Current research of idiopathic normal pressure hydrocephalus:Pathogenesis,diagnosis and treatment

Idiopathic normal pressure hydrocephalus(iNPH)is caused by impaired cerebrospinal fluid absorption in the elderly;it is a surgically treatable form of dementia.Gait disturbance,dementia,and urinary incontinence are the triad of signs for iNPH.In addition to these clinical findings,imaging studies show characteristic ventricular enlargement.High Evans Index and‘disproportionately enlarged subarachnoid hydrocephalus’are other well-known imaging findings of iNPH.If the tap test shows improved symptoms,shunt surgery is performed.The disease was first described by Hakim and Adams in 1965,followed by the publication of the first,second,and third editions of the guidelines in 2004,2012,and 2020,respectively.Recent studies signal the glymphatic system and classical cerebrospinal fluid(CSF)absorption from the dural lymphatics as aetiological mechanisms of CSF retention.Research is also underway on imaging test and biomarker developments for more precise diagnosis,shunting technique options with fewer sequelae and complications,and the influence of genetics.Particularly,the newly introduced‘suspected iNPH’in the third edition of the guidelines may be useful for earlier diagnosis.However,less well-studied areas remain,such as pharmacotherapy in non-operative indications and neurological findings other than the triadic signs.This review briefly presents previous research on these and future issues.

Management of Idiopathic Chronic Hydrocephalus of the Adult in Guinea: A Prospective Study in 16 Patients

Object: Incidence of Idiopathic chronic hydrocephalus of the adult (ICHA) is increasing in Guinea due to the aging of the population. The goal of this study was to describe its epidemiology, clinical presentation, and surgical outcome in a low-resource medical environment. Method: Sixteen patients operated for a probable ICHA were prospectively studied according to a uniform protocol from June 2019 to December 2020. On computerized tomography, all operated patients had a clinical triad of gait disturbance, incontinence, dementia associated with ventriculomegaly, and transependymal edema. In addition, all patients underwent a single lumbar tap, improved clinically, and were subsequently offered a shunt consisting of a simple catheter in 37.5% and a non-adjustable high-pressure valve in 62.5%. Result: The mean age was 68.31 ± 10.4 (range 49 - 89). The sex ratio H/F was 1.67/1. Clinically, the most frequent comorbidity was a combination of hypertension and diabetes in 56.5% of cases. The mean time to diagnosis was 8.31 ± 2.75 months (range 3 - 14). The immediate postoperative mortality was 12.5% from a status epilepticus and pulmonary sepsis. In addition, we observed 2 cases of chronic subdural hematoma (12.5%) and 2 cases of shunt dysfunction (12.5%) in the first three months. The functional outcome was good in 23% of patients at one month (N = 13), 50% at three months (N = 10), and 87.5% at six months (N = 8). Conclusion: In carefully selected cases, the surgical outcome of ICHA in Guinea is comparable to high-income countries. Efforts need to be put in helping patients get covered with universal insurance and generally promote Neurosurgery in the country to improve the quality of care.

Cognitive Impairment in Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus(iNPH)is a significant cause of the severe cognitive decline in the elderly population.There is no cure for iNPH,but cognitive symptoms can be partially alleviated through cerebrospinal fluid(CSF)diversion.In the early stages of iNPH,cognitive deficits occur primarily in the executive functions and working memory supported by frontostriatal circuits.As the disease progresses,cognition declines continuously and globally,leading to poor quality of life and daily functioning.In this review,we present recent advances in understanding the neurobiological mechanisms of cognitive impairment in iNPH,focusing on(1)abnormal CSF dynamics,(2)dysfunction of frontostriatal and entorhinal-hippocampal circuits and the default mode network,(3)abnormal neuromodulation,and(4)the presence of amyloid-βand tau pathologies.

Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by abnormal cerebrospinal fluid (CSF) flow and consequent cerebral ventricular enlargement due to imbalance of CSF production and absorption. The typical triad symptoms, namely cognitive decline, gait disturbance, and urinary incontinence, are thought to be caused by disruption of CSF circulation. However, some patients may still experience symptomatic progression after functional shunting, suggesting that iNPH is far more complicated than a simple disorder of CSF circulation. Moreover, the diagnostic workup of iNPH can be challenging due to symptomatic and neuroimaging overlaps with other neurological disorders, such as Alzheimer's disease. Furthermore, accumulating studies indicate that the pathogenesis of iNPH might relate to multiple mechanisms, including abnormalities of brain development, brain extracellular matrix, synaptic function, blood flow, and cerebral metabolism. Therefore, iNPH is not an isolated entity in occurrence and development. Nevertheless, different pathogeneses may result in protein content changes in CSF, and the biomarkers in CSF may reflect the possible mechanisms involving the etiology of iNPH and are potentially useful in assisting the diagnosis and treatment selection. In this review, we summarize the main findings of CSF biomarkers and aim to outline a possible synthetic profile in assisting iNPH diagnosis and therapeutic options.

Radiological biomarkers of idiopathic normal pressure hydrocephalus:new approaches for detecting concomitant Alzheimer’s disease and predicting prognosis

Idiopathic normal pressure hydrocephalus(iNPH)is a clinical syndrome characterized by cognitive decline,gait disturbance,and urinary incontinence.As iNPH often occurs in elderly individuals prone tomany types of comorbidity,a differential diagnosis with other neurodegenerative diseases is crucial,especially Alzheimer’s disease(AD).A growing body of published work provides evidence of radiological methods,including multimodal magnetic resonance imaging and positron emission tomography,which may help noninvasively differentiate iNPH from AD or reveal concurrent AD pathology in vivo.Imaging methods detecting morphological changes,white matter microstructural changes,cerebrospinal fluid circulation,and molecular imaging have been widely applied in iNPH patients.Here,we review radiological biomarkers using different methods in evaluating iNPH pathophysiology and differentiating or detecting concomitant AD,to noninvasively predict the possible outcome postshunt and select candidates for shunt surgery.

Analysis of related factors affecting prognosis of shunt surgery in patients with secondary normal pressure hy- drocephalus

Objective： The management of se- condary normal pressure hydrocephalus （sNPH） is controversial. Many factors may affect the surgery effect. The purpose of this study was to identify the possible fac- tors influencing prognosis and provide theoretical basis for clinical treatment of sNPH. Methods： A retrospective study was carried out to investigate the results of 31 patients with sNPH who under- went ventriculoperitoneal shunt surgery from January 2007 to December 2011. We processed the potential influencing factors by univariate analysis and the result further by mul- tivariate logistic regression analysis. Results： Factors including age, disease duration and Glasgow coma scale （GCS） score before surgery significantly influenced the prognosis of sNPH （P〈0.05）. Further logistic regression analysis showed that all the three factors are independent influencing factors. Conclusion： Age, disease duration and GCS score before surgery have positive predictive value in estimating favorable response to surgical treatment for sNPH.

Markers for neural degeneration and regeneration:novel highly sensitive methods for the measurement of thrombin and activated protein C in human cerebrospinal fluid

Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases.Thrombin,a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor,activated protein C(aPC),is considered neuroprotective.While levels of thrombin and aPC activity are readily measured in the blood,similar assays in the cerebrospinal fluid(CSF)have not been described.The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF.CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group,while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control.Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity.Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride.Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed.Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls,suggesting the involvement of these factors in neuro-inflammation.CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections,and low in normal pressure hydrocephalus patients.Quantification of endogenous thrombin inhibitors protease nexin 1,amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF.In conclusion,this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF.This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders.The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center(approval No.4245-17-SMC)on October 18,2018.

Hakim-Adams syndrome secondary to syphilis

Normal pressure hydrocephalus (NPH) secondary to syphilis is an atypical form of neurosyphilis with an unusual clinical presentation and uncommon neuroimaging findings. A case of Syndrome de Hakim-Adams occurring in a 79-year-old male was admitted for investigation of a dementia syndrome. The patient presented with clinical features and neuroimaging compatible with NPH. Syphilis serology was reactive and compatible with active disease. The patient was treated with crystalline penicillin (4 million units every 4 hours for 21 days) and was assessed again after three months, when his cognition and gait had improved and the urinary incontinence had resolved. According to this information, we describe a case of syphilis mimicking normal pressure hydrocephalus, making clear the importance of the investigation of sexually transmitted diseases in the differential diagnosis of dementia, even in patients without established risk supposedly.