Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disorder. The majority of cases are sporadic, although multiple familial forms have been identified. The pathophysiology of ALS/motor neuron disease (MND) is generally attributed to impaired RNA metabolism, oxidative stress, and abnormal protein aggregation. The role of inflammation remains poorly described. Paraneoplastic motor neuron disease is an elusive and controversial diagnosis, although paraneoplastic associations have been described, especially in association with hematologic malignancies.

Case 1- A 54-year-old male with human immunodeficiency virus (HIV) controlled on highly active antiretroviral therapy (HAART) presented with a chronic, progressive, bulbar-onset motor syndrome. Exam revealed hyperreflexia, atrophy, and fasciculations, and EMG revealed chronic and active denervation in cervical, thoracic, and lumbar segments. Magnetic resonance imaging (MRI) revealed T2/FLAIR hyperintensity of the corticospinal tracts, as well as a left temporal mass determined to represent anaplastic astrocytoma. He was also found to have renal clear cell carcinoma, WHO grade 3. He had transient mild response to plasma exchange, but ultimately died following complications of an aspiration event. No evidence of motor neuron loss or TDP-43 accumulation was seen in the motor/premotor cortex on autopsy. Case 2- A 72-year-old female presented with a rapidly progressive limb-onset motor syndrome. After sustaining a pathologic thoracic vertebral fracture, bone biopsy revealed evidence of a lymphoproliferative disorder. Serum protein electrophoresis revealed an IgM kappa monoclonal gammopathy, and bone marrow biopsy confirmed non-Hodgkin lymphoma (NHL). She was treated with high-dose corticosteroids, rituximab, and plasma exchange, with only transient improvement with the latter. She died due to respiratory failure and urosepsis.

Rapidly progressive motor neuron disease temporally associated with malignancy may represent a rare paraneoplastic neurologic syndrome. With new insight into the interface of neuroinflammation and neurodegeneration, paraneoplastic MND should be re-examined.