Pupils, grip, and a urine ratio: testing the system without a lumbar puncture
The discovery of a selective norepinephrine deficit came from a lumbar puncture — cerebrospinal fluid, collected invasively, once. That is fine for a study and useless for routine care. So the practical question is: can the same system be read from the outside?
Several candidate measures already exist:
- Pupillometry. Pupil size reflects noradrenergic activity, and it can be measured in seconds (Kang and Banaji (2020)). In a human drug study, the NRI atomoxetine raised baseline pupil diameter, and the change correlated with behavioural improvement (O’Callaghan et al. (2025)).
- Handgrip endurance. In the source study, the norepinephrine pathway correlated with how long a patient could sustain a handgrip (Spearman rho = 0.62, right hand, patient-only analysis, n = 38 (the combined patient group, larger than the n=16 ME/CFS arm)) (Aregawi et al. (2026)). A cheap, bedside measure — though a single unreplicated correlation.
- Urinary VMA/HVA ratio. A ratio of norepinephrine to dopamine metabolites, reflecting the DBH step — but caveat: urine reflects mostly peripheral turnover, and peripheral norepinephrine is if anything elevated in ME/CFS, so it may not track the central deficit.
Put together, these could form a non-invasive battery to stratify patients — and, combined with a timing test, to capture the PEM crash: measure pupil and grip every few hours for 72 hours after a controlled exertion, and see whether they dip and recover on the same curve as symptoms. If the deficit causes PEM, that curve should exist.
The caveats are real. None of these measures has been validated together in ME/CFS; each is affected by other things (light, drugs, effort, salt); and the underlying deficit is unreplicated. But the point is that the system is testable without an invasive procedure — which is what would make it clinically useful and would allow the replication study that the field actually needs.