Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.

BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

Physiological and pathological roles of the thymus and value of thymectomy in myasthenia gravis: a narrative review.

Background and Objective: Myasthenia gravis (MG) is a well-elucidated autoimmune disorder affecting the neuromuscular junction. Given the relationship between MG and thymic pathologies, with T cell and antibody-mediated pathogenesis, surgical (i.e., thymectomy) and non-surgical approaches remain a mainstay of management of the disease. This review seeks to outline the involvement of the thymus in the development of lymphocytes leading to MG. Methods: Different databases were searched exploring the role of thymectomy in treatment and outcomes in various MG patient subpopulations, including in ocular versus generalized disease, different age groups, and antibody status. Key Content and Findings: Overall, the findings of multiple studies and reviews provide evidence to support the efficacy and long-term success of thymectomy in the management of MG; outcomes have included remission status, symptom severity, and need for adjunctive therapy. However, the heterogeneity in the MG population suggests that there are multiple factors that may confound the results of thymectomy and still need further examination. Separately, other autoimmune diseases develop following thymectomy, and further research is required to elucidate this susceptibility. Finally, our review will discuss the different surgical approaches for thymectomy, including their advantages, limitations, and perioperative complications. Conclusions: Overall, in light of the known pathogenesis and association of the thymus with MG, thymectomy remains an extremely effective approach for long-term management and improved clinical outcomes.

Measuring treatment adverse event burden in myasthenia gravis: Single-center prospective evaluation utilizing the Adverse Event Unit (AEU).

INTRODUCTION/AIMS: We developed a patient- and physician-weighted consensus unit called the adverse event unit (AEU) that quantifies and compares adverse event (AE) burden among any group of medications in neurological patients. In this study we evaluated preliminary validity and feasibility of measuring AE burden with the AEU in myasthenia gravis (MG). METHODS: This is a single-center, prospective, 1-year, observational study of adult MG patients presenting for routine care between April 1, 2021 and March 31, 2022. The MG Activities of Daily Living (MG-ADL), the 15-item MG Quality of Life revised (MG-QOL15r), MG-Composite, and AEU scores were obtained at all visits. A priori primary feasibility metric was AEU completion rate equal to (within 3.8%, one-sided 95% confidence interval [CI]) or better than MG-ADL completion rate. Time to administer AEU and MG-ADL/MG-QOL15r, correlation between AEU total score and MG-QOL15r, and median AEU scores for each MG medication were evaluated. RESULTS: Fifty-four patients completed 67 study visits; side effects were reported at 75% of the visits. The study met the primary feasibility endpoint; AEU and MG-ADL were recorded at all visits. Times to administer the AEU (median 5 minutes) and MG-ADL/MG-QOL15r were similar. We observed a weak correlation of 0.29 (95% CI 0.03 to 0.51, P = .032) between AEU and MG-QOL15r scores. Non-statistically significant differences in median AEU scores were observed among MG medications. DISCUSSION: Our data demonstrate preliminary feasibility and validity of using the AEU to measure AE burden in MG. Future studies will compare AE burden among MG treatments and evaluate clinically meaningful AEU scores in MG.

Guillain-Barré Syndrome.

OBJECTIVE: This article summarizes the clinical features, diagnostic criteria, differential diagnosis, pathogenesis, and prognosis of Guillain-Barré syndrome (GBS), with insights into the current and future diagnostic and therapeutic interventions for this neuromuscular syndrome. LATEST DEVELOPMENTS: GBS is an acute, inflammatory, immune-mediated polyradiculoneuropathy that encompasses many clinical variants and divergent pathogenic mechanisms that lead to axonal, demyelinating, or mixed findings on electrodiagnostic studies. The type of antecedent infection, the development of pathogenic cross-reactive antibodies via molecular mimicry, and the location of the target gangliosides affect the subtype and severity of the illness. The data from the International GBS Outcome Study have highlighted regional variances, provided new and internationally validated prognosis tools that are beneficial for counseling, and introduced a platform for discussion of GBS-related open questions. New research has been undertaken, including research on novel diagnostic and therapeutic biomarkers, which may lead to new therapies. ESSENTIAL POINTS: GBS is among the most frequent life-threatening neuromuscular emergencies in the world. At least 20% of patients with GBS have a poor prognosis and significant residual deficits despite receiving available treatments. Research is ongoing to further understand the pathogenesis of the disorder, find new biomarkers, and develop more effective and specific treatments.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Modified Erasmus GBS Respiratory Insufficiency Score: a simplified clinical tool to predict the risk of mechanical ventilation in Guillain-Barré syndrome.

BACKGROUND: This study aimed to determine the clinical and diagnostic factors associated with mechanical ventilation (MV) in Guillain-Barré syndrome (GBS) and to simplify the existing Erasmus GBS Respiratory Insufficiency Score (EGRIS) for predicting the risk of MV. METHODS: Data from the first 1500 patients included in the prospective International GBS Outcome Study (IGOS) were used. Patients were included across five continents. Patients <6 years and patients from Bangladesh were excluded. Univariable logistic and multivariable Cox regression were used to determine which prespecified clinical and diagnostic characteristics were associated with MV and to predict the risk of MV at multiple time points during disease course. RESULTS: 1133 (76%) patients met the study criteria. Independent predictors of MV were a shorter time from onset of weakness until admission, the presence of bulbar palsy and weakness of neck flexion and hip flexion. The modified EGRIS (mEGRIS) was based on these factors and accurately predicts the risk of MV with an area under the curve (AUC) of 0.84 (0.80-0.88). We internally validated the model within the full IGOS cohort and within separate regional subgroups, which showed AUC values of 0.83 (0.81-0.88) and 0.85 (0.72-0.98), respectively. CONCLUSIONS: The mEGRIS is a simple and accurate tool for predicting the risk of MV in GBS. Compared with the original model, the mEGRIS requires less information for predictions with equal accuracy, can be used to predict MV at multiple time points and is also applicable in less severely affected patients and GBS variants. Model performance was consistent across different regions.

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74-88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.

Isolated Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Associated Hypertrophic Pachymeningitis.

ABSTRACT: A 65-year-old man with no pertinent medical history presented with 1 month of progressive holocephalic positional headaches (worse supine), photophobia, progressive gait instability resulting in multiple falls (ambulatory to walker in only 2 months), and weight loss. Testing found positive ANCA 1:160 perinuclear patter, myeloperoxidase >8.0. Cerebrospinal fluid found lymphocytic pleocytosis. We present his neuroimaging of isolated hypertrophic pachymeningitis with clinicoradiographic resolution after immunomodulatory pharmacotherapy along with histology from his meningeal biopsy. Isolated vasculitic myeloperoxidase-antineutrophil cytoplasmic antibody hypertrophic pachymeningitis is quite rare.

International Validation of the Erasmus Guillain-Barré Syndrome Respiratory Insufficiency Score.

OBJECTIVE: This study aimed to validate the Erasmus Guillain-Barré Syndrome Respiratory Insufficiency Score in the International Guillain-Barré Syndrome Outcome Study cohort, and to improve its performance and region-specificity. METHODS: We examined data from the first 1,500 included patients, aged ≥6 years and not ventilated prior to study entry. Patients with a clinical variant or mild symptoms were also included. Outcome was mechanical ventilation within the first week from study entry. Model performance was assessed regarding the discriminative ability (area under the receiver operating characteristic curve) and the calibration (observed vs predicted probability of mechanical ventilation), in the full cohort and in Europe/North America and Asia separately. We recalibrated the model to improve its performance and region-specificity. RESULTS: In the group of 1,023 eligible patients (Europe/North America n = 842, Asia n = 104, other n = 77), 104 (10%) required mechanical ventilation within the first week from study entry. Area under the curve values were ≥0.80 for all validation subgroups. Mean observed proportions of mechanical ventilation were lower than predicted risks: full cohort 10% versus 21%, Europe/North America 9% versus 21%, and Asia 17% versus 23%. After recalibration, predicted risks for the full cohort and Europe/North America corresponded to observed proportions. INTERPRETATION: This prospective, international cohort study validated the Erasmus Guillain-Barré Syndrome Respiratory Insufficiency Score, and showed that the model can be used in the full spectrum of Guillain-Barré syndrome patients. In addition, a more accurate, region-specific version of the model was developed for patients from Europe/North America. ANN NEUROL 2022;91:521-531.

Neck Flexion Strength as a Predictor of Need for Intubation in Guillain-Barre Syndrome.

OBJECTIVES: Respiratory failure in Guillain-Barre syndrome (GBS) is common. Forced vital capacity (FVC) is the gold standard for monitoring respiratory muscle strength in GBS. In some clinical situations, FVC testing could be delayed or unavailable, thus there is a need for accurate, fast, and device-free bedside respiratory evaluation. METHODS: We examined neck flexion strength in 23 GBS patients as a possible predictor of the need for subsequent intubation and as a predictor of FVC change. RESULTS: Intubation was required by 100% of patients with neck flexion strength of Medical Research Council grade ≤3. A correlation between neck flexion strength and FVC could not be determined. CONCLUSIONS: Significant weakness of neck flexion (Medical Research Council grade ≤3) at the time of admission correlates with poor respiratory status as measured by the need for intubation in patients with GBS.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

BACKGROUND AND OBJECTIVES: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. METHODS: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. RESULTS: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. DISCUSSION: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS. TRIAL REGISTRATION INFORMATION: NCT01582763.

Urine specific gravity to identify and predict hydration need in ALS.

Introduction: Multiple factors contribute to increased risk of dehydration in amyotrophic lateral sclerosis (ALS), which contributes to shortened survival independent of nutritional status. The assessment of hydration by doubly labeled water is restricted due to the limited availability of this gold standard technique for clinical use. This prompted us to examine the utility of urine-specific gravity (USG) as a predictor of hydration need in ALS subjects. Material and Methods: Using data from a multicenter study of 80 ALS subjects with 250 visits, we conducted a secondary analysis of the original data set from doubly labeled water experiments. We used a cross-section of the data (one visit per 75 subjects) in the model selection step ("test set"), and a repeated measures analysis in the validation step with data from 63 subjects and 142 follow-up visits. The sensitivity to detect inadequate water turnover rate (a surrogate for water intake) was the goal of the predictive model presented for clinical use. Results and discussion: The final predictive model to estimate water requirement included USG, gender, body mass index, and the ALSFRS gross motor subscale score. We developed a best-fit equation to estimate water intake from USG, determine hydration status, and improve clinical care of real-world ALS subjects.

A Unique Presentation of Fahr's Syndrome Secondary to Hypoparathyroidism.

Fahr's syndrome is a rare condition characterized by deposition of bilateral symmetric calcium deposits in the basal ganglia and cerebellar region, leading to neurological and psychiatric sequelae. Herein we describe a case of a 62-year-old female presented with aphasia, bilateral lower limb rigidity, tremors, and gait disturbance. Her past medical history included thyroidectomy and radiation therapy 10 years back due to papillary carcinoma of the thyroid gland. On examination, she had poor speech, resting tremor, walking difficulty, and decreased power in all limbs with rigidity. Her Chvostek and Trousseau signs were positive. Serum investigations revealed hypocalcemia and low levels of parathyroid hormone and thyroid-stimulating hormone. Brain magnetic resonance imaging revealed calcified lesions in basal ganglia, thalami, and dentate nuclei. She was diagnosed with Fahr's syndrome due to hypoparathyroidism, and she was managed with calcium gluconate, vitamin D, salt-free albumin, and levodopa-carbidopa, improving her condition. The patient was then discharged on calcium gluconate, calcitriol, recombinant parathyroid hormone, and levodopa-carbidopa with follow-up.

Effect of riluzole on weight in short-term and long-term survivors of amyotrophic lateral sclerosis.

INTRODUCTION: Riluzole is the first disease-modifying therapy for amyotrophic lateral sclerosis (ALS) approved in 1995 by the Food and Drug Administration in the USA, and is now available worldwide. It delays time to tracheostomy or death and prolongs survival. The precise mechanism of the survival prolonging effect is unknown. Malnutrition and ensuing weight loss are associated with shorter survival in ALS. Given the life-prolonging effects of riluzole and nutritional maintenance, we examined the relationship between riluzole and weight in ALS patients. Materials and Methods: Using data from the National ALS Center of Excellence clinic database at the University of Vermont Medical Center, we stratified 244 patients into cohorts based on riluzole use, and duration of survival from the baseline visit into short-term (≤3 years) and long-term (>3 years) survivors. We examined average monthly weight change in patients during the first year after the baseline visit, and the last year before death. Results and Discussion: In 156 short-term survivors taking riluzole compared to those not taking riluzole, there was a 37% attenuation of weight loss in the first year after baseline, and 46% attenuation of weight loss in the last year before death. Seventy-four n long-term survivors on riluzole showed reduced weight decline in the first year after the baseline visit. We speculate that one mechanism by which riluzole may affect survival is by attenuating weight loss and possibly maintaining nutritional status and body composition, although this warrants prospective study.

Axial muscle weakness.

Axial myopathy is a rare neuromuscular disorder characterised by selective involvement of the paraspinal muscles, and presenting either as a bent spine and/or dropped head syndrome. The axial muscles can be involved in various conditions, including neuromuscular disease, movement disorders, spinal disease and metabolic disorders. There have been recent descriptions of disorders with selective axial muscle involvement, but overall axial myopathy remains under-recognised. Here, we review disorders of axial muscle function, provide guidance on interpreting axial muscles imaging and suggest a diagnostic algorithm to evaluate patients with axial muscles weakness.