NPH is a syndrome characterized by gait apraxia, dementia, and incontinence with normal CSF pressure and dilated ventricles. The designation “normal” is misleading because continuous intracranial monitoring has demonstrated the presence of waves of increased ICP, particularly during rapid eye movement (REM) sleep.² It has been suggested that these abnormal CSF pressure spikes, called B waves, slowly increase ventricular size by exerting intermittent high pressure on the brain parenchyma that results in ischemic damage. Abnormalities of the aging brain parenchyma may make it more susceptible to these forces.³ However, the exact pathogenesis of NPH is still a matter of debate. Theories regarding the underlying pathophysiology of NPH are discussed in a later section. Despite the uncertainty regarding its evolution, NPH is a syndrome that is treatable by CSF diversion (i.e., shunt insertion).

Arrested Hydrocephalus

Some patients with hydrocephalus reach a state in which ventricular size remains unchanged in the absence of a shunt or in the presence of a nonfunctioning one. It is well accepted that careful follow-up is still required, particularly in children, because of reported cases of sudden death, sometimes years after the initial diagnosis. Neuropsychological testing may be useful in identifying subtle cognitive deterioration, which may precede the return of active symptoms. In adults, this may simply reflect an underlying pathologic process that may have spontaneously resolved, such as posttraumatic or posthemorrhagic hydrocephalus.

Isolated Fourth Ventricle Syndrome

The term “entrapped fourth ventricle” has also been used to describe the situation in which the fourth ventricle no longer communicates with the third ventricle, as well as the basal cisterns. Patients with prolonged infection or multiple shunt operations are particularly at risk for this syndrome. It is thought that secondary aqueduct stenosis from adhesions, obstruction of the foramina of Luschka or Magendie, or infective debris pooling in the basal cisterns may be responsible for this condition. Patients may have the typical symptoms and signs of hydrocephalus or more atypical symptoms such as lower cranial nerve dysfunction. Occasionally, an entrapped fourth ventricle is an incidental finding on imaging.

Slit Ventricle Syndrome

The lateral ventricles may collapse in some patients secondary to overshunting or remain at a fixed size because of subependymal gliosis. This may lead to intermittent or complete shunt malfunction. Patients may experience raised ICP without ventricular enlargement, and therefore imaging findings may be falsely reassuring in such cases (unresponsive ventricles). Symptomatic patients may respond to a change in valve setting if a programmable valve is in situ or to revision surgery (change of valve or incorporation of an antisiphon device to prevent overdrainage). Patients with progressive neurological deterioration secondary to raised ICP may require subtemporal decompression. When the ventricles are slit intermittently, endoscopic third ventriculostomy may be possible during periods of relative ventricular dilation. Please see Chapter 186 for a discussion of these issues in children, including shunt removal.

Pathophysiology (see also Chapter 33)

Formation, Circulation, and Reabsorption

The total volume of CSF in the cranial-spinal axis is approximately 150 mL, distributed equally between the two compartments. However, net CSF production is about 0.35 mL/min (500 mL/day), which results in a CSF turnover rate of approximately three to four times per day. Intracranially, CSF is produced mainly by the choroid plexus of the ventricles (70% to 80%).⁴ The remaining amount is produced by the ependymal lining of the ventricles, by the brain’s capillary bed, and by metabolic water production. The proportion of CSF produced in the ventricular system is unequal; the vast majority of CSF produced by the choroid plexus is from the lateral ventricles, although small amounts are produced in the third and fourth ventricles. CSF is formed by filtration of plasma through fenestrated capillaries and active transport of water and solutes through the epithelial cells of the choroid plexus at the blood-CSF barrier.

CSF circulates through the ventricular system and exits through the foramina of Luschka and Magendie into the cerebellomedullary cistern and onward to the spinal cavity and the subarachnoid spaces of the cerebral convexities. Circulation of CSF is thought to be driven by hydrostatic pressure generated by cerebral arterial pulsation and changes in venous pressure secondary to respiration, change of posture, and other mechanisms.⁵^,⁶ CSF is resorbed by arachnoid villi that protrude from the subarachnoid space into the lumen of the dural sinuses. Solutes pass via one-way bulk flow into the venous circulation. The exact mechanism of this process has not been fully elucidated but may involve differential pressure between CSF and the venous system and one-way valves formed by overlapping endothelial cells lining the arachnoid villi.⁵ Figure 34-1 illustrates the concepts just discussed.

FIGURE 34-1 Circulation of cerebrospinal fluid.

Cerebrospinal Fluid Obstruction and Sequelae

Experimental models of acute ventricular obstruction have provided an understanding of the pathophysiologic processes occurring after disruption of the CSF circulation. Initial rapid ventricular dilation is followed by effacement of the cerebral sulci, fissures, and basal cisterns. Transependymal passage of CSF occurs through either an intact or disrupted ependymal lining and results in periventricular edema. Absorption of CSF occurs in the edematous white matter via alternative pathways, such as direct absorption into blood via the blood vessels.⁷ Destruction of tracts secondary to edema and subsequent gliosis of damaged tissue are believed to occur within the periventricular white matter, with relative sparing of gray matter.⁸ The resulting white matter damage and reduction in cerebral blood volume may progress to cerebral atrophy. This concept may explain the persistence of neurological deficits in some patients despite successful reduction of ventricular volume after shunt surgery. As a result of some or all of these processes, pathologic compensation for raised ICP may be reached. In a minority of cases, CSF production is reduced because of atrophy of the choroid plexus.⁷

Progressive Ventriculomegaly in the Context of Normal Pressure and the Concept of Combined Dementia

The confounding situation of progressive ventricular dilation in patients with NPH has led to many theories regarding the underlying pathophysiologic processes occurring in this condition. Hakim and Adams originally proposed that as ventricular enlargement progresses, the biomechanical forces required to maintain the ventricles in a dilated state are smaller.⁹ Distortion of tissue, including white matter tracts and blood vessels, may lead to damage and ischemia. Loss of elasticity within the brain parenchyma may result in a pressure gradient between the ventricles and periventricular tissue. The resulting excess fluid in the interstitial space may lead to failure of drainage of toxic metabolites. There is also evidence of disruption of cerebral blood flow or distortion of blood vessels, which is believed to lead to watershed ischemia and deep lacunar infarcts. The pattern of disruption of cerebral blood flow in white matter has been demonstrated to take the form of a U-shaped relationship with distance from the ventricles, with the maximal reduction occurring adjacent to the ventricles and progressive normalization toward the subcortical white matter.¹⁰

NPH is also thought to be a CSF circulation disorder resulting from an imbalance between production and absorption. Abnormalities in the aging brain may make it uniquely susceptible to intermittent spikes of B waves and result in progressive ventriculomegaly. It has been demonstrated that resistance to CSF outflow increases in a nonlinear fashion with advancing age despite a decrease in the rate of CSF production, which also occurs with increasing age.¹¹ Failure of efficient CSF turnover may also result in an accumulation of potentially toxic metabolic products, such as β-amyloid peptides (Aβ) and tau protein. Such aggregates are thought to be neurotoxic and contribute to small-vessel damage and subsequent leakage of additional toxic metabolites into the interstitial space.¹² Moreover, it has been proposed that the two changes noted in aging, reduced CSF production and increased resistance to CSF outflow, may be implicated in a common pathway in the pathophysiology of Alzheimer’s disease and NPH. A predominance of reduced CSF production and turnover may be manifested as Alzheimer’s disease, and conversely, NPH may result from a predominant increase in CSF outflow resistance. A spectrum of disease may exist, including a subset of patients who either have both conditions or have risks for the development of both even if one process is predominant.¹³

Initial Features of Hydrocephalus

Both communicating and obstructive hydrocephalus may give rise to the same symptoms and signs (i.e., those of hydrocephalus or raised ICP). Alternatively, both types may be associated with normal CSF pressure or spontaneously arrest. The initial features specific to NPH are discussed in the following section. Table 34-2 lists the common symptoms and signs in patients with acute versus chronic hydrocephalus.

TABLE 34-2 Common Initial Features of Acute versus Chronic Hydrocephalus

ACUTE—RAISED INTRACRANIAL PRESSURE

Headaches

Nausea and vomiting

Deterioration in gait or balance

Papilledema

Upgaze palsy—setting sun sign

Parinaud’s syndrome—pressure on the suprapineal recess

Abducens palsy—long intracranial course

CHRONIC

Headaches

Deterioration in gait or balance

Urinary incontinence

Cognitive and attention deficits (subcortical dementia)

Personality changes (e.g., aggression, apathy)

Empty sella

Impingement or atrophy of the corpus callosum

Normal-Pressure Hydrocephalus

Clinical Findings and Differential Diagnoses

The concept of a “symptomatic occult hydrocephalus with ‘normal’ CSF pressure” was described by Hakim and Adams in 1965 in their landmark paper of observations based on three cases, two secondary and one idiopathic.⁹ Current guidelines deal primarily with idiopathic as opposed to secondary NPH, which occurs after trauma (such as the two patients in 1965), subarachnoid hemorrhage, intracranial surgery, or meningitis. The manifestations of secondary NPH may be delayed, sometimes many years after the incident in question. Most cases seen by clinicians are of the idiopathic variety. Despite advances in the diagnosis and management of this condition, the exact pathogenesis of NPH remains uncertain. The classic finding in patients with NPH is a clinical triad of symptoms—gait disturbance, dementia, and urinary incontinence. Patients may or may not have the complete triad of symptoms. In addition, many other symptoms have been reported, such as lethargy, apathy, impaired wakefulness, and visuospatial disturbances.

Gait Disturbance

Gait disturbance is the most common initial symptom and occurs in almost 90% of patients.⁷ Ojemann and colleagues in 1969 noted that gait disturbance could be an initial manifestation of NPH,¹⁴ thereby changing the emphasis from earlier descriptions of cognitive disturbance being the primary initial symptom. Fisher subsequently presented a series of 16 patients with shunt-responsive hydrocephalus in which gait disturbance was the initial manifestation in 12 of them.¹⁵ In that series, dementia preceded gait disturbance in 1 patient and occurred at the same time in 3 patients. However, in 11 cases of shunt failure, dementia came first in 9 patients and gait disturbance was relatively less severe or was absent.

Common initial symptoms include unsteadiness, recurrent falls, shuffling, and reduced walking speed. More advanced symptoms include difficulty initiating gait and imbalance on turning. Gait in patients with NPH is described as being “magnetic” in nature, characterized by a broad base and slow, small steps with reduced height clearance as though the feet are “stuck to the floor.” Patients may have difficulty rising from a chair or complain of their legs “giving way.”¹⁶ Patients may have disturbances in stance with a tendency to lean forward and imbalance exacerbated by eye closure.¹⁴^,¹⁷

The gait disturbance may be difficult to distinguish from other types of frontotemporal pathology. The gait abnormality is often confused with Parkinson’s disease because patients with NPH may appear to have features of lower limb parkinsonism such as rigidity, shortened stride length, and difficulties in balance and turning. This is particularly applicable in patients in whom other hallmarks of Parkinson’s disease are not present, such as tremor, lead pipe rigidity, and a mask-like facies. However, unlike patients with Parkinson’s disease, who are able to increase their stride length and walking cadence with the aid of external cueing such as counting, patients with NPH have a gait apraxia that does not respond to such aids. In addition, patients with NPH tend to mobilize with a relatively preserved arm swing.

Increased tone and brisk tendon reflexes in the legs are unusual in patients with shunt-responsive NPH, and there is absence of weakness or dysdiadochokinesis. The presence of upper motor neuron signs or lower limb weakness may be indicative of cervical myelopathy and lumbar canal stenosis, respectively. Other structural lesions of the brain and spine should be considered, such as tumors or cerebrovascular ischemic damage. Poor balance may reflect an underlying sensory neuropathy, and in such instances, diabetic neuropathy and autonomic dysfunction should be considered. However, these conditions are common in the age group of patients seen with NPH. The finding of comorbid pathologies might be significant but may not exclude patients from having a favorable outcome from shunt surgery if NPH accounts for a major proportion of the initial symptomatology.

The anatomic basis for gait disturbance in patients with NPH remains controversial. In 1947, Yakovlev proposed a theory that paraplegia in patients with hydrocephalus is caused by compression of the internal capsule fibers by the distended third ventricle. However, the general lack of upper motor neuron signs and upper limb involvement in NPH would suggest that such a theory may not account for the characteristic gait apraxia seen in this condition. Indeed, a study using motor evoked potentials and central motor conduction time in both the upper and lower limbs in patients with NPH did not demonstrate any evidence of major pyramidal tract dysfunction or subclinical upper limb involvement in patients who responded to shunt surgery. Prolonged central motor conduction time was seen in the lower limbs of patients who did not improve after surgery.¹⁷ However, such methods may be insufficiently subtle to detect small lesions or reversible white matter damage occurring as a result of tissue distortion from hydrocephalus. Pyramidal tract damage may represent progression of these lesions to an end-stage phase of NPH that cannot be reversed by surgery.

Urinary Incontinence

Urinary incontinence may be a separate symptom or may be a consequence of gait disturbance or cognitive impairment. Some patients have urinary frequency rather than true incontinence. This symptom is thought to be due to involvement of the sacral fibers of the corticospinal tract.¹⁸ Because urgency of micturition and incontinence are both common problems in older age, the clinical finding may be that of a change or worsening of urinary symptoms rather than a new problem.

Cognitive Impairment

NPH is estimated to account for less than 5% of all cases of dementia. It is essential that patients undergo neuropsychological testing to distinguish the pattern of dementia in NPH from other conditions such as age-related cognitive decline as a result of neurodegenerative processes, including Alzheimer’s disease. The pattern of NPH appears to be a subcortical frontal dysexecutive syndrome.¹⁹^,²⁰ Cognitive deficits in patients with NPH typically include memory loss, reduced attention, difficulty planning, slowness in thought, and apathy. There may be speech disturbance because of dysexecutive or motivational problems.¹⁶ This pattern differs from the cortical deficits of aphasia, apraxia, and agnosia seen in patients with Alzheimer’s disease.²¹

The most difficult differential diagnosis to consider in the context of NPH is Binswanger’s disease, a form of subcortical vascular encephalopathy. Patients with this condition exhibit a predominantly frontal cognitive deterioration and gait disturbance (ataxia or motor dysfunction, or both), although focal neurological signs may be present. The pathologic changes occurring in patients with Binswanger’s disease are believed to be the result of small-vessel ischemia and subsequent extensive white matter damage. Neuropsychological testing demonstrates features consistent with a frontal subcortical type of dementia, which is similar to the pattern noted in NPH. Similar magnetic resonance imaging (MRI) features may be seen, including ventriculomegaly and the coexistence of MRI white matter changes, such as deep white matter hyperintensities and subcortical lacunar infarctions. Table 34-3 summarizes the list of differential diagnoses for the clinical triad in NPH, aside from other hydrocephalus disorders.

TABLE 34-3 Differential Diagnoses for the Clinical Triad in Normal-Pressure Hydrocephalus, Aside from Other Hydrocephalus Disorders

DEMENTIA

Vascular

Cerebrovascular disease

Stroke

Multi-infarct dementia

Binswanger’s disease

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy

Neurodegenerative

Parkinson’s disease

Alzheimer’s disease

Progressive supranuclear palsy

Frontotemporal dementia

Corticobasal degeneration

URINARY INCONTINENCE

Structural

Bladder outflow obstruction

Benign prostatic hypertrophy

Bladder innervation

Autonomic dysregulation

Lumbar canal stenosis

Miscellaneous

Medications—anticholinergics, diuretics

Data from Idiopathic Normal-Pressure Hydrocephalus Guidelines; Relkin N, Marmarou A, Klinge P, et al. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery. 2005;57:S4; and expert opinion.

Neuroradiologic Features

Guidelines published by the Idiopathic NPH Study Group ¹⁶ include a set of imaging criteria required to justify the diagnosis of idiopathic NPH. Imaging in the form of computed tomography (CT) or MRI is required to establish the diagnosis of NPH. Important differential diagnoses to rule out include obstruction of CSF pathways as a result of tumor or similar pathology, significant cerebral atrophy, and evidence of cerebrovascular ischemia. Ventricular enlargement not entirely attributable to cerebral atrophy or congenital enlargement (Evans’ index >0.3 or comparable measure) should be present. Evans’ index is defined as the maximal width of the anterior ventricular horns divided by the maximal width of the calvaria at the level of the foramen of Monroe. An alternative measurement is the bicaudate ratio, which has been demonstrated to have excellent interobserver agreement and is more sensitive to changes in ventricular size.²² This is the minimal intercaudate distance divided by the brain width along the same line. Significant ventriculomegaly is defined as a ratio of 0.25 or greater with this method.

There should also be one of the following supportive features: enlargement of the temporal horns of the lateral ventricles not entirely attributable to hippocampus atrophy; callosal angle of 40 degrees or greater; evidence of altered brain water content, including periventricular signal changes not attributable to microvascular ischemic changes or demyelination; or aqueductal or fourth ventricular flow void on MRI. Other imaging findings were acknowledged to be supportive of the diagnosis but not required, including a brain imaging study performed before the onset of symptoms demonstrating the absence of ventriculomegaly or smaller ventricles, a radionuclide cisternogram showing delayed clearance of the radiotracer over the cerebral convexities after 48 to 72 hours, cine MRI showing an increased ventricular flow rate, or a single-photon emission computed tomography (SPECT)-acetazolamide challenge showing decreased periventricular perfusion that is not altered by acetazolamide.¹⁶

The imaging finding of deep white matter hyperintensities in a patient with NPH has been shown to be inversely correlated with shunt responsiveness.²³ Such white matter hyperintensities are probably a marker of comorbidity, with patients being more prone to general complications of surgery when they are present. However, other studies have demonstrated that the presence of these lesions may not be predictive of a poor outcome after shunt surgery. This was the subject of an MRI study by Tullberg and colleagues, who used conventional MRI sequences to examine these lesions and other MRI variables in a group of NPH patients undergoing surgery.²⁴ The authors found no correlation between the presence of these parameters and poor outcome after surgery. Akiguchi and associates further demonstrated that there was improvement in ventriculomegaly and mean total scores for white matter lesions in patients who clinically improved after surgery, thus implying that these white matter lesions may be reversible.²⁵ In this patient cohort the majority had parkinsonism (71%), but other coexisting comorbid conditions, such as small-vessel disease (29%), hypertension (41%), and diabetes (35%), were also found. Eighty-eight percent of patients had white matter lesions noted on CT or MRI. These contradictory findings illustrate the continuing debate regarding the presence of deep white matter hyperintensities and their correlation to small-vessel disease.

Supplementary Prognostic Testing

Guidelines on the value of supplementary tests conclude that a single standard for the prognostic evaluation of patients with idiopathic NPH is lacking. However, supplementary tests can increase the prognostic accuracy to greater than 90%.²⁶

Three supplementary tests are currently recommended as options:

• Lumbar puncture “tap test”

• External lumbar drainage

• Measures of CSF outflow resistance

The method of choice depends on local experience and the availability of equipment. Direct ICP measurement may be useful to exclude other more acute causes of hydrocephalus but does not contribute to prognostic assessment. Radionuclide cisternography is no longer a favored option because this technique does not improve the diagnostic accuracy of combined clinical and CT criteria in patients with presumed NPH.²⁷

A lumbar puncture “tap test” has been shown to produce a specificity of 100% with a sensitivity of 26%,²⁸ provided that it is performed at a high volume (i.e., withdrawal of 40 to 50 mL of CSF). Symptomatic improvement after removal of CSF has a high positive predictive value (73% to 100%) of a probably favorable outcome with shunt placement.²⁶ It has to be remembered that improvement after a shunt is often delayed in many patients, so a simple tap test would not be expected to reveal all patients who might benefit from a shunt. However, the low sensitivity of the “tap test” precludes using this method as a diagnostic tool for exclusion. Nonetheless, a lumbar puncture is often used as a first-line investigative tool to establish that CSF pressure is within the normal range (5 to 18 mm Hg/7 to 24 cm H₂O) and that no biochemical or microbiologic abnormalities are present. Prolonged external lumbar drainage in excess of 300 mL is associated with high sensitivity (50% to 80%), specificity (80%), and positive predictive value (80% to 100%).²⁶^,²⁸ However, this method requires inpatient stay and carries a risk for the complications of nerve root irritation, hemorrhage, and CSF infection.

Measurement of CSF outflow resistance, thought to reflect the CSF absorption pathways, is well established. Fluid is injected into a CSF space (e.g., ventricles or lumbar sac) either by bolus or infusion. CSF outflow resistance can then be calculated with a pressure-volume study and used to assess the CSF circulation for signs of disturbance.²⁹ The advantage of this technique is that it requires only day attendance and can also be performed through a preimplanted ventricular reservoir device. In the Dutch NPH study, outflow resistance greater than 18 mm Hg/mL per minute had a specificity of 87% and a sensitivity of 46%.³⁰

Current guidelines recommend that all patients suspected of having idiopathic NPH be considered for supplementary tests with one or more of the three methods.²³ Prolonged external drainage has the highest sensitivity and positive predictive value but is associated with a higher complication rate. The other two methods can be considered in an outpatient setting, but measurement of CSF outflow resistance requires specialist equipment and interpretation of results. However, measurement of CSF outflow resistance can also be used as a method of comparing CSF hydrodynamics before and after shunt insertion to investigate the shunt responsiveness of a patient in the context of deterioration or failure to respond to intervention.

It should also be noted that alternative methods are available, such as the lumbar subcutaneous shunt proposed by Mendelow’s group.³¹