Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center

Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A... Abstract BACKGROUND Treating idiopathic normal pressure hydrocephalus (iNPH) with lumboperitoneal shunts (LPSs) may cause cerebrospinal fluid (CSF) overdrainage. OBJECTIVE To investigate whether LPSs, including gravitational “add-on” and programmable pressure valves (PPVs/+GVs), reduce complications and improve outcomes. METHODS We compared PPVs/+small lumen abdominal catheters (SLs) to PPVs/+GVs using different opening pressures for supine and standing positions. We analyzed 115 patients with iNPH in 2 consequent cohorts: 48 patients receiving LPSs with PPVs/+SLs and 67 patients receiving LPSs with PPVs/+GVs. The modified Rankin Scale (mRS), Japan iNPH grading scale, Mini Mental State Examination, Frontal Assessment Battery, and CSF biomarkers were evaluated. RESULTS Comparisons of postoperative clinical factors in 64 patients in the PPV/+SL and PPV/+GV groups using 1:1 propensity score matching revealed differences in the mean (±standard deviation) postoperative mRS (2.65 ± 1.07 vs 2.16 ± 1.02, P = .049) and gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Thus, outcomes improved in the LPS group with the GV. Serious and nonserious adverse event rates for the PPV/+SL and PPV/+GV groups were 22.9% and 19.4% (P = .647) and 38% and 17.9% (P = .018), respectively, indicating higher rates of subdural collections for the PPV/+SL group. CONCLUSION This is the first study to examine LPS treatment for iNPH using a GV in tandem with a PPV. Our results suggest that the CSF shunt flow volume is restricted in the standing position and maintained in the supine position, thus improving iNPH symptoms. This may reduce intracranial CSF hypotension-related complications. Cerebrospinal fluid, Cognitive function, Hydrocephalus, Ventriculomegaly, Gravity ABBREVIATIONS ABBREVIATIONS CSF cerebrospinal fluid FAB Frontal Assessment Battery GV gravitational add-on valve ICP intracranial pressure iNPH idiopathic normal pressure hydrocephalus iNPHGS idiopathic normal pressure hydrocephalus grading scale LPS lumboperitoneal shunt MMSE Mini Mental State Examination mRS modified Rankin Scale OD overdrainage PPV programmable pressure valve SD standard deviation SL small-lumen VPS ventriculoperitoneal shunt Idiopathic normal pressure hydrocephalus (iNPH), a disease with uncertain etiology that characteristically afflicts older adults, is characterized by cognitive decline, gait and balance impairments, and urinary incontinence.1,2 iNPH is commonly treated with cerebrospinal fluid (CSF) shunts, as this is the only treatment with clear evidence of effectiveness.3 Although the mechanism for recovery following shunt treatment remains unclear, research suggests that shunts improve CSF clearance and adjust the intracranial pressure (ICP).4 Subsequent studies have demonstrated that lymphatic transport is controlled by the brain's arousal level.5,6 The volume of the interstitial space in the brain expands significantly during sleep or anesthesia when compared with the awake state.7,8 CSF shunts may also facilitate the excretion of brain extracellular metabolites, which include neurotoxic proteins such as amyloid beta (Aβ) and phosphorylated tau (p-tau).9,10 A previous study reported elevated Aβ38 and Aβ42 levels following shunt implantation, likely owing to improved CSF clearance after surgery.10 Ventriculoperitoneal shunt (VPS) implantation is currently the standard treatment for patients with iNPH.11 In Japan, however, a lumboperitoneal shunt (LPS), which is a less invasive treatment, is used more frequently.12 LPS treatment has been recognized as an effective approach for iNPH,13 though its higher revision rates compared with VPS and more-frequent complications due to CSF overdrainage (OD) are problematic.14 Although the mechanisms are unclear, OD seems to occur more frequently in tall and thin individuals. Some authors contend that the siphon effect in the standing position has the strongest influence on this mechanism.15-17 The programmable pressure valve (PPV), in which the pressure is adjusted according to the individual's ICP and body constitution, is known to be more effective than fixed pressure valves for preventing OD complications.18,19 However, the PPV cannot control the CSF shunt flow volume when there is a change in posture or an increase in ICP due to coughing or straining.20,21 This is a limitation that requires a solution. Various anti-siphon devices that control CSF shunt flow volume are available. They include siphon guards (Codman and Shurteleff; Johnson and Johnson, New Brunswick, New Jersey), small-lumen abdominal catheters (SL 43555; Medtronic Neurosurgery, Medtronic Inc, Dublin, Ireland), and gravitational “add-on” valve systems (GV; Aesculap-Miethke, Tuttlingen, Germany).22 The inner diameter (0.7 mm) of the SL catheter is smaller than that of the conventionally used abdominal catheter. The increased resistance of the SL catheter aims to prevent OD.12 However, the siphon guard effect of the SL catheter is not necessarily effective as a short abdominal catheter for LPS, as it depends on the catheter length. Some studies have reported the effectiveness of GVs for the prevention of OD in devices that automatically increase shunt pressure with changes in posture.23 The gravitational unit gradually adds resistance to the pre-set opening pressure when the valve is raised from an angle of 0° toward the upright position at an angle of 90°. While facilitating the excretion of brain extracellular metabolites, it is important to maintain a CSF flow of sufficient volume to increase the clearance of these proteins while avoiding OD complications. We hypothesized that CSF shunt with GV for iNPH would clear brain extracellular metabolites more efficiently during sleep and in the supine position. Shunt treatment guarantees a larger CSF shunt flow volume in the supine position, which indicates that shunt systems with GV can be developed to remove brain extracellular metabolites. However, to our knowledge, no studies have yet investigated the efficacy LPS with a GV. Therefore, we evaluated whether LPS treatment using a shunt system with a GV installed in tandem with a PPV would reduce complications arising from OD and improve patient outcomes. METHODS Study Design We implanted a GV, which is used to maintain higher CSF flow in the supine position, and a PPV set to low pressure in a sequential column to create an LPS. We compared this device to an SL catheter. We conducted a preliminary experiment to test a system using the siphon effect created by the 2 different types of devices to prevent excessive CSF outflow. A previous study reported that patients with iNPH require a mean (±standard deviation [SD]) vertical effective opening pressure of the entire shunt system of 27.5 ± 3.3 cmH2O, while patients with congenital hydrocephalus require a pressure of 36.3 ± 23.3 cmH2O, and patients with malresorptive hydrocephalus require a pressure of 35.9 ± 20.4 cmH2O.22 We therefore set the standing (vertical) pressure at 35 cmH2O (close to the pressures established above) and the supine (horizontal) position pressure at 10 cmH2O. The results of the experiment indicated that GVs placed into a column in sequence limit CSF flow to a greater extent while the patient is in the standing position, and maintain flow while the patient is in the supine position (Figures 1 and 2). FIGURE 1. View largeDownload slide Shunt system experiments. Based on previous studies, we set the standing (vertical) pressure at 35 cmH2O and the supine (horizontal) position pressure at 10 cmH2O. We simulated CSF “production” at 20 mL/h by injecting H2O using a syringe pump connected to the main hydrostatic pressure column. We measured the flow from the 2 types of systems under the 2 different postural conditions (vertical and horizontal) by measuring total discharge for 10 min at 5 performance levels, as follows: 0.5 (15-35 mmH2O), 1.0 (35-55 mmH2O), 1.5 (90-110 mmH2O), 2.0 (145-165 mmH2O), and 2.5 (200-220 mmH2O). FIGURE 1. View largeDownload slide Shunt system experiments. Based on previous studies, we set the standing (vertical) pressure at 35 cmH2O and the supine (horizontal) position pressure at 10 cmH2O. We simulated CSF “production” at 20 mL/h by injecting H2O using a syringe pump connected to the main hydrostatic pressure column. We measured the flow from the 2 types of systems under the 2 different postural conditions (vertical and horizontal) by measuring total discharge for 10 min at 5 performance levels, as follows: 0.5 (15-35 mmH2O), 1.0 (35-55 mmH2O), 1.5 (90-110 mmH2O), 2.0 (145-165 mmH2O), and 2.5 (200-220 mmH2O). FIGURE 2. View largeDownload slide Comparison between the small-lumen abdominal catheter and gravitational add-on valve. We measured the flow rate (mL/h) at simulated standing (35 cmH2O) and supine (10 cmH2O) positions for the 5 performance levels of the Strata NSC valve, ranging from 0.5 to 2.5. When the PPV and GV were placed in tandem and the pressure was set at level 2.5 (22.5 cmH2O) plus 15 cmH2O, the flow volume was 0 mL in the standing position. In this position, the GV led to a greater reduction in flow volume than did the small-lumen abdominal catheter at all settings, while greater flow volume was obtained at the lower level settings of 0.5 and 1.0 in the supine position. FIGURE 2. View largeDownload slide Comparison between the small-lumen abdominal catheter and gravitational add-on valve. We measured the flow rate (mL/h) at simulated standing (35 cmH2O) and supine (10 cmH2O) positions for the 5 performance levels of the Strata NSC valve, ranging from 0.5 to 2.5. When the PPV and GV were placed in tandem and the pressure was set at level 2.5 (22.5 cmH2O) plus 15 cmH2O, the flow volume was 0 mL in the standing position. In this position, the GV led to a greater reduction in flow volume than did the small-lumen abdominal catheter at all settings, while greater flow volume was obtained at the lower level settings of 0.5 and 1.0 in the supine position. We compared LPS treatment in individuals with iNPH using 2 different shunt systems designed to prevent OD. Two consecutive groups of patients were treated. The first group was treated with an SL catheter attached to a PPV, which represented the best available standard treatment (PPV/+SL group).12 The second group was treated with a GV in tandem with a PPV with different opening pressures (PPV/+GV group). We compared the PPV/+GV group to the PPV/+SL group, which was used as a control group. The components listed in sequence from proximal to distal were as follows: PPV/+SL group, lumbar catheter + Strata NSC valve + SL catheter (43555); and PPV/+GV group, lumbar catheter + GV “shunt assistant” 0-15 cmH2O (Aesculap-Miethke) + Strata NSC valve + abdominal catheter (27536). Patients The patients were reviewed retrospectively. The patients in this cohort received an LPS after attending consultations in our department and were suspected of having iNPH based on neurological manifestations and magnetic resonance imaging. Our evaluation criteria were consistent with the Japanese guidelines for iNPH.24,25 We compared the following 2 iNPH patient groups (n = 115 in total): 48 patients treated with LPS with PPV/+SL (19 women; mean age ± SD, 74.5 ± 6.3 yr; from 2010 to 2012), and 67 patients treated with LPS with PPV/+GV (21 women; 75.4 ± 5.6 yr; from 2013 to 2015; Figure 3 and Table 1). Twelve months after shunt implantation, we evaluated the patients using the modified Rankin Scale (mRS),26 iNPH grading scale (iNPHGS),27 Mini Mental State Examination (MMSE),27 and Frontal Assessment Battery (FAB).29 We also measured CSF biomarkers (soluble amyloid precursor protein [sAPPα], Aβ38, Aβ42, and p-tau).30 All patients provided prior written consent for their participation in the study, which was conducted after ethics committee approval. FIGURE 3. View largeDownload slide Subject flow diagram. GV = gravity add-on valve, iNPH = idiopathic normal pressure hydrocephalus, LPS = lumboperitoneal shunt, MMSE = Mini Mental State Examination, PPV = programmable pressure valve, p-tau = phosphorylated tau, sAPPα = soluble amyloid precursor protein alpha, SL = small-lumen abdominal catheter. FIGURE 3. View largeDownload slide Subject flow diagram. GV = gravity add-on valve, iNPH = idiopathic normal pressure hydrocephalus, LPS = lumboperitoneal shunt, MMSE = Mini Mental State Examination, PPV = programmable pressure valve, p-tau = phosphorylated tau, sAPPα = soluble amyloid precursor protein alpha, SL = small-lumen abdominal catheter. TABLE 1. Characteristics at Baseline Data for iNPH Patients Before Lumboperitoneal Shunt Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin Scale, iNPHGS: idiopathihc normal pressure hydrocephalus grading scale, MMSE: mini mental scale examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated-tau, Aβ: amyloid beta. Binomial logistic regression. Preservation prediction value was obtained by calculating the score with probability P and producing preoperative numerical values between the PPV/+SL and PPV/+GV groups. Propensity score: 0.186-0.863. *P < .05. View Large TABLE 1. Characteristics at Baseline Data for iNPH Patients Before Lumboperitoneal Shunt Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin Scale, iNPHGS: idiopathihc normal pressure hydrocephalus grading scale, MMSE: mini mental scale examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated-tau, Aβ: amyloid beta. Binomial logistic regression. Preservation prediction value was obtained by calculating the score with probability P and producing preoperative numerical values between the PPV/+SL and PPV/+GV groups. Propensity score: 0.186-0.863. *P < .05. View Large Procedure Neurologists or neurosurgeons screened the patients, and 2 neurosurgeons selected the patients for surgery. Surgeons with extensive experience in the procedure conducted both types of surgical procedures. No significant technical difference was identified between the LPS with PPV/+SL and the LPS with PPV/+GV implantation procedures.12 Implantations were conducted under general or spinal anesthesia. In the LPS technique, approximately 15 cm of the spinal catheter was inserted through the L3/4 or L2/3 interlaminar space into the lumbar subarachnoid space using the paramedian approach. In the PPV/+GV group, after using the step-down connector, the GV was placed in the lower back so that it would be vertical when the patient was in the standing position (Figure 4). Once the L-shaped connector (Aesculap-Miethke) was applied, a subcutaneous tunnel was made to the ventral side, the abdominal catheter was passed through it ventrally, and the PPV was placed subcutaneously on the ventral side. The abdominal catheter, trimmed to about 30 cm, was inserted into the abdominal cavity after being connected to the PPV. FIGURE 4. View largeDownload slide A lumbar 3-dimensional image obtained after LPS implantation with a gravity add-on valve and a Strata NSC programmable pressure valve. FIGURE 4. View largeDownload slide A lumbar 3-dimensional image obtained after LPS implantation with a gravity add-on valve and a Strata NSC programmable pressure valve. Valve Pressure Adjustment Protocol The initial pressure for the shunt system was set to its highest level of 2.5 (22.5 cmH2O). We checked the function of the shunt if no improvement in the patient's clinical symptoms were observed, when the high convexity and medial subarachnoid spaces were tight, or when acute callosal angles were observed.12 We lowered the pressure setting by 1 step (0.5 level) if symptoms did not improve at all 1 wk after the operation. If improvement was observed, but was deemed insufficient (half or less of the effects observed in the tap test, except when there was a steady improvement), we lowered the pressure setting further by 0.5-level intervals, with careful consideration of the patient's safety range. The pressure setting was increased immediately if a symptomatic subdural hematoma related to OD was found. CSF Analysis We obtained lumbar CSF before and after the LPS procedure. All CSF samples were aliquoted and stored in polypropylene tubes at –80°C until biochemical analysis.28 Shunt reservoir and lumbar CSF biomarkers were also compared.9,10 CSF biomarkers included sAPPα (Human sAPPα Assay Kit; IBL No. 27719; Immuno-Biological Laboratories Co, Ltd, Takasaki, Japan), Aβ38 (Human Amyloid β1-38 Assay Kit, IBL No. 27717; Immuno-Biological Laboratories Co, Ltd), Aβ42 (Innotest β amyloid 1–42; Innogenetics, Ghent, Belgium), and p-tau (Innotest phospho tau-181p; Innogenetics). Immunosorbent assays were used for the rest of the biomarker measurements (Table 1). Outcome Measures We compared the mRS, iNPHGS, MMSE, and FAB scores, and sAPPα, Aβ38, Aβ42, and p-tau concentrations, as well as the presence of any complications before and 12 mo after LPS. Statistical analysis Patients who underwent the PPV/+GV implantation procedure were matched using 1:1 propensity score matching to patients who underwent the PPV/+SL procedure. Propensity scores were calculated for background factors comprising preintervention mRS and FAB scores, and p-tau and Aβ42 levels (Table 1). We used nonparametric methods for the analyses, including Mann–Whitney U-tests and Pearson's chi-squared tests, to identify changes from baseline. We used an analysis of covariance to reveal differences in the changes between the patient groups. Adverse events were analyzed using a safety analysis set that included all patients who received an LPS. The significance level was set at a 2-sided P = .05. Statistical data were analyzed using SPSS version 22 (IBM Inc, Armonk, New York). RESULTS Clinical Findings The final programmable median valve pressures for the PPV/+SL and PPV/+GV groups were 1.5 (interquartile range, 1.0-2.0) and 1.0 (interquartile range, 0.5-1.5), respectively. We succeeded in using lower pressures on the pressure-adjustable GV. A comparison of postoperative clinical factors in the 64 patients in the PPV/+SL and PPV/+GV groups that was adjusted and 1:1 propensity score matched for confounding variables indicated significant differences in the mean (±SD) postoperative mRS scores (2.65 ± 1.07 vs 2.16 ± 1.0, P = .049) and iNPHGS gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Therefore, the outcomes were improved in the LPS group with the GV. No statistically significant differences in the other factors were identified (Figure 5; Table 2). The p-tau concentration was the only CSF biomarker that was significantly different between the groups. The level of p-tau was 52.1 ± 30.2 pg/mL in the PPV/+SL group and 77.0 ± 41.0 pg/mL in the PPV/+GV group (P = .015). FIGURE 5. View largeDownload slide mRS score changes after LPS implantation. FIGURE 5. View largeDownload slide mRS score changes after LPS implantation. TABLE 2. Comparisons Before and After Therapeutic Shunt Intervention After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, SD: standard deviation, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin scale, iNPHGS: idiopathic normal pressure hydrocephalus grading scale, MMSE: Mini Mental State Examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated tau, Aβ: amyloid beta. *P < .05. View Large TABLE 2. Comparisons Before and After Therapeutic Shunt Intervention After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, SD: standard deviation, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin scale, iNPHGS: idiopathic normal pressure hydrocephalus grading scale, MMSE: Mini Mental State Examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated tau, Aβ: amyloid beta. *P < .05. View Large Adverse Events Associated with LPS The incidence of nonserious adverse events was significantly different between the 2 groups (P = .018; Table 3). The rates of postoperative headache in the PPV/+SL and PPV/+GV groups were 29.2% (n = 14/48) and 14.9% (n = 10/67), respectively (P = .064). The rates of asymptomatic subdural effusions and subdural hematomas (conservatively treated) were 8.3% (n = 4/48) and 3% (n = 2/67) in the PPV/+SL and PPV/+GV groups, respectively (P = .203). The rates of chronic subdural hematomas requiring surgery were 3.9% (n = 2/48) and 0% in the PPV/+SL and PPV/+GV groups, respectively (P = .092). The proportion of patients requiring revision due to proximal catheter failure was 12.5% (n = 6/48) in the PPV/+SL group and 16.4% (n = 11/67) in the PPV/+GV group (P = .559). No statistically significant differences were found in the occurrence of serious adverse events between the 2 groups. TABLE 3. Adverse Events Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Chi-squared test: comparison of adverse events between the PPV/+SL and PPV/+GV groups after shunt insertion. *P < .05. View Large TABLE 3. Adverse Events Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Chi-squared test: comparison of adverse events between the PPV/+SL and PPV/+GV groups after shunt insertion. *P < .05. View Large DISCUSSION This is the first study to examine the use of GVs for LPS in individuals with iNPH, although research groups in Germany have already reported a multicenter open-label randomized parallel-group trial for VPS.23 The abovementioned study, called SVASONA, found that GVs reduce the risk of OD complications following VPS surgery. Selecting the appropriate opening pressure for the gravitational unit remains a critical treatment decision that is made according to the patient's body mass index. The rationale behind this setting is that the level of compensation for hydrostatic pressure (HP) changes ultimately depends on the height of the upper body and the intra-abdominal pressure (IAP). Kajimoto et al31 evaluated the ICP, IAP, HP, and perfusion pressure of the shunt system using telemetric sensors in 13 patients in both the supine and sitting positions. In the supine position, the mean (±SD) ICP, IAP, and HP were 4.6 ± 3 mm Hg, 5.7 ± 3.3 mm Hg, and 3.3 ± 1 mm Hg, respectively. As a result, the perfusion pressure was 2.2 ± 4.9 mm Hg. When patients were raised to the sitting position, the IAP increased to 14.7 ± 4.8 mm Hg, ICP decreased to –14.2 ± 4.5 mm Hg, and HP increased to 42.9 ± 3.5 mm Hg. Consequently, the perfusion pressure increased to 14 ± 6.3 mm Hg. These data are useful for determining LPS function parameters in the standing position. The LPS system with a PPV/+GV (0-15 cmH2O) has the potential to suppress the standing flow volume rate when the PPV is set to the appropriate pressure and there is sufficient supine flow volume. Changes in Neurological Symptoms and Complications after LPS Surgical Treatment Here, LPS treatment with PPV/+GV reduced nonserious OD complications when compared with LPS with PPV/+SL. However, orthostatic headache, which was observed immediately after LPS, was present even in the PPV/+GV group. We surmise that orthostatic headache occurs due to CSF leakage around the spinal catheter into the epidural space in the early postoperative period.32,33 This is a problem unique to LPS. Patients who were treated using GVs had a tendency of higher revision rates due to proximal catheter failure. As the GV must be placed in tandem with the PPV, we presume that tube kinking occurs more readily in front of or behind the GV when it is placed vertically. Technically, this catheter kinking could be avoided by directly fixing the GV or the L- or U-shaped connector to the fascia. We may be able to avoid these complications in the future if a device is developed that allows the GV to be placed horizontally. Changes in CSF Biomarkers After Shunt Implantation In our study, the p-tau levels increased significantly after shunt surgery. The level of p-tau after shunt was 52.1 ± 30.2 pg/mL in the PPV/+SL group and 77.0 ± 41.0 pg/mL in the PPV/+GV group (P = .015). This finding is consistent with those of previous reports by Moriya et al9 and Tarnaris et al.34 Pyykkö et al35 measured p-tau (Innotest phospho tau-181p; Innogenetics) in the lumbar subarachnoid and intraventricular CSF of patients with iNPH before shunt and found that the mean lumbar and ventricular levels of p-tau were 39.5 ± 15.7 pg/mL and 81.3 ± 75.5 pg/mL, respectively. The mean ventricular levels of p-tau were twice as high as that in the lumbar subarachnoid space. Collectively, these results support that p-tau in the CSF may spread into the subarachnoid space after shunt treatment, although the exact mechanisms have not yet been established. It remains unclear why elevated p-tau concentrations occur following CSF drainage. For many years, tau protein was thought to be localized and functional in the cytoplasm, though recent studies have reported that some tau protein may be secreted outside the cell under certain physiological conditions.36 Studies have also reported that tau protein can be detected in various cell culture supernatants, such as cultured cells that overexpress tau protein,37 primary cultured neurons,38,39 and neurons derived from induced pluripotent stem cells.40 These forms of extracellular tau protein secretion are different from the nonspecific release of cellular proteins due to cell death and suggest that a specific secretion mechanism may exist. Future research should investigate the presence of tau protein with an aggregation state that is involved in its extracellular release under certain physiological conditions, the participating metabolic machinery, and cell-to-cell transmission/propagation.41 Limitations This study has some limitations related to its design. First, this was a retrospective cohort study, and is thus inherently prone to selection bias. Second, clinical improvement is a subjective measure that can be difficult to precisely quantify based on patient notes in medical records. Finally, the small sample size limited the power of the study. Future prospective studies are required to verify our findings. CONCLUSION This is the first study to examine LPS with the insertion of a GV in tandem with a PPV for the treatment of iNPH. Our results suggest that CSF shunt flow volume is more restricted in the standing position and is maintained in the supine position, thus improving iNPH symptoms. This may reduce complications associated with intracranial CSF hypotension. Disclosures This work was supported in part by the Ministry of Health, Labour, and Welfare of Japan and in part by a Grant-in-Aid for Scientific Research Grant Number (B #26293326) from the Japan Society for the Promotion of Science. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Adams RD , Fisher CM , Hakim S , Ojemann RG , Sweet WH . Symptomatic occult hydrocephalus with normal cerebrospinal-fluid pressure . N Engl J Med . 1965 ; 273 ( 3 ): 117 – 126 . Google Scholar CrossRef Search ADS PubMed 2. Hakim S , Adams RD . The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure . J Neurol Sci . 1965 ; 2 ( 4 ): 307 – 327 . Google Scholar CrossRef Search ADS PubMed 3. Pinto FC , Saad F , Oliveira MF et al. Role of endoscopic third ventriculostomy and ventriculoperitoneal shunt in idiopathic normal pressure hydrocephalus . Neurosurgery . 2013 ; 72 ( 5 ): 845 – 854 . Google Scholar CrossRef Search ADS PubMed 4. Johanson CE , Duncan JA 3rd , Klinge PM , Brinker T , Stopa EG , Silverberg GD . Multiplicity of cerebrospinal fluid functions: new challenges in health and disease . Cerebrospinal Fluid Res . 2008 ; 5 ( 1 ): 10 . Google Scholar CrossRef Search ADS PubMed 5. Iliff JJ , Wang M , Liao Y et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid . Sci Transl Med . 2012 ; 4 ( 147 ): 147ra111 – 147ra111 . Google Scholar CrossRef Search ADS PubMed 6. Louveau A , Harris TH , Kipnis J . Revisiting the mechanisms of CNS immune privilege . Trends Immunol . 2015 ; 36 ( 10 ): 569 – 577 . Google Scholar CrossRef Search ADS PubMed 7. Lee H , Xie L , Yu M et al. The effect of body posture on brain glymphatic transport . J Neurosci . 2015 ; 35 ( 31 ): 11034 – 11044 . Google Scholar CrossRef Search ADS PubMed 8. Xie L , Kang H , Xu Q et al. Sleep drives metabolite clearance from the adult brain . Science . 2013 ; 342 ( 6156 ): 373 – 377 . Google Scholar CrossRef Search ADS PubMed 9. Moriya M , Miyajima M , Nakajima M , Ogino I , Arai H . Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade . PLoS One . 2015 ; 10 ( 3 ): e0119973 . Google Scholar CrossRef Search ADS PubMed 10. Nakajima M , Miyajima M , Ogino I et al. Cerebrospinal fluid biomarkers for prognosis of long-term cognitive treatment outcomes in patients with idiopathic normal pressure hydrocephalus . J Neurol Sci . 2015 ; 357 ( 1-2 ): 88 – 95 . Google Scholar CrossRef Search ADS PubMed 11. Bergsneider M , Black PM , Klinge P , Marmarou A , Relkin N . Surgical management of idiopathic normal-pressure hydrocephalus . Neurosurgery . 2005 ; 57 ( 3 suppl ): S29 – S39 . Google Scholar PubMed 12. Nakajima M , Miyajima M , Ogino I et al. Use of external lumbar cerebrospinal fluid drainage and lumboperitoneal shunts with Strata NSC valves in idiopathic normal pressure hydrocephalus: a single-center experience . World Neurosurg . 2015 ; 83 ( 3 ): 387 – 393 . Google Scholar CrossRef Search ADS PubMed 13. Kazui H , Miyajima M , Mori E et al. Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial . Lancet Neurol . 2015 ; 14 ( 6 ): 585 – 594 . Google Scholar CrossRef Search ADS PubMed 14. Miyajima M , Kazui H , Mori E , Ishikawa M , SINPHONI-2 Investigators . One-year outcome in patients with idiopathic normal-pressure hydrocephalus: comparison of lumboperitoneal shunt to ventriculoperitoneal shunt . J Neurosurg . 2016 ; 125 ( 6 ): 1483 – 1492 . Google Scholar CrossRef Search ADS PubMed 15. Freimann FB , Sprung C . Shunting with gravitational valves–can adjustments end the era of revisions for overdrainage-related events?: clinical article . J Neurosurg . 2012 ; 117 ( 6 ): 1197 – 1204 . Google Scholar CrossRef Search ADS PubMed 16. Freimann FB , Ötvös J , Chopra SS , Vajkoczy P , Wolf S , Sprung C . Differential pressure in shunt therapy: investigation of position-dependent intraperitoneal pressure in a porcine model . J Neurosurg Pediatr . 2013 ; 12 ( 6 ): 575 – 581 . Google Scholar CrossRef Search ADS PubMed 17. Meier U , Stengel D , Müller C et al. Predictors of subsequent overdrainage and clinical outcomes after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus . Neurosurgery . 2013 ; 73 ( 6 ): 1054 – 1060 . Google Scholar CrossRef Search ADS PubMed 18. Miyake H . Shunt devices for the treatment of adult hydrocephalus: recent progress and characteristics . Neurol Med Chir (Tokyo) . 2016 ; 56 ( 5 ): 274 – 283 . Google Scholar CrossRef Search ADS PubMed 19. Miyake H , Ohta T , Kajimoto Y , Nagao K . New concept for the pressure setting of a programmable pressure valve and measurement of in vivo shunt flow performed using microflow meter . J Neurosurg . 2000 ; 92 ( 1 ): 181 – 187 . Google Scholar CrossRef Search ADS PubMed 20. Bergsneider M , Yang I , Hu X , McArthur DL , Cook SW , Boscardin WJ . Relationship between valve opening pressure, body position, and intracranial pressure in normal pressure hydrocephalus: paradigm for selection of programmable valve pressure setting . Neurosurgery . 2004 ; 55 ( 4 ): 851 – 859 . Google Scholar CrossRef Search ADS PubMed 21. Farahmand D , Qvarlander S , Malm J , Wikkelsö C , Eklund A , Tisell M . Intracranial pressure in hydrocephalus: impact of shunt adjustments and body positions . J Neurol Neurosurg Psychiatry . 2015 ; 86 ( 2 ): 222 – 228 . Google Scholar CrossRef Search ADS PubMed 22. Diesner N , Freimann F , Clajus C , Kallenberg K , Rohde V , Stockhammer F . Female gender predisposes for cerebrospinal fluid overdrainage in ventriculoperitoneal shunting . Acta Neurochir . 2016 ; 158 ( 7 ): 1273 – 1278 . Google Scholar CrossRef Search ADS PubMed 23. Lemcke J , Meier U , Müller C et al. Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA) . J Neurol Neurosurg Psychiatry . 2013 ; 84 ( 8 ): 850 – 857 . Google Scholar CrossRef Search ADS PubMed 24. Ishikawa M . Guideline Committee for Idiopathic Normal Pressure Hydrocephalus, Japanese Society of Normal Pressure Hydrocephalus. Clinical guidelines for idiopathic normal pressure hydrocephalus . Neurol Med Chir (Tokyo) . 2004 ; 44 ( 4 ): 222 – 223 . Google Scholar CrossRef Search ADS PubMed 25. Mori E , Ishikawa M , Kato T et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition . Neurol Med Chir (Tokyo) . 2012 ; 52 ( 11 ): 775 – 809 . Google Scholar CrossRef Search ADS PubMed 26. van Swieten JC , Koudstaal PJ , Visser MC , Schouten HJ , van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients . Stroke . 1988 ; 19 ( 5 ): 604 – 607 . Google Scholar CrossRef Search ADS PubMed 27. Kubo Y , Kazui H , Yoshida T et al. Validation of grading scale for evaluating symptoms of idiopathic normal-pressure hydrocephalus . Dement Geriatr Cogn Disord . 2008 ; 25 ( 1 ): 37 – 45 . Google Scholar CrossRef Search ADS PubMed 28. Folstein MF , Folstein SE , McHugh PR . “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975 ; 12 ( 3 ): 189 – 198 . Google Scholar CrossRef Search ADS PubMed 29. Dubois B , Slachevsky A , Litvan I , Pillon B . The FAB: a Frontal Assessment Battery at bedside . Neurology . 2000 ; 55 ( 11 ): 1621 – 1626 . Google Scholar CrossRef Search ADS PubMed 30. Miyajima M , Nakajima M , Ogino I , Miyata H , Motoi Y , Arai H . Soluble amyloid precursor protein alpha in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus . Eur J Neurol . 2013 ; 20 ( 2 ): 236 – 242 . Google Scholar CrossRef Search ADS PubMed 31. Kajimoto Y , Ohta T , Miyake H et al. Posture-related changes in the pressure environment of the ventriculoperitoneal shunt system . J Neurosurg . 2000 ; 93 ( 4 ): 614 – 617 . Google Scholar CrossRef Search ADS PubMed 32. Kaijima M , Fukuda H , Yamamoto K . Post-operative complications peculiar to lumboperitoneal shunt: possible consequences due to side leakage of CSF from around the inserted spinal tube into the lumbar epidural space [in Japanese] . No Shinkei Geka . 2011 ; 39 ( 5 ): 497 – 504 . Google Scholar PubMed 33. Matsubara T , Ishikawa E , Hirata K et al. A new mechanism of cerebrospinal fluid leakage after lumboperitoneal shunt: a theory of shunt side hole–case report . Neurol Med Chir (Tokyo) . 2014 ; 54 ( 7 ): 572 – 577 . Google Scholar CrossRef Search ADS PubMed 34. Tarnaris A , Toma AK , Chapman MD , Keir G , Kitchen ND , Watkins LD . Use of cerebrospinal fluid amyloid-beta and total tau protein to predict favorable surgical outcomes in patients with idiopathic normal pressure hydrocephalus . J Neurosurg . 2011 ; 115 ( 1 ): 145 – 150 . Google Scholar CrossRef Search ADS PubMed 35. Pyykkö OT , Lumela M , Rummukainen J et al. Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus . PLoS One . 2014 ; 9 ( 3 ): e91974 . Google Scholar CrossRef Search ADS PubMed 36. Simón D , García-García E , Gómez-Ramos A et al. Tau overexpression results in its secretion via membrane vesicles . Neurodegener Dis . 2012 ; 10 ( 1-4 ): 73 – 75 . Google Scholar CrossRef Search ADS PubMed 37. Chai X , Dage JL , Citron M . Constitutive secretion of tau protein by an unconventional mechanism . Neurobiol Dis . 2012 ; 48 ( 3 ): 356 – 366 . Google Scholar CrossRef Search ADS PubMed 38. Kanmert D , Cantlon A , Muratore CR et al. C-terminally truncated forms of tau, but not full-length tau or its C-terminal fragments, are released from neurons independently of cell death . J Neurosci . 2015 ; 35 ( 30 ): 10851 – 10865 . Google Scholar CrossRef Search ADS PubMed 39. Karch CM , Jeng AT , Goate AM . Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies . J Biol Chem . 2012 ; 287 ( 51 ): 42751 – 42762 . Google Scholar CrossRef Search ADS PubMed 40. Bright J , Hussain S , Dang V et al. Human secreted tau increases amyloid-beta production . Neurobiol Aging . 2015 ; 36 ( 2 ): 693 – 709 . Google Scholar CrossRef Search ADS PubMed 41. Frost B , Jacks RL , Diamond MI . Propagation of tau misfolding from the outside to the inside of a cell . J Biol Chem . 2009 ; 284 ( 19 ): 12845 – 12852 . Google Scholar CrossRef Search ADS PubMed Operative Neurosurgery Speaks! Audio abstracts available for this article at www.operativeneurosurgery-online.com. COMMENT Utilization of ventriculoperitoneal (VP) shunts for idiopathic normal pressure hydrocephalus (iNPH) has overshadowed lumboperitoneal (LP) shunts, due to historically higher rates of shunt malfunction.1, 2 Although randomized clinical trials have comprehensively explored optimal valve settings in VP shunts for iNPH, optimizing LP shunts has lagged far behind.3 Thus, the authors should be commended for valiantly chartering into an ill-defined practice in NPH surgery: the optimal LP shunt configuration. This retrospective study of 115 patients compared programmable pressure valves (PPV) with small-lumen (SL) abdominal catheter versus PPV with gravitational “add-on” valve system (GV) in tandem. Following propensity score matching, PPV/+SL fared higher postoperative modified Rankin Scores (mRS) and iNPH grading scale (iNPHGS) gait disturbances compared to the PPV/+GV at 12-month follow up. While the conclusions—“more hardware, ergo better outcomes”—sound more like a talking point from industry representatives, the GV did statistically improve postoperative outcomes. When appropriately matched to historical controls, the add-on valve trended to a lower rate of nonserious adverse events, including subdural hematomas, putatively because the GV suppresses flow volume rate in the standing position to prevent intracranial hypotension. However, some of their improvement in outcome measures may reflect refinement in their techniques over time. Lastly, the GV valve tacked to the fascia in a vertical configuration may have reduced the rate of catheter kinking. The safety and efficacy of the add-on devices have been validated in the Shunt Valves plus shunt Assistant versus Shunt valves alone for controlling Overdrainage in idiopathic Normal pressure hydrocephalus in Adults (SVASONA) randomized clinical trial.4 The GV compared to PPV decreased subdural effusions, overdrainage, and underdrainage at 12-months. However, the study was limited to ventriculoperitoneal shunts, and the allocation groups included either PPV or GV, not PPV in tandem with PPV (PPV/+GV) as in the present review. Nevertheless, long-term outcome studies with gravitational shunts maintain a low complication rate: 3% catheter dislocation/fracture, 5% underdrainage, and 9% overdrainage according to a 5-year follow-up study in VP shunting.5 We look forward to similar long-term studies with GV in LP shunts. Mohamed Macki Jason Schwalb Detroit, Michigan 1. Abubaker K Ali Z Raza K Bolger C Rawluk D O’Brien D . Idiopathic intracranial hypertension: lumboperitoneal shunts versus ventriculoperitoneal shunts–case series and literature review . Br J Neurosurg . 2011 ; 25 ( 1 ): 94 - 99 . Google Scholar CrossRef Search ADS PubMed 2. McGirt MJ Woodworth G Thomas G Miller N Williams M Rigamonti D . Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes . J Neurosurg . 2004 ; 101 ( 4 ): 627 - 632 . Google Scholar CrossRef Search ADS PubMed 3. Boon AJ Tans JT Delwel EJ , et al. Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid . J Neurosurg . 1997 ; 87 ( 5 ): 687 - 693 . Google Scholar CrossRef Search ADS PubMed 4. Lemcke J Meier U Muller C , et al . Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA) . J Neurol Neurosurg Psychiatry . 2013 ; 84 ( 8 ): 850 - 857 . Google Scholar CrossRef Search ADS PubMed 5. Kiefer M Eymann R . Gravitational shunt complications after a five-year follow-up . Acta Neurochir Suppl . 2010 ; 106 : 107 - 112 . Google Scholar CrossRef Search ADS PubMed Operative Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Liang Chen, MD Department of Neurosurgery Huashan Hospital Shanghai, China Chinese: Liang Chen, MD Department of Neurosurgery Huashan Hospital Shanghai, China Close English: Roberto Jose Diaz, MD, PhD Department of Neurological Surgery University of Miami Miller School of Medicine Miami, Florida English: Roberto Jose Diaz, MD, PhD Department of Neurological Surgery University of Miami Miller School of Medicine Miami, Florida Close Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Close Italian: Michele Rizzi, MD “Claudio Munari” Epilepsy Surgery Center ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Italian: Michele Rizzi, MD “Claudio Munari” Epilepsy Surgery Center ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Close Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Close Spanish: Carlos Pérez-López, MD, PhD Department of Neurological Surgery Universitary Hospital La Paz Madrid, Spain Spanish: Carlos Pérez-López, MD, PhD Department of Neurological Surgery Universitary Hospital La Paz Madrid, Spain Close Russian: Natalia Denisova, MD Novosibirsk Federal Centre of Neurosurgery Novosibirsk, Russia Russian: Natalia Denisova, MD Novosibirsk Federal Centre of Neurosurgery Novosibirsk, Russia Close Korean: Tae Gon Kim, MD Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Korean: Tae Gon Kim, MD Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Greek: Alexiou A Georgios, MD Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Greek: Alexiou A Georgios, MD Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Operative Neurosurgery Oxford University Press

Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center

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Congress of Neurological Surgeons
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© Congress of Neurological Surgeons 2018.
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2332-4252
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2332-4260
D.O.I.
10.1093/ons/opy044
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Abstract

Abstract BACKGROUND Treating idiopathic normal pressure hydrocephalus (iNPH) with lumboperitoneal shunts (LPSs) may cause cerebrospinal fluid (CSF) overdrainage. OBJECTIVE To investigate whether LPSs, including gravitational “add-on” and programmable pressure valves (PPVs/+GVs), reduce complications and improve outcomes. METHODS We compared PPVs/+small lumen abdominal catheters (SLs) to PPVs/+GVs using different opening pressures for supine and standing positions. We analyzed 115 patients with iNPH in 2 consequent cohorts: 48 patients receiving LPSs with PPVs/+SLs and 67 patients receiving LPSs with PPVs/+GVs. The modified Rankin Scale (mRS), Japan iNPH grading scale, Mini Mental State Examination, Frontal Assessment Battery, and CSF biomarkers were evaluated. RESULTS Comparisons of postoperative clinical factors in 64 patients in the PPV/+SL and PPV/+GV groups using 1:1 propensity score matching revealed differences in the mean (±standard deviation) postoperative mRS (2.65 ± 1.07 vs 2.16 ± 1.02, P = .049) and gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Thus, outcomes improved in the LPS group with the GV. Serious and nonserious adverse event rates for the PPV/+SL and PPV/+GV groups were 22.9% and 19.4% (P = .647) and 38% and 17.9% (P = .018), respectively, indicating higher rates of subdural collections for the PPV/+SL group. CONCLUSION This is the first study to examine LPS treatment for iNPH using a GV in tandem with a PPV. Our results suggest that the CSF shunt flow volume is restricted in the standing position and maintained in the supine position, thus improving iNPH symptoms. This may reduce intracranial CSF hypotension-related complications. Cerebrospinal fluid, Cognitive function, Hydrocephalus, Ventriculomegaly, Gravity ABBREVIATIONS ABBREVIATIONS CSF cerebrospinal fluid FAB Frontal Assessment Battery GV gravitational add-on valve ICP intracranial pressure iNPH idiopathic normal pressure hydrocephalus iNPHGS idiopathic normal pressure hydrocephalus grading scale LPS lumboperitoneal shunt MMSE Mini Mental State Examination mRS modified Rankin Scale OD overdrainage PPV programmable pressure valve SD standard deviation SL small-lumen VPS ventriculoperitoneal shunt Idiopathic normal pressure hydrocephalus (iNPH), a disease with uncertain etiology that characteristically afflicts older adults, is characterized by cognitive decline, gait and balance impairments, and urinary incontinence.1,2 iNPH is commonly treated with cerebrospinal fluid (CSF) shunts, as this is the only treatment with clear evidence of effectiveness.3 Although the mechanism for recovery following shunt treatment remains unclear, research suggests that shunts improve CSF clearance and adjust the intracranial pressure (ICP).4 Subsequent studies have demonstrated that lymphatic transport is controlled by the brain's arousal level.5,6 The volume of the interstitial space in the brain expands significantly during sleep or anesthesia when compared with the awake state.7,8 CSF shunts may also facilitate the excretion of brain extracellular metabolites, which include neurotoxic proteins such as amyloid beta (Aβ) and phosphorylated tau (p-tau).9,10 A previous study reported elevated Aβ38 and Aβ42 levels following shunt implantation, likely owing to improved CSF clearance after surgery.10 Ventriculoperitoneal shunt (VPS) implantation is currently the standard treatment for patients with iNPH.11 In Japan, however, a lumboperitoneal shunt (LPS), which is a less invasive treatment, is used more frequently.12 LPS treatment has been recognized as an effective approach for iNPH,13 though its higher revision rates compared with VPS and more-frequent complications due to CSF overdrainage (OD) are problematic.14 Although the mechanisms are unclear, OD seems to occur more frequently in tall and thin individuals. Some authors contend that the siphon effect in the standing position has the strongest influence on this mechanism.15-17 The programmable pressure valve (PPV), in which the pressure is adjusted according to the individual's ICP and body constitution, is known to be more effective than fixed pressure valves for preventing OD complications.18,19 However, the PPV cannot control the CSF shunt flow volume when there is a change in posture or an increase in ICP due to coughing or straining.20,21 This is a limitation that requires a solution. Various anti-siphon devices that control CSF shunt flow volume are available. They include siphon guards (Codman and Shurteleff; Johnson and Johnson, New Brunswick, New Jersey), small-lumen abdominal catheters (SL 43555; Medtronic Neurosurgery, Medtronic Inc, Dublin, Ireland), and gravitational “add-on” valve systems (GV; Aesculap-Miethke, Tuttlingen, Germany).22 The inner diameter (0.7 mm) of the SL catheter is smaller than that of the conventionally used abdominal catheter. The increased resistance of the SL catheter aims to prevent OD.12 However, the siphon guard effect of the SL catheter is not necessarily effective as a short abdominal catheter for LPS, as it depends on the catheter length. Some studies have reported the effectiveness of GVs for the prevention of OD in devices that automatically increase shunt pressure with changes in posture.23 The gravitational unit gradually adds resistance to the pre-set opening pressure when the valve is raised from an angle of 0° toward the upright position at an angle of 90°. While facilitating the excretion of brain extracellular metabolites, it is important to maintain a CSF flow of sufficient volume to increase the clearance of these proteins while avoiding OD complications. We hypothesized that CSF shunt with GV for iNPH would clear brain extracellular metabolites more efficiently during sleep and in the supine position. Shunt treatment guarantees a larger CSF shunt flow volume in the supine position, which indicates that shunt systems with GV can be developed to remove brain extracellular metabolites. However, to our knowledge, no studies have yet investigated the efficacy LPS with a GV. Therefore, we evaluated whether LPS treatment using a shunt system with a GV installed in tandem with a PPV would reduce complications arising from OD and improve patient outcomes. METHODS Study Design We implanted a GV, which is used to maintain higher CSF flow in the supine position, and a PPV set to low pressure in a sequential column to create an LPS. We compared this device to an SL catheter. We conducted a preliminary experiment to test a system using the siphon effect created by the 2 different types of devices to prevent excessive CSF outflow. A previous study reported that patients with iNPH require a mean (±standard deviation [SD]) vertical effective opening pressure of the entire shunt system of 27.5 ± 3.3 cmH2O, while patients with congenital hydrocephalus require a pressure of 36.3 ± 23.3 cmH2O, and patients with malresorptive hydrocephalus require a pressure of 35.9 ± 20.4 cmH2O.22 We therefore set the standing (vertical) pressure at 35 cmH2O (close to the pressures established above) and the supine (horizontal) position pressure at 10 cmH2O. The results of the experiment indicated that GVs placed into a column in sequence limit CSF flow to a greater extent while the patient is in the standing position, and maintain flow while the patient is in the supine position (Figures 1 and 2). FIGURE 1. View largeDownload slide Shunt system experiments. Based on previous studies, we set the standing (vertical) pressure at 35 cmH2O and the supine (horizontal) position pressure at 10 cmH2O. We simulated CSF “production” at 20 mL/h by injecting H2O using a syringe pump connected to the main hydrostatic pressure column. We measured the flow from the 2 types of systems under the 2 different postural conditions (vertical and horizontal) by measuring total discharge for 10 min at 5 performance levels, as follows: 0.5 (15-35 mmH2O), 1.0 (35-55 mmH2O), 1.5 (90-110 mmH2O), 2.0 (145-165 mmH2O), and 2.5 (200-220 mmH2O). FIGURE 1. View largeDownload slide Shunt system experiments. Based on previous studies, we set the standing (vertical) pressure at 35 cmH2O and the supine (horizontal) position pressure at 10 cmH2O. We simulated CSF “production” at 20 mL/h by injecting H2O using a syringe pump connected to the main hydrostatic pressure column. We measured the flow from the 2 types of systems under the 2 different postural conditions (vertical and horizontal) by measuring total discharge for 10 min at 5 performance levels, as follows: 0.5 (15-35 mmH2O), 1.0 (35-55 mmH2O), 1.5 (90-110 mmH2O), 2.0 (145-165 mmH2O), and 2.5 (200-220 mmH2O). FIGURE 2. View largeDownload slide Comparison between the small-lumen abdominal catheter and gravitational add-on valve. We measured the flow rate (mL/h) at simulated standing (35 cmH2O) and supine (10 cmH2O) positions for the 5 performance levels of the Strata NSC valve, ranging from 0.5 to 2.5. When the PPV and GV were placed in tandem and the pressure was set at level 2.5 (22.5 cmH2O) plus 15 cmH2O, the flow volume was 0 mL in the standing position. In this position, the GV led to a greater reduction in flow volume than did the small-lumen abdominal catheter at all settings, while greater flow volume was obtained at the lower level settings of 0.5 and 1.0 in the supine position. FIGURE 2. View largeDownload slide Comparison between the small-lumen abdominal catheter and gravitational add-on valve. We measured the flow rate (mL/h) at simulated standing (35 cmH2O) and supine (10 cmH2O) positions for the 5 performance levels of the Strata NSC valve, ranging from 0.5 to 2.5. When the PPV and GV were placed in tandem and the pressure was set at level 2.5 (22.5 cmH2O) plus 15 cmH2O, the flow volume was 0 mL in the standing position. In this position, the GV led to a greater reduction in flow volume than did the small-lumen abdominal catheter at all settings, while greater flow volume was obtained at the lower level settings of 0.5 and 1.0 in the supine position. We compared LPS treatment in individuals with iNPH using 2 different shunt systems designed to prevent OD. Two consecutive groups of patients were treated. The first group was treated with an SL catheter attached to a PPV, which represented the best available standard treatment (PPV/+SL group).12 The second group was treated with a GV in tandem with a PPV with different opening pressures (PPV/+GV group). We compared the PPV/+GV group to the PPV/+SL group, which was used as a control group. The components listed in sequence from proximal to distal were as follows: PPV/+SL group, lumbar catheter + Strata NSC valve + SL catheter (43555); and PPV/+GV group, lumbar catheter + GV “shunt assistant” 0-15 cmH2O (Aesculap-Miethke) + Strata NSC valve + abdominal catheter (27536). Patients The patients were reviewed retrospectively. The patients in this cohort received an LPS after attending consultations in our department and were suspected of having iNPH based on neurological manifestations and magnetic resonance imaging. Our evaluation criteria were consistent with the Japanese guidelines for iNPH.24,25 We compared the following 2 iNPH patient groups (n = 115 in total): 48 patients treated with LPS with PPV/+SL (19 women; mean age ± SD, 74.5 ± 6.3 yr; from 2010 to 2012), and 67 patients treated with LPS with PPV/+GV (21 women; 75.4 ± 5.6 yr; from 2013 to 2015; Figure 3 and Table 1). Twelve months after shunt implantation, we evaluated the patients using the modified Rankin Scale (mRS),26 iNPH grading scale (iNPHGS),27 Mini Mental State Examination (MMSE),27 and Frontal Assessment Battery (FAB).29 We also measured CSF biomarkers (soluble amyloid precursor protein [sAPPα], Aβ38, Aβ42, and p-tau).30 All patients provided prior written consent for their participation in the study, which was conducted after ethics committee approval. FIGURE 3. View largeDownload slide Subject flow diagram. GV = gravity add-on valve, iNPH = idiopathic normal pressure hydrocephalus, LPS = lumboperitoneal shunt, MMSE = Mini Mental State Examination, PPV = programmable pressure valve, p-tau = phosphorylated tau, sAPPα = soluble amyloid precursor protein alpha, SL = small-lumen abdominal catheter. FIGURE 3. View largeDownload slide Subject flow diagram. GV = gravity add-on valve, iNPH = idiopathic normal pressure hydrocephalus, LPS = lumboperitoneal shunt, MMSE = Mini Mental State Examination, PPV = programmable pressure valve, p-tau = phosphorylated tau, sAPPα = soluble amyloid precursor protein alpha, SL = small-lumen abdominal catheter. TABLE 1. Characteristics at Baseline Data for iNPH Patients Before Lumboperitoneal Shunt Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin Scale, iNPHGS: idiopathihc normal pressure hydrocephalus grading scale, MMSE: mini mental scale examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated-tau, Aβ: amyloid beta. Binomial logistic regression. Preservation prediction value was obtained by calculating the score with probability P and producing preoperative numerical values between the PPV/+SL and PPV/+GV groups. Propensity score: 0.186-0.863. *P < .05. View Large TABLE 1. Characteristics at Baseline Data for iNPH Patients Before Lumboperitoneal Shunt Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 Unmatched (bivariate) Matched 1:1 PPV/+SL PPV/+GV Total P-value PPV/+SL PPV/+GV Total P-value Patients [number] 48 67 115 32 32 64  Sex: women [number (%)] 19 (40%) 21 (31%) 40 (35%) .360 14 (44%) 9 (28%) 23 (36%) .193  Age (yr) [mean ± SD] 74.5 ± 6.3 75.4 ± 5.6 75.0 ± 5.9 .921 75.3 ± 6.0 75.5 ± 5.7 75.4 ± 5.8 .619  BMI (kg/m2) [mean ± SD] 23.5 ± 3.6 24.1 ± 3.4 23.8 ± 3.5 .498 23.3 ± 3.6 23.9 ± 3.1 23.6 ± 3.3 .627  DESH [number (%)] 38 (79%) 56 (84%) 94 (82%) .546 26 (81%) 26 (81%) 52 (81%) 1.000 Clinical findings [mean ± SD]  mRS 3.04 ± 0.80 2.76 ± 0.68 2.88 ± 0.74 *.042 3.09 ± 0.86 2.81 ± 0.62 2.95 ± 0.74 .088  iNPHGS-total 5.96 ± 2.42 5.72 ± 2.22 5.82 ± 2.30 .538 6.19 ± 2.64 5.47 ± 2.05 5.76 ± 2.38 .244  Gait disturbance 2.42 ± 0.82 2.24 ± 0.79 2.32 ± 0.80 .313 2.47 ± 0.92 2.19 ± 0.75 2.33 ± 0.84 .249  Cognitive impairment 1.92 ± 1.05 1.73 ± 0.90 1.81 ± 0.97 .227 2.03 ± 1.09 1.71 ± 0.69 1.87 ± 0.92 .133  Urinary incontinence 1.73 ± 1.14 1.83 ± 1.03 1.79 ± 1.08 .729 1.78 ± 1.21 1.74 ± 0.97 1.75 ± 1.09 .853 Neuropsychological Test [mean ± SD]  MMSE 22.6 ± 5.0 21.7 ± 6.5 22.1 ± 5.9 .635 21.8 ± 5.6 22.6 ± 4.7 22.2 ± 5.2 .751  FAB 12.0 ± 3.4 10.3 ± 3.9 11.0 ± 3.8 *.017 11.4 ± 3.9 10.9 ± 2.8 11.1 ± 3.4 .339 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 146.7 ± 75.4 155.3 ± 73.4 151.7 ± 74.1 .471 151.9 ± 84.3 148.9 ± 70.4 150.4 ± 77.1 .973  p-tau (pg/mL) 23.8 ± 10.2 31.1 ± 14.5 28.1 ± 14.5 *.005 24.4 ± 10.2 25.7 ± 7.8 25.1 ± 9.1 .282  Aβ38 (pg/mL) 2261 ± 1711 2500 ± 1297 2414 ± 1457 .102 2453 ± 1748 2483 ± 1503 2468 ± 1617 .582  Aβ42 (pg/mL) 383 ± 209 561 ± 234 487 ± 240 *<.001 416 ± 202 484 ± 157 459 ± 172 .182  Aβ38/Aβ42 6.45 ± 4.55 5.05 ± 3.48 5.55 ± 3.94 .088 6.49 ± 3.58 5.64 ± 4.30 5.86 ± 3.92 .338  Aβ42/p-tau 18.12 ± 10.28 21.25 ± 11.14 19.94 ± 10.85 .175 20.25 ± 9.99 20.75 ± 9.08 20.50 ± 9.81 .914 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin Scale, iNPHGS: idiopathihc normal pressure hydrocephalus grading scale, MMSE: mini mental scale examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated-tau, Aβ: amyloid beta. Binomial logistic regression. Preservation prediction value was obtained by calculating the score with probability P and producing preoperative numerical values between the PPV/+SL and PPV/+GV groups. Propensity score: 0.186-0.863. *P < .05. View Large Procedure Neurologists or neurosurgeons screened the patients, and 2 neurosurgeons selected the patients for surgery. Surgeons with extensive experience in the procedure conducted both types of surgical procedures. No significant technical difference was identified between the LPS with PPV/+SL and the LPS with PPV/+GV implantation procedures.12 Implantations were conducted under general or spinal anesthesia. In the LPS technique, approximately 15 cm of the spinal catheter was inserted through the L3/4 or L2/3 interlaminar space into the lumbar subarachnoid space using the paramedian approach. In the PPV/+GV group, after using the step-down connector, the GV was placed in the lower back so that it would be vertical when the patient was in the standing position (Figure 4). Once the L-shaped connector (Aesculap-Miethke) was applied, a subcutaneous tunnel was made to the ventral side, the abdominal catheter was passed through it ventrally, and the PPV was placed subcutaneously on the ventral side. The abdominal catheter, trimmed to about 30 cm, was inserted into the abdominal cavity after being connected to the PPV. FIGURE 4. View largeDownload slide A lumbar 3-dimensional image obtained after LPS implantation with a gravity add-on valve and a Strata NSC programmable pressure valve. FIGURE 4. View largeDownload slide A lumbar 3-dimensional image obtained after LPS implantation with a gravity add-on valve and a Strata NSC programmable pressure valve. Valve Pressure Adjustment Protocol The initial pressure for the shunt system was set to its highest level of 2.5 (22.5 cmH2O). We checked the function of the shunt if no improvement in the patient's clinical symptoms were observed, when the high convexity and medial subarachnoid spaces were tight, or when acute callosal angles were observed.12 We lowered the pressure setting by 1 step (0.5 level) if symptoms did not improve at all 1 wk after the operation. If improvement was observed, but was deemed insufficient (half or less of the effects observed in the tap test, except when there was a steady improvement), we lowered the pressure setting further by 0.5-level intervals, with careful consideration of the patient's safety range. The pressure setting was increased immediately if a symptomatic subdural hematoma related to OD was found. CSF Analysis We obtained lumbar CSF before and after the LPS procedure. All CSF samples were aliquoted and stored in polypropylene tubes at –80°C until biochemical analysis.28 Shunt reservoir and lumbar CSF biomarkers were also compared.9,10 CSF biomarkers included sAPPα (Human sAPPα Assay Kit; IBL No. 27719; Immuno-Biological Laboratories Co, Ltd, Takasaki, Japan), Aβ38 (Human Amyloid β1-38 Assay Kit, IBL No. 27717; Immuno-Biological Laboratories Co, Ltd), Aβ42 (Innotest β amyloid 1–42; Innogenetics, Ghent, Belgium), and p-tau (Innotest phospho tau-181p; Innogenetics). Immunosorbent assays were used for the rest of the biomarker measurements (Table 1). Outcome Measures We compared the mRS, iNPHGS, MMSE, and FAB scores, and sAPPα, Aβ38, Aβ42, and p-tau concentrations, as well as the presence of any complications before and 12 mo after LPS. Statistical analysis Patients who underwent the PPV/+GV implantation procedure were matched using 1:1 propensity score matching to patients who underwent the PPV/+SL procedure. Propensity scores were calculated for background factors comprising preintervention mRS and FAB scores, and p-tau and Aβ42 levels (Table 1). We used nonparametric methods for the analyses, including Mann–Whitney U-tests and Pearson's chi-squared tests, to identify changes from baseline. We used an analysis of covariance to reveal differences in the changes between the patient groups. Adverse events were analyzed using a safety analysis set that included all patients who received an LPS. The significance level was set at a 2-sided P = .05. Statistical data were analyzed using SPSS version 22 (IBM Inc, Armonk, New York). RESULTS Clinical Findings The final programmable median valve pressures for the PPV/+SL and PPV/+GV groups were 1.5 (interquartile range, 1.0-2.0) and 1.0 (interquartile range, 0.5-1.5), respectively. We succeeded in using lower pressures on the pressure-adjustable GV. A comparison of postoperative clinical factors in the 64 patients in the PPV/+SL and PPV/+GV groups that was adjusted and 1:1 propensity score matched for confounding variables indicated significant differences in the mean (±SD) postoperative mRS scores (2.65 ± 1.07 vs 2.16 ± 1.0, P = .049) and iNPHGS gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Therefore, the outcomes were improved in the LPS group with the GV. No statistically significant differences in the other factors were identified (Figure 5; Table 2). The p-tau concentration was the only CSF biomarker that was significantly different between the groups. The level of p-tau was 52.1 ± 30.2 pg/mL in the PPV/+SL group and 77.0 ± 41.0 pg/mL in the PPV/+GV group (P = .015). FIGURE 5. View largeDownload slide mRS score changes after LPS implantation. FIGURE 5. View largeDownload slide mRS score changes after LPS implantation. TABLE 2. Comparisons Before and After Therapeutic Shunt Intervention After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, SD: standard deviation, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin scale, iNPHGS: idiopathic normal pressure hydrocephalus grading scale, MMSE: Mini Mental State Examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated tau, Aβ: amyloid beta. *P < .05. View Large TABLE 2. Comparisons Before and After Therapeutic Shunt Intervention After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 After Before/After (P-value) PPV/+SL PPV/+GV Total SL/GV (P-value) SL GV Total Patients [Number] 32 32 64 32 32 64 Clinical findings [mean ± SD]  mRS 2.65 ± 1.07 2.16 ± 1.02 2.41 ± 1.07 *.049 *.014 *<.0001 *<.0001  iNPHGS-total 4.47 ± 2.83 3.44 ± 2.06 3.95 ± 2.51 .095 *.001 *<.0001 *<.0001  Gait disturbance 1.97 ± 1.03 1.39 ± 0.92 1.68 ± 1.01 *.011 *.001 *<.0001 *<.0001  Cognitive impairment 1.50 ± 1.14 1.09 ± 0.69 1.30 ± 0.95 .150 *.003 *<.0001 *<.0001  Urinary incontinence 1.25 ± 1.16 1.00 ± 0.80 1.13 ± 1.00 .544 *.003 *<.0001 *<.0001 Neuropsychological Test [mean ± SD]  MMSE 23.8 ± 5.4 25.2 ± 4.1 24.5 ± 4.8 .357 *.002 *<.0001 *<.0001  FAB 13.0 ± 3.7 12.0 ± 3.3 12.5 ± 3.5 .182 *.018 .086 *.004 CSF biomarker [mean ± SD]  sAPPα (ng/mL) 153.9 ± 73.7 202 ± 114.7 178.9 ± 99.3 .132 .642 *<.0001 *.008  p-tau (pg/mL) 52.1 ± 30.2 77.0 ± 41.0 64.8 ± 37.9 *.015 *.009 *<.0001 *<.0001  Aβ38 (pg/mL) 3745 ± 2193 3421 ± 1528 3581 ± 1877 .815 *<.0001 *.003 *<.0001  Aβ42 (pg/mL) 578 ± 274 667 ± 335 623 ± 308 .372 *.003 *.005 *<.0001  Aβ38/Aβ42 6.49 ± 3.58 6.08 ± 4.12 6.28 ± 3.84 .338 .758 .432 .400  Aβ42/-p-tau 13.38 ± 8.48 11.28 ± 8.48 12.31 ± 7.82 .357 *.001 *<.0001 *<.0001 PPV: programmable pressure valve, SL: small inner-lumen abdominal catheter, GV: gravitational “add-on” valve, SD: standard deviation, BMI: body mass index, DESH: disproportionately enlarged subarachnoid-space hydrocephalus, mRS: modified Rankin scale, iNPHGS: idiopathic normal pressure hydrocephalus grading scale, MMSE: Mini Mental State Examination, FAB: Frontal Assessment Battery, sAPPα: soluble amyloid precursor protein alpha, p-tau: phosphorylated tau, Aβ: amyloid beta. *P < .05. View Large Adverse Events Associated with LPS The incidence of nonserious adverse events was significantly different between the 2 groups (P = .018; Table 3). The rates of postoperative headache in the PPV/+SL and PPV/+GV groups were 29.2% (n = 14/48) and 14.9% (n = 10/67), respectively (P = .064). The rates of asymptomatic subdural effusions and subdural hematomas (conservatively treated) were 8.3% (n = 4/48) and 3% (n = 2/67) in the PPV/+SL and PPV/+GV groups, respectively (P = .203). The rates of chronic subdural hematomas requiring surgery were 3.9% (n = 2/48) and 0% in the PPV/+SL and PPV/+GV groups, respectively (P = .092). The proportion of patients requiring revision due to proximal catheter failure was 12.5% (n = 6/48) in the PPV/+SL group and 16.4% (n = 11/67) in the PPV/+GV group (P = .559). No statistically significant differences were found in the occurrence of serious adverse events between the 2 groups. TABLE 3. Adverse Events Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Chi-squared test: comparison of adverse events between the PPV/+SL and PPV/+GV groups after shunt insertion. *P < .05. View Large TABLE 3. Adverse Events Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Parameter PPV/+SL PPV/+GV P-value No. of patients 48 67 Serious adverse events  No. of patients (%) 11 (22.9%) 13 (19.4%) .647  Subdural hematoma requiring surgery 2 (4.1%) 0 (0%) .092  Shunt tube—total events 6 (12.5%) 11 (16.4%) .559  Shunt tube migration requiring revision 2 (4.1%) 1 (1.5%) .375  Shunt tube rupture requiring revision 0 (0%) 1 (1.5%) .395  Shunt tube obstruction requiring revision 4 (7.8%) 9 (13.4%) .394  Meningitis 1 (2.1%) 1 (1.5%) .811  Cerebral infarction 2 (4.1%) 1 (1.5%) .375  Death 1 (2.1%) 0 (0%) .235 Nonserious adverse events  No. of patients (%) 18 (38%) 12 (17.9%) *.018  Postural headache 14 (29.2%) 10 (14.9%) .064  Asymptomatic subdural effusion and subdural hematoma (conservative treatment) 4 (8.3%) 2 (3.0%) .203 Chi-squared test: comparison of adverse events between the PPV/+SL and PPV/+GV groups after shunt insertion. *P < .05. View Large DISCUSSION This is the first study to examine the use of GVs for LPS in individuals with iNPH, although research groups in Germany have already reported a multicenter open-label randomized parallel-group trial for VPS.23 The abovementioned study, called SVASONA, found that GVs reduce the risk of OD complications following VPS surgery. Selecting the appropriate opening pressure for the gravitational unit remains a critical treatment decision that is made according to the patient's body mass index. The rationale behind this setting is that the level of compensation for hydrostatic pressure (HP) changes ultimately depends on the height of the upper body and the intra-abdominal pressure (IAP). Kajimoto et al31 evaluated the ICP, IAP, HP, and perfusion pressure of the shunt system using telemetric sensors in 13 patients in both the supine and sitting positions. In the supine position, the mean (±SD) ICP, IAP, and HP were 4.6 ± 3 mm Hg, 5.7 ± 3.3 mm Hg, and 3.3 ± 1 mm Hg, respectively. As a result, the perfusion pressure was 2.2 ± 4.9 mm Hg. When patients were raised to the sitting position, the IAP increased to 14.7 ± 4.8 mm Hg, ICP decreased to –14.2 ± 4.5 mm Hg, and HP increased to 42.9 ± 3.5 mm Hg. Consequently, the perfusion pressure increased to 14 ± 6.3 mm Hg. These data are useful for determining LPS function parameters in the standing position. The LPS system with a PPV/+GV (0-15 cmH2O) has the potential to suppress the standing flow volume rate when the PPV is set to the appropriate pressure and there is sufficient supine flow volume. Changes in Neurological Symptoms and Complications after LPS Surgical Treatment Here, LPS treatment with PPV/+GV reduced nonserious OD complications when compared with LPS with PPV/+SL. However, orthostatic headache, which was observed immediately after LPS, was present even in the PPV/+GV group. We surmise that orthostatic headache occurs due to CSF leakage around the spinal catheter into the epidural space in the early postoperative period.32,33 This is a problem unique to LPS. Patients who were treated using GVs had a tendency of higher revision rates due to proximal catheter failure. As the GV must be placed in tandem with the PPV, we presume that tube kinking occurs more readily in front of or behind the GV when it is placed vertically. Technically, this catheter kinking could be avoided by directly fixing the GV or the L- or U-shaped connector to the fascia. We may be able to avoid these complications in the future if a device is developed that allows the GV to be placed horizontally. Changes in CSF Biomarkers After Shunt Implantation In our study, the p-tau levels increased significantly after shunt surgery. The level of p-tau after shunt was 52.1 ± 30.2 pg/mL in the PPV/+SL group and 77.0 ± 41.0 pg/mL in the PPV/+GV group (P = .015). This finding is consistent with those of previous reports by Moriya et al9 and Tarnaris et al.34 Pyykkö et al35 measured p-tau (Innotest phospho tau-181p; Innogenetics) in the lumbar subarachnoid and intraventricular CSF of patients with iNPH before shunt and found that the mean lumbar and ventricular levels of p-tau were 39.5 ± 15.7 pg/mL and 81.3 ± 75.5 pg/mL, respectively. The mean ventricular levels of p-tau were twice as high as that in the lumbar subarachnoid space. Collectively, these results support that p-tau in the CSF may spread into the subarachnoid space after shunt treatment, although the exact mechanisms have not yet been established. It remains unclear why elevated p-tau concentrations occur following CSF drainage. For many years, tau protein was thought to be localized and functional in the cytoplasm, though recent studies have reported that some tau protein may be secreted outside the cell under certain physiological conditions.36 Studies have also reported that tau protein can be detected in various cell culture supernatants, such as cultured cells that overexpress tau protein,37 primary cultured neurons,38,39 and neurons derived from induced pluripotent stem cells.40 These forms of extracellular tau protein secretion are different from the nonspecific release of cellular proteins due to cell death and suggest that a specific secretion mechanism may exist. Future research should investigate the presence of tau protein with an aggregation state that is involved in its extracellular release under certain physiological conditions, the participating metabolic machinery, and cell-to-cell transmission/propagation.41 Limitations This study has some limitations related to its design. First, this was a retrospective cohort study, and is thus inherently prone to selection bias. Second, clinical improvement is a subjective measure that can be difficult to precisely quantify based on patient notes in medical records. Finally, the small sample size limited the power of the study. Future prospective studies are required to verify our findings. CONCLUSION This is the first study to examine LPS with the insertion of a GV in tandem with a PPV for the treatment of iNPH. Our results suggest that CSF shunt flow volume is more restricted in the standing position and is maintained in the supine position, thus improving iNPH symptoms. This may reduce complications associated with intracranial CSF hypotension. Disclosures This work was supported in part by the Ministry of Health, Labour, and Welfare of Japan and in part by a Grant-in-Aid for Scientific Research Grant Number (B #26293326) from the Japan Society for the Promotion of Science. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Adams RD , Fisher CM , Hakim S , Ojemann RG , Sweet WH . Symptomatic occult hydrocephalus with normal cerebrospinal-fluid pressure . N Engl J Med . 1965 ; 273 ( 3 ): 117 – 126 . Google Scholar CrossRef Search ADS PubMed 2. Hakim S , Adams RD . The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure . J Neurol Sci . 1965 ; 2 ( 4 ): 307 – 327 . Google Scholar CrossRef Search ADS PubMed 3. Pinto FC , Saad F , Oliveira MF et al. Role of endoscopic third ventriculostomy and ventriculoperitoneal shunt in idiopathic normal pressure hydrocephalus . Neurosurgery . 2013 ; 72 ( 5 ): 845 – 854 . Google Scholar CrossRef Search ADS PubMed 4. Johanson CE , Duncan JA 3rd , Klinge PM , Brinker T , Stopa EG , Silverberg GD . Multiplicity of cerebrospinal fluid functions: new challenges in health and disease . Cerebrospinal Fluid Res . 2008 ; 5 ( 1 ): 10 . Google Scholar CrossRef Search ADS PubMed 5. Iliff JJ , Wang M , Liao Y et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid . Sci Transl Med . 2012 ; 4 ( 147 ): 147ra111 – 147ra111 . Google Scholar CrossRef Search ADS PubMed 6. Louveau A , Harris TH , Kipnis J . Revisiting the mechanisms of CNS immune privilege . Trends Immunol . 2015 ; 36 ( 10 ): 569 – 577 . Google Scholar CrossRef Search ADS PubMed 7. Lee H , Xie L , Yu M et al. The effect of body posture on brain glymphatic transport . J Neurosci . 2015 ; 35 ( 31 ): 11034 – 11044 . Google Scholar CrossRef Search ADS PubMed 8. Xie L , Kang H , Xu Q et al. Sleep drives metabolite clearance from the adult brain . Science . 2013 ; 342 ( 6156 ): 373 – 377 . Google Scholar CrossRef Search ADS PubMed 9. Moriya M , Miyajima M , Nakajima M , Ogino I , Arai H . Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade . PLoS One . 2015 ; 10 ( 3 ): e0119973 . Google Scholar CrossRef Search ADS PubMed 10. Nakajima M , Miyajima M , Ogino I et al. Cerebrospinal fluid biomarkers for prognosis of long-term cognitive treatment outcomes in patients with idiopathic normal pressure hydrocephalus . J Neurol Sci . 2015 ; 357 ( 1-2 ): 88 – 95 . Google Scholar CrossRef Search ADS PubMed 11. Bergsneider M , Black PM , Klinge P , Marmarou A , Relkin N . Surgical management of idiopathic normal-pressure hydrocephalus . Neurosurgery . 2005 ; 57 ( 3 suppl ): S29 – S39 . Google Scholar PubMed 12. Nakajima M , Miyajima M , Ogino I et al. Use of external lumbar cerebrospinal fluid drainage and lumboperitoneal shunts with Strata NSC valves in idiopathic normal pressure hydrocephalus: a single-center experience . World Neurosurg . 2015 ; 83 ( 3 ): 387 – 393 . Google Scholar CrossRef Search ADS PubMed 13. Kazui H , Miyajima M , Mori E et al. Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial . Lancet Neurol . 2015 ; 14 ( 6 ): 585 – 594 . Google Scholar CrossRef Search ADS PubMed 14. Miyajima M , Kazui H , Mori E , Ishikawa M , SINPHONI-2 Investigators . One-year outcome in patients with idiopathic normal-pressure hydrocephalus: comparison of lumboperitoneal shunt to ventriculoperitoneal shunt . J Neurosurg . 2016 ; 125 ( 6 ): 1483 – 1492 . Google Scholar CrossRef Search ADS PubMed 15. Freimann FB , Sprung C . Shunting with gravitational valves–can adjustments end the era of revisions for overdrainage-related events?: clinical article . J Neurosurg . 2012 ; 117 ( 6 ): 1197 – 1204 . Google Scholar CrossRef Search ADS PubMed 16. Freimann FB , Ötvös J , Chopra SS , Vajkoczy P , Wolf S , Sprung C . Differential pressure in shunt therapy: investigation of position-dependent intraperitoneal pressure in a porcine model . J Neurosurg Pediatr . 2013 ; 12 ( 6 ): 575 – 581 . Google Scholar CrossRef Search ADS PubMed 17. Meier U , Stengel D , Müller C et al. Predictors of subsequent overdrainage and clinical outcomes after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus . Neurosurgery . 2013 ; 73 ( 6 ): 1054 – 1060 . Google Scholar CrossRef Search ADS PubMed 18. Miyake H . Shunt devices for the treatment of adult hydrocephalus: recent progress and characteristics . Neurol Med Chir (Tokyo) . 2016 ; 56 ( 5 ): 274 – 283 . Google Scholar CrossRef Search ADS PubMed 19. Miyake H , Ohta T , Kajimoto Y , Nagao K . New concept for the pressure setting of a programmable pressure valve and measurement of in vivo shunt flow performed using microflow meter . J Neurosurg . 2000 ; 92 ( 1 ): 181 – 187 . Google Scholar CrossRef Search ADS PubMed 20. Bergsneider M , Yang I , Hu X , McArthur DL , Cook SW , Boscardin WJ . Relationship between valve opening pressure, body position, and intracranial pressure in normal pressure hydrocephalus: paradigm for selection of programmable valve pressure setting . Neurosurgery . 2004 ; 55 ( 4 ): 851 – 859 . Google Scholar CrossRef Search ADS PubMed 21. Farahmand D , Qvarlander S , Malm J , Wikkelsö C , Eklund A , Tisell M . Intracranial pressure in hydrocephalus: impact of shunt adjustments and body positions . J Neurol Neurosurg Psychiatry . 2015 ; 86 ( 2 ): 222 – 228 . Google Scholar CrossRef Search ADS PubMed 22. Diesner N , Freimann F , Clajus C , Kallenberg K , Rohde V , Stockhammer F . Female gender predisposes for cerebrospinal fluid overdrainage in ventriculoperitoneal shunting . Acta Neurochir . 2016 ; 158 ( 7 ): 1273 – 1278 . Google Scholar CrossRef Search ADS PubMed 23. Lemcke J , Meier U , Müller C et al. Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA) . J Neurol Neurosurg Psychiatry . 2013 ; 84 ( 8 ): 850 – 857 . Google Scholar CrossRef Search ADS PubMed 24. Ishikawa M . Guideline Committee for Idiopathic Normal Pressure Hydrocephalus, Japanese Society of Normal Pressure Hydrocephalus. Clinical guidelines for idiopathic normal pressure hydrocephalus . Neurol Med Chir (Tokyo) . 2004 ; 44 ( 4 ): 222 – 223 . Google Scholar CrossRef Search ADS PubMed 25. Mori E , Ishikawa M , Kato T et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition . Neurol Med Chir (Tokyo) . 2012 ; 52 ( 11 ): 775 – 809 . Google Scholar CrossRef Search ADS PubMed 26. van Swieten JC , Koudstaal PJ , Visser MC , Schouten HJ , van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients . Stroke . 1988 ; 19 ( 5 ): 604 – 607 . Google Scholar CrossRef Search ADS PubMed 27. Kubo Y , Kazui H , Yoshida T et al. Validation of grading scale for evaluating symptoms of idiopathic normal-pressure hydrocephalus . Dement Geriatr Cogn Disord . 2008 ; 25 ( 1 ): 37 – 45 . Google Scholar CrossRef Search ADS PubMed 28. Folstein MF , Folstein SE , McHugh PR . “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975 ; 12 ( 3 ): 189 – 198 . Google Scholar CrossRef Search ADS PubMed 29. Dubois B , Slachevsky A , Litvan I , Pillon B . The FAB: a Frontal Assessment Battery at bedside . Neurology . 2000 ; 55 ( 11 ): 1621 – 1626 . Google Scholar CrossRef Search ADS PubMed 30. Miyajima M , Nakajima M , Ogino I , Miyata H , Motoi Y , Arai H . Soluble amyloid precursor protein alpha in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus . Eur J Neurol . 2013 ; 20 ( 2 ): 236 – 242 . Google Scholar CrossRef Search ADS PubMed 31. Kajimoto Y , Ohta T , Miyake H et al. Posture-related changes in the pressure environment of the ventriculoperitoneal shunt system . J Neurosurg . 2000 ; 93 ( 4 ): 614 – 617 . Google Scholar CrossRef Search ADS PubMed 32. Kaijima M , Fukuda H , Yamamoto K . Post-operative complications peculiar to lumboperitoneal shunt: possible consequences due to side leakage of CSF from around the inserted spinal tube into the lumbar epidural space [in Japanese] . No Shinkei Geka . 2011 ; 39 ( 5 ): 497 – 504 . Google Scholar PubMed 33. Matsubara T , Ishikawa E , Hirata K et al. A new mechanism of cerebrospinal fluid leakage after lumboperitoneal shunt: a theory of shunt side hole–case report . Neurol Med Chir (Tokyo) . 2014 ; 54 ( 7 ): 572 – 577 . Google Scholar CrossRef Search ADS PubMed 34. Tarnaris A , Toma AK , Chapman MD , Keir G , Kitchen ND , Watkins LD . Use of cerebrospinal fluid amyloid-beta and total tau protein to predict favorable surgical outcomes in patients with idiopathic normal pressure hydrocephalus . J Neurosurg . 2011 ; 115 ( 1 ): 145 – 150 . Google Scholar CrossRef Search ADS PubMed 35. Pyykkö OT , Lumela M , Rummukainen J et al. Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus . PLoS One . 2014 ; 9 ( 3 ): e91974 . Google Scholar CrossRef Search ADS PubMed 36. Simón D , García-García E , Gómez-Ramos A et al. Tau overexpression results in its secretion via membrane vesicles . Neurodegener Dis . 2012 ; 10 ( 1-4 ): 73 – 75 . Google Scholar CrossRef Search ADS PubMed 37. Chai X , Dage JL , Citron M . Constitutive secretion of tau protein by an unconventional mechanism . Neurobiol Dis . 2012 ; 48 ( 3 ): 356 – 366 . Google Scholar CrossRef Search ADS PubMed 38. Kanmert D , Cantlon A , Muratore CR et al. C-terminally truncated forms of tau, but not full-length tau or its C-terminal fragments, are released from neurons independently of cell death . J Neurosci . 2015 ; 35 ( 30 ): 10851 – 10865 . Google Scholar CrossRef Search ADS PubMed 39. Karch CM , Jeng AT , Goate AM . Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies . J Biol Chem . 2012 ; 287 ( 51 ): 42751 – 42762 . Google Scholar CrossRef Search ADS PubMed 40. Bright J , Hussain S , Dang V et al. Human secreted tau increases amyloid-beta production . Neurobiol Aging . 2015 ; 36 ( 2 ): 693 – 709 . Google Scholar CrossRef Search ADS PubMed 41. Frost B , Jacks RL , Diamond MI . Propagation of tau misfolding from the outside to the inside of a cell . J Biol Chem . 2009 ; 284 ( 19 ): 12845 – 12852 . Google Scholar CrossRef Search ADS PubMed Operative Neurosurgery Speaks! Audio abstracts available for this article at www.operativeneurosurgery-online.com. COMMENT Utilization of ventriculoperitoneal (VP) shunts for idiopathic normal pressure hydrocephalus (iNPH) has overshadowed lumboperitoneal (LP) shunts, due to historically higher rates of shunt malfunction.1, 2 Although randomized clinical trials have comprehensively explored optimal valve settings in VP shunts for iNPH, optimizing LP shunts has lagged far behind.3 Thus, the authors should be commended for valiantly chartering into an ill-defined practice in NPH surgery: the optimal LP shunt configuration. This retrospective study of 115 patients compared programmable pressure valves (PPV) with small-lumen (SL) abdominal catheter versus PPV with gravitational “add-on” valve system (GV) in tandem. Following propensity score matching, PPV/+SL fared higher postoperative modified Rankin Scores (mRS) and iNPH grading scale (iNPHGS) gait disturbances compared to the PPV/+GV at 12-month follow up. While the conclusions—“more hardware, ergo better outcomes”—sound more like a talking point from industry representatives, the GV did statistically improve postoperative outcomes. When appropriately matched to historical controls, the add-on valve trended to a lower rate of nonserious adverse events, including subdural hematomas, putatively because the GV suppresses flow volume rate in the standing position to prevent intracranial hypotension. However, some of their improvement in outcome measures may reflect refinement in their techniques over time. Lastly, the GV valve tacked to the fascia in a vertical configuration may have reduced the rate of catheter kinking. The safety and efficacy of the add-on devices have been validated in the Shunt Valves plus shunt Assistant versus Shunt valves alone for controlling Overdrainage in idiopathic Normal pressure hydrocephalus in Adults (SVASONA) randomized clinical trial.4 The GV compared to PPV decreased subdural effusions, overdrainage, and underdrainage at 12-months. However, the study was limited to ventriculoperitoneal shunts, and the allocation groups included either PPV or GV, not PPV in tandem with PPV (PPV/+GV) as in the present review. Nevertheless, long-term outcome studies with gravitational shunts maintain a low complication rate: 3% catheter dislocation/fracture, 5% underdrainage, and 9% overdrainage according to a 5-year follow-up study in VP shunting.5 We look forward to similar long-term studies with GV in LP shunts. Mohamed Macki Jason Schwalb Detroit, Michigan 1. Abubaker K Ali Z Raza K Bolger C Rawluk D O’Brien D . Idiopathic intracranial hypertension: lumboperitoneal shunts versus ventriculoperitoneal shunts–case series and literature review . Br J Neurosurg . 2011 ; 25 ( 1 ): 94 - 99 . Google Scholar CrossRef Search ADS PubMed 2. McGirt MJ Woodworth G Thomas G Miller N Williams M Rigamonti D . Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes . J Neurosurg . 2004 ; 101 ( 4 ): 627 - 632 . Google Scholar CrossRef Search ADS PubMed 3. Boon AJ Tans JT Delwel EJ , et al. Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid . J Neurosurg . 1997 ; 87 ( 5 ): 687 - 693 . Google Scholar CrossRef Search ADS PubMed 4. Lemcke J Meier U Muller C , et al . Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA) . J Neurol Neurosurg Psychiatry . 2013 ; 84 ( 8 ): 850 - 857 . Google Scholar CrossRef Search ADS PubMed 5. Kiefer M Eymann R . Gravitational shunt complications after a five-year follow-up . Acta Neurochir Suppl . 2010 ; 106 : 107 - 112 . Google Scholar CrossRef Search ADS PubMed Operative Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Liang Chen, MD Department of Neurosurgery Huashan Hospital Shanghai, China Chinese: Liang Chen, MD Department of Neurosurgery Huashan Hospital Shanghai, China Close English: Roberto Jose Diaz, MD, PhD Department of Neurological Surgery University of Miami Miller School of Medicine Miami, Florida English: Roberto Jose Diaz, MD, PhD Department of Neurological Surgery University of Miami Miller School of Medicine Miami, Florida Close Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Close Italian: Michele Rizzi, MD “Claudio Munari” Epilepsy Surgery Center ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Italian: Michele Rizzi, MD “Claudio Munari” Epilepsy Surgery Center ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Close Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Close Spanish: Carlos Pérez-López, MD, PhD Department of Neurological Surgery Universitary Hospital La Paz Madrid, Spain Spanish: Carlos Pérez-López, MD, PhD Department of Neurological Surgery Universitary Hospital La Paz Madrid, Spain Close Russian: Natalia Denisova, MD Novosibirsk Federal Centre of Neurosurgery Novosibirsk, Russia Russian: Natalia Denisova, MD Novosibirsk Federal Centre of Neurosurgery Novosibirsk, Russia Close Korean: Tae Gon Kim, MD Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Korean: Tae Gon Kim, MD Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Greek: Alexiou A Georgios, MD Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Greek: Alexiou A Georgios, MD Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Operative NeurosurgeryOxford University Press

Published: Apr 23, 2018

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