Cerebrospinal fluid (CSF) plays a role in homeostatic hormonal signaling, chemical buffering, circulations of nutrients, and neurodevelopment. The two lateral ventricles drain into the third ventricle through the foramina of Monro. The third ventricle subsequently drains into the fourth ventricle through the narrowest portion of the ventricular system called the cerebral aqueduct. The roof of the fourth ventricle is bounded by the vermis of the cerebellum and the fastigium. CSF production is to a degree dependent on blood perfusion. In instances of increased intracranial pressure (ICP) with subsequent decreased cerebral perfusion, there will be a decrease in CSF production. CSF flows through net bulk flow from the lateral ventricles through the foramen of Monro into the third ventricle, then on into the fourth ventricle through the cerebral aqueduct. The pathways of CSF reabsorption include the ependymal layer of the ventricular system, and endothelial layer of the brain parenchyma.

This chapter focuses on aspects of hydrocephalus that are common to all ages with a particular emphasis on the aging brain and the so called normal pressure hydrocephalus (NPH) syndrome, which is a chronic disease that likely evolved over a period of years. It has been clear for decades that the rate of ventricular dilatation and the state of brain maturation have a significant impact on the pathology, and possibly the pathogenesis of brain damage. Idiopathic NPH has been distinguished from chronic adult hydrocephalus associated with prior meningitis, brain trauma, or subarachnoid hemorrhage. The initial displacement may be at the expense of the subarachnoid compartment, the venous compartment, and the extracellular compartment with negligible damage to brain cells. Blood flow hypoperfusion leads to hypoxic-ischemic changes in the white matter, physical stretching compromises axon integrity, and retarded turnover of the cerebrospinal fluid (CSF) alters the extracellular microenvironment.

This chapter first focuses on the ethics of animal models and then discusses the formal requirements general to any experimental model and the specific requirements for models of hydrocephalus. It also discusses the recent and current research areas in experimental hydrocephalus. Ethical standards for experimental studies involving animals are legally set by laws and regulations. Animal models resemble human disease by conditions which are genetically determined, naturally acquired, or induced by the investigator. Shunted animal models provide a unique potential for insight into questions concerning the destructive effects of hydrocephalus on the brain and its development, as it is rarely possible to obtain brain tissue from humans with hydrocephalus. Most of the hydrocephalus animal models are neonatal or juvenile animals and the majority of research is thus directed at congenital or pediatric hydrocephalus.

Genetic studies in animal models have started to open new ways for understanding the underlying molecular pathophysiology of hydrocephalus. Human hydrocephalus can be classified as syndromic versus non-syndromic, and congenital versus acquired. Comparative twin studies have been performed to analyze the genetic influences in congenital structural defects including hydrocephalus. Familial hydrocephalus has long been suggested as a heritable disease, with heterogeneous causes, which may result from distinct monogenic or multifactorial disorders. Congenital hydrocephalus (CHC) is usually the consequence of deficient brain development and perturbed cellular function, implicating the important roles that CHC genes play during brain development. The majority of identified hydrocephalus loci and genes are from genetic analysis in hydrocephalic animal models. The pathophysiology of hydrocephalus in the ventricular system has been extensively studied through either down- or up-regulation of certain targeted gene expression, followed by comparative morphological and molecular studies.

This chapter presents the existing data concerning the epidemiology of selected forms of hydrocephalus, concentrating on congenital and infantile hydrocephalus and idiopathic and secondary normal pressure hydrocephalus (NPH). The epidemiology of congenital and infantile hydrocephalus has been explored in several studies. Casmiro et al. based the diagnosis on absence of known causes of secondary NPH, impaired gait, and CT scans showing findings indicative of NPH. The chapter explores the epidemiology of idiopathic normal pressure hydrocephalus (iNPH) in a Norwegian county of 220000 inhabitants, by actively informing the public and professional health workers about the condition, asking for referral of suspected individuals on a broad clinical basis. The lack of universally accepted guidelines for the diagnosis of iNPH, and the lack of powerful tests to predict shunt success, probably also contribute to the relative low rate of diagnosis, and consequently, of surgery.

Several theories have been proposed to explain the pathophysiology of gait dysfunction in normal pressure hydrocephalus (NPH). The variety of potential targets includes midbrain compression or atrophy, cortical dysfunction, cortical-subcortical or intracortical circuit abnormalities, postural disturbance, dopamine signaling abnormalities, and regional cerebral blood flow (rCBF) depression. This chapter presents objective measures of gait dysfunction that have been used clinically, and highlights some of the major theories postulated to explain gait dysfunction in NPH. Gait dysfunction in NPH has characteristic features that include a slow pace, short stride length, wide stance, and low foot-floor elevation. Objective measures of gait can be used to quantify the pattern of walking and step-taking, focusing on walking speed, stride length, cadence, equilibrium, and posture. Recognition of cortical involvement in locomotion stems from multiple research efforts evaluating gait in healthy individuals and those with cognitive disturbances.

Structural and functional brain imaging have helped to elucidate the neural pathways involved in hydrocephalic cognitive impairment. In addition, studies of brain metabolism and blood flow, molecular imaging, and cerebrospinal fluid (CSF) physiology have provided novel windows into the pathogenesis of dementia in idiopathic normal pressure hydrocephalus (iNPH). A number of pathophysiologic mechanisms have been identified that are potentially relevant to the pathogenesis of the cognitive symptoms of iNPH, namely, mechanical distortion, pressure effects, and cerebrovascular compromise. A possible synthesis of these mechanisms would be that an imbalance of CSF production and clearance leads to progressive ventricular enlargement. The profile of cognitive impairments in iNPH is recognizably that of a subcortical pathological process. Deficiencies in attention, working memory, set shifting, response inhibition and other aspects of executive functioning are commonly observed in iNPH and can be seen early in the disease course.

This chapter provides an overview of incontinence and lower urinary tract symptoms in normal pressure hydrocephalus (NPH), and covers areas including dementia and incontinence, differential diagnosis, physiology and pathophysiology, symptoms, evaluation, and treatment. The relationship between gait disturbances, dementia, and incontinence has profound importance because of the potential heightened risk of falls. In the central nervous system, there are two main areas involved in the motor control and reciprocal coordination of lower urinary tract function. Our understanding of lower urinary tract dysfunction in NPH is limited by a lack of detailed knowledge of the supraspinal pathways involved in the control of micturition. Urodynamic studies may be the most important investigative procedures performed in patients with significant urinary symptoms and idiopathic NPH (iNPH), as the results will help identify etiologies and guide treatments. Patients may be treatment refractory to standard doses or may require higher than recommended doses or combination therapies.

The recent and rapid increase of the elderly population in developed nations has heightened the social importance of precise diagnosis and appropriate treatment for idiopathic normal pressure hydrocephalus (iNPH). This chapter reviews various assessment batteries that have been used in iNPH to date. There are many NPH assessing scales, most of which aim to assess level of general activity, severity of respective NPH symptoms, response to interventions such as cerebrospinal fluid (CSF) drainage tests or shunt surgery, and short and long term outcome. Comparative study of the specificity and sensitivity of the neuropsychological tests is necessary to determine the most reliable test for prediction of shunt surgery. The scale consists of the four domains of gait, neuropsychology, balance, and continence. The improvement of cognitive impairment was the major factor in reducing care-giver burden.

The recently updated Japanese guidelines draw attention to a specific MRI pattern of disproportionately enlarged subarachnoid space hydrocephalus (DESH), believed to be pathognomonic of idiopathic normal pressure hydrocephalus (iNPH). This chapter discusses why establishing the diagnosis of NPH remains a challenge fifty years after its classic description. The original diagnosis of NPH relied upon the presence of mild dementia, gait, and urinary difficulties (Hakim's triad) seen in association with ventriculomegaly on pneumo-encephalogram. More sensitive cognitive evaluation of iNPH patients requires specific tests for the assessment of subcortical frontal lobe deficits such as the Rey Auditory Verbal Learning Test, Stroop test, Grooved Pegboard, Trail Making A and B Test, and digit span test. This diagnostic test provides information about cerebrospinal fluid (CSF) dynamics and predicts outcome. It consists in either removal of CSF accompanied by pre and post functional evaluation, or an infusion (bolus or continuous) test.