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Five Decades of Infusion Testing in Idiopathic Normal Pressure Hydrocephalus: A Biomarker in Search of a Gold Standard
Sahuquillo J, Al-Nusaif M, Torrecilla M, Durduran T, Poca M.. Preprints.org, 2026-09-01
Topic: Plasma and spinal-fluid biomarkers
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of gait impairment, cognitive decline, and urinary dysfunction in older adults, yet identifying patients most likely to benefit from cerebrospinal fluid (CSF) diversion remains a major diagnostic challenge. For more than five decades, the lumbar infusion test , introduced by Katzman and Hussey in 1970, has served as the principal method for assessing CSF absorptive capacity through measurement of resistance to CSF outflow (Rout). This narrative review examines the historical development, physiological basis, and contemporary clinical application of infusion testing in iNPH, with particular emphasis on the diagnostic and prognostic value of Rout. We critically review the evidence supporting the Rout thresholds recommended by current international, Japanese, and American Academy of Neurology guidelines and reassess their performance using a Bayesian framework. Recalculation of likelihood ratios from published meta-analyses demonstrates that none of the commonly proposed Rout thresholds (10-18 mmHg·min/mL) achieves the prognostic performance typically associated with a strong rule-in or rule-out test. We argue that this limited performance reflects not only methodological heterogeneity in infusion-testing protocols but also a more fundamental problem: the absence of a universally accepted reference standard for iNPH. We further examine the limitations of using postoperative clinical improvement as a surrogate reference standard, including variability in outcome definitions, delayed treatment effects, and the potential for circular reasoning. Finally, we review emerging CSF proteomic biomarkers of neuroinflammation, axonal injury, and concomitant Alzheimer-type pathology that may complement hydrodynamic assessment by capturing the balance between reversible hydrocephalus-related dysfunction and irreversible neurodegenerative burden. We conclude that Rout should be regarded as a valuable but incomplete biomarker and that future progress will likely depend on multimodal, probabilistically interpreted models integrating CSF hydrodynamics, neuroimaging, and molecular biomarkers to improve prognostic stratification and establish more robust diagnostic frameworks for iNPH.
Key findings
- Recalculation of likelihood ratios from published meta-analyses demonstrates that none of the commonly proposed Rout thresholds (10-18 mmHg·min/mL) achieves the prognostic performance typically associated with a strong rule-in or rule-out test.
- We conclude that Rout should be regarded as a valuable but incomplete biomarker and that future progress will likely depend on multimodal, probabilistically interpreted models integrating CSF hydrodynamics, neuroimaging, and molecular biomarkers to improve prognostic stratification and establish more robust diagnostic frameworks for iNPH.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 47 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size, effect reported and studied in people because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 29 of the 62 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Preprints.org) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 29 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 62 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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APA 7th
Sahuquillo, J., Al-Nusaif, M., Torrecilla, M., Durduran, T., & Poca, M. (2026). Five Decades of Infusion Testing in Idiopathic Normal Pressure Hydrocephalus: A Biomarker in Search of a Gold Standard. Preprints.org. https://doi.org/10.20944/preprints202609.0061.v1
Vancouver
Sahuquillo J, Al-Nusaif M, Torrecilla M, Durduran T, Poca M. Five Decades of Infusion Testing in Idiopathic Normal Pressure Hydrocephalus: A Biomarker in Search of a Gold Standard. Preprints.org. 2026. doi:10.20944/preprints202609.0061.v1.
BibTeX
@article{sahuquillo2026-ce4cd8f3,
author = {Sahuquillo, J. and Al-Nusaif, M. and Torrecilla, M. and Durduran, T. and Poca, M.},
title = {{Five Decades of Infusion Testing in Idiopathic Normal Pressure Hydrocephalus: A Biomarker in Search of a Gold Standard}},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202609.0061.v1},
url = {https://doi.org/10.20944/preprints202609.0061.v1}
}