiatric services with increased frequency of confusional episodes and intermittent psychotic symptoms. She had a 19-year history of atypical epileptic seizures and cognitive decline. Detailed review of history and clinical investigations revealed that she had accumulated sufficient features to meet diagnostic criteria for systemic lupus erythematosus (SLE). She had previously had lymphopenia and a malar rash; she had positive antinuclear, anti-Ro (anti-Sjögren's-syndrome-related antigen A) and anti-SM (anti-Smith Antibody) antibodies, and elevated erythrocyte sedimentation rate. The seizures, cognitive impairment and psychosis were attributable to neuropsychiatric SLE. Treatment with immune-modulating therapy, cyclophosphamide, resulted in significant improvement in subjective and objective clinical presentation. Neuropsychiatric SLE should be considered a potential differential diagnosis for patients presenting with seizures, psychotic symptoms or cognitive decline. A detailed clinical evaluation with review of the medical history and appropriate laboratory analyses allows this diagnosis to be made, and appropriate treatment to be initiated.

Treatment for IgG and IgA paraproteinaemic neuropathy.

BACKGROUND: Paraproteinaemic neuropathy refers to those neuropathies associated with a monoclonal gammopathy or paraprotein. The most common of these present with a chronic, predominantly sensory, symmetrical neuropathy, similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but with relatively more sensory involvement, both clinically and neurophysiologically. The optimal treatment for neuropathies associated with IgG and IgA monoclonal gammopathy of uncertain significance is not known. This is an update of a review first published in 2007. OBJECTIVES: To assess the effects of any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. SEARCH METHODS: On 18 January 2014 we searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, CENTRAL, MEDLINE and EMBASE. We also checked bibliographies for controlled trials of treatments for IgG or IgA paraproteinaemic peripheral neuropathy. We checked clinical trials registries for ongoing studies in November 2014. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs using any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. We excluded people with IgM paraproteins. We excluded people where the monoclonal gammopathy was considered secondary to an underlying disorder. We included participants of any age with a diagnosis of monoclonal gammopathy of uncertain significance with a paraprotein of the IgG or IgA class and a neuropathy. Included participants were not required to fulfil specific electrophysiological diagnostic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to select studies, extract data and analyse results. One trial author provided additional data and clarification. MAIN RESULTS: We identified one RCT, with 18 participants, that fulfilled the predetermined inclusion criteria. The trial compared plasma exchange to sham plasma exchange in participants with IgG or IgA paraproteinaemic neuropathy over a three-week follow-up period. We identified four other studies but these were not RCTs or quasi-RCTs. The included RCT did not report our predefined primary outcome measure, change in disability six months after randomisation. The trial revealed a modest benefit of plasma exchange in the weakness component of the Neuropathy Disability Score (NDS, now the Neuropathy Impairment Score); the mean improvement with plasma exchange was 17 points (95% confidence interval (CI) 5.2 to 28.8 points) versus 1 point (95% CI -7.7 to 9.7 points) in the sham exchange group at three weeks' follow-up (mean difference (MD) 16.00; 95% CI 1.37 to 30.63, low quality evidence). There was no statistically significant difference in the overall NDS (MD 18.00; 95% CI -2.03 to 38.03, low quality evidence), vibration thresholds or neurophysiological indices. Adverse events were not reported. The trial was at low risk of bias overall, although limitations of trial size and duration reduce the quality of the evidence in support of its conclusions. AUTHORS' CONCLUSIONS: The evidence from RCTs for the treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More RCTs of treatments are required. These should have adequate follow-up periods and contain larger numbers of participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition. Observational or open trial data provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with prednisolone, intravenous immunoglobulin, and corticosteroids. These interventions show potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal use and the long-term benefits need to be considered and validated with well-designed RCTs.

Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness.

OBJECTIVES: We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP). METHODS: One hundred thirty-seven patients (GBS: 55, CIDP: 59, IgM-MGUSP: 23) with a new diagnosis or clinical relapse assessed both scales. Patients with GBS/CIDP were examined at 0, 1, 3, 6, and 12 months; patients with IgM-MGUSP at 0, 3, and 12. We subjected all data to Rasch analyses, and calculated for each patient the magnitude of change on both scales using the minimal clinically important difference (MCID) related to the individual standard errors (SEs). A responder was defined as having an MCID-SE ≥1.96. Individual scores on both measures were correlated with the EuroQoL thermometer (heuristic responsiveness). RESULTS: The I-RODS showed a significantly higher proportion of meaningful improvement compared with the INCAT-ONLS findings in GBS/CIDP. For IgM-MGUSP, the lack of responsiveness during the 1-year study did not allow a clear separation. Heuristic responsiveness was consistently higher with the I-RODS. CONCLUSION: The I-RODS more often captures clinically meaningful changes over time, with a greater magnitude of change, compared with the INCAT-ONLS disability scale in patients with GBS and CIDP. The I-RODS offers promise for being a more sensitive measure and its use is therefore suggested in future trials involving patients with GBS and CIDP.

Levetiracetam for neuropathic pain in adults.

BACKGROUND: Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. The efficacy of levetiracetam for relief of neuropathic pain has not previously been reviewed. OBJECTIVES: To assess the analgesic efficacy and adverse events of levetiracetam in chronic neuropathic pain conditions in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6) (via the Cochrane Library), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organisation Clinical Trials Registry Platform) to 3 July 2014, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks duration or longer, comparing levetiracetam with placebo or another active treatment in adults with chronic neuropathic pain conditions. Studies had to have a minimum of 10 participants per treatments arm. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction; intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison; 8 to 12 weeks duration; parallel design); second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with at least 200 participants in the comparison; and third tier evidence from data involving fewer than 200 participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both. MAIN RESULTS: We included six studies: five small, cross-over studies with 174 participants, and one parallel group study with 170 participants. Participants were treated with levetiracetam (2000 mg to 3000 mg daily) or placebo for between four and 14 weeks. Each study included participants with a different type of neuropathic pain; central pain due to multiple sclerosis, pain following spinal cord injury, painful polyneuropathy, central post-stroke pain, postherpetic neuralgia, and post-mastectomy pain.None of the included studies provided first or second tier evidence. The evidence was very low quality, downgraded because of the small size of the treatment arms, and because studies reported results using last observation carried forward (LOCF) imputation for withdrawals or using only participants who completed the study according to the protocol, where there were greater than 10% withdrawals. There were insufficient data for a pooled efficacy analysis in particular neuropathic pain conditions, but individual studies did not show any analgesic effect of levetiracetam compared with placebo. We did pool results for any outcome considered substantial pain relief (≥ 50% pain intensity reduction or 'complete' or 'good' responses on the verbal rating scale) for four studies with dichotomous data; response rates across different types of neuropathic pain was similar with levetiracetam (10%) and placebo (12%), with no statistical difference (risk ratio 0.9; 95% confidence interval (CI) 0.4 to1.7).We pooled data across different conditions for adverse events and withdrawals. Based on very limited data, significantly more participants experienced an adverse event with levetiracetam than with placebo (number needed to treat for an additional harmful event (NNH) 8.0 (95% CI 4.6 to 32)). There were significantly more adverse event withdrawals with levetiracetam (NNH 9.7 (6.7 to 18)). AUTHORS' CONCLUSIONS: The amount of evidence for levetiracetam in neuropathic pain conditions was very small and potentially biased because of the methods of analysis used in the studies. There was no indication that levetiracetam was effective in reducing neuropathic pain, but it was associated with an increase in participants who experienced adverse events and who withdrew due to adverse events.

Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.

BACKGROUND: Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010. OBJECTIVES: To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain. SEARCH METHODS: On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain. SELECTION CRITERIA: We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 16% of participants stopped the drug due to adverse effects. Serious adverse events were rare. AUTHORS' CONCLUSIONS: There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.

Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews.

BACKGROUND: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009. OBJECTIVES: To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use. METHODS: We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation. MAIN RESULTS: No studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine. AUTHORS' CONCLUSIONS: Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.