Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurodegenerative disease in the elderly with enlarged ventricles and normal or slightly elevated cerebrospinal fluid pressure, clinically characterized by an insidious onset and gradual progression of impairments of gait, balance, cognition, with urinary incontinence 1).
Normal Pressure Hydrocephalus first became recognized on March 10, 1964 as a distinct medical syndrome by Salomón Hakim, M.D., Ph.D.
The classic triad of magnetic apraxia, urinary incontinence, and dementia remain relevant into the 21(st) century as being the basis for symptomatic diagnosis and predicting potential benefit from ventriculoperitoneal shunting, though they have been greatly augmented by the addition of modern neuroimaging, particularly MRI.
Modern criteria recognize a wider range of diagnostic criteria, and new positive and negative prognostic indicators for treatment benefit have been discovered, though the mainstay remains initial drainage of a large volume of cerebrospinal fluid and monitoring for clinical improvement. Even with our advances in understanding both primary and secondary normal pressure hydrocephalus, diagnosis, management, and counseling remain challenging in this disorder 2).
In people over 65 years old, pooled prevalence obtained from specific population studies was 1.3%, almost 50-fold higher than that inferred from door-to-door surveys of dementia or Parkinsonism. Prevalence may be even higher in assisted-living and extended-care residents, with up to 11.6% of patients fulfilling the criteria for suspected iNPH and 2.0% of patients showing permanent improvement after cerebrospinal fluid (CSF) diversion. The only prospective population-based survey that reported iNPH incidence estimated 1.20 cases/1000 inhabitants/year, 15-fold higher than estimates obtained from studies based on hospital catchment areas. The incidence of shunt surgery for iNPH and SRiNPH obtained from incident cases of hospital catchment areas appears to be fewer than two cases and one case/100,000 inhabitants/year, respectively. Unfortunately, there is no population-based study reporting the real values for these two parameters.
The prevalence of iNPH is high—for example, in Japan among people older than 65, the prevalence is between 0.5% and 2.9% 4)and the syndrome is both underdiagnosed and undertreated.
It is recommended that INPH be classified into probable, possible, and unlikely categories. It is hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH 5).
All patients with idiopathic normal pressure hydrocephalus (INPH) who underwent shunting in Sweden in 2008-2010 were compared to age- and sex-matched population-based controls. Inclusion criteria were age 60-85 years and no dementia. The 10 most important vascular risk factor (VRFs) and cerebrovascular and peripheral vascular disease were prospectively assessed using blood samples, clinical examinations, and standardized questionnaires. Assessed VRFs were hypertension, hyperlipidemia, diabetes, obesity, psychosocial factors, smoking habits, diet, alcohol intake, cardiac disease, and physical activity.
In total, 176 patients with INPH and 368 controls participated. Multivariable logistic regression analysis indicated that hyperlipidemia (odds ratio [OR] 2.380; 95% confidence interval [CI] 1.434-3.950), diabetes (OR 2.169; 95% CI 1.195-3.938), obesity (OR 5.428; 95% CI 2.502-11.772), and psychosocial factors (OR 5.343; 95% CI 3.219-8.868) were independently associated with INPH. Hypertension, physical inactivity, and cerebrovascular and peripheral vascular disease were also overrepresented in INPH. Moderate alcohol intake and physical activity were overrepresented among the controls. The population-attributable risk percentage was 24%.
The findings confirm that patients with INPH have more VRFs and lack the protective factors present in the general population. Almost 25% of cases of INPH may be explained by VRFs. This suggests that INPH may be a subtype of vascular dementia. Targeted interventions against modifiable VRFs are likely to have beneficial effects on INPH 6).
Although the exact pathogenesis of NPH is unknown, many possible causes have been postulated, including cerebrovascular ischemia. Studies have demonstrated that periventricular blood flow and cerebrovascular autoregulation are reduced.
It is also thought that biomechanical changes, such as the combination of tissue distortion caused by ventricular dilation, CSF and interstitial fluid stasis, and impaired autoregulation may result in failure of drainage of neurotoxic compounds such as amyloid-b.
Increased CSF stroke volume through the aqueduct has also been demonstrated in the NPH population despite normal CSF pressures. The reaction of the cerebral mantle to all or some of these processes is poorly understood. It is thought that white matter tract connections serving the cortex could be disrupted in a variety of ways, including disconnection, swelling, stretching, and compression. Therefore, it is possible that some types of disruption may be more tolerable (i.e., more reversible) than others.
Only a few studies have seized the opportunity to reevaluate the theories of pathogenesis of NPH using developments in imaging techniques.
The disorders of Alzheimer disease, vascular dementia and normal pressure hydrocephalus are all causes of dementia in the elderly population. It is often the case that it is clinically very difficult to tell these diseases apart. All three forms of dementia share the same risk factors, which for the most part are vascular risk factors. Bateman proposes that there is an underlying vascular pathophysiology behind these conditions, which is related to the strength of the pulse waves induced in the craniospinal cavity by the arterial vascular tree. It is proposed the manifestation of the dementia in any one patient is dependant on the way that the pulsations interact with the brain and its venous and perivascular drainage. This interaction is predominately dependant on the compliance of the craniospinal cavity and the chronicity of the increased pulse wave stress 7).
Experimental animal model
Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed.
Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement.
Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus 8).
Disturbed cerebrospinal fluid (CSF) dynamics are part of the pathophysiology of normal pressure hydrocephalus (NPH).
A study investigated the contribution of established CSF dynamic parameters to mean pulse amplitude (AMP), a prognostic variable defined as mean amplitude of cardiac-related intracranial pressure pulsations during 10 min of lumbar infusion test, with the aim of clarifying the physiological interpretation of the variable. AMP(mean) and CSF dynamic parameters were determined from infusion tests performed on 18 patients with suspected NPH. Using a mathematical model of CSF dynamics, an expression for AMP(mean) was derived and the influence of the different parameters was assessed. There was high correlation between modelled and measured AMP(mean) (r = 0.98, p < 0.01). Outflow resistance and three parameters relating to compliance were identified from the model. Correlation analysis of patient data confirmed the effect of the parameters on AMP(mean) (Spearman’s ρ = 0.58-0.88, p < 0.05). Simulated variations of ±1 standard deviation (SD) of the parameters resulted in AMP(mean) changes of 0.6-2.9 SD, with the elastance coefficient showing the strongest influence. Parameters relating to compliance showed the largest contribution to AMP(mean), which supports the importance of the compliance aspect of CSF dynamics for the understanding of the pathophysiology of NPH 9).
Elderly presenting with gait abnormality, cognitive decline, and urinary incontinence, with enlarged ventricles of the brain but normal or slightly elevated cerebrospinal fluid (CSF) pressure 10) 11).
Postural stability in NPH is predominantly affected by deficient vestibular functions, which did not improve after spinal tap test. Conditions which improved best were mainly independent from visual control and are based on proprioceptive functions 12).
The natural course of iNPH is symptom progression over time, with worsening in gait, balance and cognitive symptoms. This deterioration is only partially reversible.
Currently there is no pathological hallmark for iNPH 13).
It is frequently present with cerebral vasculopathy; significantly increased prevalence of cardiovascular disease iNPH patients, which provide evidence that cardiovascular disease is involved as an exposure in the development of iNPH 14).
Idiopathic normal pressure hydrocephalus (iNPH) may present, besides the classic triad of symptoms, extrapiramidal parkinsonian like movement disorders.
There is no accurate test for diagnosing normal pressure hydrocephalus or for screening for patients who will benefit from shunt surgery.
Shunting is possibly effective in iNPH (96% chance subjective improvement, 83% chance improvement on timed walk test at 6 months) (3 Class III). Serious adverse event risk was 11% (1 Class III). Predictors of success included elevated Ro (1 Class I, multiple Class II), impaired cerebral blood flow reactivity to acetazolamide (by SPECT) (1 Class I), and positive response to either external lumbar drainage (1 Class III) or repeated lumbar punctures. Age may not be a prognostic factor (1 Class II). Data are insufficient to judge efficacy of radionuclide cisternography or aqueductal flow measurement by MRI.
There is limited Class I evidence that impaired cerebral blood flow (CBF) reactivity to acetazolamide is a predictor of successful CSF shunting, but single photon emission computed tomography (SPECT) is not a practical screening tool for NPH.
There remains a lack of consensus about the role of individual imaging modalities in characterizing specific features of the condition and predicting the success of CSF shunting. Variability of clinical presentation and imperfect responsiveness to shunting are obstacles to the application of novel imaging techniques. Few studies have sought to interpret imaging findings in the context of theories of NPH pathogenesis 15).
Although attempts at predictive methodology, such as highvelocity aqueductal flow rate measurement on MRI, have achieved widespread acceptance in clinical practice, there is no Class I evidence (only 1 Class II study and 2 Class III studies) available to support this 16).
NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as periventricular hyperintensity (PVH). Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis 17).
An MRI-based diagnostic scheme used in a multicenter prospective study (Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement [SINPHONI]) appears to suggest that features of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) are meaningful in the evaluation of NPH 18).
CT or MRI
In a retrospective cohort study, Kojoukhova et al evaluated brain CT or MRI scans of 390 patients with suspected iNPH. Based on a 24-h intraventricular pressure monitoring session, patients were classified into a non-NPH (n = 161) or probable iNPH (n = 229) group. Volumes of cerebrospinal fluid compartments (lateral ventricles, sylvian and suprasylvian subarachnoid spaces and basal cisterns) were visually assessed. Disproportionally enlarged subarachnoid spaces, flow void, white matter changes, medial temporal lobe atrophy and focally dilated sulci were evaluated. Moreover, we measured quantitative markers: Evans’ index (EI), the modified cella media index, mean width of the temporal horns and callosal angle.
iNPH was more likely in patients with severe volumetric disproportion between the suprasylvian and sylvian subarachnoid spaces than in those without disproportion (OR 7.5, CI 95 % 4.0-14.1, P < 0.0001). Mild disproportion (OR 2.6, CI 95 % 1.4-4.6, P = 0.001) and narrow temporal horns (OR per 1 mm 0.91, CI 95 % 0.84-0.98, P = 0.014) were also associated with an iNPH diagnosis. Other radiological markers had little association with the iNPH diagnosis in the final combined multivariate model. Interestingly, EI was higher in non-NPH than iNPH patients (0.40 vs. 0.38, P = 0.039). Preoperative radiological markers were not associated with shunt response.
Visually evaluated disproportion was the most useful radiological marker in iNPH diagnostics. Narrower temporal horns also supported an iNPH diagnosis, possibly since atrophy was more pronounced in the non-NPH than iNPH group 19).
The Evans index is useful as a marker of ventricular volume and thus has been proposed as a helpful biomarker in the diagnosis of normal pressure hydrocephalus (NPH)
Unfortunately it is a very rough marker of ventriculomegaly, and varies greatly depending on the location and angle of the slice.
As such Evans’ index has little role to play in day-to-day reporting.
Phase contrast magnetic resonance imaging
Although gait is the primary indicator for treatment candidacy and outcome, additional monitoring tools are needed. Line Tracing Test (LTT) and Serial Dotting Test (SDT), two psychomotor tasks, have been introduced as potential outcome measures20).
Lumbar infusion test
see Lumbar infusion test.
Cerebrospinal fluid tap test
Cerebrospinal fluid tap test (CSF-TT), are often used in practice to provide further predictive value in detecting suitable patients for shunting.
Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal-pressure hydrocephalus. Alzheimer disease hallmark lesions amyloid beta (Aβ) and hyperphosphorylated tau protein (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini mental state examination scores. Concomitant Aβ and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between Aβ-immunostained area fraction in tissue and Aβ42 (42-amino-acid form of Aβ) in cerebrospinal fluid (CSF). Levels of Aβ42 were significantly lower in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of Aβ (Aβ42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus 21).
Secondary normal pressure hydrocephalus (NPH) does indeed exist and should be differentiated from iNPH based on outcome as well as clinical, pathophysiological, and epidemiological characteristics but should not be considered as a separate entity. Evaluation of patients with NPH to identify a known cause is recommended because the response to treatment varies considerably. Although clinical presentation is often the same, a multitude of primary etiologies can lead to the development of sNPH. The most common etiologies of sNPH include SAH, traumatic brain injury, intracranial malignancies, meningitis, and stroke. Further studies are required to investigate differences in management and outcome among the diverse etiologies of sNPH 22).
In Alzheimer’s disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH.
APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Data further support the view that the iNPH syndrome is a distinct dementing disease 24).
Shunt surgery has been established as the only durable and effective treatment for idiopathic normal pressure hydrocephalus
To maximise the benefits of shunt treatment, surgery should be performed soon after diagnosis 25).
The results of a prospective multicentre study on patients with iNPH diagnosed solely on clinical and radiological criteria support shunt surgery in patients presenting with symptoms and signs and MRI findings suggestive of iNPH 26).
Endoscopic third ventriculostomy
The only randomized trial of endoscopic third ventriculostomy (ETV) for idiopathic normal pressure hydrocephalus (iNPH) compares it to an intervention which is not a standard practice (VP shunting using a non-programmable valve). The evidence from this study is inconclusive and of very low quality. Clinicians should be aware of the limitations of the evidence. There is a need for more robust research on this topic to be able to determine the effectiveness of ETV in patients with iNPH 27).
Twelve of 56 patients with NPH-like symptoms presented with morphological aqueductal stenosis (AS) (21.4 %). Patent aqueduct and non-patent aqueduct groups had similar values of mean opening lumbar pressure (8.2 vs. 8.1 mmHg), and mean opening pulse amplitude (3.1 vs. 2.9 mmHg). Mean pressure in the plateau stage (28.6 vs. 23.2 mmHg), and mean pulse amplitude in the plateau stage (12.5 vs. 10.6 mmHg) were higher in the patent aqueduct group. These differences were not statistically significant. Only Rout was significantly higher in the patent aqueduct group (13.6 vs. 10.1 mmHg/ml/min). One-third of NPH patients with AS presented Rout >12 mmHg/ml/min.
No differences in mean pressure or pulse amplitude during basal and plateau epochs of the lumbar infusion test in NPH patients were detected, regardless of aqueductal patency. However, Rout was significantly higher in patients with patent aqueduct 29).
Bir et al., retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant.
The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race.
Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database 30).
A detailed screening process included neurological, neurosurgical and neuropsychological evaluations, followed by cerebrospinal fluid (CSF) tap test (TT) and resistance outflow (Ro) measurement. Outcome was evaluated through the Japanese NPH grading scale-revised (JNPHGSR) and the motor (third) section of the Unified Parkinson’s Disease Rating Scale (UPDRS-m). Friedman’s analysis of variance with Wilcoxon post-hoc test was used to evaluate the difference in JNPHGSR and UPDRS-m scores between pre-treatment and follow-up (12 months) in the two groups, while Kruskal-Wallis statistic and post-hoc Mann-Whitney test was used to compare the change in JNPHGSR and UPDRS-m scores between the two groups.
32/54 (59%) patients (mean age 73.2) screened in 36 months met the inclusion criteria, but only 30 were enrolled (two refused surgery), 15 in each group. Preoperative 123I-Ioflupane-cerebral SPECT (DaTSCAN) revealed striatal dopaminergic deficit in 14/30 patients (46.5%). At the final 12 months follow-up, both groups improved JNPHGSR and UPRDS-m scores. The UPDRS-m score improvement was significant in both groups, but greater in group A (p0.003); JNPHGSR score improvement was similar in the two groups.
iNPH associated with parkinsonism may be a frequent finding. In these cases, patients may benefit from VP shunt plus dopamine oral therapy 31).
From 2008 to 2013, consecutive patients diagnosed with INPH based on clinical and radiological criteria were included in a single-centre study. All patients received programmable-valve ventriculoperitoneal shunts. Outcome measures were assessed at baseline, 3, 6 and 12months post-operatively. Outcomes included gait time and scores on the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III), the Addenbrooke’s Cognitive Examination Revised (ACE-R) and the Mini-Mental State Examination (MMSE). Thresholds for improvements were set a priori as ⩾20% decrease in gait time, ⩾10point decrease in UPDRS-III score, ⩾5point increase in ACE-R score and ⩾2point increase in MMSE score at last follow-up. The proportion of patients improving varied between measures, being gait time (60%), UPDRS-III (69%), MMSE (63%), and ACE-R (56%). Overall, improvement in at least one outcome measure was observed in 85% of patients and 38% improved in gait time, UPDRS-III score and cognitive scores. Only 15% of patients experienced no improvement on any measure. This study demonstrates that the majority of INPH patients can sustain improvements in multiple symptoms up to 12months after shunting 32).
A study included 29 patients with a mean age of 73.9 years; 62.1% were male and 65.5% had hypertension. Clinical improvement (complete or partial) was observed in 58% after one year and in 48% by the end of the follow-up period (mean follow-up time was 37.8 months). Older age, presence of hypertension, and surgery-related complications were more prevalent in the group responding poorly to treatment. One patient died, 20.7% experienced severe complications, and 69% were dependent (mRS ≥ 3) by the end of the follow-up period. Age at diagnosis was independently associated with poorer clinical response at one year and a higher degree of dependency by the end of follow-up.
Symptomatic benefits offered by VPS were partial and transient; treatment was associated with a high complication rate and poor functional outcomes in the long term, especially in the oldest patients 33).
Fifty-one patients were included after confirmation of the diagnosis by extensive clinical and diagnostic investigations. Surgery included ventriculoatrial or ventriculoperitoneal shunting with differential pressure valves in the majority of patients. For each of the cardinal symptoms, postoperative outcome was assessed separately with the Krauss Improvement Index, yielding a value between 0 (no benefit) and 1 (optimal benefit) for the overall outcome.
Mean age at surgery was 70.2 years (range, 50-87 years). Thirty patients were women, and 21 were men. Short-term (18.8 +/- 16.6 months) follow-up was available for 50 patients. The Krauss Improvement Index was 0.66 +/- 0.28. Long-term (80.9 +/- 51.6 months) follow-up was available for 34 patients. The Krauss Improvement Index was 0.64 +/-0.33. Twenty-nine patients died during the long-term follow-up at a mean age of 75.8 years (range, 55-95 years). The major causes of death were cardiovascular disorders: cardiac failure (n = 7) and cerebral ischemia (n = 12). Other causes were pneumonia (n = 2), acute respiratory distress syndrome (n = 1), pulmonary embolism (n = 1), cancer (n = 2), renal failure (n = 1), and unknown (n = 3). There was no shunt-related mortality.
Idiopathic normal pressure hydrocephalus patients may benefit from shunting over the long term when rigorous selection criteria are applied. Shunt-related mortality is negligible. The main cause of death is vascular comorbidity 34).