Gluten-related neurological disorders (GRD) are increasingly recognized as part of a broad spectrum of extraintestinal manifestations of gluten sensitivity, most commonly presenting with distal symmetric axonal polyneuropathy, small fiber neuropathy, sensory neuronopathy, or cerebellar ataxia. In contrast, pure motor involvement is distinctly uncommon and remains underrepresented in current diagnostic frameworks, including European Society guidelines, which do not list multifocal motor neuropathy (MMN) as a classical manifestation. This creates a significant diagnostic challenge when patients present with progressive motor deficits, particularly when the clinical picture overlaps with motor neuron disease. Haddouali et al. describe a 50-year-old man with a history of dermatitis herpetiformis and chronic diarrhea who developed a slowly progressive, asymmetric motor syndrome over five years. His presentation—marked by asymmetric weakness, muscle atrophy, and areflexia without sensory involvement or cranial nerve abnormalities—closely mimicked amyotrophic lateral sclerosis (ALS), leading to initial diagnostic consideration of a neurodegenerative process.
Electrophysiological studies demonstrated an asymmetric reduction in compound muscle action potentials without conduction block or temporal dispersion, while needle electromyography revealed chronic neurogenic changes with reduced recruitment, supporting a lower motor neuron pattern. Cerebrospinal fluid analysis showed albuminocytologic dissociation (protein 0.75 g/L), suggesting an inflammatory or immune-mediated neuropathy. Serologic testing revealed positive anti-GD3 IgM antibodies, with equivocal anti-GM1 antibodies, aligning with prior reports of antiganglioside antibodies in gluten-related neuropathies. Magnetic resonance imaging of the brachial plexus demonstrated diffuse bilateral hypertrophy on T1-weighted sequences with STIR hyperintensity and no contrast enhancement, further supporting an inflammatory process affecting peripheral nerves. Extensive evaluation excluded alternative autoimmune, infectious, metabolic, and nutritional causes.
Therapeutically, the patient received a standard course of intravenous immunoglobulin (0.4 g/kg/day for five days) with minimal objective improvement in Neuropathy Impairment Score and INCAT disability score. In contrast, strict adherence to a gluten-free diet led to gradual and sustained clinical improvement over subsequent months, with continued recovery at one-year follow-up. Notably, symptom exacerbation occurred with gluten exposure, accompanied by recurrence of dermatologic manifestations, providing a compelling temporal and mechanistic link. These findings suggest that, unlike classical MMN, this phenotype may be driven by gluten-mediated immune mechanisms rather than conventional antiganglioside-mediated conduction block pathology. Proposed mechanisms include antibody cross-reactivity (e.g., transglutaminase 6), immune complex–mediated injury, T-cell–mediated neurotoxicity, and direct effects of gluten-derived peptides.
This case challenges conventional diagnostic paradigms by demonstrating that GRD may rarely present as a pure motor neuropathy mimicking ALS, a distinction with profound prognostic and therapeutic implications. It also reinforces that negative celiac serologies do not exclude gluten-related disease, particularly when testing occurs after dietary restriction.
Clinical Pearl:
In patients with asymmetric, progressive, or IVIg-resistant motor neuropathy—especially when accompanied by dermatologic or gastrointestinal features—screen for gluten-related disorders, as this may represent a rare but potentially reversible ALS mimic.
QUESTION:
Which of the following findings most strongly supports a gluten-related cause of motor neuropathy in this patient?
A) Albuminocytologic dissociation in CSF
B) Positive anti-ganglioside antibodies
C) Lack of response to IVIg
D) Improvement with a gluten-free diet
Correct Answer:
D. Clinical improvement following gluten withdrawal provides the most direct evidence of a causal relationship. While CSF abnormalities and antiganglioside antibodies support an immune-mediated neuropathy, they are nonspecific, and IVIg nonresponse helps differentiate from classical MMN but does not establish etiology.