N-acetylcysteine is a thiol-containing compound and a precursor of glutathione, with mechanistic plausibility for ALS, including reducing oxidative stress, regulating neuroinflammation, and mitigating mitochondrial dysfunction. Preclinical studies have yielded conflicting results on whether N-acetylcysteine can delay the onset of motor impairment and prolong survival in ALS mouse models. Several case studies of oral or subcutaneous administration of N-acetylcysteine in patients with ALS did not demonstrate convincing benefits. Clinical trials to date have also failed to demonstrate efficacy in slowing ALS progression. While N-acetylcysteine shows theoretical promise, further research is needed to clarify its therapeutic role in ALS. At present, ALSUntangled does not support the use of N-acetylcysteine as a treatment to slow ALS progression.

ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.

Introduction/Aims Guidelines for the management of chronic inflammatory demyelinating polyneuropathy (CIDP) recommend corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange for first-line therapies and subcutaneous immunoglobulin (SCIg) as a maintenance option. Literature on clinical experience with SCIg in CIDP maintenance therapy is limited. This study outlines practical approaches to SCIg transition and management optimization, considering the varying dosing recommendations in prescribing information and clinical guidelines.Methods This retrospective, multicenter study analyzed anonymized patient medical records from eight US centers. Patients with CIDP who transitioned to SCIg were included, and clinical practices regarding SCIg therapy management were analyzed.Results These 20 cases presented practical and clinical considerations for successful SCIg transition and maintenance. Switching decisions were guided by patient-physician assessment of treatment goals, benefits, and risks. The most common reason for switching (70%) was preference for site of care. Eight patients (40%) transitioned to a dose equivalent to their baseline IVIg dose. Overall, 12/19 patients (63%) remained stable following transition. Relapse-free rates were higher in patients who transitioned to a higher (67%) or lower (75%) than baseline dose versus those who received an equivalent dose (50%). All relapsed patients restabilized after increasing their SCIg dose. The final mean (SD) SCIg dose was 0.32 (0.15) g/kg/week. SCIg was well tolerated; 11 patients (55%) reported better tolerance versus IVIg.Discussion These patient cases provide practical guidance for SCIg therapy in CIDP maintenance, emphasizing individualized dosing strategies, ongoing monitoring, and patient-centered engagement. The findings help inform clinical decision-making to optimize long-term therapeutic outcomes.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.

High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz−/− or Alix−/− mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers. In skeletal muscle mitochondria, CRL5Ozz and Alix regulate the levels of the ATP transporter Slc25A4; loss of either protein in mice alters Slc25A4, causing mitochondrial defects, metabolic changes, and a shift from oxidative to glycolytic fibers.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.

Alpha-lipoic acid (ALA) is a naturally occurring fatty acid. It serves as an essential cofactor for enzymatic reactions in mitochondrial energy production, is a potent antioxidant and has anti-inflammatory effects, which are plausible mechanisms in slowing ALS progression. In ALS preclinical studies, ALA slowed motor function decline and improved survival. There were self-reported cases of improved muscle strength in ALS patients when ALA was taken with numerous additional supplements, making it difficult to discern its efficacy. One small, 6-month open-label study showed improved quality of life, fatigue, and mood after participants took it with B vitamins and amino acids for the first 3 months. So far, no clinical trials have been published in people living with amyotrophic lateral sclerosis (PALS). Given the insufficient clinical data, we cannot endorse ALA and will support more research on its efficacy in slowing ALS progression.

Pyridostigmine (Mestinon®, Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.

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.

Facial-onset sensory and motor neuronopathy (FOSMN) is a rare, progressive neurodegenerative disorder characterized by sensory loss and motor deficits, primarily affecting the face and upper extremities. The condition begins with sensory impairments in the trigeminal nerve distribution, extending to involve the scalp, neck, upper limbs, and trunk. Symptoms include facial weakness, bulbar disturbances (dysphonia, dysarthria, dysphagia, and sialorrhea), and lower motor neuron signs (weakness, atrophy, fasciculation, and cramps) in the limbs. A hallmark of FOSMN is the diminished or absent corneal reflex, indicating trigeminal nerve involvement and leading to potential complications like neurotrophic keratitis (NK), which can cause corneal ulceration and blindness. The etiology of FOSMN remains uncertain, with theories proposing autoimmune or neurodegenerative origins. Diagnosis is challenging due to the overlap with other ocular surface disorders, necessitating careful examination and differential diagnosis. Management focuses on symptomatic relief, including eye protection to prevent corneal complications. Awareness and early detection of ocular symptoms in FOSMN are crucial for preventing severe outcomes like NK and blindness.

Inflammatory neuropathies constitute a collection of prevalent and manageable pathologies resulting from a humoral or cellular immune response directed towards distinct components of the peripheral nervous system. These pathologies can manifest acutely, as exemplified by Guillain-Barré syndrome (GBS) and its subtypes, or chronically, as seen in the case of chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, or nodal-paranodal disorders. Diagnosis primarily relies upon clinical manifestations and electromyographic studies, aimed at facilitating timely initiation of treatment.

Abstract Spinal muscular atrophy is an incurable inherited disease caused by lower motor neuron death from mutations of the survival motor neuron genes. Intrathecal therapy with the antisense oligonucleotide, nusinersen, has been demonstrated to be beneficial in children with this disease, but the experience in adults, particularly ambulatory patients, is limited. We present a prospective observational case series from a single center using nusinersen therapy where we categorize 6 adult patients with spinal muscular atrophy into 2 functional categories: ambulatory (n = 3) or nonambulatory (n = 3). All received therapy that was administered intrathecally every 4 months. We monitored the course and laboratory data for 1 year and observed for side effects. There was no significant deterioration for 1 year. There was some minor improvement particularly in subjective changes. The benefit seems to decrease after 3 months. No significant complications were observed.

The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.

ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation. Currently, there are no pre-clinical ALS models, case reports, or trials for psilocybin and ALS in the context of disease modifying therapy. Depending on dosing, there can be a high risk of psychological side effects including hallucinations and physical harm. Based on the above information, we do not currently support the use of psilocybin as a means to slow ALS progression.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5–75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45–47 or 45–48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

OBJECTIVE:To analyze cases of polyneuropathy in inclusion body myositis (IBM) and to report three cases with inflammatory polyneuropathy. BACKGROUND:Inclusion body myositis (IBM) is a progressive disabling myopathy of unknown etiology affecting proximal and distal muscles. There is a debate about the association of neuropathy in IBM because of its distal distribution of muscle weakness and EMG findings of neuropathic and myopathic features. Moreover, the etiology of IBM remains controversial; it is argued to be either a degenerative disease characterized by abnormal protein accumulation like beta-amyloid or primarily an autoimmune disorder characterized by inflammatory infiltrates. DESIGN/METHODS:We reviewed the records of 44 patients diagnosed with IBM in our center. 17 of whom had neuropathy with etiology were identified in the majority. A sural nerve biopsy was performed on three of the remaining individuals, where the cause of neuropathy was not recognized. RESULTS:A muscle biopsy of 44 patients diagnosed with IBM showed inflammation and rimmed vacuoles. Of these, 17 patients had polyneuropathy. Most of these cases had identifiable causes of neuropathy like diabetes, vitamin deficiency, and others. Sural nerve biopsy in three of those with no identifiable cause of neuropathy was performed and showed demyelination, axonal degeneration, and inflammatory infiltration but no amyloid deposits. CONCLUSIONS:Our study adds to the literature regarding the association of polyneuropathy with IBM. We identified three patients diagnosed with IBM who also exhibited inflammatory polyneuropathy, indicating that autoimmune etiology might be involved. However, the possibility of coincidental findings cannot be ruled out. This emphasizes that nerve biopsy can be a useful tool for patients presenting with IBM and neuropathy without a clear cause. Our findings highlight the need for further studies to explore the association and determine the extent to which the autoimmune mechanism contributes to this disorder. Disclosure: Dr. Abualhayjaa has nothing to disclose. Dr. Abualhayja'a has nothing to disclose. Mr. Null has nothing to disclose. Dr. Bertorini has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Bertorini has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for UCB. Dr. Bertorini has received publishing royalties from a publication relating to health care.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.