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Background and ObjectivesMyasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG.MethodsIn this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available atclinicaltrials.gov/ct2/show/NCT02473965.ResultsThe primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated.DiscussionIn this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different.Trial Registration InformationThe trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) andclinicaltrials.gov(identifierNCT02473965).Classification of EvidenceThis study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

ObjectiveTo evaluate the safety and efficacy of efgartigimod in patients with generalized myasthenia gravis (MG) enrolled in the ADAPT+ long-term extension study.BackgroundTreatment with efgartigimod, a human IgG1 antibody Fc-fragment that blocks neonatal Fc receptor, resulted in clinically meaningful improvement (CMI) in MG-specific outcome measures in the ADAPT phase 3 clinical trial. All patients who completed ADAPT were eligible to enroll in its ongoing open-label, 3-year extension study, ADAPT+.Design/MethodsEfgartigimod (10 mg/kg IV) was administered in cycles of once-weekly infusions for 4 weeks, with subsequent cycles initiated based on clinical evaluation. Efficacy was assessed during each cycle utilizing Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scales.ResultsNinety-one percent of ADAPT patients (151/167) entered ADAPT+. As of February 2021, 106 AChR-Ab+ and 33 AChR-Ab– patients had received at least 1 dose of open-label efgartigimod (including 66 ADAPT placebo [PBO] patients). The mean (SD) study duration was 363 (114) days, resulting in 138 patient-years of observation. Similar incidence rates per patient year (IR/PY) of serious adverse events were seen in ADAPT (efgartigimod: 0.11; placebo: 0.29) compared to ADAPT+ (0.25). Five deaths (acute myocardial infarction, COVID-19 pneumonia/septic shock, bacterial pneumonia/MG crisis, malignant lung neoplasm, and unknown [multiple cardiovascular risk factors identified on autopsy]) occurred; none were considered related to efgartigimod by the investigator. AEs were predominantly mild or moderate. CMI was observed in AChR-Ab+ patients during each cycle (up to 10 cycles) at magnitudes comparable to improvements observed at week 3 of cycle 1 (mean[SE] improvements: MG-ADL, –5.1[0.34]; QMG, –4.7[0.41]). Clinical improvements mirrored maximal reductions in total IgG and AChR-Abs across all cycles.ConclusionsThis analysis suggests the efficacy of long-term treatment with efgartigimod was consistent across multiple cycles. No new safety signals were identified, despite being conducted before vaccine availability during the COVID-19 pandemic.

ObjectivesTo estimate patient-acceptable symptom state (PASS) cut points for myasthenia gravis (MG) health scales.MethodsWe conducted an electronic survey that included the Myasthenia Gravis Impairment Index (MGII), EuroQol 5-Dimension (EQ5D), and a simple PASS question. PASS-anchored thresholds were estimated for the MGII questionnaire through receiver operating characteristic curves. We used the MGII PASS cut point in a validation cohort of 257 patients to estimate PASS thresholds for other clinically relevant health scales such as the Quantitative Myasthenia Gravis Scale (QMGS), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Composite (MGC), and Myasthenia Quality of Life (MG-QoL15).ResultsOne hundred twenty-four of ≈250 invited patients answered the electronic survey (49% response rate), and 80 considered their current symptom state acceptable (PASS-positive). They had lower MGII scores than PASS-negative patients (7.76 ± 9.37 vs 25.0 ± 13.7, p < 0.0001) and better EQ5D scores (0.86 ± 0.17 vs 0.69 ± 0.18, p < 0.0001). The MGII questionnaire threshold for PASS was ≤10 points. With the use of this threshold in an independent dataset of 257 patients, all patients in remission or minimal manifestation status were PASS-positive. In addition, some patients in Classes I, II, and IIIA also achieved PASS status. PASS thresholds for the QMGS, MG-ADL, MGC, and MG-QoL15 were ≤7, 2, 3, and 8 points, respectively.ConclusionsWe have estimated thresholds for commonly used myasthenia health scales reflecting patient-acceptable states in patients with MG. These thresholds indicate a global state of well being, rather than a change in scores, or being better. Therefore, PASS thresholds can be used as secondary endpoints for myasthenia research.

ObjectiveTo explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG).MethodsIn this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1–29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29–43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44–99). Primary endpoint: change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints: change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores; safety.ResultsForty-three patients were randomized (rozanolixizumab: 21 patients; placebo: 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo: QMG (LS mean: −1.8 vs −1.2; difference: −0.7; 95% UCL: 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean: −1.8 vs −0.4; difference: −1.4; 95% UCL: −0.4), and MGC (LS mean: −3.1 vs −1.2; difference: −1.8; 95% UCL: 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab: 57%; placebo: 14%).ConclusionWhile change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422).Classification of evidenceThis study provides class I evidence that for patients with gMG, rozanolixizumab is well tolerated, but did not significantly improve QMG score.

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

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-Barre 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 anMCID-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.

A report of the Canadian Task Force on the Periodic Health Examination was the first to propose clinical practice recommendations based on evidence in the medical literature, and proposed a rating scheme.1 From that original publication, the categorization of evidence has evolved, with this journal requiring clinical therapeutic studies to provide the level of evidence provided by a report.2 The most rigorous Class I evidence derives from a well-performed randomized controlled clinical trial (RCT). Such trials limit the probability of bias and systematic errors by randomization and masking of treatment assignment. In contrast, Class IV evidence is characterized by retrospective analyses, which have numerous sources of potential bias. However, randomized trials are often not possible because of resource limitations, whether they are financial or organizational. In this issue of Neurology ®, Hehir et al.3 identified benefit for rituximab in muscle-specific kinase antibody myasthenia gravis (anti-MuSK MG). Although strictly the report provides Class IV evidence, their unique trial design suggests much greater confidence in rituximab as an effective therapy.

Objective:To study responsiveness and meaningful change of the Myasthenia Gravis Impairment Index (MGII) and its relative efficiency compared to other measures.Methods:We enrolled 95 patients receiving prednisone, IV immunoglobulin (IVIg), or plasma exchange (PLEX) and 54 controls. Patients were assessed with the MGII and other measures—including the Quantitative Myasthenia Gravis Score, Myasthenia Gravis Composite, and Myasthenia Gravis Activities of Daily Living—at baseline and 3–4 weeks after treatment. Statistical markers of responsiveness included between-groups and within-group differences, and we estimated the relative efficiency of the MGII compared to other measures. Patient-meaningful change was assessed with an anchor-based method, using the patient's impression of change. We determined the minimal detectable change (MDC) and the minimal important difference (MID) at the group and individual level.Results:Treated patients had a higher change in MGII scores than controls (analysis of covariance p < 0.001). The ocular domain changed more with prednisone than with IVIg/PLEX (effect size 0.67 and 0.13, analysis of covariance p = 0.001). The generalized domain changed more with IVIg/PLEX than with prednisone (effect size 0.50 and 0.22, analysis of covariance p = 0.07). For the total MGII score, the individual MDC95 was 9.1 and the MID was 5.5 for individuals and 8.1 for groups. Relative efficiency ratios were >1 favoring the MGII.Conclusions:The MGII demonstrated responsiveness to prednisone, IVIg, and PLEX in patients with myasthenia. There is a differential response in ocular and generalized symptoms to type of therapy. The MGII has higher relative efficiency than comparison measures and is viable for use in clinical trials.

Objective: We aimed to develop a measure of myasthenia gravis impairment using a previously developed framework and to evaluate reliability and validity, specifically face, content, and construct validity. Methods: The first draft of the Myasthenia Gravis Impairment Index (MGII) included examination items from available measures enriched with newly developed, patient-reported items, modified after patient input. International neuromuscular specialists evaluated face and content validity via an e-mail survey. Test–retest reliability was assessed in stable patients at a 3-week interval and interrater reliability was evaluated in the same day. Construct validity was assessed through correlations between the MGII and other measures and by comparing scores in different patient groups. Results: The first draft was assessed by 18 patients, and 72 specialists answered the survey. The second draft had 7 examination and 22 patient-reported items. Field testing included 200 patients, with 54 patients completing the reliability studies. Test–retest reliability of the total score was good (intraclass correlation coefficient 0.92; 95% confidence interval 0.79–0.94), as was interrater reliability of the examination component (intraclass correlation coefficient 0.81; 95% confidence interval 0.79–0.94). The MGII correlated well with comparison measures, with higher correlations with the MG–activities of daily living ( r = 0.91) and MG-specific quality of life 15-item scale ( r = 0.78). When assessing different patient groups, the scores followed expected patterns. Conclusions: The MGII was developed using a patient-centered framework of myasthenia-related impairments and incorporating patient input throughout the development process. It is reliable in an outpatient setting and has demonstrated construct validity. Responsiveness studies are under way.

Objective: Both IV immunoglobulin (IVIg) and plasma exchange (PLEX) are immunomodulatory treatments used to treat patients with myasthenia gravis (MG), but the choice of which treatment to administer to patients is limited due to lack of evidence from adequately powered, masked, randomized, standardized trials. Methods: We randomized 84 patients with moderate to severe MG defined as a Quantitative Myasthenia Gravis Score for disease severity (QMGS) of >10.5 and worsening weakness to IVIg (Gamunex®, Talecris Biotherapeutics) 1 g/kg/day for 2 consecutive days or PLEX (Caridian Spectra) 1.0 plasma volume exchanges for 5 exchanges. The patients were evaluated at day 14 after treatment for the primary efficacy parameter of change in QMGS and secondary clinical and electrophysiologic parameters and were followed for a total of 60 days. Results: Both IVIg and PLEX reduced the QMGS, and IVIg was comparable to PLEX in efficacy. The dropout rate was the same for both treatment arms and both treatments were well-tolerated. The presence of acetylcholine receptor antibodies and greater baseline disease severity predicted a better response to therapy. The postintervention status revealed that the same proportion of patients improved with treatment: 69% on IVIg and 65% on PLEX. The duration of improvement was similar with both treatments. Conclusions: IVIg has comparable efficacy to PLEX in the treatment of patients with moderate to severe MG. Both treatments are well-tolerated, and the duration of effect is comparable. Either treatment may be offered to patients depending on availability of resources. Classification of evidence: This study provides Class I evidence that IVIg and PLEX have comparable efficacy and are equally tolerated in adult patients with moderate to severe MG within 2 weeks of treatment.

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.

Successful screening for neuropathy in patients with diabetes is available using the 10 g Semmes-Weinstein monofilament (Mid-Delta Health Systems, Inc., Belzoni, MS) (touch/pressure sensation) and the Neurothesiometer (Horwell Scientific, London, UK; vibration perception threshold). In healthy volunteers and patients with a broad range of diabetic sensorimotor neuropathy, we show that the predictive value of either test for diabetic sensorimotor neuropathy depends on the toe surface tested. These results establish the importance of standardized screening methods for diabetic sensorimotor neuropathy in the clinic and in clinical research trials.

Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. Neurology ® 2011;76:1–1

We compared 42 myasthenia gravis (MG) patients with thymoma with 42 generalized MG patients without thymoma using a modified Osserman classification. The mean Osserman grades at diagnosis, 6 months, and 5 and 10 years post-thymectomy did not differ between groups. Our results indicate that thymoma is not a negative determinant for the long-term clinical outcome of MG.

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

Objective: The aim of this study was to evaluate the accuracy of different methods for evaluation of small fiber neuropathy (SFN) using intra epidermal nerve fiber density (IENFD) as the reference standard. Background IENFD is the current standard for evaluation of SFN but limited by invasiveness, expense and availability. Heat-induced neurogenic vasodilation by Laser Doppler Imaging (LDI), cold detection thresholds (CDT) and heat perception (HP) are noninvasive nerve function alternatives whose accuracy relative to morphological IENFD is unknown. Design/Methods: We performed a retrospective chart review of 75 patients suspected of having SFN at the Toronto General Hospital, University Health Network from 2008-2011. A detailed history and clinical examination, laboratory studies, nerve conduction studies (NCS), CDT, HP, LDI and IENFD were performed in all patients. We quantitatively compared the results of clinical evaluation including pain on the visual analogue scale (VAS), LDI, CDT and HP relative to IENFD for the diagnosis of SFN. Results: The mean IENFD was 7.52 +/- 4.12 with a median value of 7.59 and interquartile range of 4.64-10.91 (25% to 75%). 34.7% had abnormal IENFD and 65.3% had normal IENFD according to published criteria (normal defined as > 5.4 fibers/mm). Low-magnitude correlation was observed between IENFD and CDT (R2 =0.0812, p Conclusions: None of the objective measures reflected IENFD with very good diagnostic validity, but of these small fiber non-invasive methods, CDT had the highest level of accuracy, while we could not demonstrate acceptable performance of LDI. Alternate non-invasive methods for the determination of small fiber function or morphology are urgently needed. Disclosure: Dr. Ebadi has nothing to disclose. Dr. Perkins has nothing to disclose. Dr. Katzberg has received personal compensation for activities with Genzyme as a speaker and participant on an advisory board. Dr. Katzberg has received research support from Griffolds Biotherapeutics. Dr. Bril has received personal compensation for activities with Talecris Biotherapeutics as a consultant. Dr. Bril has received research support from Talecris Biotherapeutics.

Objective: To study if one or more FcR polymorphisms are correlated with response to IVIG treatment in Myasthenia Gravis (MG). Background Intravenous immunoglobulin (IVIG) is an effective treatment of moderate to severe MG, but only about 60% of patients respond to treatment, and there are no clear predictors of response. Fc receptors play an important role in the mechanism of action of IVIG, so genetic variation of these might predict response to treatment. Design/Methods: 71 patients who participated in previous studies of IVIG efficacy, and new patients treated with IVIG for worsening MG were included. Patients were considered responders if the quantitative myasthenia gravis score (QMGS) improved by > 3.5 units 14 days after treatment. Polymorphisms within the FCγR2A, FCγR2B, FCγR3A and FCγR3B (NA1/NA2) genes were genotyped and the rates of treatment response were analyzed by each genotype. Results: The mean age was 56 years and 59% of patients were female. The mean QMGS at baseline was 13.4 ± 4.5. The FCγR2B-232I/I genotype was significantly more common in responders (94%) compared to non-responders (77%) (p=0.04). None of the other polymorphisms were associated with response. Patients with the FCγR2B 232I/I genotype had a higher QMGS at baseline (14 ± 5) compared to heterozygotes (10 ±2, p=0.025) and higher baseline QMGS was associated with response to treatment (responders: 15 ± 5; non-responders 12 ±4, p=0.01). Multivariate logistic regression analysis showed that only the baseline QMGS independently predicted response to IVIG (p=0.036). Conclusions: We found that the FCγR2B I/I genotype is associated with greater disease severity in MG and this, in turn, predicts a better response to IVIG. Although confirmation of this finding in larger population samples is required, the finding that the wild type inhibitory FcγR predisposes to more severe disease suggests that the FCγR2B does not act by directly inhibiting the pathogenic antibodies in MG. Supported by: An unrestricted educational grant from Talecris Biotherapeutics for clinician-initiated research. Disclosure: Dr. Barnett Tapia has nothing to disclose. Dr. Grinberg has nothing to disclose. Dr. Ghani has nothing to disclose. Dr. Rogaeva has nothing to disclose. Dr. St George-Hyslop has received personal compensation for activities with Finnegan LLC. Dr. Katzberg has received personal compensation for activities with Genzyme as a speaker and participant on an advisory board. Dr. Katzberg has received research support from Griffolds Biotherapeutics. Dr. Bril has received personal compensation for activities with Talecris Biotherapeutics as a consultant. Dr. Bril has received research support from Talecris Biotherapeutics.

by ERIK STALBERG and JOZE V. TRONTELJ, 303 pp., ill., New York, Raven Press, 1994. $79.00 The second edition of this book is a welcome update of the standard reference text for anyone using single fiber electromyography (SFEMG) in the laboratory. This updated text continues the excellent traditions set in the first book by …