Radiological predictors of shunt response in the diagnosis and treatment of idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis.

BACKGROUND: Patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) may improve clinically following cerebrospinal fluid (CSF) diversion (shunt) surgery, though the predictors of shunt response remain debated. Currently, radiological features play an important role in the diagnosis of iNPH, but it is not well established which radiological markers most precisely predict shunt responsive iNPH. OBJECTIVE: To conduct a systematic review and meta-analysis to identify radiological predictors of shunt responsiveness, evaluate their diagnostic effectiveness, and recommend the most predictive radiological features. METHODS: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR were searched for original studies investigating radiological predictors of shunt response in iNPH patients. Included studies were assessed using the ROBINS-1 tool, and eligible studies were evaluated using a univariate meta-analysis. RESULTS: Overall, 301 full-text papers were screened, of which 28 studies were included, and 26 different radiological features were identified, 5 of these met the inclusion criteria for the meta-analysis: disproportionately enlarged subarachnoid space (DESH), callosal angle, periventricular white matter changes, cerebral blood flow (CBF), and computerized tomography cisternography. The meta-analysis showed that only callosal angle and periventricular white matter changes significantly differentiated iNPH shunt responders from non-responders, though both markers had a low diagnostic odds ratio (DOR) of 1.88 and 1.01 respectively. None of the other radiological markers differentiated shunt responsive from shunt non-responsive iNPH. CONCLUSION: Callosal angle and periventricular changes are the only diagnostically effective radiological predictors of shunt responsive iNPH patients. However, due to the DORs approximating 1, they are insufficient as sole predictors and are advised to be used only in combination with other diagnostic tests of shunt response. Future research must evaluate the combined use of multiple radiological predictors, as it may yield beneficial additive effects that may allow for more robust radiological shunt response prediction.

Can preoperative brain imaging features predict shunt response in idiopathic normal pressure hydrocephalus? A PRISMA review.

PURPOSE: This systematic literature review aimed to identify brain computed tomography (CT) and magnetic resonance imaging (MRI) features that could be used to discriminate idiopathic normal pressure hydrocephalus (iNPH) shunt responders from non-responders. METHODS: PubMed, Embase, Web of Science, and Cochrane were searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only original research articles reporting preoperative CT and/or MRI features and iNPH shunt response evaluated by changes in gait, dementia, and urinary incontinence were included. Title and abstract screening and full-text article evaluation were done by two authors. Data on patient demographics and inclusion criteria, brain image evaluation, shunting methods, and shunt response evaluation were recorded. RESULTS: The search resulted in 1274 studies after removing duplicates. Twenty-seven studies were chosen for final review. Both structural (i.e., callosal angle, disproportionately enlarged subarachnoid space hydrocephalus (DESH), and temporal horn diameter) and physiological brain imaging (including aqueductal flow measurement and brain perfusion) had been examined. Fourteen out of 27 studies found no difference in any assessed imaging parameters between responders and non-responders, and none of the examined imaging parameters was repeatedly and consistently reported as significantly different between the two groups. CONCLUSIONS: No brain imaging parameters were consistently and repeatedly reported as different between iNPH shunt responders and non-responders.

Cerebrospinal fluid and venous biomarkers of shunt-responsive idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH. OBJECTIVE: To conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately. METHODS: Original studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses. RESULTS: The study included 13 studies; seven addressed lumbar CSF levels of amyloid-ß 1-42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-ß 1-42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (- 0.55 SMD, p = 0.04) and Total-Tau (- 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-ß 1-42 (- 0.26 SMD, p = 0.55) or the other included biomarkers. CONCLUSION: This meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-ß 1-42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.

Clinical predictors of shunt response in the diagnosis and treatment of idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis.

BACKGROUND: Positive shunt response (SR) remains the gold standard for diagnosing idiopathic normal pressure hydrocephalus (iNPH). However, multiple pathologies mimic iNPH symptoms, making it difficult to select patients who will respond to shunt surgery. Although presenting features, extended lumbar drainage (ELD), infusion test (IT), intracranial pressure monitoring (ICPM), and tap test (TT) have been used to predict SR, uncertainty remains over which diagnostic test to choose. OBJECTIVE: To conduct a systematic review and meta-analysis to identify clinical predictors of shunt responsiveness, evaluate their diagnostic effectiveness, and recommend the most effective diagnostic tests. METHODS: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR were searched for original studies investigating clinical predictors of SR in iNPH patients. Included studies were assessed using the QUADAS-2 tool, and eligible studies were evaluated using univariate and bivariate meta-analyses. RESULTS: Thirty-five studies were included. Nine studies discussed the diagnostic use of presenting clinical features, 8 studies ELD, 8 studies IT, 11 studies ICPM, and 6 studies TT. A meta-analysis of 21 eligible studies was conducted for TT, ELD, IT, and ICPM. ICPM yielded the highest diagnostic effectiveness, with diagnostic odds ratio (DOR) = 50.9 and area under curve (AUC) = 0.836. ELD yielded DOR = 27.70 and AUC = 0.753, IT had DOR = 5.70 and AUC = 0.729, and TT scored DOR = 3.86 and AUC = 0.711. CONCLUSION: Intraparenchymal ICPM is statistically the most effective diagnostic test, followed by ELD, IT, and lastly TT. Due to the higher accessibility of TT and IT, they are recommended to be used first line, using a timed-up-and-go improvement ≥ 5.6 s or a Rout cut-off range between 13 and 16 mmHg, respectively. Patients who test negative should ideally be followed up with ICPM, using mean ICP wave amplitude [Formula: see text] 4 mmHg, or 1- to 4-day ELD with an MMSE cut-off improvement [Formula: see text] 3. Future research must use standardized methodologies for each diagnostic test and uniform criteria for SR to allow better comparison.

Relative Position of the Third Characteristic Peak of the Intracranial Pressure Pulse Waveform Morphology Differentiates Normal-Pressure Hydrocephalus Shunt Responders and Nonresponders.

INTRODUCTION: The diversion of cerebrospinal fluid (CSF) remains the principal treatment option for patients with normal-pressure hydrocephalus (NPH). External lumbar drain (ELD) and overnight intracranial pressure (ICP) monitoring are popular prognostic tests for differentiating which patients will benefit from shunting. Using the morphological clustering and analysis of continuous intracranial pulse (MOCAIP) algorithm to extract morphological metrics from the overnight ICP signal, we hypothesize that changes in the third peak of the ICP pulse pressure waveform can be used to differentiate ELD responders and nonresponders. MATERIALS AND METHODS: Our study involved 66 patients (72.2 ± 9.8 years) undergoing evaluation for possible NPH, which included overnight ICP monitoring and ELD. ELD outcome was based on clinical notes and divided into nonresponders and responders. MOCAIP was used to extract mean ICP, ICP wave amplitude (waveAmp), and a metric derived to study P3 elevation (P3ratio). RESULTS: Of the 66 patients, 7 were classified as nonresponders and 25 as significant responders. The mean ICP and waveAmp did not vary significantly (p = 0.19 and p = 0.41) between the outcome groups; however, the P3ratio did show a significant difference (p = 0.04). CONCLUSION: Initial results suggest that the P3ratio might be used as a prognostic indicator for ELD outcome.

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus.

OBJECTIVES: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. METHODS: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. RESULTS: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58). CONCLUSIONS: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

Feasibility of radiological markers in idiopathic normal pressure hydrocephalus.

BACKGROUND: Various radiological markers have been proposed for diagnostics in idiopathic normal pressure hydrocephalus (iNPH). We examined the usefulness of radiological markers in the diagnostics and prediction of shunt response in iNPH. METHOD: In this retrospective cohort study, we evaluated brain CT or MRI scans of 390 patients with suspected iNPH. Based on a 24-h intraventricular pressure monitoring session, patients were classified into a non-NPH (n = 161) or probable iNPH (n = 229) group. Volumes of cerebrospinal fluid compartments (lateral ventricles, sylvian and suprasylvian subarachnoid spaces and basal cisterns) were visually assessed. Disproportionally enlarged subarachnoid spaces, flow void, white matter changes, medial temporal lobe atrophy and focally dilated sulci were evaluated. Moreover, we measured quantitative markers: Evans' index (EI), the modified cella media index, mean width of the temporal horns and callosal angle. RESULTS: iNPH was more likely in patients with severe volumetric disproportion between the suprasylvian and sylvian subarachnoid spaces than in those without disproportion (OR 7.5, CI 95 % 4.0-14.1, P < 0.0001). Mild disproportion (OR 2.6, CI 95 % 1.4-4.6, P = 0.001) and narrow temporal horns (OR per 1 mm 0.91, CI 95 % 0.84-0.98, P = 0.014) were also associated with an iNPH diagnosis. Other radiological markers had little association with the iNPH diagnosis in the final combined multivariate model. Interestingly, EI was higher in non-NPH than iNPH patients (0.40 vs. 0.38, P = 0.039). Preoperative radiological markers were not associated with shunt response. CONCLUSIONS: Visually evaluated disproportion was the most useful radiological marker in iNPH diagnostics. Narrower temporal horns also supported an iNPH diagnosis, possibly since atrophy was more pronounced in the non-NPH than iNPH group.

Cerebral perfusion measured by dynamic susceptibility contrast MRI is reduced in patients with idiopathic normal pressure hydrocephalus.

PURPOSE: To demonstrate in idiopathic normal pressure hydrocephalus (iNPH) patients by dynamic susceptibility contrast MRI a reduced preoperative cerebral blood flow (CBF) which correlates with the severity of clinical symptoms and predicts shunt outcome. MATERIALS AND METHODS: In cortical, subcortical, periventricular regions and along peri-and paraventricular profiles absolute perfusion values were estimated by multi-slice DSC MRI in 21 iNPH patients and 16 age-matched healthy individuals (HI). Relative CBF (rCBF), calculated with the occipital cortex as internal reference, was used for comparison between groups and for correlation analysis between regional rCBF and symptoms or outcome. RESULTS: iNPH patients showed significantly decreased rCBF in the basal medial frontal cortex, hippocampus, lentiform nucleus, periventricular white matter (PVWM), central grey matter and the global parenchyma as compared to HI. iNPH patients with higher preoperative rCBF in the PVWM performed better in clinical tests. A lower overall preoperative function resulted in a more obvious recovery after shunt insertion. Shunt-responders had higher rCBF values in the basal medial frontal cortex than non-responders. CONCLUSION: DSC MRI perfusion is a potentially useful diagnostic tool in iNPH and perfusion based criteria might be possible predictors of shunt response.

Assessment of CSF Dynamics Using Infusion Study: Tips and Tricks.

Idiopathic normal pressure hydrocephalus, secondary chronic hydrocephalus, and other cerebrospinal fluid (CSF) disorders are often challenging to diagnose. Since shunt surgery is usually the only therapeutic option and carries significant morbidity, optimal patient selection is crucial. The tap test is the most commonly used prognostic test to confirm the diagnosis but lacks sensitivity. The lumbar infusion study (LIS) appears to be a better option, offering additional information on brain dynamics without increasing morbidity. However, this technique remains underused. In this narrative review, supported by the extensive experience of several European expert centers, we detail the physiological basis, indications, and CSF dynamics parameters that can be measured. We also discuss technical modalities and variations, including one versus 2 needles, patient positioning, and the site of CSF measurement, as well as in vivo shunt testing. Finally, we discuss the limitations and morbidity associated with the LIS. This review aims to assist teams wishing to incorporate LIS into their screening tools for chronic hydrocephalus and other CSF disorders.

Artificial Intelligence for Prediction of Shunt Response in Idiopathic Normal Pressure Hydrocephalus: A Systematic Review.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible cause of dementia, typically treated with shunt surgery, although outcomes vary. Artificial intelligence (AI) advancements could improve predictions of shunt response (SR) by analyzing extensive data sets. METHODS: We conducted a systematic review to assess AI's effectiveness in predicting SR in iNPH. Studies using AI or machine learning (ML) algorithms for SR prediction were identified through searches in MEDLINE, EMBASE, and Web of Science up to September 2023, adhering to Synthesis Without Meta-Analysis reporting guidelines. RESULTS: Out of 3541 studies identified, 33 were assessed for eligibility, and 8 involving 479 patients were included. Study sample sizes varied from 28 to 132 patients. Common data inputs included imaging/radiomics (62.5%) and demographics (37.5%), with Support Vector Machine being the most frequently used ML algorithm (87.5%). Two studies compared multiple algorithms. Only four studies reported the Area Under the Curve (AUC) values, which ranged between 0.80 and 0.94. The results highlighted inconsistency in outcome measures, data heterogeneity, and potential biases in the models used. CONCLUSIONS: While AI shows promise for improving iNPH management, there is a need for standardized data and extensive validation of AI models to enhance their clinical utility. Future research should aim to develop robust and generalizable AI models for more effective diagnosis and management of iNPH.

Novel cerebrospinal fluid biomarkers correlating with shunt responsiveness in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer's disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-ß 1-42 (Aß1-42) to serve as predictors of shunt response. METHODS: We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC-MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness. RESULTS: We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = - 0.46, log2(fold change (FC)) = - 0.25, p < 0.001), ANXA4 (R = 0.46, log2(FC) = 0.32, p < 0.001), MIF (R = -0.49, log2(FC) = - 0.20, p < 0.001) and B3GAT2 (R = 0.54, log2(FC) = 0.20, p < 0.001). In addition, five biomarker candidates were selected based on their strong correlation with gait speed change 1 year after shunt installation: ITGB1 (R = - 0.48, p < 0.001), YWHAG (R = - 0.41, p < 0.01), OLFM2 (R = 0.39, p < 0.01), TGFBI (R = - 0.38, p < 0.01), and DSG2 (R = 0.37, p < 0.01). Concentrations of the CSF AD core biomarkers did not differ significantly with shunt responsiveness. CONCLUSION: FABP3, MIF, ANXA4, B3GAT2, ITGB1, YWHAG, OLFM2, TGFBI and DSG2 in CSF are promising prognostic biomarker candidates to predict shunt responsiveness in iNPH patients.

The Quest for Predicting Sustained Shunt Response in Normal-Pressure Hydrocephalus: An Analysis of the Callosal Angle's Utility.

BACKGROUND: Diagnosing normal-pressure hydrocephalus (NPH) and selecting patients who will experience a sustained benefit from fluid diversion surgery remains challenging. This study seeks to evaluate the association between the callosal angle (CA) and the long-term postoperative response to ventriculoperitoneal shunt surgery in a different subgroup population than previously studied to assess its generalizability. METHODS: We studied 72 patients with idiopathic NPH who underwent ventriculoperitoneal shunt surgery and had at least 18 months of follow-up between 2000 and 2016. We recorded their pre- and postoperative symptoms according to the NPH Eide scale and their comorbidities with the Kiefer index. Their CA, as well as Evans' Index, ventricular height, and transependymal signal were measured. Multivariable statistical models were used to determine which factors were associated with postoperative improvement while we controlled for the presence of the NPH triad. RESULTS: Fifty-nine patients (82%) demonstrated a successful response to surgery at their first postoperative follow-up. However, this declined to 54 patients (75%) at 1 year and 45 (62.5%) patients at their last follow-up. When we controlled for the presence of the triad of symptoms, the CA significantly predicted a good, sustained response to surgery; for every degree decrease in the CA, a patient is 4% more likely to experience benefit from surgery. CONCLUSIONS: The CA is a useful preoperative prognostic tool for predicting which patients will experience a sustained benefit from surgery. Further studies are required to clarify this disease in the context of old age, comorbidity, and possible concomitant neurodegenerative diseases.