Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Idiopathic normal pressure hydrocephalus (iNPH) is a treatable neurological syndrome in the elderly. Although the magnetic resonance imaging (MRI) findings of tight high-convexity and medial subarachnoid spaces and the ventriculo-peritoneal (VP) shunt with programmable valve are reportedly useful for diagnosis and treatment, respectively, their clinical significance remains to be validated. We conducted a multicenter prospective study (Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement: SINPHONI) to evaluate the utility of the MRI-based diagnosis for determining the 1-year outcome after VP shunt with the Codman-Hakim programmable valve.</p> <p>Methods</p> <p>Twenty-six centers in Japan were involved in this study. Patients aged between 60 and 85 years with one or more of symptoms (gait, cognitive, and urinary problems) and MRI evidence of ventriculomegaly and tight high-convexity and medial subarachnoid spaces received VP shunt using the height/weight-based valve pressure-setting scheme. The primary endpoint was a favorable outcome (improvement of one level or more on the modified Rankin Scale: mRS) at one year after surgery, and the secondary endpoints included improvement of one point or more on the total score of the iNPH grading scale. Shunt responder was defined by more than one level on mRS at any evaluation point in one year.</p> <p>Results</p> <p>The full analysis set included 100 patients. A favorable outcome was achieved in 69.0% and 80.0% were shunt responders. When measured with the iNPH grading scale, the one-year improvement rate was 77.0%, and response to the surgery at any evaluation point was detected in 89.0%. Serious adverse events were recorded in 15 patients, three of which were events related to surgery or VP shunt. Subdural effusion and orthostatic headache were reported as non-serious shunt-related adverse events, which were well controlled with readjustment of pressure.</p> <p>Conclusions</p> <p>The MRI-based diagnostic scheme is highly useful. Tight high-convexity and medial subarachnoid spaces, and enlarged Sylvian fissures with ventriculomegaly, defined as disproportionately enlarged subarachnoid-space hydrocephalus (DESH), are worthwhile for the diagnosis of iNPH. This study is registered with ClinicalTrials.gov, number NCT00221091.</p

Longitudinal morphological changes during recovery from brain deformation due to idiopathic normal pressure hydrocephalus after ventriculoperitoneal shunt surgery.

The present study aimed to examine time-dependent change in cerebrospinal fluid distribution and various radiological indices for evaluating shunt effectiveness in patients with idiopathic normal pressure hydrocephalus (iNPH). This study included 54 patients with iNPH who underwent MRI before and after ventriculoperitoneal shunt surgery. The volume of the total ventricles and subarachnoid spaces decreased within 1 month after shunting. However, more than 1 year after shunting, the volume of the total ventricles decreased, whereas that of the total subarachnoid spaces increased. Although cerebrospinal fluid distribution changed considerably throughout the follow-up period, the brain parenchyma expanded only 2% from the baseline brain volume within 1 month after shunting and remained unchanged thereafter. The volume of the convexity subarachnoid space markedly increased. The changing rate of convexity subarachnoid space per ventricle ratio (CVR) was greater than that of any two-dimensional index. The brain per ventricle ratio (BVR), callosal angle and z-Evans index continued gradually changing, whereas Evans index did not change throughout the follow-up period. Both decreased ventricular volume and increased convexity subarachnoid space volume were important for evaluating shunt effectiveness. Therefore, we recommend CVR and BVR as useful indices for the diagnosis and evaluation of treatment response in patients with iNPH

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia.

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH

Gait Assessment Using Three-Dimensional Acceleration of the Trunk in Idiopathic Normal Pressure Hydrocephalus.

Background:The subjective evaluation of pathological gait exhibits a low inter-rater reliability. Therefore, we developed a three-dimensional acceleration of the trunk during walking to assess the pathological gait quantitatively.Methods:We evaluated 97 patients who underwent the cerebrospinal tap test and were diagnosed with idiopathic normal pressure hydrocephalus (iNPH) and 68 healthy elderlies. The gait features of all patients were evaluated and classified as one of the following: freezing of gait, wide-based gait, short-stepped gait, shuffling gait, instability, gait festination, difficulty in changing direction, and balance disorder in standing up. All gait features of 68 healthy elderlies were treated as normal. Trunk acceleration was recorded automatically by a smartphone placed on the umbilicus during a 15-foot walking test. Two novel indices were created. The first index was a trunk acceleration index, which was defined as (forward acceleration fluctuation) + (vertical acceleration fluctuation) - (lateral acceleration fluctuation) based on the multivariate logistics regression model, and the second index was created by multiplying the forward acceleration with the vertical acceleration. Additionally, 95% confidence ellipsoid volume of the three-dimensional accelerations was assessed.Results:Forward and vertical acceleration fluctuations were significantly associated with the probability of an iNPH-specific pathological gait. The trunk acceleration index demonstrated the strongest association with the probability of an iNPH-specific pathological gait. The areas under the receiver-operating characteristic curves for detecting 100% probability of an iNPH-specific pathological gait were 86.9% for forward acceleration fluctuation, 88.0% for vertical acceleration fluctuation, 82.8% for lateral acceleration fluctuation, 89.0% for trunk acceleration index, 88.8% for forward × vertical acceleration fluctuation, and 87.8% for 95% confidence ellipsoid volume of the three-dimensional accelerations.Conclusions:The probability of a pathological gait specific to iNPH is high at the trunk acceleration fluctuation, reduced in the forward and vertical directions, and increased in the lateral direction

Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-β. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-β. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-β, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis

Fluid Distribution Pattern in Adult-Onset Congenital, Idiopathic, and Secondary Normal-Pressure Hydrocephalus: Implications for Clinical Care

ObjectiveIn spite of growing evidence of idiopathic normal-pressure hydrocephalus (NPH), a viewpoint about clinical care for idiopathic NPH is still controversial. A continuous divergence of viewpoints might be due to confusing classifications of idiopathic and adult-onset congenital NPH. To elucidate the classification of NPH, we propose that adult-onset congenital NPH should be explicitly distinguished from idiopathic and secondary NPH.MethodsOn the basis of conventional CT scan or MRI, idiopathic NPH was defined as narrow sulci at the high convexity in concurrent with enlargement of the ventricles, basal cistern and Sylvian fissure, whereas adult-onset congenital NPH was defined as huge ventricles without high-convexity tightness. We compared clinical characteristics and cerebrospinal fluid distribution among 85 patients diagnosed with idiopathic NPH, 17 patients with secondary NPH, and 7 patients with adult-onset congenital NPH. All patients underwent 3-T MRI examinations and tap-tests. The volumes of ventricles and subarachnoid spaces were measured using a 3D workstation based on T2-weighted 3D sequences.ResultsThe mean intracranial volume for the patients with adult-onset congenital NPH was almost 100 mL larger than the volumes for patients with idiopathic and secondary NPH. Compared with the patients with idiopathic or secondary NPH, patients with adult-onset congenital NPH exhibited larger ventricles but normal sized subarachnoid spaces. The mean volume ratio of the high-convexity subarachnoid space was significantly less in idiopathic NPH than in adult-onset congenital NPH, whereas the mean volume ratio of the basal cistern and Sylvian fissure in idiopathic NPH was &gt;2 times larger than that in adult-onset congenital NPH. The symptoms of gait disturbance, cognitive impairment, and urinary incontinence in patients with adult-onset congenital NPH tended to progress more slowly compared to their progress in patients with idiopathic NPH.ConclusionCerebrospinal fluid distributions and disease progression were significantly different among the patients with adult-onset congenital NPH, idiopathic NPH and secondary NPH. This finding indicates that the pathogenesis of adult-onset congenital NPH may differ from those of idiopathic and secondary NPH. Therefore, adult-onset congenital NPH should be definitively distinguished from the categories of idiopathic and secondary NPH