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

Normal pressure hydrocephalus (NPH), a syndrome discovered by Hakim and Adams [1], classically presents with dementia, gait disturbance, and urinary incontinence [23]. Idiopathic NPH (iNPH) is the most common form of adult-onset hydrocephalus, and the current gold standard for diagnosing iNPH is shunt response (SR), which is also the treatment [21, 23, 37, 45, 51, 65]. Although clinical improvement has been reported in up to 90% of patients following shunt surgery [34], this value has also been as low as 46.7% [5]. For example, Hebb and Cusimano [23] found that 59% of iNPH patients improved post-shunt, with long-term improvement reported in only 29%. This disparity in reported outcomes reflects the difficulty in selecting suitable patients for shunt surgery as many pathologies mimic iNPH symptoms [41, 43, 57].

Existing iNPH guidelines, such as the widely cited Japanese iNPH guidelines (2012) [44], a narrative review, outline various clinical tests that can be used in aiding iNPH diagnosis. Alongside Hakim’s triad, radiological and biochemical markers, these include the tap test (TT), infusion test (IT), extended lumbar drainage (ELD), and intracranial pressure monitoring (ICPM) [44]. However, the current guidelines [44] do not include explicit diagnostic parameters and cut-off values for each test. Hence, in practice, there is a lack of consistency in the method and evaluation of each test.

The current literature is outdated with regard to the analysis of the diagnostic tests and the presenting factors which may predict SR. In the most recent literature review, Nunn et al. [48] was published last year and investigated the accuracy of ELD. This review [48] included 4 papers of which only one was published after 2003. Furthermore, the last systematic reviews to investigate the diagnosis of iNPH were Relkin et al. (2005) [56] and Hebb and Cusimano (2001) [23]. While both investigated multiple iNPH diagnostic features, there was little comparison within and between diagnostic tests, and no meta-analysis was performed [23, 55]. Therefore, to fill this gap in the literature, this review aims to evaluate the diagnostic effectiveness of presenting features, TT, IT, ELD, and ICPM, by incorporating the latest primary research.

The literature search retrieved a total of 7179 papers, of which 359 papers underwent full-text review and 35 studies were included (Fig. 1). The QUADAS-2 tool [69] scored all included studies at low to moderate risk of bias overall, none scoring high risk (Fig. 2a). No significant publication bias was detected by Egger’s test (p = 0.0847) (Fig. 2b) [9].

Correctly identifying suitable patients for shunt surgery remains challenging but crucial, as unlike secondary NPH, a large proportion of iNPH patients have poor shunt outcomes. Given that both up to 41% of iNPH patients do not have a positive SR [23], as well as shunting carrying a significant procedural risk of 22–28% [31, 70], the need for an accurate diagnostic test to predict SR is apparent. Hence, this review offers guidance as to which clinical tests and patient factors are most effective in predicting SR.

Our meta-analysis of 21 studies concluded that ICPM is the most effective clinical predictor of SR, followed by ELD, IT, and TT. The findings suggest that a patient with shunt-responsive iNPH is 50.1 × more likely to have positive ICPM than a shunt-unresponsive iNPH patient, compared to 27.7 × more likely with ELD. In comparison, a patient with shunt-responsive iNPH is only 5.7 × more likely to have a positive IT and only 3.86 × more likely to have positive TT.

The most predictive indicator of SR is a mean pulse amplitude cut-off of ≥ 4 mmHg, in 70% of recording times in dynamic ICPM [17, 19, 29]. The meta-analysis is a reliable indicator of ICPM effectiveness as the methodology of the studies included was similar, all using intraparenchymal ICP monitors and assessing similar index parameters, reflected by the relatively small spread of data (Fig. 3h). However, we found several limitations within the included studies. In papers with Eide as principal author, which comprised 5 of the 7 included ICPM studies [12, 13, 16‐18], there were notable differences in patient selection, with Sorteberg et al. [61] selecting patients with triad symptoms and ventriculomegaly for ICPM, while Eide and Stanisic [17] and others used the Relkin guidelines (Table 5) [56]. Moreover, 4 of these studies selected patients retrospectively from the same unit between 2002 and 2008, raising concerns about patient selection bias; additionally some patients may have been excluded from retrospective analysis in one study but included in another [13, 16‐18]. Ultimately, further research is needed in multicenter settings, with more attention on complications, which Eide neglected. Overall, given the limitations of the included ICPM studies, the findings of the meta-analysis for ICPM must be interpreted with caution. Although TT is thought to simulate a shunt procedure making it an accurate assessment of the effect of a physiological reduction of CSF circulating volume, its high false-negative rates may deprive many patients of the potential benefits of shunt surgery. ICPM could help identify these patients when used as a second-line test given its higher specificity. The mechanism of ICPM’s greater accuracy may be due to its ability to uncover CSF pathology, which affects the compliance of brain parenchyma, by direct analysis of its reflection in ICP values. However, as the pathophysiology of iNPH remains unknown [44], the biological mechanism behind the statistical diagnostic superiority of ICPM remains elusive. Regardless of this, a significant advantage of ICPM is that it utilizes objective cut-off values based on monitor readings, and, therefore, is not subject to assessor bias like in some subjective assessments of ELD or TT improvement. ICPM is negatively regarded due to a high perceived risk of complications. However, it must be noted that intraparenchymal ICPM has been found to be much safer than external ventricular drain (EVD)-ICPM: Raboel et al. [54] reported a 5% infection risk for intraparenchymal ICPM versus 27% for EVD-ICPM [22]. In line with this, Vonhoff et al. [64] reported no patients with major complications and only 7% with minor complications, such as accidental removal of the probe, in 152 adults undergoing hydrocephalus ICPM. Although currently less accurate than invasive ICPM, non-invasive ICPM, using transcranial Doppler ultrasonography or MRI, might provide an entirely complication-free assessment of SR in the future [22, 54].

ELD is the second most effective test. Despite ELD techniques and response criteria varying significantly between studies, there was relatively low spread in the data (Fig. 3c, Fig. 3g), indicating that ELD is highly accurate regardless of methodological heterogeneity. That said, 3-point MMSE improvement after 1-day ELD had the highest sensitivity and specificity and hence should be given preference [19]. Furthermore, as Chotai et al. [8] found that 1-day ELD is as effective as 4-day ELD, a 1-day ELD should be used to avoid procedural complications and financial costs of a 4-day ELD. However, it must be noted that the study by Chotai et al. [8] had several weaknesses, particularly supplementary tests, such as radionucleotide cisternography and MRI, being used, which hinders drawing valid conclusions regarding ELD as a sole diagnostic test for SR. Interestingly, the Japanese NPH guidelines [44] recommend TT over ELD, citing fewer complications in the TT, while still reporting higher sensitivity and specificity of ELD. However, we only found 3 cases of infections and no other long-term significant complications in 8 ELD studies (n = 425), consistent with Walchenbach et al. [65] who reported only 2 major complications (n = 49) without long-term sequelae. We conclude that the much higher diagnostic effectiveness of ELD relative to TT and IT outweighs the potential complication risk, which has been decreasing in the last decade most likely due to evolving ELD techniques [8].

The financial burden of ICPM and ELD is regarded by many as significant obstacle to clinical implementation. In 2006, Burnett et al. [6] found that an undiagnosed NPH patient would incur mean costs of $108,842. In comparison, it costs $7000 to insert a shunt and $2870 for an ELD, both values signifying the cost of the respective devices only [6]. However, given the low NPV and specificity of ELD, it may incur additional costs by not selecting shunt-responsive patients (Table 4). This could be avoided by using a highly specific diagnostic test, namely ICPM; however, the same authors reported that a hypothetical diagnostic test with specificity = 80% would incur $83,000 per quality-adjusted life year, due to the complexity of prolonged clinical monitoring which may exceed cost-effectiveness thresholds [6]. That said, since 2006, many studies reported ICPM and ELD specificity to be > 80% [13, 15, 17, 20, 47]; hence, we recommend an update on the current cost-effectiveness of both tests.

Given the high accessibility of IT and TT, they can be used as first-line diagnostic procedures. Patients who test negatively, but have a high index of clinical suspicion, should be followed up with ICPM, or alternatively with ELD, as these tests have significantly higher specificity and sensitivity. For IT, we recommend using Rout with a cut-off range between 13 and 16 mmHg [4, 35, 39], as well as CSFPP with a cut-off ≥ 4 mmHg [15] as predictive parameters of SR. These should be used in conjunction with PPPA [29], PpL [29], PLIV [58], and IE [2], for which future research must identify optimal cut-off values. For TT, TUG is reported as the most accurate, specifically an absolute time (≥ 5.6-s improvement) is advised [73], although there was no clear consensus on which parameter is best. The authors also recommend that TT should be followed up with an MRI assessing cerebral perfusion post-TT, to improve its sensitivity [24, 64]. The patient’s age, symptom severity, and co-morbidities all influence SR outcomes and should be considered in patient selection [3, 35, 39, 44, 61]. The longer symptoms are present before surgery, the worse the prognosis is [38, 39]; hence, early identification and treatment are critical.

In 2001, Hebb and Cusimano [23] stated that more prospective studies, which shunt iNPH patients regardless of their diagnostic test results, were needed to yield precise overall sensitivities and specificities of each test. Twenty years later, we found that this remains the most significant limitation of the literature. Given that in many studies the results of the diagnostic test influence the decision to shunt, accurate false-negative values are difficult to ascertain. We emphasize the importance that future research must aim to shunt all patients to allow for highly valid conclusions on diagnostic efficiency to be derived.

Radiology is also pivotal in the diagnosis of iNPH; however, until recently, studies have not been able to show an association between radiological features and SR [33]. The iNPH Radscale may potentially play an important role in SR prediction and is a promising new tool in the iNPH patient workup [32]. However, due to its relatively recent introduction in 2017, there is currently insufficient literature evaluating its use. Although Kockum et al. [32] have reported 98.5% predictive accuracy of NPH Radscale, another study found it to be unable to predict motor outcomes post-shunting [35]. Nonetheless, the literature on the role of radiology in iNPH is extensive; hence, the authors believe that a separate meta-analysis on the role of radiological tools in the prediction of SR is required. Additionally, biochemical markers have been hypothesized to be valuable in the diagnosis of iNPH. As reported by Leinonen et al. [36], the most important biomarker indicating iNPH may be abnormally low CSF TNF-α concentrations. Nevertheless, this study, as well as a systematic review by Pfanner et al. [50] recently in 2017, reported that no biomarker was able to predict SR. However, Zhang et al. [74] in 2020 reported that studies had found that high concentrations of vascular endothelial growth factor in the CSF may be associated with worse SR. A meta-analysis of both radiology and biochemical markers, together with this meta-analysis, can give more extensive guidance regarding the clinical prediction of SR.

Intraparenchymal ICPM is statistically the most effective diagnostic test, followed by ELD, IT, and lastly TT. The best clinical predictors of SR were found to be a mean ICP wave amplitude \(\ge\) 4 mmHg and secondly using a 1- to 4-day ELD with an MMSE cut-off improvement \(\ge\) 3. If IT is used, Rout with a cut-off range between 13 and 16 mmHg, in conjunction with a CSFPP cut-off of ≥ 4 mmHg, should be used. Additionally, for TT, a TUG improvement of ≥ 5.6 s can be used. Despite the statistical superiority of ICPM and ELD, the financial cost associated with their use as well as the potential for complications renders it most useful in identifying SR patients with negative IT or TT results. The latter are clinically easier to perform with low complication rates and hence may be used as first-line diagnostic tests to predict SR. When used in addition to diagnostic tests, the severity of symptoms, patient age, and co-morbidities may aid in predicting SR. In the future, standardized methodologies for each diagnostic test and uniform criteria for SR must become the norm to draw better comparisons.