Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.

Objective Cerebrospinal fluid (CSF) shunting can improve symptoms of elderly patients' idiopathic normal pressure hydrocephalus (iNPH). However, adjunctive means for confirming the diagnosis remain unavailable. We have previously reported the specific increase of leucine-rich alpha-2-glycoprotein (LRG) in iNPH CSF, and the present study investigates its potential clinical applications. Methods We performed CSF tap test (TT) on 90 patients (mean age 73.4 years) and shunting in 52 patients (mean age 73.5 years), evaluating symptom improvement and higher cerebral functions—mini-mental state examination (MMSE) and Frontal Assessment Battery (FAB) before and 12 months after shunting. LRG and tau protein concentrations in TT CSF were simultaneously measured using enzyme-linked immunosorbent assay. We then compared the predictive value of these concentrations with TT results regarding successful shunting outcomes. Results Positive combinations of TT and LRG concentrations of 67 ng/ml or higher, gave 81.6% sensitivity and 78.6% specificity. Therefore we used LRG (67 ng/ml) and tau (200 pg/ml) cut-off values, dividing patients into four groups. In group A (LRG ≥ 67 ng/ml and tau < 200 pg/ml) 31 of 34 patients (91.2%) had a positive TT and all operated 22 patients were shunt responders. Dementia MMSE and FAB scores in them increased from a baseline of 22.05(SE ± 0.96) to 25.65 (±0.85) and 11.38 (±0.68) to 13.08 (±0.57) respectively. In group B, (LRG ≥ 67 ng/ml and tau ≥ 200 pg/ml), the mean MMSE score increased from 17.62 (±2.03) to 21.62 (±1.96), and the FAB decreased slightly from 9.25 (±1.15) to 10.5 (±1.59), without improvement beyond the range of dementia. In group C, (LRG < 67 ng/ml, tau < 200 pg/ml), the mean MMSE score improved from 22.06 (±1.25) to 24.29 (±1.23) and the FAB score improved slightly from 12.0 (±0.72) to 12.87 (±0.72). Finally, in group D, (LRG < 67 ng/ml, tau ≥ 200 pg/ml), there was almost no improvement in MMSE score Conclusions A combination of positive TT and biomarkers quantification such as LRG and tau protein, can reliably predict shunting outcome in iNPH patients.

Purpose: Since a case of hydrocephalus in humans considered to be caused by ciliary dysfunction was first reported by Greenstone et al. in 1984, numerous papers on the correlation between ciliary function and hydrocephalus have been published. Methods: We reviewed the published literature on primary ciliary dyskinesia in humans causing hydrocephalus, focusing on articles specifically examining the relation between ciliary function and hydrocephalus and its treatment. In addition, the authors’ experience is briefly discussed. Results: Full texts of 16 articles reporting cases of human hydrocephalus (including ventriculomegaly) due to defects in ependymal ciliary function or primary ciliary dyskinesia observed in clinical practice were extracted. In recent years, studies on animal models, especially employing knockout mice, have revealed genetic mutations that cause hydrocephalus via ciliary dysfunction. However, a few reports on the onset of hydrocephalus in human patients with primary ciliary dyskinesia have confirmed that the incidence of this condition was extremely low compared to that in animal models. Conclusion: In humans, it is rare for hydrocephalus to develop solely because of abnormalities in the cilia, and it is highly likely that other factors are also involved along with ciliary dysfunction.

In Japan, idiopathic normal pressure hydrocephalus (iNPH) currently is treated mainly with lumboperitoneal (LP) shunts. Our aim was to evaluate whether LP shunting via the use of Medtronic Strata NSC programmable valves was as effective as ventriculoperitoneal shunting in the treatment of patients with iNPH from the perspectives of safety and symptomatic improvement rate. The clinical records of 51 iNPH patients (mean age, 75 years; males, 29), who underwent placement of Medtronic Strata NSC LP shunt systems were reviewed retrospectively as a cohort. LP shunting was evaluated with the modified Rankin Scale, the Japan Normal-Pressure Hydrocephalus Grading Scale, the Mini-Mental State Examination, the Frontal Assessment Battery, and the Trail-Making Test A as outcome measures. Modified Rankin Scale scores improved from 3.2 to 2.2 (P < 0.01), indicating a 64% response rate 12 months after treatment. Total Japan Normal-Pressure Hydrocephalus Grading Scale scores decreased from 6.5 to 4.0 (P < 0.01), indicating a response rate of 81%. Mini-Mental State Examination scores improved from 22.2 to 25.4 (P < 0.01), Frontal Assessment Battery scores improved from 11.7 to 13.4 (P < 0.05), and Trail-Making Test A scores improved from 122.3 to 112.7 (P = 0.60). During the 12-month follow-up period, complications requiring surgery were observed in 6 cases (11.8%). LP shunts showed effectiveness rates that were similar to those of ventriculoperitoneal shunts. Despite the relatively high complication rate, LP shunts can be recommended for the treatment of patients with iNPH because of their minimal invasiveness and lack of lethal complications.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer’s disease (AD) pathology is debated. Objective: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. Methods: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low ( n = 24; mean age 75.7 years [SD 5.3]) and high ( n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. Results: Cognitive function improved early in the low p-Tau group and was maintained thereafter ( p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year ( p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R ² = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. Conclusions: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

The prognosis of cognitive improvement after cerebrospinal fluid (CSF) shunting in idiopathic normal pressure hydrocephalus (iNPH) remains uncertain, with no reports on CSF biomarkers related to long-term cognitive prognosis. We performed a preliminary study of CSF biomarker protein levels for cognitive outcome prognostication of two-year outcomes after shunt treated iNPH in 36 patients (13 women) with a median age of 75years (IQR 69-78). CSF biomarkers included soluble amyloid precursor proteins (sAPP, sAPPα, sAPPβ), amyloid β (Aβ)1-38, Aβ1-42 and phosphorylated tau (p-tau), lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace, and cystatin C. The results clearly showed that p-tau levels (sensitivity of 71.4%, specificity of 77.8%, cut-off value of 22.0pg/mL), Aβ1-38/Aβ1-42 ratio (77.8%, 81%, 3.58), and the Aβ1-42/p-tau ratio (76%, 72.7%, 14.6) in preoperative CSF have the potential to determine postoperative prognosis. Improved cognition may be associated with the improvement in CSF circulation after LPS, which likely induces cystatin C and L-PGDS and switches synthesis from Aβ1-42 to Aβ1-38.