Primary CNS vasculitis: insights into clinical, neuropathological, and neuroradiological characteristics.

Background and objectives: Primary CNS vasculitis (PCNSV) is a rare inflammatory disorder that affects the blood vessels of the central nervous system (CNS). We aimed to analyze the neurological presentations, clinical follow-up, and long-term outcomes of patients with primary central nervous system vasculitis. Methods: We conducted a retrospective analysis of medical records to assess the neurological presentation, rate of remission, and functional status at the last follow-up in patients with primary central nervous system vasculitis seen in our center in the last 13 years (2010-2023). Results: We identified five patients, whose median age at symptom onset was 31 years (range: 15-41 years), including four male individuals (80%) from Muslim Arab (n = 4) and Ashkenazi Jewish (n = 1) backgrounds. Symptoms persisted for a median of 36 weeks (range: 3 weeks to 4 years) before diagnosis, with one case exceeding 3 years. Follow-up lasted a median of 56 months (range: 20-161 months). Clinical symptoms varied, presenting unilateral weaknesses (n = 2), cognitive and gait abnormality (n = 1), headaches (n = 1), and epileptic seizures (n = 1). MRI scans revealed abnormalities in the basal ganglia, corona radiata, parietal, and frontal lobes, showing hemorrhage, vasogenic edema, restricted diffusion, and enhancement post-gadolinium. All patients reported progressive holocephalic headaches and cognitive changes with overall progressive symptoms. Initial neurological examinations revealed abnormalities in all patients and included one or more of the following: cognitive or visual impairment (n = 2), seizures (n = 1), and unilateral UMN signs (n = 2) at the initial neurological examination, all but one patient required walking aids including (cane 2, wheelchair, bedridden 1). Patients were stable (n = 2), deteriorated (n = 1), or improved (n = 2). Following treatment, two patients still required ambulatory aids, with one using a cane and the other using a wheelchair, while the remaining three did not require any ambulatory aids. Discussion: The study on PCNSV highlights varied symptoms and diagnostic challenges, including delayed diagnosis and a spectrum of neurological issues from cognitive impairments to seizures. Brain biopsies showed lymphocytic infiltration, thrombi, and necrosis. Immunotherapy significantly improved clinical and radiological outcomes. Over 56 months of follow-up, outcomes varied from stability and deterioration to improvement.

Real-World experience with efgartigimod in patients with myasthenia gravis.

Recommendations for the treatment of myasthenia gravis (MG) have been difficult to develop because of limited evidence from large randomized controlled trials. New drugs and treatment approaches have recently been shown to be effective in phase 3 studies in seropositive generalized (g) MG. One such drug is efgartigimod, a human-Fc-fragment of IgG1, with a high affinity for the endosomal FcRn. We conducted a multicenter study to evaluate the real-world clinical and safety effects of efgartigimod in 22 gMG patients. We evaluated the strategies for the timing of re-treatment with it. The participants received a total of 59 efgartigimod -treatment cycles. The median number of cycles was 2 (range 1-6). Twenty patients (86.3%) improved by at least 2 MG-ADL points after the first treatment cycle. The median MG-ADL score at baseline was 6.5 (range: 3-17) and 2.5 (range: 0-9) post-treatment (p < 0.001). A consistent improvement of at least 2 points in the MG-ADL score after each cycle occurs in 18 patients. The effect duration of the treatment was usually between 4 and 12 weeks. Two major clinical patterns of treatment response were found. Treatment with efgartigimod was also associated with significant reductions of prednisone doses Overall, the treatment was safe and associated with only minor adverse events. The single fatality was apparently due tosevere respiratory failure. We found that efgartigimod is clinically effective, may be used as a steroid sparing agent and is generally safe for gMG patients. We recommend a personalized preventive treatment approach until clinical stabilization, followed by discontinuation and periodic evaluations.

Paraneoplastic neuropathies and peripheral nerve hyperexcitability disorders.

Peripheral neuropathy is a common referral for patients to the neurologic clinics. Paraneoplastic neuropathies account for a small but high morbidity and mortality subgroup. Symptoms include weakness, sensory loss, sweating irregularity, blood pressure instability, severe constipation, and neuropathic pain. Neuropathy is the first presenting symptom of malignancy among many patients. The molecular and cellular oncogenic immune targets reside within cell bodies, axons, cytoplasms, or surface membranes of neural tissues. A more favorable immune treatment outcome occurs in those where the targets reside on the cell surface. Patients with antibodies binding cell surface antigens commonly have neural hyperexcitability with pain, cramps, fasciculations, and hyperhidrotic attacks (CASPR2, LGI1, and others). The antigenic targets are also commonly expressed in the central nervous system, with presenting symptoms being myelopathy, encephalopathy, and seizures with neuropathy, often masked. Pain and autonomic components typically relate to small nerve fiber involvement (nociceptive, adrenergic, enteric, and sudomotor), sometimes without nerve fiber loss but rather hyperexcitability. The specific antibodies discovered help direct cancer investigations. Among the primary axonal paraneoplastic neuropathies, pathognomonic clinical features do not exist, and testing for multiple antibodies simultaneously provides the best sensitivity in testing (AGNA1-SOX1; amphiphysin; ANNA-1-HU; ANNA-3-DACH1; CASPR2; CRMP5; LGI1; PCA2-MAP1B, and others). Performing confirmatory antibody testing using adjunct methods improves specificity. Antibody-mediated demyelinating paraneoplastic neuropathies are limited to MAG-IgM (IgM-MGUS, Waldenström's, and myeloma), with the others associated with cytokine elevations (VEGF, IL6) caused by osteosclerotic myeloma, plasmacytoma (POEMS), and rarely angiofollicular lymphoma (Castleman's). Paraneoplastic disorders have clinical overlap with other idiopathic antibody disorders, including IgG4 demyelinating nodopathies (NF155 and Contactin-1). This review summarizes the paraneoplastic neuropathies, including those with peripheral nerve hyperexcitability.

Towards a practical use of text mining approaches in electrodiagnostic data.

Healthcare professionals produce abounding textual data in their daily clinical practice. Text mining can yield valuable insights from unstructured data. Extracting insights from multiple information sources is a major challenge in computational medicine. In this study, our objective was to illustrate how combining text mining techniques with statistical methodologies can yield new insights and contribute to the development of neurological and neuromuscular-related health information. We demonstrate how to utilize and derive knowledge from medical text, identify patient groups with similar diagnostic attributes, and examine differences between groups using demographical data and past medical history (PMH). We conducted a retrospective study for all patients who underwent electrodiagnostic (EDX) evaluation in Israel's Sheba Medical Center between May 2016 and February 2022. The data extracted for each patient included demographic data, test results, and unstructured summary reports. We conducted several analyses, including topic modeling that targeted clinical impressions and topic analysis to reveal age- and sex-related differences. The use of suspected clinical condition text enriched the data and generated additional attributes used to find associations between patients' PMH and the emerging diagnosis topics. We identified 6096 abnormal EMG results, of which 58% (n = 3512) were males. Based on the latent Dirichlet allocation algorithm we identified 25 topics that represent different diagnoses. Sex-related differences emerged in 7 topics, 3 male-associated and 4 female-associated. Brachial plexopathy, myasthenia gravis, and NMJ Disorders showed statistically significant age and sex differences. We extracted keywords related to past medical history (n = 37) and tested them for association with the different topics. Several topics revealed a close association with past medical history, for example, length-dependent symmetric axonal polyneuropathy with diabetes mellitus (DM), length-dependent sensory polyneuropathy with chemotherapy treatments and DM, brachial plexopathy with motor vehicle accidents, myasthenia gravis and NMJ disorders with botulin treatments, and amyotrophic lateral sclerosis with swallowing difficulty. Summarizing visualizations were created to easily grasp the results and facilitate focusing on the main insights. In this study, we demonstrate the efficacy of utilizing advanced computational methods in a corpus of textual data to accelerate clinical research. Additionally, using these methods allows for generating clinical insights, which may aid in the development of a decision-making process in real-life clinical practice.

Dual positivity for anti-MOG and oligoclonal bands: Unveiling unique clinical profiles and implications.

BACKGROUND: Distinguishing between MOG-associated disease (MOGAD) and multiple sclerosis (MS) presents a considerable challenge, as there are instances of overlapping clinical presentations. This complexity is further magnified in cases where patients concurrently exhibit both anti-myelin oligodendrocyte glycoprotein (anti-MOG) positivity and detectable oligoclonal bands (OCBs) This retrospective study investigates the clinical and imaging attributes of dual-positive patients, those with both anti-MOG positivity and OCBs, The study aims to show potential areas of overlap between multiple sclerosis (MS) and MOGAD. METHODS: Utilizing data gathered from three medical centers, we evaluated a cohort of 45 patients, stratifying them into two groups: those exclusively positive for anti-MOG antibodies and those displaying dual positivity. Our analysis encompassed a wide range of clinical and imaging parameters. The statistical techniques employed comprised Fisher's Exact Test along with Benjamini-Hochberg correction to ensure robustness of the findings. RESULTS: The study involved 45 patients with anti-MOG antibodies; 30 exhibited isolated anti-MOG positivity without OCBs, while 15 were dual-positive. The first group's average age was 10±7 years, compared to 28±17 years in the double-positive group (p = 0.001). CSF analysis showed no significant differences in pleocytosis, protein levels, or opening pressure between the groups. In the exclusive anti-MOG positivity cohort, 9 out of 15 patients received IVIG treatment; a larger subgroup with dual positivity chose anti-CD20 treatment. Notably, papilledema incidence was higher in the single-positive group (p = 0.014). Optic nerve enhancement (p = 0.0038) and nerve thickening (p = 0.0017) were markedly elevated in the single-positive population, with a trend towards pre-chiasmatic lesions (p = 0.06). Double-positive cases exhibited more polyfocal presentation (p = 0.013) and higher attacks per case (p = 0.002, HR=10.2, 95 % CI: 2.19 to 49.23). The double-positive group had more brain lesions (p = 0.0063) but no significant distinctions in other aspects. CONCLUSION: The results emphasize the challenges inherent in differentiating between MS and a more MOGAD. While the data suggest two plausible scenarios-either falling within the spectrum of MS or representing an intensified MOGAD-we recognize the need for stronger evidence to definitively classify these instances. This study underscores the imperative for thorough investigations to ascertain whether these cases align with the MS spectrum or denote an inflammatory variant of MOGAD.

Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Patients With Melanoma.

BACKGROUND AND OBJECTIVES: Neurologic immune-related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune checkpoint inhibitors (ICIs) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICIs and examined the effect of n-irAEs on survival outcomes in a large cohort of patients with melanoma. METHODS: We conducted a retrospective analysis of patients with advanced melanoma treated with ICIs at Ella Institute for Immuno-oncology and Melanoma between January 1, 2015, and April 20, 2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAEs, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's effect on survival. RESULTS: ICI was administered to 937 patients. At least one irAE occurred in 73.5% (n = 689) of them. Among the study population, 8% (n = 76) developed a n-irAE, with a median age of 66 years in female and 68 years in male patients at onset. The median follow-up after n-irAE was 1,147 days (IQR: 1,091.5 range: 3,938). Fewer irAEs occurred in patients older than 70 years (median: 3 events, p = 0.04, CI 2.5-4.7) while specifically colitis and pneumonitis were more common in the 18-60 age group (p = 0.03, 95% CI 0.8-0.38, p = 0.009, 95% CI 0.06-0.2). Grade ≥ 3 toxicity was seen in 35.5% of patients across age groups. The median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR = 0.4, 95% CI 0.32-0.77) or any irAE (HR = 0.7195% CI 0.56-0.88) was associated with longer survival. DISCUSSION: N-irAEs are a relatively common complication of ICIs (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-n-irAEs which occurred less frequently in the elderly population. Rechallenge did not result in life-threatening AEs. Development of any irAEs was associated with longer survival; this association was stronger with n-irAEs.

Nerve Conduction Differences in a Large Clinical Population: The Role of Age and Sex.

BACKGROUND: The normal limits of nerve conduction studies are commonly determined by testing healthy subjects. However, in comprehensive real-life nerve conduction electrodiagnostic (EDX) evaluations, multiple nerves are tested, including normal nerves, for purposes of comparison with abnormal ones. OBJECTIVE: This study aims to evaluate the average values of normal nerve conduction studies in a large population and examined the influence of age and sex. METHODS: EDX parameters were extracted from an electronic database of studies performed from May 2016 to February 2022. Established normal values were used to determine the classification of a nerve study as normal. RESULTS: We identified 10,648 EDX reports with 5077 normally interpreted nerve conduction studies (47.6%) of which 57% (n = 2890) were for females. The median age of studies with no abnormalities was 45.1 years (range < 1 to 92) overall and 42.5 years (range: 0.16 -89.5 years) for males and 47.5 years (range:<1 -91.7) for females. Correlations between age and amplitude, latency, and velocity (p < 0.001) were observed in most nerves. Amplitude correlated negatively with age in adults in all nerves with a mean of -0.44 (range: -0.24 to -0.62). However, in the pediatric population (age < 18 years), amplitude as well as velocity increased significantly with age. In the adult cohort, sex differences were noted, where females had higher mean sensory nerve action potentials in ulnar, median, and radial evaluations (p < 0.001). In older patients (aged > 70 years) with normally interpreted EDX studies (845 records of 528 patients), sural responses were present in 97%. CONCLUSIONS: This real-life study confirms that advanced aging is associated with decreased nerve conduction amplitudes, increased latency, and the slowing of conduction velocity. The findings also indicate higher sensory amplitudes and conduction velocities in females. Sural nerve responses were identified in most adults over age 70.

Clinicoradiologic Criteria for the Diagnosis of Stroke-like Episodes in MELAS.

Background and Objectives: Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria. Methods: We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance. Results: Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, p < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, p < 0.01), more commonly reported hearing loss (91% vs 5%, p < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, p < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, p < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, p = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, p < 0.01), and no large vessel occlusion on CTA (0% vs 100%, p < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917). Discussion: Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy. Classification of Evidence: This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.

Clinical, Neurophysiologic, and Pathologic Features in Patients With Early-Onset Postradiation Neuropathy.

OBJECTIVES: The objective of this study was to study early-onset radiation-induced neuropathy reviewing neurologic course, steroid response, and available nerve biopsies. METHODS: Patients coded with radiation-induced neuropathy within 6 months of radiation were reviewed from January 1,1999, to August 31, 2022. Patients had to have electrodiagnostically confirmed neuropathy localized within or distal to radiation fields. Neurologic course and nerve biopsies were reviewed. RESULTS: Twenty-eight patients (16 male and 12 female patients, mean age 63.8 years) were identified. The average radiation dose was 4,659 cGy (range 1,000-7,208). Tumor infiltration was not observed on MRI and PET. Postradiation onsets averaged 2 months (range 0-5). Localizations included brachial (n = 4) plexopathies, lumbosacral (n = 12) plexopathies, radiculopathies (n = 10), and mononeuropathies (n = 2). Neuropathic pain (n = 25) and weakness (n = 25) were typical. The clinical courses were subacute monophasic (n = 14), chronic progressive (n = 8), or static (n = 1), and 5 were without follow-up. Nerve biopsies (n = 8) showed an inflammatory ischemic process with perivascular inflammatory infiltrates (n = 7) or microvasculitis (n = 2). Nine patients, 7 with monophasic courses, received steroid burst therapy with symptom improvement in 8. No patients recovered entirely back to baseline. DISCUSSION: In contrast to chronic radiation-induced neuropathy, early-onset patients most commonly have painful monophasic courses with residual deficits, possibly steroid responsive. An ischemic inflammatory pathogenesis is suggested.

Accelerated Aging in LMNA Mutations Detected by Artificial Intelligence ECG-Derived Age.

OBJECTIVE: To demonstrate early aging in patients with lamin A/C (LMNA) gene mutations after hypothesizing that they have a biological age older than chronological age, as such a finding impacts care. PATIENT AND METHODS: We applied a previously trained convolutional neural network model to predict biological age by electrocardiogram (ECG) [Artificial Intelligence (AI)-ECG age] to LMNA patients evaluated by multiple ECGs from January 1, 2003, to December 31, 2019. The age gap was the difference between chronological age and AI-ECG age. Findings were compared with age-/sex-matched controls. RESULTS: Thirty-one LMNA patients who had a total of 271 ECGs were studied. The median age at symptom onset was 22 years (range, <1-53 years; n=23 patients); eight patients were asymptomatic family members carrying the LMNA mutation. Cardiac involvement was detected by ECG and echocardiogram in 16 patients and consisted of ventricular arrhythmias (13), atrial fibrillation (12), and cardiomyopathy (6). Four patients required cardiac transplantation. Fourteen patients had neurological manifestations, mainly muscular dystrophy. LMNA mutation carriers, including asymptomatic carriers, were 16 years older by AI-ECG than non-LMNA carriers, suggesting accelerated biological age. Most LMNA patients had an age gap of more than 10 years, compared with controls (P<.001). Consecutive AI-ECG analysis showed accelerated aging in the LMNA group compared with controls (P<.0001). There were no significant differences in age-gap among LMNA patients based on phenotype. CONCLUSION: AI-ECG predicted that LMNA patients have a biological age older than chronological age and accelerated aging even in the absence of cardiac abnormalities by traditional methods. Such a finding could translate into early medical intervention and serve as a disease biomarker.

Clinical score for early diagnosis and treatment of stroke-like episodes in MELAS syndrome.

BACKGROUND AND OBJECTIVES: Stroke-like episodes (SLEs) in patients with MELAS syndrome are often initially misdiagnosed as acute ischemic stroke (AIS), resulting in treatment delay. We aimed to determine clinical features that may distinguish SLEs from AISs and explore the benefit of early L-arginine treatment on patient outcomes. METHODS: We looked retrospectively for MELAS patients admitted between January 2005 and January 2022 and compared them to an AIS cohort with similar lesion topography. MELAS patients who received L-arginine within 40 days of their first SLE were defined as the early treatment group and the remaining as late or no treatment group. RESULTS: Twenty-three SLEs in 10 MELAS patients and 21 AISs were included. SLE patients had significantly different features: they were younger, more commonly reported hearing loss, lower body mass index, had more commonly a combination of headache and/or seizures at presentation, serum lactate was higher, and hemiparesis was less common. An SLE Early Clinical Score (SLEECS) was constructed by designating one point to each above features. SLEECS ≥ 4 had 80% sensitivity and 100% specificity for SLE diagnosis. Compared to late or no treatment, early treatment group patients (n = 5) had less recurrent SLEs (total 2 vs. 11), less seizures (14% vs. 25%, p = 0.048), lower degree of disability at first and last follow-up (modified ranking scale, mRS 2 ± 0.7 vs. 4.2 ± 1, p = 0.005; 2 ± 0.7 vs. 5.8 ± 0.5, p < 0.001, respectively), and a lower mortality (0% vs. 80% p = 0.048). CONCLUSIONS: The SLEECS model may aid in the early diagnosis and treatment of SLEs and lead to improved clinical outcomes.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis.

OBJECTIVES: Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. METHODS: Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM). RESULTS: Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. CONCLUSIONS: We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Nitrofurantoin and Minocycline-Associated Vasculitic Neuropathy: Case Reports and Literature Review.

BACKGROUND: Vasculitic neuropathies usually present acutely to subacutely, with an asymmetric pattern, involving multiple peripheral nerve territories. Drug-induced vasculitis is an often overlooked etiology of vasculitic neuropathy. METHODS: We present the first reported case of nitrofurantoin-associated and an illustrative case of minocycline-associated vasculitic neuropathy, with a review of the literature. RESULTS: The first patient is a 60-year-old woman who developed axonal sensorimotor peripheral neuropathy after nitrofurantoin use, with a superficial radial nerve biopsy confirming vasculitis. The second patient is a 23-year-old woman, with a history of acne vulgaris treated with minocycline, who presented with a subacute right common peroneal mononeuropathy followed by a left deep peroneal mononeuropathy, with elevated antinuclear, perinuclear-antineutrophil cytoplasmic, and myleoperoxidase antibodies, and MPO titers, and a sural nerve biopsy showing large arteriole vasculitis. Finally, we provide a comprehensive review of previously published cases. CONCLUSIONS: Medications should be considered as a trigger for medication-induced vasculitic neuropathy. Accurate diagnosis would ensure timely treatment.

Electrocardiogram-Artificial Intelligence and Immune-Mediated Necrotizing Myopathy: Predicting Left Ventricular Dysfunction and Clinical Outcomes.

Objective: To characterize the utility of an existing electrocardiogram (ECG)-artificial intelligence (AI) algorithm of left ventricular dysfunction (LVD) in immune-mediated necrotizing myopathy (IMNM). Patients and Methods: A retrospective cohort observational study was conducted within our tertiary-care neuromuscular clinic for patients with IMNM meeting European Neuromuscular Centre diagnostic criteria (January 1, 2000, to December 31, 2020). A validated AI algorithm using 12-lead standard ECGs to detect LVD was applied. The output was presented as a percent probability of LVD. Electrocardiograms before and while on immunotherapy were reviewed. The LVD-predicted probability scores were compared with echocardiograms, immunotherapy treatment response, and mortality. Results: The ECG-AI algorithm had acceptable accuracy in LVD prediction in 74% (68 of 89) of patients with IMNM with available echocardiograms (discrimination threshold, 0.74; 95% CI, 0.6-0.87). This translates into a sensitivity of 80.0% and specificity of 62.8% to detect LVD. Best cutoff probability prediction was 7 times more likely to have LVD (odds ratio, 6.75; 95% CI, 2.11-21.51; P=.001). Early detection occurred in 18% (16 of 89) of patients who initially had normal echocardiograms and were without cardiorespiratory symptoms, of which 6 subsequently advanced to LVD cardiorespiratory failure. The LVD probability scores improved for patients on immunotherapy (median slope, -3.96; R = -0.12; P=.002). Mortality risk was 7 times greater with abnormal LVD probability scores (hazard ratio, 7.33; 95% CI, 1.63-32.88; P=.009). Conclusion: In IMNM, an AI-ECG algorithm assists detection of LVD, enhancing the decision to advance to echocardiogram testing, while also informing on mortality risk, which is important in the decision of immunotherapy escalation and monitoring.

Plexus MRI helps distinguish the immune-mediated neuropathies MADSAM and MMN.

BACKGROUND: Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy. OBJECTIVES: To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases. METHODS: Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic. RESULTS: Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG. CONCLUSION: Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

Clinical and electrophysiological findings in C9ORF72 ALS.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder of motor neurons in which the cause is mostly unknown. Early identification of genetic ALS cases, of which C9ORF72 (C9ALS) is the most frequent, can have important implications for evaluation, prognosis, and therapeutics. Here, we aimed to characterize the clinical and electrophysiological hallmarks of C9ALS and investigate differences from C9ORF72 negative ALS (non-C9ALS). METHODS: We retrospectively reviewed clinical and electrodiagnostic (EDX) data for all genetically confirmed C9ALS cases seen between 1/1/2012 and 10/1/2020 who met Gold Coast criteria and compared them 1:1 with non-C9ALS patients within the same time frame. RESULTS: A total of 99 C9ALS and 99 non-C9ALS cases were identified. Compared to non-C9ALS, C9ALS demonstrated higher prevalence in women, lesser racial variability, stronger family history of ALS, and higher frequency of upper motor neuron signs. EDX testing of C9ALS showed higher median sensory nerve and lower fibular compound muscle action potential amplitudes. DISCUSSION: Although the differences between C9ALS and non-C9ALS reached statistical significance in certain nerve conduction parameters, they were not sufficient to discriminate between groups on a case-by-case basis. Genetic testing is required to identify C9ALS patients.

LRP4-IgG service line testing in seronegative myasthenia gravis and controls.

BACKGROUND: LRP4 is a post-synaptic membrane protein that promotes acetylcholine (AChR) clustering on the crest of post-synaptic neuromuscular folds. Autoantibodies against LRP4 are suggested to account for myasthenia gravis (MG) patients negative for antibodies to AChR. OBJECTIVES: To report a clinical experience with service-line LRP4-IgG cell-based testing in electrodiagnostically confirmed MG patients and controls. METHODS: We identified all Mayo patients undergoing MG evaluations with send out LRP4-IgG antibody testing by cell-based assay, having clinical-electrodiagnostic (EDX) testing. To be included, muscle acetylcholine receptor binding (AChR-Bi) and muscle-specific tyrosine kinase (MuSK) antibodies had to be absent prior to LRP4-IgG testing. Follow-up AChR-Bi antibody testing was reviewed. Also tested for LRP4-IgGs were 119 healthy subjects. RESULTS: Identified were 25 generalized MG, 24 ocular MG, and 55 patients initially considered to have MG prior to negative EDX testing. No seronegative patients with EDX confirmed MG had LRP4-IgG positivity but five non-MG patients did: Guillain-Barre syndrome with fatigue (N = 1); multiple cranial neuropathies (N = 1); functional neurologic disorders (N = 3). Of healthy subjects, 4% (5/119) were LRP4-IgG positive (N = 5) or had a borderline result (N = 1). Of MG patients with repeat AChR-Bi testing, 40% (10/25) seroconverted (5 with ocular MG and 5 with generalized MG) (median AChR IgG value: 0.34 nmol/L, range 0.2-20.9 nmol/L, median followup 26 months, range 2-72 months). CONCLUSION: Clinical review of LRP4-IgG commercial cell-based testing suggests lack of diagnostic utility in seronegative EDX-confirmed MG. The clinical utility of LRP4-IgG testing is not substantiated in service line testing. In contrast, repeat testing for AChR-Bi antibodies is shown clinically useful.

Cancer and immune-mediated necrotizing myopathy: a longitudinal referral case-controlled outcomes evaluation.

OBJECTIVES: To investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications. METHODS: IMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1). RESULTS: A total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325-0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33-0.78, P = 0.002). Most patients responded to treatment (137/147, P < 0.001). Death and treatment response did not significantly differ between cancer [23% (8/34); 88% (29/33)] and non-cancer patients [19% (23/118); 92% (108/118)]. In total, 13% (20/152) of patients died during follow-up compared with 14% (41/290) of medicine and 16% (46/290) of neurology controls (P = 0.8). Seropositives had greater life expectancy than seronegatives (P = 0.01). CONCLUSIONS: Greater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.