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Outcome of Surgery for Idiopathic Normal Pressure Hydrocephalus: Role of Preoperative Static and Pulsatile Intracranial Pressure
Accepted Manuscript Outcome of surgery for idiopathic normal pressure hydrocephalus: Role of preoperative static and pulsatile intracranial pressure Per Kristian Eide, Wilhelm Sorteberg PII:
S1878-8750(15)01234-6
DOI:
10.1016/j.wneu.2015.09.067
Reference:
WNEU 3253
To appear in:
World Neurosurgery
Received Date: 2 July 2015 Revised Date:
17 September 2015
Accepted Date: 19 September 2015
Please cite this article as: Eide PK, Sorteberg W, Outcome of surgery for idiopathic normal pressure hydrocephalus: Role of pre-operative static and pulsatile intracranial pressure, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.09.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Surgery for iNPH
Outcome of surgery for idiopathic normal pressure hydrocephalus: Role of pre-operative static and pulsatile intracranial pressure
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Per Kristian Eide1,2, Wilhelm Sorteberg1
Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway;
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Faculty of Medicine, University of Oslo, Oslo, Norway.
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1
Funding
Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Short title
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Corresponding author:
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Surgery for idiopathic normal pressure hydrocephalus
Per Kristian Eide, MD PhD
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Professor/Section chief
Department of Neurosurgery Oslo University Hospital - Rikshospitalet Pb 4950 Nydalen,
N-0424 Oslo, Norway
Phone: +47-23074321. Fax: +47-23074310 [email protected]/[email protected]
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ACCEPTED MANUSCRIPT Surgery for iNPH Abbreviation list CSF – cerebrospinal fluid CT – computer tomography
ICH – intracerebral hemorrhage ICP – intracranial pressure ISF – interstitial fluid
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iNPH – idiopathic normal pressure hydrocephalus
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ETV – endoscopic third ventriculostomy
MRI – magnetic resonance imaging
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MWA – mean ICP wave amplitude
REK - Regional Committee for Medical and Health Research Ethics RT – rise time
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RTC – rise time coefficient
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ACCEPTED MANUSCRIPT Surgery for iNPH Abstract Objectives To examine the outcome of surgery for idiopathic normal pressure hydrocephalus (iNPH) and how outcome relates to the pre-operative static and pulsatile intracranial pressure
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(ICP).
Methods An observational cohort study included all iNPH patients managed at our department during the years 2002-2012 in whom over-night ICP monitoring was part of pre-operative work-
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up. Clinical data were retrieved from a quality registry and ICP scores from a pressure database. Results The study included 472 patients, 316 in the surgery group and 156 in the non-surgery
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group. Among those treated surgically, 278 (90%) showed clinical improvement (Responders) while 32 (10%) had no improvement (Non-responders). Among Responders, only about 1/3 reached the best clinical scores; moreover, the difference in clinical score between Responders and Non-responders declined with time after surgery, particularly after 3-4 years. The surgery
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was accompanied by acute intracranial hematomas in 11 patients (3.5%), of whom 4 (1.3%) died. Survival (age at death) was significantly higher among the Responders than in Non-responders. While the static ICP was normal in all patients, the pulsatile ICP was significantly higher in
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Responders than in Non-responders.
Conclusions The pulsatile ICP was higher in shunt Responders than Non-responders. While the
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clinical improvement declined over time and the majority did not experience complete relief of symptoms, shunt Responders lived significantly longer than Non-responders. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular the aspect of brain water disturbance.
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Key words: Normal pressure hydrocephalus, intracranial pressure, shunt surgery, outcome, complications.
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ACCEPTED MANUSCRIPT Surgery for iNPH Introduction The so-called normal pressure hydrocephalus (iNPH) syndrome was described 50 years ago (1). Patients with the triad symptoms of unsteady and ataxic gait, urinary incontinence and cognitive
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impairment (dementia), combined with enlarged cerebral ventricles and normal lumbar
cerebrospinal fluid (CSF) pressure improved clinically following CSF diversion surgery (shunt implantation) (25). Shunt surgery (and in a few cases endoscopic third ventrciulostomy) is the
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treatment of choice, though the results of surgery for iNPH is still a matter of controversy (10, 24).
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The pathophysiology of iNPH remains an enigma. As symptoms improve following CSF diversion surgery (18), it is generally accepted that CSF circulation disturbance is involved. The clinical improvement may be linked to improved cerebral metabolism (14), as well as improved intracranial pressure-volume relationship (8). Despite the term normal pressure hydrocephalus,
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it is controversial how the ICP becomes altered in iNPH. Further knowledge on this matter is crucial since the only current treatment for iNPH is surgical, which goal is to reduce the ICP. In our department, we have for more than a decade monitored the static and pulsatile ICP
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over-night as part of the pre-operative work-up in iNPH patients. In this observational cohort study, we examined the outcome of surgery for iNPH with regard to clinical outcome, severe
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complications (intracranial bleeds), and survival. We further evaluated how the pre-operative static and pulsatile ICP scores related to the outcome of surgery.
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ACCEPTED MANUSCRIPT Surgery for iNPH MATERIAL AND METHODS Patient material The study included all iNPH patients that underwent ICP monitoring as part of their pre-
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operative work-up in the Department of Neurosurgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway during the years 2002-2012.
The study was approved by the Oslo University Hospital – Rikshospitalet as a quality
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study (Approval 2014/4720). The Regional Committee for Medical and Health Research Ethics (REK) of Health Region South-East, Norway was informed in writing, and had no objections to
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the study (reference 2014/528). Information was retrieved from Neurovascular-Hydrocephalus Quality Register (REK Approval 11/6692).
Patient management & follow-up
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The department’s routine for management of iNPH is described shortly. Patients with suspected iNPH are usually referred from local neurological departments based on symptoms indicative of iNPH and imaging findings of ventriculomegaly. In some patients, a tap test or infusion test has
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been done prior to referral. At our department, a clinical assessment is done, and ICP monitoring is carried out over-night. Indication for CSF diversion surgery is based on the combination of
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clinical findings, presence of co-morbidity, imaging findings and results of the ICP monitoring. Thus, patients should meet the clinical and imaging criteria for iNPH, and the ICP measurements was a final decision maker. With regard to the ICP scores, we primarily use the mean ICP wave (MWA) values, recommending shunting in patients with MWA values above upper normal threshold values during the night period, i.e. MWA >4 mmHg on average and >5 mmHg in minimum 10% of recording time from 11 p.m. until 7 a.m. (6).
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ACCEPTED MANUSCRIPT Surgery for iNPH A NPH grading scale (Appendix A) is used to assess the severity of symptoms. Assessment was done prior to ICP monitoring/surgery and then at intervals during follow-up. Clinical improvement was defined as an increase in clinical score on the NPH grading scale.
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Imaging includes computer tomography (CT) scanning and/or magnetic resonance
imaging (MRI). During the last years MRI phase-contrast imaging has also been included. The quantitative imaging of ventricular size or other imaging indices of CSF circulation was not a
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part of the present study, and is therefore not commented on.
The ordinary treatment is shunt surgery (ventriculo-peritoneal shunt). Either of two types
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of shunt valves were used: Codman Hakim Programmable valve (Codman, Johnsen & Johnsen, Raynham, MA, USA), or Mietke ProGAV valve (Aesculap AG, Tuttlingen, Germany). In rare cases with questionable aqueduct stenosis, an endoscopic third ventriculostomy (ETV) is done, either soon after the ICP monitoring or some weeks later.
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After surgery, the patients are followed in our outpatient clinic or they are contacted by phone. According to this department’s routine, clinical control was done after 3-6 months, 12 months and then annually. Suspected shunt failure is accompanied with either of the following:
revision.
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Adjustment of shunt valve opening pressure, continuous over-night ICP monitoring, or shunt-
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The Neurovascular-Hydrocephalus Quality Register stores the clinical information,
including pre-operative and follow-up data. The death dates of all patients are provided from the Norwegian Folk Registry.
Pre-operative monitoring of static and pulsatile ICP
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ACCEPTED MANUSCRIPT Surgery for iNPH We have previously described our clinical routine for ICP monitoring (6). Placement of the solid ICP sensor is done under local anesthesia within the operating room. A small burr hole is made in the frontal region, a small opening made in the dura, and the sensor placed 1-2 cm into the
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brain parenchyma after being tunneled subcutaneously. Most commonly the Codman ICP
MicroSensor (Codman, Johnson & Johnson, Raynham, MA, USA) was used, and in some patients the Raumedic NeuroVent P sensor (Raumedic AG, Münchberg, GE).
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The patient is transferred to the neuro-intermediate ward, the ICP sensor becomes
connected to a computerized system for continuous recording, and the monitoring is continued
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over-night, with real-time presentation of the continuous ICP signals. Assessment of the ICP measurements is done by the attending doctor in the subsequent morning. The continuous ICP raw data files are stored in a pressure database on the hospital server. For the present study, the continuous ICP recordings were retrieved from the pressure
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database, and analyzed according to a method previously described (3). According to the automatic routine, the cardiac induced ICP waves are identified in the signal and for every subsequent 6-second time window the static ICP is characterized as the mean ICP. The pulsatile
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ICP is characterized as the mean ICP wave amplitude (pressure difference from diastolic minimum to systolic maximum pressure, MWA), the mean ICP wave rise time (time difference
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from diastolic minimum to systolic maximum pressure), and the mean ICP wave rise time coefficient (pressure difference divided by time difference from diastolic minimum to systolic maximum pressure). In order to compare patients, we considered only the recordings from 11 p.m. until 7 a.m.
Statistical analysis
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ACCEPTED MANUSCRIPT Surgery for iNPH All statistical analyses were performed using the SPSS software version 22 (IBM Corporation, Armonk, NY). Between-group differences for repeated measures were analysed using linear mixed models with a random intercept. In addition, independent sample t-tests between the two
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groups were performed at each follow-up time. Survival was assessed using Kaplan-Meier plots with using log-rank test to determine differences between groups. The ICP scores were used in decision making for shunting, and we did not determine predictive values of ICP scores for shunt
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response. Statistical significance was accepted at the .05 level.
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RESULTS Patient material
During the years 2002-2012 a total of 472 patients underwent assessment for iNPH including continuous over-night ICP monitoring (Table 1). Surgery for iNPH was done in 316 patients.
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Compared with the 156 non-surgery patients, those treated surgically were more often women, they were older, and with longer duration and severity of symptoms (Table 1). Shunt surgery was done in 310/316 patients (98.1%), and ETV in the other 6/316 (1.9%).
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With regard to shunt valve, we used a Codman Hakim programmable valve in 303 patients (opening pressure median 12 cm H2O; ranges 6-20 cm H2O), and a Mietke ProGAV valve in the
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other 7 patients (opening pressure 5-6/20-25 cm H2O). The shunt was ventriculo-peritoneal (VP) in 309 patients and ventriculo-atrial (VA) in one patient. One shunt-revision was required in 40/310 patients (12.9%), two shunt-revisions in 6/310 (1.9%) patients and three shunt-revisions in 1/310 (0.3%) patients.
Outcome of surgery
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ACCEPTED MANUSCRIPT Surgery for iNPH Clinical improvement Following surgery, clinical improvement, that means improvement on the NPH grading scale (Appendix A), was observed in 278/310 patients (89.8%), while 32/310 patients (10.3%) showed
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no improvement (Table 1). Four patients died from intracerebral hemorrhage (ICH) after the shunt surgery, while two patients were lost to follow-up. Fig. 1 shows the changes in NPH score over time for those that did improve (Responders; n=278) and those that did not improve
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clinically (Non-responders; n=32). Linear mixed model analyses for repeated measurements revealed significant overall differences between Responders/Non-responders whether
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considering Total NPH score (P<0.001; Fig. 1a), Gait sub-score (P<0.001; Fig. 1b), Incontinence sub-score (P<0.001; Fig. 1c), or Cognitive sub-score (P<0.001; Fig. 1d). Among the Responders, the clinical improvement was most evident during the first 2-3 years after surgery, and then declined. After 4 years, the decline in total NPH score was still
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evident (Fig. 1a). While improvement of the gait sub-score lasted the longest (Fig. 1b), the improvement in incontinence (Fig. 1c) and cognitive scores (Fig. 1d) were more short lasting. After 3-4 years, the improvement in cognitive function was hence less evident.
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Among the 310 surgically treated patients, 46 (15%) reached a maximum NPH score of 15, 58 patients (19%) a maximum NPH score of 14, and another 46 (15%) a maximum NPH
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score of 13. Thus, only 34% of patients reached the best NPH scores 14-15 and only 48% the best scores 13-15.
With regard to follow-up of the non-surgery group, 14/156 (9%) reported a spontaneous
improvement of symptoms, while 77/156 (49.4%) had no clinical improvement or worsening of symptoms (Table 1). We had no clinical follow-up of the remainder 65 patients (41.6%).
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ACCEPTED MANUSCRIPT Surgery for iNPH Severe complications After ICP monitoring, intracranial bleeds were seen in 6/472 patients (1.3%), i.e. ICH in 5 and acute subdural hematoma in 1 (Table 1). There was no surgical mortality related to ICP
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monitoring.
CSF diversion surgery for iNPH was accompanied with ICH in 6/316 patients (1.9%; Table 1). In addition, 5/316 patients (1.6%) developed acute subdural hematoma after median 22
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months (ranges 2 – 29 months after surgery) and another 22/316 patients (7%) developed chronic subdural hematoma median 3 months (ranges 1 to 53 months) after surgery. Surgical mortality of
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shunt surgery was 1.3% (4/316 patients), all caused by ICH.
Survival
Patients in the surgery group lived significantly longer as compared to those in the non-surgery
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group (P=0.01; Fig. 2a); median age at death was hence 83.7 years versus 81.9 years. Within the surgery group, the Responders died at a significantly older age than the Non-
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responders; median age at death was 85.2 years versus 80.7 years (P=0.02; Fig. 2b).
Static and pulsatile ICP before surgery
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Pre-operative ICP scores among Responders and None-responders of the surgery group is presented in Table 2, left. While the static ICP was normal (<15 mmHg) and did not differ between Responders/Non-responders, the pulsatile ICP differed significantly between groups. This was most evident for the ICP wave amplitude, but also significant for the ICP wave rise time and the ICP wave rise time coefficient. Figure 3 presents differences in mean ICP wave amplitude (MWA) between the Responders and Non-responders, including differences in
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ACCEPTED MANUSCRIPT Surgery for iNPH average values (Fig. 3a), differences in percentages of amplitude >5 mmHg (Fig. 3b) and >6 mmHg (Fig. 3c), respectively. The ICP wave amplitudes were hence higher and the rise time to some extent longer in Responders as compared to the Non-responders.
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With regard to the non-surgery group (Table 2, right), the pulsatile ICP was significantly lower in those with spontaneous clinical improvement (Responders) as compared to those with no improvement (Non-responders; Table 2, right). The static ICP did not differ between the two
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groups.
DISCUSSION
This observational cohort study provides evidence that surgery improves clinical function in iNPH, even though the clinical improvement declines after 3-4 years, and the majority has
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lasting symptoms of variable severity. The survival (age at death) was significantly increased in patients responding to the surgery than in those not responding. The iNPH patients improving clinically following CSF diversion have abnormal pre-operative pulsatile ICP despite of normal
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static ICP.
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Outcome of surgery
The outcome of surgery for iNPH is balanced between the opportunity for clinical improvement and the risk of complications. The risk aspect is important given their old age at inclusion (median age >70 years) and increased occurrence of cardiovascular disease (5). The present data underline that surgery for iNPH is accompanied with a definitive risk. Surgical 1-month mortality was hence 1.3% caused by cerebral hemorrhage. In addition, acute subdural hematoma occurred in 1.6% after median 22 months, and chronic subdural hematoma 12
ACCEPTED MANUSCRIPT Surgery for iNPH in 7% after median 3 months. Although several reports have documented the risk of surgery for iNPH (15, 23), our numbers with regard to intracranial bleeds are higher than usually quoted in the literature (24). This discrepancy may possibly be related to the present study reporting this
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department’s entire experience over many years with a long follow-up time. In series with smaller patient numbers, there is a higher risk for underreporting of complications.
It should also be noticed that surgery for iNPH carries additional risks such as risk of
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infection and shunt failure, requiring shunt revision. We have previously reported our infection rate, which for NPH is about 4% (11).
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In this cohort, 278/310 (90%) reported clinical improvement following surgery. This compares with the best clinical results of recent observational studies including a significant number of patients (9, 20, 24), though older studies have reported lower response rate (10). With regard to prediction of shunt response in iNPH, the present results compare with those using
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extended lumbar drainage (ELD); a test by many considered to be the best for predicting shuntresponsive iNPH (19, 20). The dis-advantages of both tests are the need for hospitalization and the tests carrying a certain risk of complications. This, in contrast to less invasive tests such as
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spinal tap tests and spinal infusion studies (25), which can be carried out on an outpatient basis. Having a lower complication risk, their predictive value in iNPH is, however, also lower (19).
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The total risk for surgically treated iNPH patients are the sum of the risks linked to the predicting test and the shunt surgery itself. We prefer a test with high predictive accuracy as this reduces the number of iNPH patients being shunted. As shown in our patient cohort, the risk linked to ICP monitoring is quite low when compared to that of shunt surgery. The present data further extend existing knowledge by showing that the clinical improvement declines over time, in particular 3-4 years after surgery. The cognitive
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ACCEPTED MANUSCRIPT Surgery for iNPH improvement had the shortest duration, while improvement in gait was the longest lasting. Others also have reported a reduction in clinical effect over time following iNPH surgery (15). Another important aspect is that only a fraction of our patients reached a maximum clinical
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response after surgery. Hence, among 310 followed-up, only 104 (34%) reached a maximum NPH score of 14-15. These numbers indicate that current surgical modalities do not “cure”
iNPH; at best, clinical improvement can be anticipated only to a certain extent and for only a
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certain period of time. Although we use shunts with adjustable valves to tailor the CSF diversion, lack of improvement could in some patients possibly be caused by sub-optimal amount of CSF
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drainage.
The degree and quality of clinical improvement depends on the method used for clinical assessment. There is currently no consensus on how to quantify clinical improvement in iNPH. Different scoring systems exist, ranging from advanced testing systems to simpler self-reporting
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assessments (16). Our NPH grading scale has certain weaknesses (16). An advantage, however, is that we used the same clinical grading scale throughout the observation period, which makes it possible to compare patients, and assess alterations over time.
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Even though surgery for iNPH carries risks and the clinical improvement declines over time, survival (age at death) was presently significantly increased in the surgery group as
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compared to the non-surgery group. Moreover, within the surgery group, patients with clinical improvement lived significantly longer than those with no clinical improvement (median age at death 85.2 versus 80.7 years). We are not aware of other studies exploring survival in iNPH patients. Whether or not shunt surgery adds years of life to the iNPH patients ought to be addressed in future studies.
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ACCEPTED MANUSCRIPT Surgery for iNPH Static and pulsatile ICP in iNPH The name normal pressure hydrocephalus includes a statement that the ICP is normal. The rational for the name was the observations of normal lumbar CSF pressures (1). Our observations
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of normal static ICP (mean ICP) support the assumption of a normal ICP in iNPH. We also found comparable frequency of short-lasting elevations in ICP (>15 or 20 mmHg; usually
referred to as B-waves) between Responders/Non-responders. Others have also reported that the
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occurrence of B waves is not increased in iNPH (22). Therefore, the term normal pressure
hydrocephalus can be justified; however, normal pressure then refers to only a normal static ICP.
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In contrast to B-waves, the pulsatile ICP refers to the single ICP waves related to the corresponding single cardiac contractions. We have previously reported that B-waves and single ICP waves do not associate (7). In the present study, the pulsatile ICP was abnormal in patients responding to surgery even though the static ICP was normal. Hence, we found significantly
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higher ICP wave amplitude and ICP wave rise time coefficient in Responders than in Nonresponders. The ICP wave amplitude levels observed in our Responders compare with those seen in patients treated for severe aneurysmal subarachnoid hemorrhage within the intensive care unit
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(4). In addition, the ICP wave characteristics also related to outcome among the non-surgery patients. Patients in the non-surgery group that did not improve spontaneously had higher ICP
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wave amplitudes than those who did improve spontaneously. Advantages with the present cohort are the high number of patients and the prolonged time of clinical follow-up. Except from our previous report (6), older studies exploring single ICP waves in iNPH have included fewer patients (2).
In this department, monitoring of ICP, including both static pulsatile ICP (MWA), has been implemented as clinical routine, and used to aid selection of patients for shunting. Based
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ACCEPTED MANUSCRIPT Surgery for iNPH on previous experience, for the individual patient, we consider ICP wave amplitudes (MWA) > 4 mmHg on average during night and >5 mmHg in >10% of recording time as the upper normal threshold (6). Since the ICP scores were used to aid indication for shunting, this material does
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not allow determining the predictive values of thresholds of ICP scores regarding shunt response.
sound.
Pulsatile ICP and the pathophysiology of iNPH
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On the other hand, the high shunt response rate suggests that our current thresholds for MWA are
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Based on the present findings, one may speculate on why the pulsatile ICP is abnormal in iNPH patients responding to surgery. From previous experience, we know that the pulsatile ICP becomes normalized following CSF diversion, at the same time that the clinical function is improved (8).
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Recently the paravascular pathway for transport of fluid and waste solutes in the brain, denoted the glymphatic pathway, was described (12). According to this model, CSF flows transependymal and trans-pial and mixes freely with the interstitial fluid (ISF), while larger-size
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molecules such as amyloid-β is transported along the vessel wall from the arterial to the venous side (12). Of particular interest for the present results, are the observations that the arterial
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pulsations are driving the glymphatic circulation (13). Failure of glymphatic circulation might cause stagnation of water in the paravascular space, thereby restricting the arterial pulsations; this again could increase the transfer of pulsatile force from the arterial side. Water stagnation in the paravascular and interstitial space could also impair the intracranial compliance, causing abnormal pulsatile ICP. Another possible mechanism could be impaired cerebral pulsation absorber mechanisms; a previous report showed an inverse relationship between a cerebral
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ACCEPTED MANUSCRIPT Surgery for iNPH pulsation absorber index and ICP wave amplitudes (21). The effects described above could then be counteracted by the CSF diversion surgery. We presently found that the clinical improvement of CSF diversion declined with time
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after surgery, and that surgical CSF diversion only to some extent relieved symptoms. We have previously shown that abnormal pulsatile ICP in iNPH is accompanied by sub-ischemia, and following CSF diversion sub-ischemia may be lasting despite of a normalized pulsatile ICP (8).
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These observations could relate to a neuro-degenerative nature of iNPH. In this context, it is paramount that the paravascular pathway has an important role in the clearance of waste solutes
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from the brain (12). In iNPH, impaired water exchange would be accompanied by reduced clearance of soluble amyloid-β, which might increase deposition of amyloid-β in the brain of iNPH patients. In concordance with this, brain biopsies from iNPH patients have shown accumulation of amyloid-β. This again links iNPH to Alzheimer’s disease (17). Deposition of
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amyloid-β in iNPH is possibly only to a limited extent prevented by CSF diversion. Thus, while surgery for iNPH modifies the pulsatile ICP, the clearance of waste solutes related to neurodegeneration is not affected. All together, we believe these findings indicate that
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neurodegeneration is part of iNPH; it hence requires the need for understanding the underlying neurobiology in iNPH. Consequently, current treatment regimens for iNPH address only some
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aspects of iNPH, and therefore need to be refined.
CONCLUSIONS
The pulsatile ICP was higher in shunt Responders than Non-responders. While the clinical improvement declined over time and the majority did not experience complete relief of symptoms, patients responding to shunting lived significantly longer than those not responding
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ACCEPTED MANUSCRIPT Surgery for iNPH to shunting. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular
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the aspect of brain water disturbance.
ACKNOWLEDGEMENTS
The authors thank Are Hugo Pripp, PhD, Department of Biostatistics, Epidemiology and Health
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Economics, Oslo University Hospital, Oslo, for statistical help during preparation of the paper.
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DISCLOSURE
Per Kristian Eide MD PhD has a financial interest in the software company (dPCom AS, Oslo) manufacturing the software (Sensometrics Software) used for analysis of the ICP recordings.
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Wilhelm Sorteberg MD PhD reports no disclosures.
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ACCEPTED MANUSCRIPT Surgery for iNPH FIGURE LEGENDS Fig. 1. Symptoms. The change in clinical severity is shown during follow-up for patients categorized as Responders (n=278; continuous line) or Non-responders (n=32, dotted line). As
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compared to pre-operative scores, the change in clinical state is presented as changes in (a) total NPH score, (b) gait score, (c) incontinence score, and (d) cognitive score. The error bars are the 95% confidence intervals (CI). Depending on time after surgery, significant differences are
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indicated by *P<0.05, **P<0.01, ***P<0.001 (t-test).
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Fig. 2. Survival. (a) Comparison of survival (age at death) between patients treated surgically (n=316, green line) or non-surgically (n=156, blue line). Patients in the surgery group lived significantly longer than patients in the non-surgery group (p=0.01; log rank test). (b) Comparison of survival (age at death) between patients in the surgery group who improved
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clinically (Responders, blue line, n=278) or not improved clinically (Non-responders, green line, n=32). Responders lived significantly longer than Non-responders (p=0.02; log rank test).
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Fig. 3. Pulsatile ICP. Differences in pulsatile ICP between Responders (n=278) and Nonresponders (n=32) are presented as (a) average of MWA, (b) percentage of MWA >5 mmHg, and
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(c) percentage of MWA >6 mmHg. The box-plots shows median values, 25th and 75th percentiles, and ranges. Significant difference indicated by * (P<0.001; t-test).
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hydrocephalus: pathophysiology and diagnosis by CSF biomarkers. Neurology 80:1385-1392, 2013. 15.
Klassen BT, Ahlskog JE: Normal pressure hydrocephalus: how often does the diagnosis
hold water? Neurology 77:1119-1125, 2011.
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Ishikawa M, Takeda M: Validation of grading scale for evaluating symptoms of idiopathic normal-pressure hydrocephalus. Dement Geriatr Cogn Disord 25:37-45, 2008. Leinonen V, Koivisto AM, Savolainen S, Rummukainen J, Tamminen JN, Tillgren T,
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Lenfeldt N, Hansson W, Larsson A, Birgander R, Eklund A, Malm J: Three-day CSF
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drainage barely reduces ventricular size in normal pressure hydrocephalus. Neurology 79:237242, 2012.
19. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM: The value of supplemental prognsotic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus.
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Park E-H, Eide PK, Zurakowski D, Madsen JR: Impaired pulsation absorber mechanism
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Stephensen H, Andersson N, Eklund A, Malm J, Tisell M, Wikkelso C: Objective B
wave analysis in 55 patients with non-communicating and communicating hydrocephalus. J Neurol Neurosurg Psychiatry 76:965-970, 2005.
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Stranjalis G, Kalamatianos T, Koutsarnakis C, Loufardaki M, Stavrinou L, Sakas DE:
Twelve-year hospital outcomes in patients with idiopathic hydrocephalus. Acta neurochirurgica. Supplement 113:115-117, 2012. Toma AK, Papadopoulos MC, Stapleton S, Kitchen ND, Watkins LD: Systematic review
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of the outcome of shunt surgery in idiopathic normal-pressure hydrocephalus. Acta Neurochir (Wien) 155:1977-1980, 2013.
Williams MA, Relkin NR: Diagnosis and management of idiopathic normal-pressure
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hydrocephalus. Neurology. Clinical practice 3:375-385, 2013.
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Table 1. Demographic, clinical, management and outcome data of the management groups Surgery Group Non-surgery Group 316 156 No (%) † 70/86 165/151 Gender (F/M) † 74 (43 - 90 72 (28 - 86) Age mean (yrs) Pre-operative symptoms 2 (0 - 15) Duration of symptoms (yrs) 2 (1 - 15)* NPH score 11 (5 - 14) Total score 10 (3 - 14) † † 4 (1 – 5) Gait score 3 (1 – 5) † Incontinence score 3 (1 - 5) 4 (1 - 5) † 4 (2 – 5) Cognitive score 3 (1 - 5) Management Shunt 310 (98.1%) Codman Hakim Programmable valve 303 (95.9%) Mietke ProGAV valve 7 (2.2%) ETV 6 (1.9%) Bleeding complications to ICP ICH 2 (0.6%) 3 (1.9%) Acute subdural hematoma 1 (0.3%) Mortality Bleeding complications to Shunt/ETV ICH 6 (1.9%) Acute subdural hematoma 5 (1.6%) Chronic subdural hematoma 22 (7.0%) Mortality 4 (1.3%) Clinical improvement during follow-up Improved clinical function (Responders) 278 (88.0%) 14 (9.0%) No improved clinical function (Non-responders) 32 (10.1%) 77 (49.4%) Lost to follow-up 6 (1.9%) 65 (41.6%) NPH: Normal pressure hydrocephalus; ETV: Endoscopic third ventriculostomy; ICP: intracranial pressure; ICH: intracerebral hematoma. * p<0.05; †p<0.001; significant differences between patient groups (one-way ANOVA).
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Table 2 The pre-operative static and pulsatile ICP scores Surgery Group Non-surgery Group Improved function No improved function Significance No improved Significance Improved (Responders) function function (Non-Responders) (Non-Responders) (Responders) Static ICP Mean ICP Average (mmHg) 7.5 + 3.9 6.5 + 3.8 ns 5.3 + 4.7 6.9 + 3.6 ns 7 + 10 4+9 ns 3+4 5+8 ns Percentage >15 mmHg Percentage >20 mmHg 2+3 1+1 ns 1+1 ns Pulsatile ICP Mean wave amplitude (MWA) Average (mmHg) 5.8 + 1.7 3.9 + 1.6 <0.001 3.2 + 0.5 3.8 + 0.8 0.01 Percentage >5 mmHg 58 + 31 21 + 31 <0.001 3+3 15 + 18 0.02 Percentage >6 mmHg 37 + 31 12 + 25 <0.001 1+1 6 + 10 ns Mean wave rise time (RT) 0.25 + 0.04 ns 0.23 + 0.06 0.23 + 0.05 ns Average (sec) 0.26 + 0.03 Percentage >0.20 sec 91 + 18 85 + 25 0.01 69 + 35 76 + 30 ns Percentage >0.25 sec 69 + 30 67 + 32 0.04 48 + 36 51 + 34 ns Mean wave rise time coeff. (RTC) 16.9 + 8.3 <0.001 16.9 + 7.2 18.4 + 6.5 ns Average (mmHg/sec) 23.6 + 7.5 Percentage >20 mmHg/sec 58 + 31 25 + 33 <0.001 25 + 36 32 + 32 ns Percentage >30 mmHg/sec 20 + 25 11 + 25 ns 11 + 21 10 + 19 ns * ICP parameters recorded from 11 pm to 7 am. ICP. Significant differences between groups were determined by independent samples t-test (ns: non-significant).
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Highlights
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The pulsatile ICP was higher in shunt Responders than Non-responders. The clinical improvement declined over time and the majority did not experience complete relief of symptoms, Patients responding to shunting lived significantly longer than those not responding. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular the aspect of brain water disturbance
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Abbreviation list CSF – cerebrospinal fluid CT – computer tomography
ICH – intracerebral hemorrhage ICP – intracranial pressure ISF – interstitial fluid
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iNPH – idiopathic normal pressure hydrocephalus
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ETV – endoscopic third ventriculostomy
MRI – magnetic resonance imaging
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MWA – mean ICP wave amplitude
REK - Regional Committee for Medical and Health Research Ethics RT – rise time
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RTC – rise time coefficient
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Supplemental Table 1. The NPH Grading Scale used at the Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo Scale Clinical performance NPH Score Gait disturbance 5 Normal gait. 4 Gait is abnormal, but walking is possible without support. Imbalance when turning with short steps. Widened base and occasional falling. 3 A cane is needed. Independent walking is possible but is unstable or the patient falls. 2 Support from another person is needed. Ambulating is possible with help. 1 Patient is bedridden or not able to ambulate. Urinary incontinence 5 No subjective or objective incontinence. 4 Urinary urgency. Rare incontinence. 3 Occasional urinary incontinence. 2 Continuous urinary incontinence. 1 Both urinary and fecal incontinence. Dementia 5 Normal. 4 Memory problems exist reported by patient or family. 3 Important memory problems with more or less severe behavior disturbances. 2 Severe dementia. 1 Vegetative. 15 Total score
S1878-8750(15)01234-6
DOI:
10.1016/j.wneu.2015.09.067
Reference:
WNEU 3253
To appear in:
World Neurosurgery
Received Date: 2 July 2015 Revised Date:
17 September 2015
Accepted Date: 19 September 2015
Please cite this article as: Eide PK, Sorteberg W, Outcome of surgery for idiopathic normal pressure hydrocephalus: Role of pre-operative static and pulsatile intracranial pressure, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.09.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Surgery for iNPH
Outcome of surgery for idiopathic normal pressure hydrocephalus: Role of pre-operative static and pulsatile intracranial pressure
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Per Kristian Eide1,2, Wilhelm Sorteberg1
Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway;
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Faculty of Medicine, University of Oslo, Oslo, Norway.
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Funding
Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Short title
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Corresponding author:
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Surgery for idiopathic normal pressure hydrocephalus
Per Kristian Eide, MD PhD
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Professor/Section chief
Department of Neurosurgery Oslo University Hospital - Rikshospitalet Pb 4950 Nydalen,
N-0424 Oslo, Norway
Phone: +47-23074321. Fax: +47-23074310 [email protected]/[email protected]
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ACCEPTED MANUSCRIPT Surgery for iNPH Abbreviation list CSF – cerebrospinal fluid CT – computer tomography
ICH – intracerebral hemorrhage ICP – intracranial pressure ISF – interstitial fluid
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iNPH – idiopathic normal pressure hydrocephalus
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ETV – endoscopic third ventriculostomy
MRI – magnetic resonance imaging
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MWA – mean ICP wave amplitude
REK - Regional Committee for Medical and Health Research Ethics RT – rise time
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RTC – rise time coefficient
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ACCEPTED MANUSCRIPT Surgery for iNPH Abstract Objectives To examine the outcome of surgery for idiopathic normal pressure hydrocephalus (iNPH) and how outcome relates to the pre-operative static and pulsatile intracranial pressure
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(ICP).
Methods An observational cohort study included all iNPH patients managed at our department during the years 2002-2012 in whom over-night ICP monitoring was part of pre-operative work-
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up. Clinical data were retrieved from a quality registry and ICP scores from a pressure database. Results The study included 472 patients, 316 in the surgery group and 156 in the non-surgery
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group. Among those treated surgically, 278 (90%) showed clinical improvement (Responders) while 32 (10%) had no improvement (Non-responders). Among Responders, only about 1/3 reached the best clinical scores; moreover, the difference in clinical score between Responders and Non-responders declined with time after surgery, particularly after 3-4 years. The surgery
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was accompanied by acute intracranial hematomas in 11 patients (3.5%), of whom 4 (1.3%) died. Survival (age at death) was significantly higher among the Responders than in Non-responders. While the static ICP was normal in all patients, the pulsatile ICP was significantly higher in
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Responders than in Non-responders.
Conclusions The pulsatile ICP was higher in shunt Responders than Non-responders. While the
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clinical improvement declined over time and the majority did not experience complete relief of symptoms, shunt Responders lived significantly longer than Non-responders. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular the aspect of brain water disturbance.
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Key words: Normal pressure hydrocephalus, intracranial pressure, shunt surgery, outcome, complications.
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ACCEPTED MANUSCRIPT Surgery for iNPH Introduction The so-called normal pressure hydrocephalus (iNPH) syndrome was described 50 years ago (1). Patients with the triad symptoms of unsteady and ataxic gait, urinary incontinence and cognitive
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impairment (dementia), combined with enlarged cerebral ventricles and normal lumbar
cerebrospinal fluid (CSF) pressure improved clinically following CSF diversion surgery (shunt implantation) (25). Shunt surgery (and in a few cases endoscopic third ventrciulostomy) is the
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treatment of choice, though the results of surgery for iNPH is still a matter of controversy (10, 24).
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The pathophysiology of iNPH remains an enigma. As symptoms improve following CSF diversion surgery (18), it is generally accepted that CSF circulation disturbance is involved. The clinical improvement may be linked to improved cerebral metabolism (14), as well as improved intracranial pressure-volume relationship (8). Despite the term normal pressure hydrocephalus,
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it is controversial how the ICP becomes altered in iNPH. Further knowledge on this matter is crucial since the only current treatment for iNPH is surgical, which goal is to reduce the ICP. In our department, we have for more than a decade monitored the static and pulsatile ICP
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over-night as part of the pre-operative work-up in iNPH patients. In this observational cohort study, we examined the outcome of surgery for iNPH with regard to clinical outcome, severe
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complications (intracranial bleeds), and survival. We further evaluated how the pre-operative static and pulsatile ICP scores related to the outcome of surgery.
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ACCEPTED MANUSCRIPT Surgery for iNPH MATERIAL AND METHODS Patient material The study included all iNPH patients that underwent ICP monitoring as part of their pre-
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operative work-up in the Department of Neurosurgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway during the years 2002-2012.
The study was approved by the Oslo University Hospital – Rikshospitalet as a quality
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study (Approval 2014/4720). The Regional Committee for Medical and Health Research Ethics (REK) of Health Region South-East, Norway was informed in writing, and had no objections to
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the study (reference 2014/528). Information was retrieved from Neurovascular-Hydrocephalus Quality Register (REK Approval 11/6692).
Patient management & follow-up
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The department’s routine for management of iNPH is described shortly. Patients with suspected iNPH are usually referred from local neurological departments based on symptoms indicative of iNPH and imaging findings of ventriculomegaly. In some patients, a tap test or infusion test has
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been done prior to referral. At our department, a clinical assessment is done, and ICP monitoring is carried out over-night. Indication for CSF diversion surgery is based on the combination of
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clinical findings, presence of co-morbidity, imaging findings and results of the ICP monitoring. Thus, patients should meet the clinical and imaging criteria for iNPH, and the ICP measurements was a final decision maker. With regard to the ICP scores, we primarily use the mean ICP wave (MWA) values, recommending shunting in patients with MWA values above upper normal threshold values during the night period, i.e. MWA >4 mmHg on average and >5 mmHg in minimum 10% of recording time from 11 p.m. until 7 a.m. (6).
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ACCEPTED MANUSCRIPT Surgery for iNPH A NPH grading scale (Appendix A) is used to assess the severity of symptoms. Assessment was done prior to ICP monitoring/surgery and then at intervals during follow-up. Clinical improvement was defined as an increase in clinical score on the NPH grading scale.
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Imaging includes computer tomography (CT) scanning and/or magnetic resonance
imaging (MRI). During the last years MRI phase-contrast imaging has also been included. The quantitative imaging of ventricular size or other imaging indices of CSF circulation was not a
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part of the present study, and is therefore not commented on.
The ordinary treatment is shunt surgery (ventriculo-peritoneal shunt). Either of two types
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of shunt valves were used: Codman Hakim Programmable valve (Codman, Johnsen & Johnsen, Raynham, MA, USA), or Mietke ProGAV valve (Aesculap AG, Tuttlingen, Germany). In rare cases with questionable aqueduct stenosis, an endoscopic third ventriculostomy (ETV) is done, either soon after the ICP monitoring or some weeks later.
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After surgery, the patients are followed in our outpatient clinic or they are contacted by phone. According to this department’s routine, clinical control was done after 3-6 months, 12 months and then annually. Suspected shunt failure is accompanied with either of the following:
revision.
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Adjustment of shunt valve opening pressure, continuous over-night ICP monitoring, or shunt-
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The Neurovascular-Hydrocephalus Quality Register stores the clinical information,
including pre-operative and follow-up data. The death dates of all patients are provided from the Norwegian Folk Registry.
Pre-operative monitoring of static and pulsatile ICP
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ACCEPTED MANUSCRIPT Surgery for iNPH We have previously described our clinical routine for ICP monitoring (6). Placement of the solid ICP sensor is done under local anesthesia within the operating room. A small burr hole is made in the frontal region, a small opening made in the dura, and the sensor placed 1-2 cm into the
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brain parenchyma after being tunneled subcutaneously. Most commonly the Codman ICP
MicroSensor (Codman, Johnson & Johnson, Raynham, MA, USA) was used, and in some patients the Raumedic NeuroVent P sensor (Raumedic AG, Münchberg, GE).
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The patient is transferred to the neuro-intermediate ward, the ICP sensor becomes
connected to a computerized system for continuous recording, and the monitoring is continued
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over-night, with real-time presentation of the continuous ICP signals. Assessment of the ICP measurements is done by the attending doctor in the subsequent morning. The continuous ICP raw data files are stored in a pressure database on the hospital server. For the present study, the continuous ICP recordings were retrieved from the pressure
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database, and analyzed according to a method previously described (3). According to the automatic routine, the cardiac induced ICP waves are identified in the signal and for every subsequent 6-second time window the static ICP is characterized as the mean ICP. The pulsatile
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ICP is characterized as the mean ICP wave amplitude (pressure difference from diastolic minimum to systolic maximum pressure, MWA), the mean ICP wave rise time (time difference
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from diastolic minimum to systolic maximum pressure), and the mean ICP wave rise time coefficient (pressure difference divided by time difference from diastolic minimum to systolic maximum pressure). In order to compare patients, we considered only the recordings from 11 p.m. until 7 a.m.
Statistical analysis
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ACCEPTED MANUSCRIPT Surgery for iNPH All statistical analyses were performed using the SPSS software version 22 (IBM Corporation, Armonk, NY). Between-group differences for repeated measures were analysed using linear mixed models with a random intercept. In addition, independent sample t-tests between the two
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groups were performed at each follow-up time. Survival was assessed using Kaplan-Meier plots with using log-rank test to determine differences between groups. The ICP scores were used in decision making for shunting, and we did not determine predictive values of ICP scores for shunt
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response. Statistical significance was accepted at the .05 level.
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RESULTS Patient material
During the years 2002-2012 a total of 472 patients underwent assessment for iNPH including continuous over-night ICP monitoring (Table 1). Surgery for iNPH was done in 316 patients.
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Compared with the 156 non-surgery patients, those treated surgically were more often women, they were older, and with longer duration and severity of symptoms (Table 1). Shunt surgery was done in 310/316 patients (98.1%), and ETV in the other 6/316 (1.9%).
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With regard to shunt valve, we used a Codman Hakim programmable valve in 303 patients (opening pressure median 12 cm H2O; ranges 6-20 cm H2O), and a Mietke ProGAV valve in the
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other 7 patients (opening pressure 5-6/20-25 cm H2O). The shunt was ventriculo-peritoneal (VP) in 309 patients and ventriculo-atrial (VA) in one patient. One shunt-revision was required in 40/310 patients (12.9%), two shunt-revisions in 6/310 (1.9%) patients and three shunt-revisions in 1/310 (0.3%) patients.
Outcome of surgery
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ACCEPTED MANUSCRIPT Surgery for iNPH Clinical improvement Following surgery, clinical improvement, that means improvement on the NPH grading scale (Appendix A), was observed in 278/310 patients (89.8%), while 32/310 patients (10.3%) showed
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no improvement (Table 1). Four patients died from intracerebral hemorrhage (ICH) after the shunt surgery, while two patients were lost to follow-up. Fig. 1 shows the changes in NPH score over time for those that did improve (Responders; n=278) and those that did not improve
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clinically (Non-responders; n=32). Linear mixed model analyses for repeated measurements revealed significant overall differences between Responders/Non-responders whether
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considering Total NPH score (P<0.001; Fig. 1a), Gait sub-score (P<0.001; Fig. 1b), Incontinence sub-score (P<0.001; Fig. 1c), or Cognitive sub-score (P<0.001; Fig. 1d). Among the Responders, the clinical improvement was most evident during the first 2-3 years after surgery, and then declined. After 4 years, the decline in total NPH score was still
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evident (Fig. 1a). While improvement of the gait sub-score lasted the longest (Fig. 1b), the improvement in incontinence (Fig. 1c) and cognitive scores (Fig. 1d) were more short lasting. After 3-4 years, the improvement in cognitive function was hence less evident.
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Among the 310 surgically treated patients, 46 (15%) reached a maximum NPH score of 15, 58 patients (19%) a maximum NPH score of 14, and another 46 (15%) a maximum NPH
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score of 13. Thus, only 34% of patients reached the best NPH scores 14-15 and only 48% the best scores 13-15.
With regard to follow-up of the non-surgery group, 14/156 (9%) reported a spontaneous
improvement of symptoms, while 77/156 (49.4%) had no clinical improvement or worsening of symptoms (Table 1). We had no clinical follow-up of the remainder 65 patients (41.6%).
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ACCEPTED MANUSCRIPT Surgery for iNPH Severe complications After ICP monitoring, intracranial bleeds were seen in 6/472 patients (1.3%), i.e. ICH in 5 and acute subdural hematoma in 1 (Table 1). There was no surgical mortality related to ICP
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monitoring.
CSF diversion surgery for iNPH was accompanied with ICH in 6/316 patients (1.9%; Table 1). In addition, 5/316 patients (1.6%) developed acute subdural hematoma after median 22
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months (ranges 2 – 29 months after surgery) and another 22/316 patients (7%) developed chronic subdural hematoma median 3 months (ranges 1 to 53 months) after surgery. Surgical mortality of
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shunt surgery was 1.3% (4/316 patients), all caused by ICH.
Survival
Patients in the surgery group lived significantly longer as compared to those in the non-surgery
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group (P=0.01; Fig. 2a); median age at death was hence 83.7 years versus 81.9 years. Within the surgery group, the Responders died at a significantly older age than the Non-
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responders; median age at death was 85.2 years versus 80.7 years (P=0.02; Fig. 2b).
Static and pulsatile ICP before surgery
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Pre-operative ICP scores among Responders and None-responders of the surgery group is presented in Table 2, left. While the static ICP was normal (<15 mmHg) and did not differ between Responders/Non-responders, the pulsatile ICP differed significantly between groups. This was most evident for the ICP wave amplitude, but also significant for the ICP wave rise time and the ICP wave rise time coefficient. Figure 3 presents differences in mean ICP wave amplitude (MWA) between the Responders and Non-responders, including differences in
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With regard to the non-surgery group (Table 2, right), the pulsatile ICP was significantly lower in those with spontaneous clinical improvement (Responders) as compared to those with no improvement (Non-responders; Table 2, right). The static ICP did not differ between the two
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DISCUSSION
This observational cohort study provides evidence that surgery improves clinical function in iNPH, even though the clinical improvement declines after 3-4 years, and the majority has
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lasting symptoms of variable severity. The survival (age at death) was significantly increased in patients responding to the surgery than in those not responding. The iNPH patients improving clinically following CSF diversion have abnormal pre-operative pulsatile ICP despite of normal
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static ICP.
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Outcome of surgery
The outcome of surgery for iNPH is balanced between the opportunity for clinical improvement and the risk of complications. The risk aspect is important given their old age at inclusion (median age >70 years) and increased occurrence of cardiovascular disease (5). The present data underline that surgery for iNPH is accompanied with a definitive risk. Surgical 1-month mortality was hence 1.3% caused by cerebral hemorrhage. In addition, acute subdural hematoma occurred in 1.6% after median 22 months, and chronic subdural hematoma 12
ACCEPTED MANUSCRIPT Surgery for iNPH in 7% after median 3 months. Although several reports have documented the risk of surgery for iNPH (15, 23), our numbers with regard to intracranial bleeds are higher than usually quoted in the literature (24). This discrepancy may possibly be related to the present study reporting this
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department’s entire experience over many years with a long follow-up time. In series with smaller patient numbers, there is a higher risk for underreporting of complications.
It should also be noticed that surgery for iNPH carries additional risks such as risk of
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infection and shunt failure, requiring shunt revision. We have previously reported our infection rate, which for NPH is about 4% (11).
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In this cohort, 278/310 (90%) reported clinical improvement following surgery. This compares with the best clinical results of recent observational studies including a significant number of patients (9, 20, 24), though older studies have reported lower response rate (10). With regard to prediction of shunt response in iNPH, the present results compare with those using
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extended lumbar drainage (ELD); a test by many considered to be the best for predicting shuntresponsive iNPH (19, 20). The dis-advantages of both tests are the need for hospitalization and the tests carrying a certain risk of complications. This, in contrast to less invasive tests such as
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spinal tap tests and spinal infusion studies (25), which can be carried out on an outpatient basis. Having a lower complication risk, their predictive value in iNPH is, however, also lower (19).
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The total risk for surgically treated iNPH patients are the sum of the risks linked to the predicting test and the shunt surgery itself. We prefer a test with high predictive accuracy as this reduces the number of iNPH patients being shunted. As shown in our patient cohort, the risk linked to ICP monitoring is quite low when compared to that of shunt surgery. The present data further extend existing knowledge by showing that the clinical improvement declines over time, in particular 3-4 years after surgery. The cognitive
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ACCEPTED MANUSCRIPT Surgery for iNPH improvement had the shortest duration, while improvement in gait was the longest lasting. Others also have reported a reduction in clinical effect over time following iNPH surgery (15). Another important aspect is that only a fraction of our patients reached a maximum clinical
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response after surgery. Hence, among 310 followed-up, only 104 (34%) reached a maximum NPH score of 14-15. These numbers indicate that current surgical modalities do not “cure”
iNPH; at best, clinical improvement can be anticipated only to a certain extent and for only a
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certain period of time. Although we use shunts with adjustable valves to tailor the CSF diversion, lack of improvement could in some patients possibly be caused by sub-optimal amount of CSF
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drainage.
The degree and quality of clinical improvement depends on the method used for clinical assessment. There is currently no consensus on how to quantify clinical improvement in iNPH. Different scoring systems exist, ranging from advanced testing systems to simpler self-reporting
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assessments (16). Our NPH grading scale has certain weaknesses (16). An advantage, however, is that we used the same clinical grading scale throughout the observation period, which makes it possible to compare patients, and assess alterations over time.
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Even though surgery for iNPH carries risks and the clinical improvement declines over time, survival (age at death) was presently significantly increased in the surgery group as
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compared to the non-surgery group. Moreover, within the surgery group, patients with clinical improvement lived significantly longer than those with no clinical improvement (median age at death 85.2 versus 80.7 years). We are not aware of other studies exploring survival in iNPH patients. Whether or not shunt surgery adds years of life to the iNPH patients ought to be addressed in future studies.
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ACCEPTED MANUSCRIPT Surgery for iNPH Static and pulsatile ICP in iNPH The name normal pressure hydrocephalus includes a statement that the ICP is normal. The rational for the name was the observations of normal lumbar CSF pressures (1). Our observations
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of normal static ICP (mean ICP) support the assumption of a normal ICP in iNPH. We also found comparable frequency of short-lasting elevations in ICP (>15 or 20 mmHg; usually
referred to as B-waves) between Responders/Non-responders. Others have also reported that the
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occurrence of B waves is not increased in iNPH (22). Therefore, the term normal pressure
hydrocephalus can be justified; however, normal pressure then refers to only a normal static ICP.
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In contrast to B-waves, the pulsatile ICP refers to the single ICP waves related to the corresponding single cardiac contractions. We have previously reported that B-waves and single ICP waves do not associate (7). In the present study, the pulsatile ICP was abnormal in patients responding to surgery even though the static ICP was normal. Hence, we found significantly
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higher ICP wave amplitude and ICP wave rise time coefficient in Responders than in Nonresponders. The ICP wave amplitude levels observed in our Responders compare with those seen in patients treated for severe aneurysmal subarachnoid hemorrhage within the intensive care unit
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(4). In addition, the ICP wave characteristics also related to outcome among the non-surgery patients. Patients in the non-surgery group that did not improve spontaneously had higher ICP
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wave amplitudes than those who did improve spontaneously. Advantages with the present cohort are the high number of patients and the prolonged time of clinical follow-up. Except from our previous report (6), older studies exploring single ICP waves in iNPH have included fewer patients (2).
In this department, monitoring of ICP, including both static pulsatile ICP (MWA), has been implemented as clinical routine, and used to aid selection of patients for shunting. Based
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not allow determining the predictive values of thresholds of ICP scores regarding shunt response.
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Pulsatile ICP and the pathophysiology of iNPH
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On the other hand, the high shunt response rate suggests that our current thresholds for MWA are
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Based on the present findings, one may speculate on why the pulsatile ICP is abnormal in iNPH patients responding to surgery. From previous experience, we know that the pulsatile ICP becomes normalized following CSF diversion, at the same time that the clinical function is improved (8).
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Recently the paravascular pathway for transport of fluid and waste solutes in the brain, denoted the glymphatic pathway, was described (12). According to this model, CSF flows transependymal and trans-pial and mixes freely with the interstitial fluid (ISF), while larger-size
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molecules such as amyloid-β is transported along the vessel wall from the arterial to the venous side (12). Of particular interest for the present results, are the observations that the arterial
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pulsations are driving the glymphatic circulation (13). Failure of glymphatic circulation might cause stagnation of water in the paravascular space, thereby restricting the arterial pulsations; this again could increase the transfer of pulsatile force from the arterial side. Water stagnation in the paravascular and interstitial space could also impair the intracranial compliance, causing abnormal pulsatile ICP. Another possible mechanism could be impaired cerebral pulsation absorber mechanisms; a previous report showed an inverse relationship between a cerebral
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after surgery, and that surgical CSF diversion only to some extent relieved symptoms. We have previously shown that abnormal pulsatile ICP in iNPH is accompanied by sub-ischemia, and following CSF diversion sub-ischemia may be lasting despite of a normalized pulsatile ICP (8).
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These observations could relate to a neuro-degenerative nature of iNPH. In this context, it is paramount that the paravascular pathway has an important role in the clearance of waste solutes
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from the brain (12). In iNPH, impaired water exchange would be accompanied by reduced clearance of soluble amyloid-β, which might increase deposition of amyloid-β in the brain of iNPH patients. In concordance with this, brain biopsies from iNPH patients have shown accumulation of amyloid-β. This again links iNPH to Alzheimer’s disease (17). Deposition of
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amyloid-β in iNPH is possibly only to a limited extent prevented by CSF diversion. Thus, while surgery for iNPH modifies the pulsatile ICP, the clearance of waste solutes related to neurodegeneration is not affected. All together, we believe these findings indicate that
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neurodegeneration is part of iNPH; it hence requires the need for understanding the underlying neurobiology in iNPH. Consequently, current treatment regimens for iNPH address only some
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aspects of iNPH, and therefore need to be refined.
CONCLUSIONS
The pulsatile ICP was higher in shunt Responders than Non-responders. While the clinical improvement declined over time and the majority did not experience complete relief of symptoms, patients responding to shunting lived significantly longer than those not responding
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the aspect of brain water disturbance.
ACKNOWLEDGEMENTS
The authors thank Are Hugo Pripp, PhD, Department of Biostatistics, Epidemiology and Health
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Economics, Oslo University Hospital, Oslo, for statistical help during preparation of the paper.
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DISCLOSURE
Per Kristian Eide MD PhD has a financial interest in the software company (dPCom AS, Oslo) manufacturing the software (Sensometrics Software) used for analysis of the ICP recordings.
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Wilhelm Sorteberg MD PhD reports no disclosures.
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ACCEPTED MANUSCRIPT Surgery for iNPH FIGURE LEGENDS Fig. 1. Symptoms. The change in clinical severity is shown during follow-up for patients categorized as Responders (n=278; continuous line) or Non-responders (n=32, dotted line). As
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compared to pre-operative scores, the change in clinical state is presented as changes in (a) total NPH score, (b) gait score, (c) incontinence score, and (d) cognitive score. The error bars are the 95% confidence intervals (CI). Depending on time after surgery, significant differences are
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indicated by *P<0.05, **P<0.01, ***P<0.001 (t-test).
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Fig. 2. Survival. (a) Comparison of survival (age at death) between patients treated surgically (n=316, green line) or non-surgically (n=156, blue line). Patients in the surgery group lived significantly longer than patients in the non-surgery group (p=0.01; log rank test). (b) Comparison of survival (age at death) between patients in the surgery group who improved
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clinically (Responders, blue line, n=278) or not improved clinically (Non-responders, green line, n=32). Responders lived significantly longer than Non-responders (p=0.02; log rank test).
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Fig. 3. Pulsatile ICP. Differences in pulsatile ICP between Responders (n=278) and Nonresponders (n=32) are presented as (a) average of MWA, (b) percentage of MWA >5 mmHg, and
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(c) percentage of MWA >6 mmHg. The box-plots shows median values, 25th and 75th percentiles, and ranges. Significant difference indicated by * (P<0.001; t-test).
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Table 1. Demographic, clinical, management and outcome data of the management groups Surgery Group Non-surgery Group 316 156 No (%) † 70/86 165/151 Gender (F/M) † 74 (43 - 90 72 (28 - 86) Age mean (yrs) Pre-operative symptoms 2 (0 - 15) Duration of symptoms (yrs) 2 (1 - 15)* NPH score 11 (5 - 14) Total score 10 (3 - 14) † † 4 (1 – 5) Gait score 3 (1 – 5) † Incontinence score 3 (1 - 5) 4 (1 - 5) † 4 (2 – 5) Cognitive score 3 (1 - 5) Management Shunt 310 (98.1%) Codman Hakim Programmable valve 303 (95.9%) Mietke ProGAV valve 7 (2.2%) ETV 6 (1.9%) Bleeding complications to ICP ICH 2 (0.6%) 3 (1.9%) Acute subdural hematoma 1 (0.3%) Mortality Bleeding complications to Shunt/ETV ICH 6 (1.9%) Acute subdural hematoma 5 (1.6%) Chronic subdural hematoma 22 (7.0%) Mortality 4 (1.3%) Clinical improvement during follow-up Improved clinical function (Responders) 278 (88.0%) 14 (9.0%) No improved clinical function (Non-responders) 32 (10.1%) 77 (49.4%) Lost to follow-up 6 (1.9%) 65 (41.6%) NPH: Normal pressure hydrocephalus; ETV: Endoscopic third ventriculostomy; ICP: intracranial pressure; ICH: intracerebral hematoma. * p<0.05; †p<0.001; significant differences between patient groups (one-way ANOVA).
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Table 2 The pre-operative static and pulsatile ICP scores Surgery Group Non-surgery Group Improved function No improved function Significance No improved Significance Improved (Responders) function function (Non-Responders) (Non-Responders) (Responders) Static ICP Mean ICP Average (mmHg) 7.5 + 3.9 6.5 + 3.8 ns 5.3 + 4.7 6.9 + 3.6 ns 7 + 10 4+9 ns 3+4 5+8 ns Percentage >15 mmHg Percentage >20 mmHg 2+3 1+1 ns 1+1 ns Pulsatile ICP Mean wave amplitude (MWA) Average (mmHg) 5.8 + 1.7 3.9 + 1.6 <0.001 3.2 + 0.5 3.8 + 0.8 0.01 Percentage >5 mmHg 58 + 31 21 + 31 <0.001 3+3 15 + 18 0.02 Percentage >6 mmHg 37 + 31 12 + 25 <0.001 1+1 6 + 10 ns Mean wave rise time (RT) 0.25 + 0.04 ns 0.23 + 0.06 0.23 + 0.05 ns Average (sec) 0.26 + 0.03 Percentage >0.20 sec 91 + 18 85 + 25 0.01 69 + 35 76 + 30 ns Percentage >0.25 sec 69 + 30 67 + 32 0.04 48 + 36 51 + 34 ns Mean wave rise time coeff. (RTC) 16.9 + 8.3 <0.001 16.9 + 7.2 18.4 + 6.5 ns Average (mmHg/sec) 23.6 + 7.5 Percentage >20 mmHg/sec 58 + 31 25 + 33 <0.001 25 + 36 32 + 32 ns Percentage >30 mmHg/sec 20 + 25 11 + 25 ns 11 + 21 10 + 19 ns * ICP parameters recorded from 11 pm to 7 am. ICP. Significant differences between groups were determined by independent samples t-test (ns: non-significant).
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The pulsatile ICP was higher in shunt Responders than Non-responders. The clinical improvement declined over time and the majority did not experience complete relief of symptoms, Patients responding to shunting lived significantly longer than those not responding. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular the aspect of brain water disturbance
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Abbreviation list CSF – cerebrospinal fluid CT – computer tomography
ICH – intracerebral hemorrhage ICP – intracranial pressure ISF – interstitial fluid
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iNPH – idiopathic normal pressure hydrocephalus
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ETV – endoscopic third ventriculostomy
MRI – magnetic resonance imaging
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MWA – mean ICP wave amplitude
REK - Regional Committee for Medical and Health Research Ethics RT – rise time
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RTC – rise time coefficient
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Supplemental Table 1. The NPH Grading Scale used at the Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo Scale Clinical performance NPH Score Gait disturbance 5 Normal gait. 4 Gait is abnormal, but walking is possible without support. Imbalance when turning with short steps. Widened base and occasional falling. 3 A cane is needed. Independent walking is possible but is unstable or the patient falls. 2 Support from another person is needed. Ambulating is possible with help. 1 Patient is bedridden or not able to ambulate. Urinary incontinence 5 No subjective or objective incontinence. 4 Urinary urgency. Rare incontinence. 3 Occasional urinary incontinence. 2 Continuous urinary incontinence. 1 Both urinary and fecal incontinence. Dementia 5 Normal. 4 Memory problems exist reported by patient or family. 3 Important memory problems with more or less severe behavior disturbances. 2 Severe dementia. 1 Vegetative. 15 Total score