Introduction
Idiopathic normal pressure hydrocephalus (iNPH) is a progressive syndrome that predominantly occurs among individuals older than the age of 60, with a prevalence ranging from 0.51 to 2.94% in this age group [
1]. It is characterized by the clinical triad of gait disturbance, cognitive impairments, and urinary incontinence, with typical brain imaging demonstrating the presence of dilated ventricles, wide Sylvian fissures, and high convexity tightness [
2]. Symptoms usually improve after surgical intervention; however, the prognosis is also influenced by factors such as the severity of disease, the timing of the intervention, and comorbidities [
3]. Cognitive impairments are dominated by pronounced frontal lobe dysfunctions [
3], and gait disorders are also known as frontal gait or higher-level gait disorders [
4]. Primitive reflexes, which serve as indicators of frontal lobe dysfunction [
5], have the potential to provide objective evidence of these impairments, particularly in individuals exhibiting diminished coordination.
The grasp reflex is a primitive reflex that is defined as the involuntary flexion-adduction movement of the digits in response to distally moving pressure contact applied to a particular area of the palm without any intention to use the object [
6,
7]. It is universally present in human foetuses and infants but is suppressed as the central nervous system matures [
5,
8,
9]. The recurrence of the grasp reflex in adulthood is linked to localized brain lesions or diffuse neurodegeneration involving the medial frontal lobes and/or their efferent connections, exemplified by anterior cerebral artery infarction and progressive supranuclear palsy (PSP) [
10,
11]. However, there is currently no research on the grasp reflex in iNPH patients, despite its prevalence among a large proportion of patients with iNPH in clinical practice.
The grasp reflex reveals a wide range of clinical correlations and potential implications. In Alzheimer's disease (AD), vascular dementia (VaD), and other aetiologies of dementia, the grasp reflex is associated with severe dysfunctions in daily living activities [
12,
13], motor dysfunctions, behavioural abnormalities [
13,
14], and personality changes [
15,
16]. Despite individual exceptions [
13,
17], this reflex has also been found to be related to the severity of cognitive dysfunction [
14,
18‐
21]. Moreover, the grasp reflex is associated with urinary symptoms in patients with corticobasal degeneration (CBD) [
22] and affects walking gait among preschool children [
23]. Another aspect that piques our curiosity is whether these associations persist in iNPH patients and the degree to which their intensity is correlated with other symptoms.
The grasp reflex has been documented as a reversible phenomenon that becomes increasingly difficult to elicit as patients’ conditions improve [
24,
25]. Additionally, patients may be able to release the reflex voluntarily after haematoma evacuation or tumour removal surgery [
7]. Thomas et al. reported the disappearance of grasp reflexes in two patients with normal pressure hydrocephalus after high-volume CSF removal [
26]. However, current publications on the evolution of grasp reflexes are predominantly concentrated in case reports, with few large-sample studies to substantiate their universality.
Therefore, the aims of this study were as follows: (1) to develop a standard procedure for investigating the prevalence, intensity and changes in the grasp reflex in patients with iNPH and (2) to examine whether differences exist between iNPH patients with or without grasp reflexes and to assess the correlation of the grasp reflex with gait, motor skills, cognitive symptoms, urinary symptoms, and behavioural symptoms. We hypothesized that patients with iNPH exhibiting grasp reflexes will exhibit heightened severity of gait, motor, cognitive, urinary and behavioural symptoms, such that the intensity of these symptoms will increase concomitantly with the strength of the grasp reflex. We also hypothesized that surgical intervention can alleviate the intensity of the grasp reflex.
Discussion
This is the first study to investigate the grasp reflex in iNPH patients. We elucidated that approximately 50.3% of patients with iNPH exhibited a positive grasp reflex, with a bilateral predominance. Furthermore, the intensity of the grasp reflex was significantly correlated with the severity of gait as well as with cognitive, urinary, motor, and behavioural symptoms. Surgical interventions led to a reduction or maintenance of the reflex intensity in 72.3% of iNPH patients. Changes in reflex intensity were correlated with changes in stride length and psychomotor speed, but no correlation was observed with changes in iNPHGS total scores.
Previous studies describing grasp reflexes have covered ‘weak, moderate, and strong’, ‘complete or incomplete closure’, and ‘persistent or nonpersistent contractions’ [
7,
24,
39]. We believe that specifying the degree of these responses may be challenging for nonexamining physicians. Hence, we adopted a more easily quantifiable four-category classification system for grasp reflexes: absent (0 points), elicited under distraction (1 point), elicited but suppressible (2 points), and elicited and nonsuppressible (3 points). In fully conscious patients, significant modifications related to varying degrees of patient attention are observed in the grasp reflex. In general, grasp reflexes are more easily triggered when the subject’s attention is diverted. Moreover, the ability to release reflexes is not only associated with training effects and extensor muscle strength but also closely related to the capacity to concentrate [
7,
40]. In our study, patients exhibiting reflexes only when disturbed were assigned a score of 1. Remarkably, most patients could voluntarily relax the reflex. Conversely, patients who were unable to cease grasping despite commands scored 3 points, thus highlighting ineffective attention concentration. Our scoring method reflected an increasing impairment of attention in patients. On the other hand, the significant correlation between grasp reflex and both the WMS-R ACI score, as well as the CBT-FES score, also supported this observation.
In healthy adults and elderly individuals, the prevalence of grasp reflexes typically falls within the range of 0% to 5.88% [
12,
21,
41‐
45]. In practice, our method never elicits a reflex in healthy elderly individuals. In patients with localized brain injury, the prevalence of grasp reflexes ranges from 8 to 18% [
46,
47]. If the injury is an anterior cerebral artery infarction or lacunar infarct, the prevalence of the grasp reflex will increase to 25–40% [
10,
45,
48,
49]. In AD, VaD, and other aetiologies of dementia, the prevalence of grasp reflexes ranges from 0% to 33.9% (the respective prevalences are shown in Table
4) [
11,
17,
19,
50‐
53]. Importantly, two studies reported a 50% probability among patients with PD and patients with CBD. However, both studies had small sample sizes—only 8 patients with PD [
20] and 10 patients with CBD [
22]. This raises concerns about potential problems due to the small sample size. Even when restricting our analysis to patients able to elicit the reflex under focused attention, our study identified abnormalities in 50.3% of the patients. Therefore, we can conclude that the grasp reflex is a relatively common phenomenon in patients with iNPH.
Table 4
The prevalence of grasp reflexes in various disease
AD | 0–33.9% |
VaD | 0–21% |
PD and PDD | 0–50% |
PSP | 0–19% |
CBD | 0–50% |
LBD | 6.25–15% |
FTD | 0–4.17% |
Research has indicated that a unilateral grasp reflex suggests damage to the contralateral frontal lobe [
47], while a bilateral grasp reflex lacks specific localizing value and is often associated with generalized and vague lesions [
54]. The grasp reflex in most patients with focal brain injuries is bilateral or contralateral to the lesion. In CBD, grasp reflexes commonly appear unilaterally, aligning with the strikingly asymmetric features of CBD [
22,
55,
56]. In instances where grasp reflexes are positive in patients with AD, PD, or VaD, the probabilities of bilateral reflexes are 76–94%, 82%, and 51%, respectively [
12,
57]. This is consistent with the diffuse or focal nature of lesions characteristic of each disease. Among our positive patients, 69% displayed positivity on both sides, and the remaining patients exhibited unilateral positivity. In addition, 36% (53/147) of patients showed varying reflex intensities on both sides. Three reasons may be associated with the asymmetry observed in patients with iNPH. First, as the grasp reflex is considered a release sign indicating cortical disinhibition, this may suggest asymmetric cortical disinhibition. Second, this difference could be attributed to the distribution of periventricular or subcortical white matter lesions. Third, asymmetrical ventricular enlargement may also contribute to this phenomenon.
However, the pathophysiologic basis of grasp reflexes in iNPH patients remains unclear. In patients with AD and subcortical infarction, the appearance of grasp reflexes has been found to be associated with ventricular enlargement [
18,
49]. Schuster and Casper proposed a hypothesis (cited by Bucy and De Renzi): there exists a hypothetical inhibitory pathway originating from the bilateral medial surface of the superior frontal convolution and of the cingulate gyrus, descending through the white matter anterior and lateral to the frontal horn before leading towards the bilateral central area. The extreme degree of hydrocephalus caused compression of the occipito-frontal fasciculus region by the superolateral angle of the lateral ventricles or a marked increase in intracranial tension, both of which may result in the grasp reflex [
46,
54]. We speculate that patients with iNPH may conform to the abovementioned hypothesis.
Odenheimer et al. [
58] reported that the incidence of grasp reflexes increases with age. However, our study, in line with others [
13,
14,
59], suggested that the distribution of grasp reflexes is not affected by age. In Burn et al.'s research, the presence of grasp reflexes in AD patients was associated with a younger age of onset and a longer disease duration [
18]; these findings were not corroborated in our study. This disparity may be due to the different probabilities of patients exhibiting grasp reflexes between the two studies. In their research, this probability was 7.3% (13/161), whereas in our study, it was 50.3% (74/147).
Our study revealed that patients in the positive control group exhibited higher iNPHGS scores than patients in the negative control group, and the reflex intensity was positively correlated with those scores. In PD, grasp reflexes are exclusively observed in Hoehn and Yahr stage III and IV patients [
60]. They have also been found specifically in AD patients with Global Deterioration Scale stages 6 and 7 [
61,
62]. These findings suggest that the grasp reflex is sensitive to disease severity in iNPH patients. Moreover, although there was no statistically significant difference in mRS scores between the two groups in our study, there was an increasing trend in the correlation with increased reflex scores. Studies have indicated that individuals with dementia who exhibit grasp reflexes often experience more functional problems [
12,
13], and with the deterioration of function, the mean activity rating of the reflex also tends to increase [
63]. The observed discrepancies may arise from the inherent imprecision of our measurement scale. Moreover, despite greater disease severity possibly being the primary explanation for functional impairments, we found that grasp reflex intensity reliably reflects the extent of functional impairments in iNPH patients.
In a cohort of 201 dementia patients with grasp reflexes, the prevalence of gait, balance, posture, and tone abnormalities was 89.6%, 89.0%, 83.1%, and 72.1%, respectively. Moreover, 28.8% of the patients displayed bradykinesia [
12]. Alterations in grasp reflexes have been observed in conjunction with gradual deterioration in both gait and posture among AD patients [
62]. In our study, the positive group demonstrated prolonged completion time in the TUG test and higher UPDRS part III scores, and both of these variables were correlated with the intensity of the grasp reflex. Despite the lack of significant differences in the number of steps during the TUG test or in the FBS values, they still exhibited a correlation with reflex intensity. Furthermore, there was no significant improvement in the UPDRS part III scores of patients in the positive group after surgery. Studies have suggested that gait disturbances in patients with iNPH are linked to disrupted connectivity between the supplementary motor area and subcortical structures, as well as insufficient inhibitory control from the premotor and subcortical regions [
64,
65]. Furthermore, striatal dopaminergic dysfunction serves as the pathophysiological basis for gait disturbances and parkinsonian signs [
66]. The intersection between these regions and areas responsible for inhibiting the grasp reflex can explain the correlation between them [
67,
68].
Many studies of dementia patients have consistently demonstrated that individuals with grasp reflexes exhibit more profound cognitive dysfunction [
12,
14,
18,
20,
21,
40,
62], and our patients with iNPH are no exception to this pattern. Moreover, our study demonstrated a more comprehensive relationship, indicating close correlations between grasp reflexes and executive function, psychomotor speed, working memory, and attention. On the other hand, Simpson et al. demonstrated that grasp reflexes are associated with depressive symptoms in patients with vascular dementia [
16]. Our study also indicated that patients with grasp reflexes present more neuropsychiatric issues. Due to the strong correlation between grasp reflexes and prefrontal cortical functions such as cognition, emotion, and memory [
67], we consider the grasp reflex to be an adjunctive tool for assessing cognitive-behavioural impairments in patients with iNPH. Given the greater postoperative cognitive improvement observed in the positive group, we hypothesize that this phenomenon may be attributed to their inferior baseline performance.
In AD patients, the prevalence of grasp reflexes has been found to be more than twice as high in those with permanent double incontinence than in those with incipient incontinence and approximately 11 times greater than that in continent individuals [
69]. Our findings are consistent with the results of previous studies, indicating that patients with positive grasp reflexes exhibit more severe urinary problems. The overlap between the cortical mechanisms controlling the micturition reflex and mediating the perception of bladder distension and those inhibiting the grasp reflex forms the basis for the correlation between the two [
70‐
72].
Our study represents the first investigation of reflex changes based on a large sample size. In our study, a reduction in reflex intensity was observed in 41.7% of patients following surgical intervention; however, overall, this improvement did not reach statistical significance at the group level. Lenfeldt et al. reported that in patients with iNPH, significant improvements in motor performance following CSF drainage were accompanied by enhanced activation in supplementary motor areas [
73]. This mechanism may also be attributed to the neural substrate underlying the reduction in reflex intensity in our patients. Additionally, our study revealed significant correlations between reductions in reflex intensity and improvements in the number of steps of the TUG test and TMT-A. However, further validation with a larger sample size is necessary to determine whether changes in reflex intensity can accurately predict postoperative alterations in stride length and psychomotor speed. Furthermore, the changes in reflex intensity showed no significant correlation with changes in iNPHGS total scores, indicating that grasp reflexes do not have predictive value for postoperative outcomes, contrary to the hypothesis proposed by Thomas et al. [
26].
This study has five main limitations. First, this study did not include a healthy or disease control group. Second, the retrospective review of clinical records employed in this study is susceptible to errors stemming from variations among examiners in technique or the reliability of documenting abnormalities. Third, the scoring method and classification used were not validated. Different assessment methods and scoring criteria may lead to disparate prevalence rates across various studies. Fourth, this manuscript lacked the inclusion of imaging findings and examinations of AD biomarkers, which could better elucidate the underlying anatomical and pathophysiological mechanisms of the grasp reflex in iNPH patients. Fifth, in the analysis of changes in the grasp reflex after the operation, we were unable to obtain reflex data at one year postoperatively or beyond for all patients who underwent surgery due to the limitations of retrospective research. Nevertheless, this retrospective study was rooted in substantive observations from more than a decade of clinical practice. We did not observe such widespread grasp reflexes in healthy ageing or in patients with other neurodegenerative diseases. Additionally, each clinical practitioner underwent rigorous training before assuming their position. Furthermore, we are actively engaged in a prospective validation study aimed at validating the feasibility of our methodology. Finally, we have been conducting studies on the grasp reflex based on various neuroimaging techniques with the aim of providing valuable insights into the mechanisms underlying the grasp reflex in iNPH patients. Prospective studies on the comorbidity of iNPH and AD are also ongoing.