science revisited

Spinal bulbar muscular atrophy (Kennedy’s disease) is an X-linked inherited disease caused by a trinucleotide expansion in the androgen receptor gene. The abnormal protein forms aggregates that are toxic to motor neurons. The affected male patients have diffuse fasciculations, cramping, proximal muscle weakness, dysarthria, and dysphagia. They also have gynecomastia, testicular atrophy, and reduced fertility. Nerve conduction studies will often demonstrate a coexistent sensory neuropathy. With this disease, the lifespan is only mildly shortened and treatment, at present, is only symptomatic. Recent clinical trials assessed the use of testosterone inhibitors to prevent translocation of the mutant androgen receptor into the nucleus. However, no significant beneficial effect was observed.

Table 29.1. Upper (UMN) and lower (LMN) motor neuron signs

Investigations

All patients with a suspected MND should have nerve conduction studies and electromyography (EMG), to confirm or exclude LMN involvement. EMG should show evidence of acute and chronic denervation. Fibrillation potentials and positive sharp waves are evidence of acute denervation. Fasciculations have also been proposed as evidence of acute denervation, particularly when a diagnosis of ALS is being considered (Awaji criteria). Signs of chronic denervation on EMG include the presence of large-amplitude motor units, reflecting the presence of reinnervation. Convincing EMG evidence of motor neuron degeneration requires pathological findings in at least two muscles innervated by different nerves and roots. Excluding multifocal motor neuropathy (MMN) is very important in the evaluation of individuals with predominately LMN findings; MMN is diagnosed by identifying conduction block in motor nerves across noncompressible sites with preserved sensory responses.

An MND workup should include imaging of the neuroaxis in most patients to exclude structural lesions that can mimic MND. Findings suggestive but not pathognomonic for ALS include corticospinal tract hyperintensities and a T₂-weighted hypointense rim in the precentral cortex on magnetic resonance imaging (MRI).

The need for other body imaging depends on the clinical history. As there have been several case reports of paraneoplastic MND improvement after removal of a renal cell carcinoma, abdominal ultrasonography would be reasonable in most patients to exclude that diagnosis. Other investigations for paraneoplastic disorders include a chest radiograph, testicular ultrasonography, mammography, and pelvic ultrasonography (Box 29.2).

Blood work should be drawn to rule out potentially treatable causes of MND mimics. All patients should have a creatine kinase (CK), vitamin B₁₂, thyroid-stimulating hormone (TSH), and calcium done. If there is any hint of an inflammatory condition present (i.e. prior history of rheumatological condition, rash, substantial night sweats, or rapid weight loss), then inflammatory serum markers should also be drawn (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], p- and c-anti-neutrophilic cytoplasmic antibody [ANCA], antinuclear antibody [ANA], rheumatoid factor [RF] complement levels, and an anti-ENA [extractable nuclear antigen] screen). If a patient has a predominately LMN presentation with hyporeflexia, anti-GM1 antibodies should also be tested to rule out MMN. Although anti-GM1 antibodies can be positive in degenerative MND, strongly positive anti-GM1 antibodies raise the suspicion of MMN and argue for a therapeutic trial of intravenous immunoglobulin (IVIG). If the history is suggestive of a paraneoplastic syndrome, one could consider testing for anti-Hu and anti-Yo (if female) antibodies.