Investigators of a retrospective study found that approximately one-third of patients with triple-seronegative myasthenia gravis (tSNMG) had treatment-refractory disease, challenging the perception that antibody-negative myasthenia gravis (MG) generally follows a milder clinical course. Researchers analyzed 196 patients with MG at a single neuromuscular center, identifying 26 (13.3%) who tested negative for acetylcholine receptor, muscle-specific tyrosine kinase, and low-density lipoprotein receptor-related protein 4 antibodies. Of these, nine (34.6%) met criteria for refractory disease. Compared with nonrefractory patients, those with refractory tSNMG were more frequently female (77.8% vs 14.3%), had thymic abnormalities (88.9% vs 28.6%), and reported respiratory symptoms during their disease course (88.9% vs 28.6%). Although 76.9% of patients achieved a favorable response to prednisone, fewer than half achieved pharmacologic remission or minimal manifestations at their most recent assessment. Among 12 patients who underwent thymectomy, six (50%) had favorable outcomes at one year, although responses were substantially lower in the refractory subgroup.

These findings underscore the importance of recognizing MG even when conventional antibody testing is negative and closely monitoring patients for signs of treatment resistance. Fluctuating muscle weakness, ocular or bulbar symptoms, and respiratory complaints warrant careful assessment, with repetitive nerve stimulation or single-fiber electromyography helping support diagnosis when serologic testing is inconclusive. The study also highlights the challenges of managing refractory tSNMG, including dependence on corticosteroids and variable responses to conventional immunosuppressive treatments. Azathioprine and mycophenolate mofetil produced favorable responses in some patients, whereas rituximab showed limited benefit among those with refractory disease. However, the small sample size and retrospective design prevent definitive comparisons of treatment effectiveness or identification of reliable predictors of refractoriness. An accompanying narrative review of eight studies involving 299 seronegative MG patients similarly identified substantial variability in treatment responses and outcomes. The authors emphasize the need for standardized diagnostic criteria, individualized treatment strategies, and greater inclusion of antibody-negative patients in clinical trials to improve disease management.

Reference: Veltsista D, Tzartos J, Liampas I, Kefalopoulou Z, Chroni E. Treatment challenges in triple seronegative myasthenia gravis: a single-center experience and narrative review of the literature. Acta Neurol Scand. 2026 Apr 8;2026(1):5532283. doi: 10.1155/ane/5532283.

Authors of a comprehensive review highlight the importance of recognizing peripheral neuropathy as an early warning sign of systemic amyloidosis, particularly immunoglobulin light-chain (AL) amyloidosis and hereditary transthyretin amyloidosis (ATTRv). Both conditions involve abnormal protein deposits that damage peripheral and autonomic nerves, often producing symptoms years before diagnosis. ATTRv commonly presents with progressive sensorimotor neuropathy accompanied by autonomic dysfunction, while AL amyloidosis frequently causes axonal polyneuropathy and may also involve autonomic nerves. Carpal tunnel syndrome is an especially important diagnostic clue, occurring in more than 70% of patients with ATTRv and often preceding diagnosis by more than a decade. Additional warning signs include orthostatic hypotension, unexplained weight loss, diarrhea, rapidly progressive neuropathy, and poor response to immunotherapy. Heart failure with preserved ejection fraction may accompany either condition, while macroglossia and unexplained proteinuria are particularly suggestive of AL amyloidosis. Because these symptoms overlap with more common neurologic disorders, delayed recognition can allow irreversible nerve damage and progressive organ dysfunction.

The review emphasizes considering amyloidosis when unexplained or progressive neuropathy occurs alongside autonomic symptoms, bilateral carpal tunnel syndrome, or evidence of cardiac or renal involvement. Initial evaluation for AL amyloidosis includes serum protein electrophoresis with immunofixation, serum free light-chain testing, and urine immunofixation, while suspected ATTRv warrants transthyretin gene sequencing. Tissue biopsy with Congo red staining and amyloid protein typing may be necessary to confirm and classify disease. Accurate differentiation is essential because treatment strategies differ substantially: AL amyloidosis requires therapy targeting abnormal plasma cells, including daratumumab-based regimens, whereas ATTRv polyneuropathy can be treated with transthyretin-silencing agents such as patisiran, vutrisiran, inotersen, and eplontersen. These disease-modifying therapies can slow neuropathy progression, making timely diagnosis and referral increasingly important. The authors also highlight emerging diagnostic approaches, including skin biopsy and magnetic resonance neurography, that may help identify subclinical nerve injury. Recognizing patterns of neurologic and systemic involvement early may help clinicians shorten diagnostic delays and connect patients with appropriate treatment before further disability develops.

Reference: Chompoopong P, Mauermann ML, Siddiqi H, Peltier A. Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis. Ann Neurol. 2024 Sep;96(3):423-440. doi: 10.1002/ana.26965.

Investigators of a longitudinal study of individuals genetically predisposed to amyotrophic lateral sclerosis (ALS) suggest that subtle neurologic abnormalities may emerge months or even years before clinically recognizable disease. Researchers followed approximately 210 presymptomatic carriers of ALS-associated mutations in the ongoing Pre-fALS study, identifying 20 participants who subsequently developed clinically manifest ALS. Among these individuals, 11 had a documented prodromal period of mild motor impairment (MMI), characterized by findings such as muscle twitching, cramps, subtle weakness, abnormal reflexes, or isolated denervation on electromyography (EMG). The duration varied considerably by genotype: some carriers of the SOD1 A4V mutation exhibited abnormalities only 1 to 4 months before symptom onset, while other SOD1 mutation carriers demonstrated motor changes for several years. Plasma neurofilament light chain (NfL), a biomarker of axonal injury, was elevated before clinical disease onset in 12 participants, with another four showing elevations shortly afterward. However, NfL elevations did not consistently precede motor abnormalities, highlighting variability in the earliest detectable signs of neurodegeneration.

These findings highlight the importance of recognizing persistent, unexplained motor abnormalities and facilitating timely neuromuscular evaluation, particularly in individuals with known ALS-associated genetic mutations. Mild asymmetric weakness, new or unusually brisk reflexes, fasciculations, and unexplained EMG abnormalities may warrant closer assessment even when patients do not meet established diagnostic criteria for ALS. However, these findings are not specific to ALS, and isolated muscle twitching or other nonspecific symptoms should not be interpreted as evidence of impending disease. The researchers propose recognizing MMI as an intermediate clinical state that may justify specialist evaluation, additional testing, and longitudinal monitoring rather than an immediate ALS diagnosis. Although NfL testing may eventually help identify early neurodegeneration and guide preventive interventions, its timing and diagnostic utility require further investigation. Importantly, the study involved only 20 individuals who developed genetically associated ALS, so the findings cannot yet be generalized to sporadic disease. The authors emphasize that better characterization of this early phase could shorten diagnostic delays and support future research into treatment before significant motor neuron loss occurs.

Reference: Benatar M, Granit V, Andersen PM, et al. Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Brain. 2022 Oct 21;145(10):3500-3508. doi: 10.1093/brain/awac185.