Service evaluation in a gut/brain axis clinic: are maintenance laxatives associated with stemming temporal increase in rigidity of idiopathic Parkinson’s disease?

INTRODUCTION: Constipation pre-dates the diagnosis of Parkinson’s disease (PD) by decades. Deposition of misfolded protein may begin in the gut, driven by dysbiosis (1). Successive antimicrobial exposures are associated with cumulative increase in rigidity (2), and there are biological gradients of rigidity on leucocyte-subset counts (3). Thus, our purpose here is to explore whether treating constipation in PD might be disease-modifying, by estimating any change in rigidity associated with maintenance laxative therapy.

METHODS: A retrospective service evaluation, in the setting of a gut/brain axis clinic, yielded an interrupted-time-series, relating maintenance laxative and other medication to rigidity. 79 consecutive out-patients (mean age 66 years, 45 male) with PD and obeying inclusion and exclusion criteria, attended between August 2002 and July 2014. Presentation with moderate or severe levodopa-associated motor fluctuations was an exclusion, and any data obtained after acquiring such fluctuations censored.

Assignment to laxative treatment was based on severity of constipation, all patients being encouraged, from presentation, to take adequate fluid and high residue diet. Need to introduce or modify anti-parkinsonian medication was according to doctor’s and patient’s perception of impact and progression of disease. Motor complications of levodopa were avoided by using only longer-t½ medication for as long as this upheld quality of life.

Regarding main outcome measures, objective assessment, validated against gold-standard subjective, can bring greater sensitivity to change. To this end, objective measurement of torque required, by an electric motor, to move relaxed supported forearm horizontally, through a fixed arc about the elbow at a controlled velocity, was made routinely, United Parkinson’s Disease Rating Scale (UPRDS) for rigidity in same limb (side clinically more rigid at presentation) applied.

RESULTS: There were 1493 measurements of torque required to extend (flexor-rigidity) and flex (extensor-rigidity) forearm in 79 PD-patients over 374 person-years. Each was strongly associated with UPDRS score (P<0.001 & =0.008, respectively), with 7.5 (95% CI 2.5 to 12.7) % relative increase in flexor-rigidity between score 1 (slight) and 0 (none), 48.2 (20.9 to 81.8) % between score 4 (severe) and 0, and similar magnitudes for extensor-rigidity. Before exhibition of laxative, flexor-rigidity increased by 6 (95% CI 1 to 10) % per year, plateauing during at -2 (-4 to 1) % per year, with no shift at initiation. Change in slope was significant (P=0.002). This pattern was replicated for individual laxative classes (bulk, osmotic, enterokinetic). There was no temporal change in extensor-rigidity. Limited experience with a quanylate cyclase-C receptor agonist (17 patients, 6 person-years) indicated a large downward shift in flexor- and extensor-rigidity, -19 (-1 to -34) & -16 (-6 to -24) %, respectively (P=0.04 & <0.001).

CONCLUSION: Maintenance laxative usage was associated with stemming the temporal increase in rigidity in PD, adding to the indicative evidence (1) of a continuing role of gastrointestinal dysbiosis in pathogenesis.

1. Dobbs SM et al. (2015) J Neurovirol; [Epub ahead of publication] doi 10.1007/s13365-015-0357-8

2. Dobbs SM et al. (2013) Helicobacter 18: 187–196.

3. Dobbs RJ et al. (2012) Gut Pathogens 4: 12.doi:10.1186/1757-4749-4-12.