10. Phenotypic variability in motor neuron disease: Site of onset and patterns of disease spread

Background

The clinical heterogeneity across motor neuron disease (MND) is well known, and largely attributed to differences in the relative mix of upper (UMN) and lower motor neuron (LMN) dysfunction, site of onset, and rate of disease progression. These differences hold prognostic significance and clues to patterns of disease spread. Objective understanding of motor dysfunction across these clinical phenotypes is thus pivotal for unravelling disease pathogenesis and mechanisms underpinning disease spread.

Aims

To investigate the sites of origin and patterns of disease spread across MND phenotypes using multimodal clinical and neurophysiological tools in all 4 limbs.

Methods

Patients were prospectively recruited from the Forefront Neurology Clinic (Brain and Mind Centre, Sydney) and diagnosed according to Awaji Criteria. Detailed clinical assessments were performed including classification by phenotype and site of onset. Neurophysiological studies were conducted in all 4-limbs. LMN dysfunction was investigated by recording CMAP and MUNIX responses, while UMN dysfunction was assessed using threshold tracking transcranial magnetic stimulation (TT-TMS).

Results

Lower limb TT-TMS techniques were first established in healthy subjects (n = 40). The clinical cohort consisted of 52 MND patients (31 males, 21 females, mean age 59.3 ± 6.8 yrs). Upper limb analysis showed evidence of cortical hyperexcitability with a significant reduction of averaged short interval intracortical inhibition (SICI) over both motor hemispheres, most prominently over the motor cortex contralateral to the affected upper-limb (controls 11.27 ± 1.12%; MND 3.6 ± 1.5%, $p<0.01$). Bulbar-onset patients had the greatest cortical hyperexcitability (SICI 2.6 ± 1.4%, $p<0.01$). For all phenotypes, there was a positive correlation between UMN and LMN dysfunction in the affected limbs and in faster disease progressors. This relationship was not observed in non-affected limbs (R² = 0.03, p = 0.3) or slower progressors (R² = 0.004, p = 0.7).

Conclusion

Cortical hyperexcitability was evident globally but there was heterogeneity amongst phenotypes, with bulbar-onset patients showing the greatest degree of hyperexcitability. In addition, a difference in the interplay of the two motor compartments was seen, lending pathophysiological insight into the prognostic differences between patients. Through deep phenotyping and novel testing across all compartments of the nervous system, differences in the prognosis and patterns of neuronal vulnerability in MND subtypes are thus evident. This multimodal analysis lends potential to develop robust biomarkers and offer new pathophysiological insights.