Using Cortical Tissue Immuno-analysis to Predict Outcomes in Hydrocephalus Patients
Key findings
- Idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease can be mistaken for one another because they overlap in patient age demographic, clinical presentation (cognitive decline), and radiographic appearance (ventriculomegaly)
- This meta-analysis investigated whether cortical tissue analysis for Alzheimer's disease pathology—amyloid-beta and hyperphosphorylated tau—before ventriculoperitoneal shunt placement for iNPH predicted shunt outcomes
- Data were pooled on 229 shunt-treated iNPH patients from three published studies and 36 iNPH patients who had a shunt placed at Massachusetts General Hospital
- The presence of amyloid-beta in cortical tissue predicted shunt non-responsiveness and the increased likelihood of non-responsiveness reached statistical significance for certain cortical pathology groups
- Immunohistochemical analysis of cortical tissue is a potentially useful diagnostic and prognostic tool for patients with presumed iNPH
Gait ataxia, cognitive impairment, and urinary incontinence are common symptoms of conditions affecting older adults, but when present together, they are a hallmark of normal pressure hydrocephalus. In 2015, a paper in World Neurosurgery estimated that globally, 1.3% of people over 65 years of age develop idiopathic normal pressure hydrocephalus (iNPH).
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Besides the classical triad of symptoms, the principal diagnostic feature of iNPH is severe cerebral volume loss on radiography, which is also a manifestation of Alzheimer's disease (AD). Misdiagnosis of AD-related pathology and/or simultaneous AD may impede proper treatment of iNPH, and the opposite is also true.
Researchers at Massachusetts General Hospital recently explored whether analyzing AD pathology—amyloid-beta (Aβ) and hyperphosphorylated tau (HPτ)—in cortical tissue could predict the outcome of the primary treatment for iNPH, placement of a surgical shunt to divert cerebrospinal fluid continuously. They pooled data from a systematic review and an original patient cohort.
Kristopher T. Kahle, MD, PhD, director of Pediatric Neurosurgery in the Department of Neurosurgery and director of the Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Ana B.W. Greenberg, formerly a clinical research associate in Dr. Kahle's laboratory, and colleagues conclude in Cerebral Cortex that cortical tissue analysis could be a useful diagnostic and prognostic adjunct for patients with presumed iNPH.
Methods
The researchers searched the Cochrane Library and Google Scholar (through December 5, 2022) and PubMed (through December 12, 2022) for original studies reporting the correlation of surgical shunting outcomes with comorbidity of iNPH and AD.
From 2,707 papers screened, they selected three studies (n=229 patients with iNPH) that met prespecified criteria about diagnostic methods, shunting procedure carried out (ventriculoperitoneal only), neuropathologic measures on cortical biopsy, and follow-up evaluations after shunt placement.
The meta-analysis also included data from 36 patients at Mass General who were considered to have probable iNPH, underwent shunt surgery between December 2021 and October 2022 with adequate biopsy material obtained, and had follow-up assessments within two to three months and one year after shunt placement.
Pooled Results
190 patients in the meta-analysis and 30 in the original cohort exhibited shunt responsiveness, defined as observable improvement in at least one triad symptom and an increase of ≥5 points on a modified iNPH scale.
The results of the meta-analysis were:
- Patients with Aβ+/HPτ+ pathology were more likely to exhibit shunt non-responsiveness than those with Aβ−/HPτ− (Mantel–Haenszel statistic, 1.04; P=0.94)
- Patients with Aβ+/HPτ− were significantly more likely to exhibit shunt non-responsiveness than those with Aβ−/HPτ− (M-H, 2.28; P=0.02)
- Patients with Aβ−/HPτ+ were more likely to exhibit shunt non-responsiveness than those with Aβ−/HPτ− (M-H, 1.25; P=0.82)
- Patients with Aβ+ and/or HPτ+ were more likely to exhibit shunt non-responsiveness than those with Aβ−/HPτ− (M-H, 1.88; P=0.08)
- Patients with Aβ+ were significantly more likely to exhibit shunt non-responsiveness than those with Aβ− (M-H, 2.16; P=0.03)
Issues for Future Research
These results are retrospective, but they suggest prospective tissue analysis may be a useful diagnostic and prognostic adjunct for patients with iNPH who are being considered for shunting.
Options that are less invasive than shunting, such as endoscopic third ventriculostomy and biopsy, have been shown in several studies to be as effective as shunting and have lower morbidity. However, it's still unclear whether minimally invasive techniques provide adequate longitudinal clinical improvement.
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