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. Supplementary Information The online version contains supplementary material available at 10.1007/s00701-022-05402-8.


Supplementary Figure 2:
A scatterplot matrix without machine learning imputation visualises the pairwise relationships of following parameters among all studies included in the systematic review (n=28): The following parameters are used here: Patient sample size ("Sample"), mean age of the patients ("Age"), proportion of patient sample being female ("Females"), pre-existing diabetes mellitus ("DM"), pre-existing arterial hypertension ("HTN"), gait deficits ("Gait-", 94%), cognitive deficits ("Cognition-"), urinary dysfunction ("Urine-"), mean proportion of patients being shunt-responsive ("S-R"), and proportion of complications ("Complic."), mean patient scores on the Mini Mental State Exam ("MMSE"). Furthermore, mean patient scores for Evan's Index ("EI") and mean values for Callosal Angle ("CA"). The green line is the linear regression line, and the red line is the LOESS (locally estimated scatterplot smoothing) regression line, the blue bubbles are the data points, and the blue-lined area is the ellipse. Figure 3: Forest plot indicating and visualizing the treatment effect ("TE") size in diagnostic odds ratio in the context of predicting shunt response in iNPH patients are shown for DESH (n = 4 studies), after having excluded the study with the highest proportion of females (Grahnke et al., 2018) [3]. The results remained insignificant with p=0.17 suggesting insignificant effect of the female covariate on the odds ratio of the radiological predictor (DESH) as seen in main paper Figure 6C. The size of the grey square of the "Diagnostic Odds Ratio" visually correlates to study sample size and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled odds ratio. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value. The 95% confidence intervals (CI) are shown in squared bracket ([ ]). P-value < 0.05 is deemed significant. Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t4 and p-value, and weighting of each study in percentage (%). DESH, Disproportionately Enlarged Subarachnoid space Hydrocephalus

Supplementary Figure 4:
Forest plot indicating and visualizing the treatment effect ("TE") size in diagnostic odds ratio in the context of predicting shunt response in iNPH patients are shown for DESH (n = 4 studies), after having excluded the study with the most different methodology (Agerskov et al., 2019) [3]. The results remained insignificant with p=0.06 and heterogeneity became insignicant (p=0.69). The size of the grey square of the "Diagnostic Odds Ratio" visually correlates to study sample size and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled odds ratio. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value. The 95% confidence intervals (CI) are shown in squared bracket ([ ]). Pvalue < 0.05 is deemed significant. Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t4 and p-value and weighting of each study in percentage (%). DESH, Disproportionately Enlarged Subarachnoid Space Hydrocephalus Supplementary Figure 5: Forest plots indicating and visualizing the treatment effect ("TE") size in diagnostic odds ratio in the context of predicting shunt response in iNPH patients are shown for CBF (n = 3 studies), after having excluded the study with the highest proportion of females (Kazui et al., 2013) [6]. The results remained insignificant with p=0.20 suggesting insignificant effect of the female covariate on the odds ratio of the radiological predictor (CBF) as seen in main paper Figure  6E. The size of the grey square of the "Diagnostic Odds Ratio" visually correlates to study sample size and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled odds ratio. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value. The 95% confidence intervals (CI) are shown in squared bracket ([ ]). P-value < 0.05 is deemed significant. Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t4 and pvalue, and weighting of each study in percentage (%). CBF, Cerebral Blood flow.  Table 2 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Page 5 to Page 6 Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect. Page 6 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Section and Topic
Item # Checklist item Location where item is reported Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

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Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)). Page 6 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Page 6 to Page 7 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 6 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Page 6 to Page 8 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
Page 6 to Page 8 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 6 to Page 8 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

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Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 6 to Page 8

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Page 68; Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.
Page 68; Figure 1 Study characteristics 17 Cite each included study and present its characteristics. Page 30 to Page 34; Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Page 22 to Page 23; Page 69; Figure 2 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.
Page 11 to Page 22; Page 35 to 63, Tables 2 to 21; Page 76 to 77, Figure 6 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Page 9 to Page 10 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If

Section and Topic
Item # Checklist item Location where item is reported comparing groups, describe the direction of the effect.
20c Present results of all investigations of possible causes of heterogeneity among study results.
Page 11 to Page 22 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Page 11 to Page 22 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.
Page 68, Figure 2; Supplementary material; Table 4 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Supplementary material; 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Page 5 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 5 24c Describe and explain any amendments to information provided at registration or in the protocol. N/A Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.

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Competing interests 26 Declare any competing interests of review authors. Page 1 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.