Patients
Patients (n = 137) with physical and cognitive symptoms and brain imaging findings (brain MRI) suggestive of possible NPH were evaluated at Peking Union Medical College Hospital according to the guidelines for the clinical diagnosis of idiopathic NPH (INPH) published in 2005 [21]. The patients had to be older than 40 years of age with insidious progression of symptoms (gait disturbance plus impairments in cognition, bladder control, or both) for at least 3–6 months and have normal CSF opening pressure.
History taking and clinical assessment
Age, gender, past histories, personal histories, and initial and full-blown symptoms for all patients were recorded. Patients also completed the Mini-Mental State Examination (MMSE) [22], Montreal Cognitive Assessment (MOCA), and activities of daily living (ADL) questionnaire. The iNPH Grading Scale (iNPHGS) [23] was used to rate the severity of each fundamental symptom of iNPH (gait disturbance, cognitive impairment, and urinary incontinence) on a four-point scale after a detailed interview with the patients and caregivers. All subjects underwent a CSF TT and brain MRI.
The CSF TT was performed by lumbar puncture followed by the measurement of CSF opening pressure and CSF collection. We collected 30 ml of CSF or as much as possible until the patients could no longer tolerate the procedure. The initial and terminal intracranial pressure was recorded. Before and after the procedure, cognitive function and walking ability were evaluated by the means of the 10-meter walking test and a brief executive function battery, which was previously described [24]. The time and steps that the patient took to complete the 10-meter walking test and a video of the test were recorded. The brief executive function battery included the Symbol-Digit Modalities Test, Trail Making Test A and STROOP-C. Additional evaluations were conducted at 8 hours, 24 hours and 72 hours after CSF TT. In addition to the walking and cognitive function evaluation, the urinary and fecal function questionnaire was completed by the caregiver and patients. The total symptom improvement questionnaire was evaluated by the caregiver and patients at the same time. The following criteria were used to identify responders: 1. CSF TT responders were defined as patients with reductions in their time and number of steps in the walking test at least once after the CSF TT, with decreases of 10% for both parameters or a decrease of 20% on at least one of these parameters [25]. 2. Gait was improved based on videos that were evaluated by two neurologists who were blinded to the patient’s clinical and neuroimaging characteristics. 3. The total symptom improvement questionnaire scores were partly or obviously improved. The patients who met 2 of 3 criteria were identified as CSF TT responders.
Brain MRI
Axial and sagittal spin-echo T1-weighted images were obtained by using a 1.5-T MRI unit (Signa Excite, General Electric, Milwaukee, WI, USA). We also obtained axial fast spin-echo T2-weighted, fluid-attenuated inversion recovery images and diffusion tensor imaging (DTI). The white matter lesions on the axial T2-weighted or FLAIR images were scored according to the Fazekas score. The white matter lesions were scored in different regions of the brain, including the periventricular, deep white matter and subcortical white matter lesions. Visual analyses were independently conducted by two neuroradiologists who were experienced in MRI correlates in NPH patients and who were blind to both diagnosis and CSF TT results of the subjects. The fractional anisotropy (FA) and mean diffusivity (MD) values were measured across regions of interest (ROIs) on DTI images. The ROIs were the bilateral anterior and posterior periventricular white matter that were set as circular areas with a diameter of 2 mm perpendicular to the longitudinal axis of the ipsilateral ventricle on the brain imaging slice with the lateral ventricle. The ROIs were chosen according to our pilot study data [26], which indicated that the FA and MD values in the bilateral anterior and posterior periventricular white matter were correlated with walking ability and cognition in possible NPH patients. A consistency test was performed (Cronbach's a coefficient > 0.6).
Statistical methods
If the data conformed to a normal distribution, the data are presented as the mean ± standard deviation; if the measurement data conformed to a skewed distribution, the data are presented as the median (interquartile range). The scores for various evaluation indexes before and 4 hours, 8 hours, 24 hours and 72 hours after CSF TT conformed to skewed distributions. The differences in the grooved pegboard test results before and after the CSF TT were analyzed using a nonparametric paired sign rank-sum test. The grooved pegboard test results at the three different time points after the CSF TT (i.e., 8 hours, 24 hours and 72 hours) were also compared by means of a nonparametric paired sign rank-sum test.
We compared the best improvement ratios for the grooved pegboard test performance between the CSF TT responder and nonresponder groups by means of the Mann-Whitney U test. The improvement ratio was calculated as follows: (baseline performance on the grooved pegboard test - performance after CSF TT) / the baseline performance. The best improvement ratio for the grooved pegboard test was calculated for the different times (i.e., 8 hours, 24 hours, and 72 hours) after CSF TT. The grooved pegboard test and Symbol-Digit Modalities Test performance were combined into the complex visual motor speed index. The improvement ratio for the complex visual motor speed index after CSF TT was also compared between the responder and nonresponder groups using the Mann-Whitney U test.
The correlations between the grooved pegboard test results and the iNPHGS scores, walking test results, and neuropsychological performance were also tested by means of Spearman correlations. The correlations between the grooved pegboard test results and the DTI parameters from the periventricular white matter lesions were also analyzed using the Spearman correlation method.
There were four time assessments related to the CSF TT, and the Bonferroni correction was applied for the repeated measurements. The statistical significance level was set at p < 0.05/4 = 0.01. When the Spearman's correlation analysis was used, the statistical significance level was set at p < 0.05. All statistical analyses were performed with the statistical software package SPSS for Windows (version 13.0.; SPSS Inc., Chicago, IL, USA).