CLINICAL ARTICLE J Neurosurg 126: , 2017

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1 CLINICAL ARTICLE J Neurosurg 126: , 2017 Disability risk or unimproved symptoms following shunt surgery in patients with idiopathic normal-pressure hydrocephalus: post hoc analysis of SINPHONI-2 Shigeki Yamada, MD, PhD, 1 Teruo Kimura, MD, PhD, 2 Naoto Jingami, MD, 3 Masamichi Atsuchi, MD, PhD, 4 Osamu Hirai, MD, PhD, 5 Takahiko Tokuda, MD, PhD, 6 Masakazu Miyajima, MD, PhD, 7 Hiroaki Kazui, MD, PhD, 8 Etsuro Mori, MD, PhD, 9 Masatsune Ishikawa, MD, PhD, 1 and the SINPHONI-2 Investigators 1 Normal Pressure Hydrocephalus Center, Department of Neurosurgery and Stroke Center, Rakuwakai Otowa Hospital, Kyoto; 2 Department of Neurosurgery, Dohtoh Neurosurgical Hospital, Hokkaido; 3 Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto; 4 Department of Neurosurgery, Atuchi Neurosurgical Hospital, Kagoshima; 5 Department of Neurosurgery, Shinko Hospital, Kobe; 6 Department of Molecular Pathobiology of Brain Diseases (Neurology), Kyoto Prefectural University of Medicine, Kyoto; 7 Department of Neurosurgery, Juntendo University Graduate School of Medicine, Tokyo; 8 Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka; and 9 Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Miyagi, Japan OBJECTIVE The study aim was to assess the influence of presurgical clinical symptom severity and disease duration on outcomes of shunt surgery in patients with idiopathic normal-pressure hydrocephalus (inph). The authors also evaluated the cerebrospinal fluid tap test as a predictor of improvements following shunt surgery. METHODS Eighty-three patients (45 men and 38 women, mean age 76.4 years) underwent lumboperitoneal shunt surgery, and outcomes were evaluated until 12 months following surgery. Risks for poor quality of life (Score 3 or 4 on the modified Rankin Scale [mrs]) and severe gait disturbance were evaluated at 3 and 12 months following shunt surgery, and the tap test was also conducted. Age-adjusted and multivariate relative risks were calculated using Cox proportional-hazards regression. RESULTS Of 83 patients with inph, 45 (54%) improved by 1 point on the mrs and 6 patients (7%) improved by 2 points at 3 months following surgery. At 12 months after surgery, 39 patients (47%) improved by 1 point on the mrs and 13 patients (16%) improved by 2 points. On the gait domain of the inph grading scale (inphgs), 36 patients (43%) improved by 1 point and 13 patients (16%) improved by 2 points at 3 months following surgery. Additionally, 32 patients (38%) improved by 1 point and 14 patients (17%) by 2 points at 12 months following surgery. In contrast, 3 patients (4%) and 2 patients (2%) had worse symptoms according to the mrs or the gait domain of the inphgs, respectively, at 3 months following surgery, and 5 patients (6%) and 3 patients (4%) had worse mrs scores and gait domain scores, respectively, at 12 months after surgery. Patients with severe preoperative mrs scores had a 4.7 times higher multivariate relative risk (RR) for severe mrs scores at 12 months following surgery. Moreover, patients with severe gait disturbance prior to shunt surgery had a 46.5 times greater multivariate RR for severe gait disturbance at the 12-month follow-up. Patients without improved gait following the tap test had multivariate RRs for unimproved gait disturbance of 7.54 and 11.2 at 3 and 12 months following surgery, respectively. Disease duration from onset to shunt surgery was not significantly associated with postoperative symptom severity or unimproved symptoms. CONCLUSIONS Patients with inph should receive treatment before their symptoms become severe in order to achieve an improved quality of life. However, the progression of symptoms varies between patients so specific timeframes are ABBREVIATIONS CSF = cerebrospinal fluid; inph = idiopathic normal-pressure hydrocephalus; INPHGS = inph grading scale; mrs = modified Rankin Scale; RR = relative risk; SINPHONI = study of inph on neurological improvement. SUBMITTED February 15, ACCEPTED May 13, INCLUDE WHEN CITING Published online July 15, 2016; DOI: / JNS J Neurosurg Volume 126 June 2017 AANS, 2017

2 Shunting in early-stage inph not meaningful. The authors also found that tap test scores accurately predicted shunt efficacy. Therefore, indications for shunt surgery should be carefully assessed in each patient with inph, considering the relative risks and benefits for that person, including healthy life expectancy. KEY WORDS idiopathic normal pressure hydrocephalus; gait disturbance; improvement rate; lumboperitoneal shunt Idiopathic normal-pressure hydrocephalus (inph) is an established syndrome with gait disturbance, cognitive impairments, and urinary incontinence. Typical presentation occurs in elderly patients with ventricular dilation, and inph can be treated with cerebrospinal fluid (CSF) shunt surgery. Increasing elderly populations in developed countries are expected to result in more patients with inph who may require surgical treatment; however, the ideal patient characteristics for CSF shunt surgery have not been elucidated. Some neurosurgeons assert that surgery should only be performed in patients with mild inph symptoms once those symptoms become more severe because the benefits of surgery would then be greater than its risks. The clinical outcomes of CSF shunt surgery are affected by patient age, preoperative symptom severity, comorbidities, radiological findings, duration of time from initial symptoms until shunt surgery, response to the CSF tap test, and factors related to the devices and procedures specific to the shunt surgery. 2,3,6,7,9 14,16 23 Our previous multicenter prospective cohort study of inph on neurological improvement (SINPHONI) demonstrated great improvement in symptoms after ventriculoperitoneal shunt surgery in the patients with inph. 4,5 The second study of inph on neurological improvement (SINPHONI-2), an open-label randomized controlled trial, demonstrated the efficacy of lumboperitoneal shunt surgery in elderly patients with inph. 8 Furthermore, we recently reported that the rates of both improvements and side effects for lumboperitoneal shunts in patients with inph are similar to those for ventriculoperitoneal shunts. 15 The aim of the present study was to systematically assess the influence of inph symptom severity and disease duration on the efficacy of shunt surgery by using the data collected for SINPHONI-2. Methods Participants The institutional review boards at each study site approved the study protocol of SINPHONI-2 (University Hospital Medical Information Network [UMIN] Clinical Trials no. UMIN ), which was designed by all of the SINPHONI-2 investigators (Appendix) including the biostatistician and Independent Data and Safety Monitoring Committee members, in conformity with the Guidelines for Good Clinical Practice and the Declaration of Helsinki of the World Medical Association. All patients or their representatives gave written informed consent. All clinical and radiological data were prospectively recorded in an independent protocol compliance center via a Web-based case report system. Participant details, variable definitions of inph, and protocol compliance, as well as details of data collection, including data acquisition and management, have been described elsewhere. 8,15 In brief, 102 patients diagnosed with possible inph were recruited from 20 Japanese institutes and hospitals between March 2010 and October The inclusion criteria for this study were as follows: age years at study enrollment, presentation with the clinical triad of symptoms (gait disturbance, cognitive impairment, and urinary incontinence), ventriculomegaly with an Evans index > 0.3, and disproportionately enlarged subarachnoid space hydrocephalus (DESH) observed on CT or MRI. Patients with complications such as severe disuse muscle atrophy, psychiatric disorders, or other neurological diseases were excluded from the study. Therefore, 93 patients were enrolled and were randomly assigned to an immediate surgery group (49 patients) or a postponed (3 months) surgery group (44 patients). After randomization, all participants underwent the CSF tap test and lumboperitoneal shunt surgery using a Codman Hakim programmable valve with SiphonGuard (Codman Neuro, DePuy Synthes). Responses to the CSF tap test did not influence randomization or patient management. Eighty-three patients (45 men and 38 women, mean age 76.4 years) complied with randomization and were assessed at 3 and 12 months after shunt surgery (the per protocol population). In patients suspected to have shunt malfunction, the patency of the shunt system was checked according to the CSF aspiration via shunt valve and shuntgram at the follow-up points. Measurement of Clinical Symptoms A CSF tap test consisted of removing 30 ml of CSF via lumbar tap. Clinical symptoms before and after the tap test and at the postsurgical follow-up points (3 and 12 months postsurgery) were evaluated by neurologists, psychiatrists, neuropsychologists, and/or physical therapists who were independent of the neurosurgeons performing the lumboperitoneal shunt surgeries. Gait improvement was assessed 24 hours and cognitive improvement was assessed within 7 days after the CSF tap test. 5 The gait domain of the inph grading scale (inphgs) was scored using the following 5-point grading scale: 0 = normal, 1 = dizziness or drift and dysbasia without objective gait disturbance, 2 = unstable but independent gait, 3 = walking possible with support, or 4 = walking not possible. Similarly, the cognitive domain was scored as 0 = normal, 1 = only complaints of amnesia or inattention but no objective memory and attentional impairment, 2 = minimal attentional or memory deficits, 3 = disorientation of time and place, or 4 = meaningful conversation impossible. The urinary domain was scored as 0 = normal, 1 = pollakiuria or urinary urgency, 2 = occasional incontinence, 3 = frequent incontinence, or 4 = uncontrollable incontinence. Gait J Neurosurg Volume 126 June

3 S. Yamada et al. was also quantitatively evaluated using the timed 3-m upand-go test (TUG) and the 3-m reciprocating walking test (RWT). Cognition was evaluated using the Mini-Mental State Examination (MMSE) and the frontal assessment battery (FAB). Statistical Analyses The number of patients with favorable outcomes on the modified Rankin Scale (mrs) and the total inphgs at 12 months after lumboperitoneal shunt surgery were not significantly different between the immediate and postponed surgery groups. Therefore, we pooled the data from both groups. Mean values for age at study enrollment and other continuous variables were analyzed using 1-way ANOVA. Age-adjusted relative risks and 95% confidence intervals were calculated using Cox proportionalhazards regression. We assessed the risk for poor quality of life (Grade 3 or 4 on the mrs) and the risk for continued severe gait disturbance (Grade 3 or 4 on the gait domain of the inphgs) at 3 and 12 months following shunt surgery. We also assessed the risk for unimproved symptoms, which we defined as unchanged or higher scores on the mrs and the inphgs at 3 and 12 months following surgery. To assess interactions or the effects of modifying other potential risk factors, multivariate analyses were conducted after adjustments for age, body mass index, Evans index, duration of time from symptom onset until shunt surgery, immediate surgery or postponed surgery, preoperative disability, and response to the CSF tap test. In the postponed surgery group, disease duration was calculated based on the onset of initial symptoms until study enrollment plus 3 months. Responses to the CSF tap test were defined as an increase of 1 or more points on either the mrs or each domain of the inphgs. All missing data were treated as deficit data and therefore did not affect other variables. A p value < 0.05 indicated statistical significance. All statistical analyses were performed using R software (version 3.0.1, R Foundation for Statistical Computing, Results Baseline Characteristics Characteristics of the study population prior to shunt surgery are presented in Table 1. The mean age at study enrollment increased concurrently with mrs grades. Similarly, scores on each of the 3 domains on the inphgs, as well as for the quantitative examinations of gait and cognition, gradually worsened as mrs grades increased. Figure 1 presents box-and-whisker plots of the time from initial presentation to shunt surgery against mrs scores and gait domains of the inphgs before shunt surgery. There was no significant relationship between disease duration and preoperative symptom severity. Clinical Outcomes Figure 2 shows changes in mrs scores and each of the 3 domains of the inphgs before surgery, as well as at 3 and 12 months afterward. Forty-five patients (54%) improved by 1 point on the mrs and 6 patients (7%) improved by TABLE 1. Preoperative patient characteristics Parameter Total Preop mrs Score p Value* No. of patients No. of females Mean age (yrs) <0.001 Mean duration from initial presentation until op (mos) Mean body mass index (kg/m 2 ) Mean yrs of education Mean gait disturbance <0.001 grade on inphgs Mean cognitive impairment <0.001 grade on inphgs Mean urinary disturbance <0.001 grade on inphgs Mean total grade on <0.001 inphgs Mean TUG (secs) <0.001 Mean RWT (secs) <0.001 Mean MMSE score <0.001 Mean FAB score <0.001 FAB = frontal assessment battery; MMSE = Mini-Mental State Examination; RWT = 3-m reciprocating walking test; TUG = timed 3-m up-and-go test. * One-way ANOVA. 2 points at 3 months following surgery. Furthermore, 39 patients (47%) improved by 1 point and 13 patients (16%) improved by 2 points at 12 months after surgery. On the gait domain of the inphgs, 36 patients (43%) improved by 1 point and 13 (16%) improved by 2 points at 3 months following surgery. Thirty-two patients (38%) improved by 1 point and 14 (17%) improved by 2 points at 12 months following surgery. On the cognitive domain of the inphgs, 33 patients (40%) improved by 1 point and 8 patients (10%) improved by 2 points at 12 months following surgery. Finally, 25 patients (30%) improved by 1 point on the urinary domain of the inphgs and 18 patients (22%) had a 2-point increase at 12 months following surgery. In contrast, 3 patients (4%) had mrs scores and 2 patients (2%) had gait domain scores indicating worsening symptoms at the 3-month follow-up, and 5 patients (6%) had worse mrs scores and 3 patients (4%) had worse gait domain scores at 12 months following shunt surgery. Reduced daily activity in the 5 patients with worse mrs scores at 12 months following surgery was influenced by brainstem infarction (2 patients), advanced dementia (1 patient), death from lung cancer 10 months after surgery (1 patient), and suicide 6 months after surgery (1 patient). Additionally, severe adverse events related to the shunt surgery included shunt malfunction requiring reoperation (6 patients), chronic subdural hematoma (3 patients), and compressed vertebral fracture (3 patients). The severe adverse events did not contribute to reduced daily activity J Neurosurg Volume 126 June 2017

4 Shunting in early-stage inph score (Score 3 or 4) on the mrs at 3 months following surgery was 6.7 (95% CI ) for inph patients who had had a severe preoperative status on the mrs compared with patients who had had a mild mrs score. Additionally, patients with a severe grade (Grade 3 or 4) on the gait domain of the inphgs before operation had an 18.6 times higher risk for continued severe gait disturbance at 3 months following surgery. These statistically significant associations between preoperative and postoperative severities were also observed at 12 months following shunt surgery. After adjustment for the multivariate covariates, patients with a severe preoperative mrs score had a 4.7 times higher risk for a severe mrs score at 12 months following surgery. Moreover, patients with a severe gait disturbance prior to surgery had a 46.5 times greater risk for severe gait disturbance at the 12-month follow-up. Prediction of Responses to Shunt Surgery by the CSF Tap Test Patients with unimproved mrs scores at the CSF tap test had significantly greater risks for unimproved mrs scores at the 12-month follow-up (multivariate RR 5.5, 95% CI ). Unimproved gait at the CSF tap test was also a significant predictive factor for unimproved gait following CSF shunt surgery (Tables 4 and 5). The multivariate RRs for 3 and 12 months following surgery were 7.5 ( ) and 11.2 ( ), respectively. In contrast, on the cognitive and urinary domains of the inphgs, responses to the CSF tap test were not significantly associated with responses to shunt surgery. Finally, the duration of time from symptom onset until shunt surgery was not significantly associated with postoperative symptom severity or unimproved symptoms. FIG. 1. Box-and-whisker plots of disease duration (mos), classified by mrs scores (upper) and grades for the gait domain of the inphgs (lower) prior to shunt surgery. Risk for Severe Disability Following Shunt Surgery Tables 2 and 3 present the age-adjusted and multivariate relative risks for disability or poor quality of life related to the triad of symptoms at 3 and 12 months following shunt surgery. The age-adjusted relative risk (RR) for a severe Discussion Patients with severe preoperative inph symptoms did not experience sufficient improvement following shunt surgery compared with patients with mild preoperative symptoms. In particular, the multivariate RRs for severe gait disturbance at 3 and 12 months following shunt surgery were 20.5 and 46.5, respectively, for inph patients who could not walk independently prior to surgery. Approximately half of these patients improved by only 1 point on the mrs or 1 point on the gait domain of the inphgs. It was uncommon for these patients to experience improvements of 2 points. Therefore, complete symptom reversal should not be expected following shunt surgery, indicating that the timing of the surgery during the course of inph progression is critical. At our 12-month follow-up time point, 3 patients had worse symptoms than at the preoperation time point and 2 patients had died of conditions unrelated to inph or the shunt surgery. In addition to this finding that not all patients experienced symptom improvement following shunt surgery, we previously demonstrated that 16% of patients in the postponed surgery group had worse inphgs gait domain scores by the end of the waiting period, although scores did not change for 79% of patients. 8 These results suggest that there is variability in symptom progression rates between individuals. We confirmed that there was no significant association between disease du- J Neurosurg Volume 126 June

5 S. Yamada et al. FIG. 2. Number of patients with preoperative and postoperative mrs scores and grades for the 3 domains of the inphgs. ration and preoperative symptom severity in the present study. Andrén et al. also reported variability in symptom progression during a surgery waiting period, ranging from slight improvement to marked declines in functional abilities. 1 These authors recommended performing shunt surgery soon after diagnosis to maximize the shunt benefits given findings that symptom deterioration is partially reversed by shunt surgery. However, we suggest caution when considering surgery in elderly patients with mild symptoms. In the present study we also revealed that the CSF tap test is a useful clinical tool when considering shunt surgery. Poor responses to the CSF tap test may accurately predict insufficient improvement following shunt surgery. Although the possibility of false-negative responses to the tap test cannot be eliminated, we found that an poor response to the CSF tap test contraindicates shunt surgery, especially for elderly patients or for patients with several severe comorbidities. We recently reported that the CSF tap test has a shorter time window for improved symptoms than shunt surgery. 24 Therefore, we recommend the CSF tap test as soon as possible before considering shunt surgery. Conversely, in patients diagnosed with possible inph whose symptoms have been present for > 1 year af J Neurosurg Volume 126 June 2017

6 Shunting in early-stage inph TABLE 2. Risk of disability 3 months following shunt surgery Preop Score or Grade Postop Score or Grade (no. of patients) 1 or 2 3 or 4 AA RR 95% CI p Value* M RR 95% CI p Value* mrs score 1 or Ref Ref 3 or < inphgs, gait grade 1 or Ref Ref 3 or inphgs, cognitive grade 1 or Ref Ref 3 or < <0.001 inphgs, urinary grade 1 or Ref Ref 3 or AA RR = age-adjusted relative risk; M RR = multivariate relative risk, which was adjusted for age, body mass index (kg/m 2 ), time (mos) from initial presentation until surgery, response to the CSF tap test, and conservative therapy for 3 months; Ref = reference. * χ 2 test. TABLE 3. Risk of disability 12 months following shunt surgery Preop Score or Grade Postop Score or Grade (no. of patients) 1 or 2 3 or 4 AA RR 95% CI p Value M RR 95% CI p Value mrs score 1 or Ref Ref 3 or inphgs, gait grade 1 or Ref Ref 3 or < <0.001 inphgs, cognitive grade 1 or Ref Ref 3 or inphgs, urinary grade 1 or Ref Ref 3 or TABLE 4. Risk of unimproved symptoms 3 months following shunt surgery At Tap Test Postop Grade or Score (no. of patients) Improved Unimproved AA RR 95% CI p Value M RR 95% CI p Value mrs score Improved 13 3 Ref Ref Unimproved inphgs, gait grade Improved 26 3 Ref Ref Unimproved inphgs, cognitive grade Improved 8 6 Ref Ref Unimproved inphgs, urinary grade Improved 11 4 Ref Ref Unimproved Improved = 1 point improvement on the mrs or each domain of the inphgs; unimproved = unchanged or worse score on the mrs or each domain of the inphgs. J Neurosurg Volume 126 June

7 S. Yamada et al. TABLE 5. Risk of unimproved symptoms 12 months following shunt surgery At Tap Test Postop Score or Grade (no. of patients) Improved Unimproved AA RR 95% CI p Value M RR 95% CI p Value mrs score Improved 14 2 Ref Ref Unimproved inphgs, gait grade Improved 26 3 Ref Ref Unimproved < <0.001 inphgs, cognitive grade Improved 10 4 Ref Ref Unimproved inphgs, urinary grade Improved 11 4 Ref Ref Unimproved ter the initial presentation and who have no response to the CSF tap test, shunt surgery should be considered to focus on symptom progression and MRI findings. In this study, we evaluated patients who underwent lumboperitoneal shunt implantation. However, the robust results did not differ substantially from those in the SINPHONI cohort, which was treated with ventriculoperitoneal shunt implantation. Conclusions Patients undergoing CSF shunt surgery may expect complete symptom improvement; however, those with severe gait disturbance prior to shunt surgery have a 46.5 times higher risk for continued gait disturbance than patients without severe preoperative gait symptoms. Therefore, we suggest that patients diagnosed with inph should undergo shunt surgery before symptoms become severe so as to maximize activities of daily living. However, immediate surgery is not necessarily the preferred strategy because there is considerable variability in symptom progression rates between patients. Additionally, the CSF tap test is indicated as a useful tool for predicting shunt efficacy. Therefore, decisions regarding shunt surgery should be individualized to each patient, considering the relative risks and benefits for that person, including healthy life expectancy. Appendix Co-Investigators of SINPHONI-2 Masaaki Hashimoto, MD, PhD (Noto General Hospital, Advisory Committee); Hideki Origasa, MD, PhD (University of Toyama, study statistician); Haruko Yamamoto, MD, PhD (National Cerebral and Cardiovascular Center, Independent Data and Safety Monitoring Committee); Hajime Arai, MD, PhD (Juntendo University, Advisory Committee); Koreaki Mori, MD, PhD (Kochi Medical School, Independent Data and Safety Monitoring Committee); Shigenobu Nakamura, MD, PhD (Rakuwakai Kyoto Clinical Research Center, Independent Data and Safety Monitoring Committee); Tamotsu Miki, MD, PhD (Tokyo Medical University, Independent Data and Safety Monitoring Committee); Kazunari Ishii, MD, PhD (Kinki University School of Medicine, director of Imaging Committee), Hiroji Miyake, MD, PhD (Nishinomiya Kyoritsu Neurosurgical Hospital, Advisory Committee); Nobumasa Kuwana, MD, PhD (Tokyo Kyosai Hospital, site investigator); Naoyuki Samejima, MD, PhD (Tokyo Kyosai Hospital, site investigator); Daisuke Kita, MD, PhD (Noto General Hospital, site investigator); Takahiko Tokuda, MD, PhD (Kyoto Prefectural University of Medicine, site investigator); Madoka Nakajima, MD, PhD (Juntendo University, site investigator); Mitsuhito Mase (Nagoya City University Graduate School of Medical Sciences, site investigator); Satoru Mori, MD, PhD (University of Shiga Prefecture, Advisory Committee); Yoshinaga Kajimoto, MD, PhD (Osaka Medical Collage, site investigator); Teiji Nakayama, MD, PhD (Hamamatsu Medical Centre, site investigator); Osamu Hirai, MD, PhD (Shinko Hospital, Advisory Committee); Masatoshi Takeda, MD, PhD (Osaka University Graduate School of Medicine, Advisory Committee); Chia-Cheng Chang, MD, PhD (Yokohama Minami Kyosai Hospital, site investigator); Isao Date, MD, PhD (Okayama University Graduate School of Medicine, site investigator); Masahiro Kameda, MD, PhD (Okayama University Graduate School of Medicine, site investigator); Takaharu Okada, MD, PhD (Tama-Hokubu Medical Center, site investigator); Junichiro Hamada, MD, PhD (Kanazawa University Graduate School of Medicine, site investigator); Mitsuya Watanabe, MD, PhD (Tama-Nanbu Regional Hospital, site investigator); Mitsunobu Kaijima, MD, PhD (Megumino Hospital, site investigator); Souichi Sunada, MD, PhD (Tsudanuma Central General Hospital, site investigator); Yoshihumi Hirata, MD, PhD (Kumamoto Takumadai Hospital, Advisory Committee). Acknowledgments The study is a Japanese Society of Normal Pressure Hydrocephalus project. We thank the patients for their participation. We also thank the study contributors. References 1. Andrén K, Wikkelsø C, Tisell M, Hellström P: Natural course of idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 85: , Halperin JJ, Kurlan R, Schwalb JM, Cusimano MD, Gronseth G, Gloss D: Practice guideline: Idiopathic normal pressure hydrocephalus: Response to shunting and predictors of response: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the 2008 J Neurosurg Volume 126 June 2017

8 Shunting in early-stage inph American Academy of Neurology. Neurology 85: , Hamilton R, Patel S, Lee EB, Jackson EM, Lopinto J, Arnold SE, et al: Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology. Ann Neurol 68: , Hashimoto M, Ishikawa M, Mori E, Kuwana N: Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study. Cerebrospinal Fluid Res 7:18, Ishikawa M, Hashimoto M, Mori E, Kuwana N, Kazui H: The value of the cerebrospinal fluid tap test for predicting shunt effectiveness in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS 9:1, Kahlon B, Annertz M, Ståhlberg F, Rehncrona S: Is aqueductal stroke volume, measured with cine phase-contrast magnetic resonance imaging scans useful in predicting outcome of shunt surgery in suspected normal pressure hydrocephalus? Neurosurgery 60: , Kahlon B, Sjunnesson J, Rehncrona S: Long-term outcome in patients with suspected normal pressure hydrocephalus. Neurosurgery 60: , Kazui H, Miyajima M, Mori E, Ishikawa M: Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial. Lancet Neurol 14: , Klinge P, Hellström P, Tans J, Wikkelsø C: One-year outcome in the European multicentre study on inph. Acta Neurol Scand 126: , Klinge P, Marmarou A, Bergsneider M, Relkin N, Black PM: Outcome of shunting in idiopathic normal-pressure hydrocephalus and the value of outcome assessment in shunted patients. Neurosurgery 57 (3 Suppl):S40 S52, ii v, Mahr CV, Dengl M, Nestler U, Reiss-Zimmermann M, Eichner G, Preuß M, et al: Idiopathic normal pressure hydrocephalus: diagnostic and predictive value of clinical testing, lumbar drainage, and CSF dynamics. J Neurosurg [epub ahead of print January 29, DOI: / JNS151112] 12. Malm J, Graff-Radford NR, Ishikawa M, Kristensen B, Leinonen V, Mori E, et al: Influence of comorbidities in idiopathic normal pressure hydrocephalus research and clinical care. A report of the ISHCSF task force on comorbidities in INPH. Fluids Barriers CNS 10:22, Malm J, Kristensen B, Karlsson T, Fagerlund M, Elfverson J, Ekstedt J: The predictive value of cerebrospinal fluid dynamic tests in patients with the idiopathic adult hydrocephalus syndrome. Arch Neurol 52: , Meier U, König A, Miethke C: Predictors of outcome in patients with normal-pressure hydrocephalus. Eur Neurol 51:59 67, Miyajima M, Kazui H, Mori E, Ishikawa M: One-year outcome in patients with idiopathic normal-pressure hydrocephalus: comparison of lumboperitoneal shunt to ventriculoperitoneal shunt. J Neurosurg [epub ahead of print February 12, DOI: / JNS151894] 16. Pomeraniec IJ, Bond AE, Lopes MB, Jane JA Sr: Concurrent Alzheimer s pathology in patients with clinical normal pressure hydrocephalus: correlation of high-volume lumbar puncture results, cortical brain biopsies, and outcomes. J Neurosurg 124: , Sæhle T, Farahmand D, Eide PK, Tisell M, Wikkelsö C: A randomized controlled dual-center trial on shunt complications in idiopathic normal-pressure hydrocephalus treated with gradually reduced or fixed pressure valve settings. J Neurosurg 121: , Sand T, Bovim G, Grimse R, Myhr G, Helde G, Cappelen J: Idiopathic normal pressure hydrocephalus: the CSF tap-test may predict the clinical response to shunting. Acta Neurol Scand 89: , Savolainen S, Hurskainen H, Paljärvi L, Alafuzoff I, Vapalahti M: Five-year outcome of normal pressure hydrocephalus with or without a shunt: predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 144: , Toma AK, Papadopoulos MC, Stapleton S, Kitchen ND, Watkins LD: Systematic review of the outcome of shunt surgery in idiopathic normal-pressure hydrocephalus. Acta Neurochir (Wien) 155: , Torsnes L, Blåfjelldal V, Poulsen FR: Treatment and clinical outcome in patients with idiopathic normal pressure hydrocephalus a systematic review. Dan Med J 61:A4911, Virhammar J, Laurell K, Cesarini KG, Larsson EM: Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus. AJNR Am J Neuroradiol 35: , Wikkelsø C, Hellström P, Klinge PM, Tans JT: The European inph Multicentre Study on the predictive values of resistance to CSF outflow and the CSF tap test in patients with idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 84: , Yamada S, Ishikawa M, Miyajima M, Atsuchi M, Kimura T, Kazui H, et al: Disease duration: the key to accurate CSF tap test in inph. Acta Neurol Scand [epub ahead of print], 2016 Disclosures This investigator-initiated study was supported in part by Johnson & Johnson K.K. and Nihon Medi-Physics Co., Ltd. The funding sources for the study had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The authors were never paid by a pharmaceutical company or another agency to write this article. Drs. Kazui, Mori, Ishikawa, and Mi yajima have received honoraria from the companies that manufactured the devices discussed in this article, including Johnson & Johnson K.K. (Japan), and Dr. Kazui has received honoraria from Nihon Medi-Physics Co., Ltd. (Japan). Author Contributions Conception and design: all authors. Acquisition of data: Kimura, Atsuchi, Hirai, Miyajima, Kazui, Mori, Ishikawa. Analysis and interpretation of data: all authors. Drafting the article: all authors. Approved the final version of the manuscript on behalf of all authors: Yamada. Statistical analysis: Yamada, Ishikawa. Administrative/technical/material support: all authors. Study supervision: Kimura, Jingami, Tokuda, Miyajima, Kazui, Mori, Ishikawa. Correspondence Shigeki Yamada, Normal Pressure Hydrocephalus Center, Department of Neurosurgery and Stroke Center, Rakuwakai Otowa Hospital, Otowachinji-cho 2, Yamashina-ku, Kyoto , Japan. shigekiyamada39@gmail.com. J Neurosurg Volume 126 June