Vera Bril

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

BACKGROUND Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. METHODS 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. FINDINGS During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. INTERPRETATION This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

IV immunoglobulin in patients with myasthenia gravis : A randomized controlled trial

Objective: We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study. Methods: Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days 14 and 28. Results: In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a QMG Score for Disease Severity greater than 10.5. Conclusion: This study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness due to myasthenia gravis.

Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barre syndrome

Article abstract-We compared intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) in the treatment of 50 patients with Guillain-Barre syndrome (GBS). Standard outcome measures did not differ for the two groups. Sixty-one percent of the PLEX-treated group and 69% of the IVIG-treated group improved by one disability grade at 1 month. The complication rate was higher in the PLEX-treated group. We conclude that the efficacy of IVIG in the treatment of GBS is comparable with that of PLEX and that it can be used safely, although we had a small number of patients. We did not observe a higher relapse rate with IVIG. The usefulness of combination therapy is unknown at this time. NEUROLOGY 1996;46: 100-103

Diabetic neuropathy: a review emphasizing diagnostic methods.

Diabetic sensorimotor polyneuropathy (DSP) is the most common complication of diabetes. In order to manage DSP effectively, it is necessary to formulate an accurate diagnosis and monitor subjects regularly. This review of important aspects of the diagnosis of DSP starts with a conceptual framework that includes elements of DSP epidemiology, pathophysiology, and therapy. The emphasis of the review is to present our current understanding of diagnostic methods for DSP including their utility and limitations. Screening for DSP in the diabetes clinic can be achieved successfully using simple clinical tests. Clinical neurophysiological methods are necessary to exclude other diagnoses, stage severity, and monitor the course of DSP. Novel investigative techniques are highly promising, but their usefulness in the clinic setting remains limited at this time. This article presents an overview of diagnostic methods for DSP.

Evaluation of three screening tests and a risk assessment model for diagnosing peripheral neuropathy in the diabetes clinic

Abstract Objective: with the aim of evaluating predictive power, three simple screening tests as alternates to nerve conduction tests for diagnosing diabetic peripheral neuropathy (DPN) were investigated. Results of the screening tests, along with the subjects’ demographic and clinical characteristics, were planned as the variables for the development of a risk assessment tool for predicting DPN. Design: this is a cross-sectional multi-group comparison study. The study utilized a predictive model derived from one subset of the study population, and prospectively tested in the other subset to predict the presence of neuropathy. Setting: Diabetic Neuropathy Research Clinic of the Toronto General Hospital and University Health Network in Toronto, Ontario, Canada from June 1998 to August 1999. Sample population: data come from 478 subjects consisting of non-diabetic reference subjects, and patients with type 1 and type 2 diabetes mellitus. Outcome measures: nerve conduction studies (NCS) comprised the primary defined outcome. The three screening sensory tests examined in the study were the Semmes–Weinstein 10 g monofilament examination (SWME), superficial pain sensation, and vibration by the on–off method. Results: the three screening tests are significantly and positively correlated with NCS. An increase in the number of insensate responses in the screening test is associated with an increase in the abnormal NCS score. The strength of the association between NCS and each sensory test was greater when the neuropathy severity stage of the subject was added to the model. Both the SWME and vibration by the on–off method tests demonstrated sufficient statistical power to differentiate non-diabetic control subjects from subjects with diabetes, as well as to differentiate subjects with diabetes with and without neuropathy. These two tests, when compared with NCS, also demonstrated acceptable diagnostic performance characteristics in terms of high sensitivity and specificity, total number of correctly predicted cases, and receiver-operating characteristic curves. Conclusion: this data, through the development of a model involving training and validation sets, demonstrates that the knowledge of clinical risk factors alters the interpretation of sensory tests for DPN. This finding lends further support to the validity of simple sensory testing maneuvers in the conditional diagnosis of DPN. We recommend annual screening with either the SWME or vibration by the on–off method in the primary care and diabetes clinics.

Detection of Diabetic Sensorimotor Polyneuropathy by Corneal Confocal Microscopy in Type 1 Diabetes: A concurrent validity study

OBJECTIVE We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics. RESEARCH DESIGN AND METHODS Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis. RESULTS DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm2 (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm2, sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm2, specificity 93%, positive likelihood ratio 8.5). CONCLUSIONS Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

Long-Term Clinical Outcome After Transcervical Thymectomy for Myasthenia Gravis

BACKGROUND We reviewed the long-term clinical outcome after transcervical thymectomy for generalized myasthenia gravis without thymoma in 52 patients who had this procedure at The Toronto Hospital between 1977 and 1986, and compared the results with those reported after more radical surgical approaches. METHODS Preoperative and postoperative patient evaluations were based on a modified Osserman classification. We defined complete remission as asymptomatic with normal strength and without medications for myasthenia gravis. The complete remission rate was selected as the best measure for comparison between different surgical approaches. RESULTS The 52 patients were followed up for a mean of 8.4 years (+/-6.1 years [standard deviation]). The preoperative mean Osserman grade was 2.7 compared with 0.4 at final follow-up. Complete remission occurred in 44.2% of patients. Similar results are reported after transsternal thymectomy. CONCLUSIONS Comparable results after transcervical and transsternal thymectomy favor the use of the less radical approach.

Timing and Course of Clinical Response to Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

OBJECTIVE To investigate the timing, course, and clinical characteristics of the response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). DESIGN Data were extracted from the ICE trial, a randomized, double-blind, placebo-controlled trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C). SETTING Multiple international centers. PARTICIPANTS One hundred seventeen individuals with CIDP. Intervention Treatment with IGIV-C (Gamunex, n = 59) or placebo (n = 58), with IGIV-C administered as a 2-g/kg loading dose followed by a 1-g/kg maintenance dose every 3 weeks, for up to 24 weeks. MAIN OUTCOME MEASURES The primary efficacy parameter was an improvement of 1 or more points in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Participants treated with IGIV-C were divided into subgroups based on meeting responder vs nonresponder definitions and by time to first improvement. RESULTS Among 30 responders to IGIV-C, 14 (47%) patients had improved adjusted INCAT scores by week 3, and 16 (53%) patients improved at week 6 after a second infusion. Participants who improved by week 3 were more severely disabled at baseline than those who improved at 6 weeks. In patients who improved, the number of individuals reaching maximal improvement continued to increase during maintenance therapy for up to 24 weeks. For patients with first improvement by week 3, the change in dominant-hand grip strength over time tended to parallel the INCAT score. In patients with first improvement by week 6, however, the improvement in dominant-hand grip strength preceded initial improvement in INCAT score. CONCLUSIONS Data suggest that treatment with 2 courses of IGIV-C administered 3 weeks apart may be required for initial improvement, and continued maintenance therapy may be necessary to achieve a maximal therapeutic response. Trial Registration clinicaltrials.gov Identifier: NCT00220740.

Evidence-based Guideline: Treatment of Painful Diabetic Neuropathy

To develop a scientifically sound and clinically relevant evidence‐based guideline for the treatment of painful diabetic neuropathy (PDN).

Prediction of Incident Diabetic Neuropathy Using the Monofilament Examination A 4-year prospective study

OBJECTIVE To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy. RESEARCH DESIGN AND METHODS Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis. RESULTS Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6–7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 ± 2.5 for incident neuropathy vs. 5.7 ± 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was ≤5 sensate stimuli out of 8, with 72% sensitivity, 64% specificity, positive and negative likelihood ratios of 2.5 and 0.35, and positive and negative predictive values of 87 and 46%, respectively (χ2 = 20.7, P < 0.001). Area under the ROC curve was significantly greater for the monofilament examination compared with that for other simple sensory tests. CONCLUSIONS A simple threshold of ≤5 sensate stimuli out of 8 discriminates 4-year risk of diabetic neuropathy with acceptable operating characteristics. Although there are limitations in its specificity for prediction of future neuropathy onset, the monofilament examination is appropriate as a simple diabetic neuropathy screening instrument generalizable to the clinical setting.