Upper Motor Neuron-Predominant Motor Neuron Disease: A Novel Immunotherapy-Responsive Association of GAD65 Autoimmunity
Naveen Paramasivan1, Pallab Sarker2, Anastasia Zekeridou3, Nathan Staff2, Christopher Klein2, Andrew McKeon2, Sean Pittock4, Divyanshu Dubey2
1Neurology, Mayo Clinic, 2Mayo Clinic, 3Neuroimmunology Laboratory, Mayo Clinic, 4Mayo Clinic Dept of Neurology
Objective:
We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high titer serum/CSF GAD65 antibodies (radioimmunoassay).
Background:
Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of Amyotrophic Lateral Sclerosis (ALS).
Design/Methods:
A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high titer GAD65 antibodies (≥20nmol/L in serum [equivalent to >10,000 IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5 years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG.
Results:
We identified 12 patients with high-titer serum GAD65 IgG (median 221.5 nmol/L, range: 38.7-3077 nmol/L) and motor neuronopathy confirmed by neurogenic changes in electromyography, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness compared to ALS patients. A subgroup of these patients had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography, significantly lesser worsening in mRS and mortality on long term follow-up.
Conclusions:
UMN predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, with potentially favorable results.
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