Clinical manifestations

Presentation and course

Gait impairment associated with urinary incontinence and cognitive decline is suggestive of normal pressure hydrocephalus. Gait and stance difficulties are usually an early sign, and they may appear before, shortly after, or simultaneously with intellectual changes. Urinary incontinence is typically a late symptom. Gait disturbance may be a unique presentation of normal pressure hydrocephalus, and incontinence is the most commonly missing symptom from the triad. Urinary urgency may sometimes precede the development of incontinence. Fecal incontinence is rare and appears in more advanced stages. The clinical manifestations of normal pressure hydrocephalus are insidious and, if untreated, this condition is inevitably progressive with gradual progression of dementia and advancement to an akinetic state.

Patients with normal pressure hydrocephalus walk slowly, are unsteady, and have a wide base. A review of 1716 articles describing the clinical features of normal pressure hydrocephalus identified "wide-based gait" as the most common gait dysfunction (14). Steps are short with reduced step height, a pattern of gait referred to as "magnetic gait" (31; 68).

Postural instability is also common, with increased risk of falls. Turning is awkward and en block with multiple steps. Patients often complain about leg weakness, tiredness, and occasional numbness or burning sensations. These symptoms fluctuate from day to day. In advanced stages, standing, and later sitting, may become impossible. Neurologic examination may reveal a mild degree of spasticity with increased muscle stretch reflexes in the lower extremities, and Babinski signs also may be present. Upper extremities are initially spared, but changes in handwriting, poor coordination on fine motor tasks, and postural tremor have been reported in later stages.

The gait difficulties in normal pressure hydrocephalus must be distinguished from those caused by weakness. Lower extremity strength in normal pressure hydrocephalus is preserved. Motor abilities can be tested with patients sitting or lying down by asking them to imitate walking, riding a bicycle, or other motions. Typically, they can perform these tasks without obvious deficit, and these abilities are preserved until relatively late stages. This pattern of gait disturbance indicates gait "apraxia" rather than muscle weakness.

Normal pressure hydrocephalus may have additional manifestations beyond a classic triad. Motor impairment may also affect the upper limbs, and slowing of rapid alternating movements is seen commonly in patients with normal pressure hydrocephalus; a successful shunting of hydrocephalus also improves the dexterity in the upper extremities (83).

Cognitive decline varies widely in its severity. Dementia is characterized by prominent attention deficit, memory impairment, and executive (frontal lobe) dysfunction. Most patients are apathetic; bradyphrenia and depression must be considered. Aphasia, other than anomia, and apraxia are usually not prominent. However, cognitive symptoms in normal pressure hydrocephalus are not limited to features of so-called subcortical dementia (eg, abulia, bradyphrenia, distractibility, memory deficit). Focal cortical deficits (aphasia, apraxia, agnosia) may occur as well, blurring the distinction between dementia in normal pressure hydrocephalus and the primary degenerative dementias. Behavioral symptomatology can be marked in some patients. Akinetic mutism and alteration of consciousness are found in the later stages.

Clinical vignette

A 73-year-old man with an unremarkable past medical history presented after a 3-year history of progressive forgetfulness and poor balance as well as recent onset of urinary incontinence. Examination showed impaired memory and difficulties with calculations and visuospatial skills. Language was normal. The patient’s Mini-Mental State Examination score was 23/30. The rest of the neurologic examination was notable for diminished postural reflexes and abnormal gait with signs of gait apraxia. Laboratory tests did not reveal any treatable cause of dementia. X-ray computed tomography demonstrated enlarged ventricles and hypodensity of the white matter. Lumbar puncture was performed with normal opening pressure, and 30 cc of CSF were collected. CSF analysis was normal. The patient’s gait transiently improved with better stride and improved postural reflexes.

A diagnosis of normal pressure hydrocephalus was made based on the presence of the clinical triad and typical neuroimaging studies. The patient underwent ventriculoperitoneal shunting. X-ray computed tomography obtained after the operation was unchanged from his previous imaging.

One month after shunt placement, the patient experienced significant improvement in gait and bladder control. His cognition also improved, and his repeat Mini-Mental State Examination score was 28/30. A follow-up CT demonstrated reduction of hypodensities in the periventricular white matter. The ventricular size was not significantly changed.

Biological basis

Etiology and pathogenesis

Biological basis. Hydrocephalus in normal pressure hydrocephalus is a consequence of the disequilibrium between production and absorption of CSF. It is thought that, in the majority of cases, ventricular enlargement results from an obstruction of the CSF flow around the brain convexities and insufficient absorption through the arachnoid granulations and arachnoid villi of the superior sagittal sinus. Subarachnoid hemorrhage, meningitis, head injuries, and elevated levels of CSF protein all cause scarring and fibrosis in the subarachnoid space (64). Deficiency of the arachnoid granulations and obstruction of the pacchionian villi due to meningioma of the superior sagittal sinus are other examples of this mechanism. This subtype of normal pressure hydrocephalus is often referred to as communicating hydrocephalus. Communication between the ventricles and subarachnoid space is unobstructed; however, the communication between the subarachnoid space and arachnoid granulations is not intact. Other lesions (intracranial tumors, cerebellar hematomas, nontumorous stenosis of the aqueduct of Sylvius, arachnoid cysts) can result in normal pressure hydrocephalus due to obstruction of CSF circulation within the ventricular system. This subtype of normal pressure hydrocephalus is sometimes called noncommunicating.

A relatively large proportion of patients with normal pressure hydrocephalus do not have an identifiable cause of hydrocephalus. The preponderance of evidence in these cases points to reduced absorption of CSF. Patients with normal pressure hydrocephalus (both idiopathic and secondary) have increased resistance to outflow (ROUT) of CSF (ROUT, mmHg/mL per minute), suggestive of an impediment of CSF absorption (61). This has been corroborated by pathological studies showing fibrotic changes of the leptomeninges and pacchionian villi (64). Genetic predisposition has been increasingly recognized as an important cause of normal pressure hydrocephalus, but the genetic landscape of normal pressure hydrocephalus remains unknown (99).

Normal opening pressure of CSF and abnormally high outflow resistance indicate that normal pressure is an endpoint of previously elevated intracranial pressure (61). Indeed, intracranial pressure is not always normal, and long-term monitoring has shown transient elevation of intracranial pressure. Thus, elevation of intracranial pressure causes enlargement of ventricles, and a new balance is reached with normal (ie, nonelevated) pressure but higher force, affecting a bigger ventricular surface according to Pascal's law of pressure in fluids (38). Reduced compliance of the brain, further enhanced by degenerative changes of the periventricular white matter, may also contribute to abnormal distensibility of the ventricles. Increased CSF pulse amplitude is another possible explanation for the development of hydrocephalus despite normal intracranial pressure (32).

The development of the clinical symptoms of normal pressure hydrocephalus is multifactorial. Motor fibers innervating the legs and sphincters project through the vicinity of the frontal horns of the lateral ventricles. The frontal horns of the lateral ventricles are often disproportionally expanded. Stretching of these fibers is thought to be responsible for gait and urinary symptoms. Volumetric changes after CSF removal are most pronounced in the periventricular region of the lateral ventricles and in the frontal and temporal lobes (96). Corticospinal tract fibers show signs of axonal degeneration, which can be clinically assessed by diffusion tensor imaging (42; 51). Tractography of white matter confirmed gait-related white matter structural abnormalities in motor and sensory pathways around the ventricle (102).

Early urinary involvement is characteristic of the loss of voluntary supraspinal control with bladder hyperactivity and detrusor instability, which is manifested as urinary urgency. Late frank incontinence also has a frontal component with indifference and lack of concern. Many symptoms of cognitive decline can also be accounted for by compression of the frontal white matter (deficits in attention, initiation, and other executive functions).

Compromised microcirculation due to increased intraparenchymal pressure is another putative factor in the pathogenesis of dementia and the apractic features of gait. Studies of regional cerebral blood flow in normal pressure hydrocephalus have shown regional reduction of blood flow in the periventricular white matter with gradual improvement toward the cortical regions. Induction of increased intracranial pressure further reduced cerebral blood flow in the subcortical regions (81).

Impaired vascular autoregulation with reduced cerebrovascular reactivity, suggesting a limited capacity to compensate for transitional increases of intracranial pressure, is also a feature of normal pressure hydrocephalus (24). Clinical changes do not tightly correlate with regional cerebral blood flow changes; the degree of clinical improvement has been disproportionally higher than changes of regional cerebral blood flow. This suggests that additional factors (such as demyelinization and decreased clearance of various macromolecules) may play roles in the pathogenesis of dementia in normal pressure hydrocephalus (95; 110).

Results of quantitative studies of the brain metabolism are more consistent. Jagust and colleagues found global reduction of glucose metabolism using PET; patients with normal pressure hydrocephalus had a different pattern compared to patients with Alzheimer disease (47). The decrease of glucose uptake in normal pressure hydrocephalus is lower than expected for the degree of dementia and suggests widespread cortical and subcortical dysfunction. The relationship between symptoms of normal pressure hydrocephalus and alterations of blood flow and cerebral metabolism is not firmly established. Clinical motor symptoms may be caused by blood flow abnormalities in the supplementary motor cortex, causing reversible suppression of frontal periventricular corticobasal ganglia-thalamocortical pathways. This area showed improved blood flow after a prolonged lumbar drainage, suggesting that motor function recovery in patients with normal pressure hydrocephalus after CSF removal is related to enhanced activity in medial parts of frontal motor areas that are important for motor planning (66).

Striatal dopaminergic dysfunction has been suggested in the motor phenotypic expression of normal pressure hydrocephalus (106). Reduced striatal dopamine reuptake transporter binding can be seen in more than half of these patients, and it correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike in idiopathic Parkinson disease, dopaminergic deficit in normal pressure hydrocephalus is more symmetric and prominent in the caudate nucleus (90). Absence of levodopa responsiveness, shunt-responsive parkinsonism, and post-surgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with idiopathic normal pressure hydrocephalus.

Impaired corticospinal excitability, assessed by transcranial magnetic stimulation, can result in disinhibition of the motor cortex and, thus, plays a key role in mediating the effects of frontal lobe dysfunction on motor performance in patients with normal pressure hydrocephalus (27). These abnormalities likely reflect a disturbed connectivity of the frontal motor networks rather than a direct lesion of the primary motor cortex or corticospinal tract, and shunting can normalize transcranial magnetic stimulation responses.

Ischemia of deep white matter may not be a mandatory precondition for the development of normal pressure hydrocephalus because not every patient with normal pressure hydrocephalus has abnormal blood flow studies; however, secondary microcirculation changes may be caused by stretching of periventricular white matter due to ventriculomegaly. MR imaging studies with flow quantification measuring the total blood inflow, sagittal and straight sinus outflow, aqueduct stroke volume, and arteriovenous delay did not detect any abnormalities in the periventricular regions, and the main changes showed alterations in superficial venous compliance and a reduction in the blood flow returning via the sagittal sinus (10). The overall load of the white matter changes also negatively correlated with the gait improvement after shunting, further supporting the notion that white matter lesions contribute to the irreversibility of symptoms in normal pressure hydrocephalus but not to the pathophysiological mechanisms that lead to them (21). Diffusion microstructural MR imaging may be helpful to distinguish reversible and irreversible white matter changes in this condition (54).

Altered glymphatic system has also been implicated in the pathogenesis of normal pressure hydrocephalus (100). Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS) showed abnormalities in patients with normal pressure hydrocephalus, and the group of nonresponders to shunting procedure had even lower ALPS-index than shunt responders (09).

Abnormalities of jugular venous system draining the blood from the brain can contribute to abnormal absorption of CSF. Incompetent jugular valves may allow the transmission of the high venous pressures to the subarachnoid space. This hypothesis is supported by the findings of retrograde jugular flow during Valsalva maneuver in 95% patients with normal pressure hydrocephalus, and this finding is rare in apparently normal controls (63). This test can be also used for the diagnosis of normal pressure hydrocephalus, even though its specificity and sensitivity have not been established in a larger cohort of patients.

Etiology. Approximately one half of all cases of normal pressure hydrocephalus were historically considered idiopathic without apparent cause. There is growing evidence that vascular risk factors are important in the pathogenesis of idiopathic normal pressure hydrocephalus. A population-based study identified hypertension, white matter disease, and diabetes mellitus as important risk factors for the development of communicating hydrocephalus (48). Genetic analysis using the Mendelian randomization approach also supports essential hypertension as a causal risk factor for idiopathic normal pressure hydrocephalus (28).

Subarachnoid hemorrhage, head trauma, infectious or carcinomatous meningitis, and elevated CSF protein levels (including elevation due to intraspinal tumors) are causes of secondary normal pressure hydrocephalus. Normal pressure hydrocephalus may also result from aqueductal stenosis, arachnoid cysts of the third and fourth ventricles, basilar artery ectasia, and intracranial and spinal tumors.

A familial form of normal pressure hydrocephalus with autosomal dominant inheritance has been described, and some patients also had coexisting essential tremor (121; 73). Affected first degree relatives were reported in 5% of pedigrees with normal pressure hydrocephalus, and presumed familial normal pressure hydrocephalus has a higher risk of dementia independent of the incidence of Alzheimer disease and ApoE status in these families (45). The copy number loss in the intron 2 of SFMBT1 has been identified as a susceptibility genetic variant in the Japanese population and it was also a predictive factor for a positive response to shunting (94). This was also replicated in Finnish and Norwegian patients as a risk factor for the development of hydrocephalus but not as a positive predictive factor for shunting surgery (60). Another genetic abnormality found in normal pressure hydrocephalus is a heterozygous deletion of the CWH43 gene, which was found in 15% of patients with idiopathic normal pressure hydrocephalus in one studied cohort (120). Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol-anchored proteins, and a mouse model also has hydrocephalus, gait and balance abnormalities, and decreased numbers of ependymal cilia.

Epidemiology

Normal pressure hydrocephalus has its highest prevalence in the seventh and eighth decades and is rare in people younger than 60 years (72). However, young patients ranging from neonates to young adults with secondary normal pressure hydrocephalus have been reported. The prevalence in the general population is unknown because some patients may manifest only with gait impairment and without cognitive deficits. A survey of medical records in Olmsted County, Minnesota, established the incidence of normal pressure hydrocephalus as 1.19/100,000 per year (58). The prevalence of probable idiopathic normal pressure hydrocephalus in Sweden was 0.2% in those aged 70 to 79 years and 5.9% in those aged 80 years and older (49). A population-based study in Japan identified a 7.7% prevalence at the age of 86 (46). Several authors consider prevalence and incidence of normal pressure hydrocephalus to be overestimated, and data from the Netherlands suggest the incidence of normal pressure hydrocephalus responding to shunt at about 2.2 per million per year (112).

Prevention

The pathogenesis of normal pressure hydrocephalus remains obscure, and no preventive measures are known. Risk factors for normal pressure hydrocephalus include traditional vascular risk factors, such as hypertension and diabetes mellitus (48). However, we lack controlled studies demonstrating lower incidence of hydrocephalus with better hypertension or diabetes control. The most common cause of secondary normal pressure hydrocephalus is subarachnoid hemorrhage. Approximately 10% of patients with history of subarachnoid hemorrhage will develop normal pressure hydrocephalus, and patients with a high degree of subarachnoid bleeding caused by a ruptured anterior communicating artery aneurysm had a higher risk (118).

Differential diagnosis

Dementia and gait disorder are the most conspicuous and early signs of normal pressure hydrocephalus. Given the potential for successful treatment, it is imperative to distinguish other conditions simulating the clinical picture of normal pressure hydrocephalus.

Dementing disorders. The most common cause of dementia is Alzheimer disease. Gait in Alzheimer disease is usually unremarkable until the late stages of the illness. Enlarged ventricles can be also found in Alzheimer disease because of brain atrophy (hydrocephalus ex vacuo). The degree of cortical atrophy in hydrocephalus ex vacuo is usually disproportionally more advanced than in patients with normal pressure hydrocephalus. Thus, prominent early gait disorder with relatively short history of dementia in a patient with enlarged ventricles may be more suggestive of normal pressure hydrocephalus than of Alzheimer disease. Patients with coexisting normal pressure hydrocephalus and Alzheimer disease, confirmed by brain biopsy, have diminished postoperative improvement of normal pressure hydrocephalus symptoms (40). The overlap of normal pressure hydrocephalus and Alzheimer disease may be common, and one study found the coexistence of these two entities in 89% (eight of nine cases) (22).

Another common type of dementia is dementia with Lewy bodies. This needs to be considered in patients with fluctuating cognitive impairment, visual hallucinations, and mild extrapyramidal features with shuffling gait. Neuroimaging is usually diagnostic in differentiating normal pressure hydrocephalus and dementia with Lewy bodies.

Multiinfarct dementia and Binswanger disease can have similar clinical manifestations, but MRI or CT usually detects signs of multiple strokes. Features seen in multiinfarct dementia not characteristic of normal pressure hydrocephalus include high Hachinski ischemia scale score, presence of multiple infarctions on CT or MRI, focal neurologic deficit, and history of stroke. The presence of associated disease-causing gait changes (osteoarthritis or spinal canal stenosis) may obscure normal pressure hydrocephalus, and these patients should be followed closely for progression and appearance of cognitive deficits. Vascular pathology may be also very common in patients with normal pressure hydrocephalus (64).

Movement disorders. Patients with Parkinson disease also have hypokinetic gaits with a reduced gait velocity and highly variable stride length. Broad-based gait with outward rotated feet and diminished height of the steps can help differentiate normal pressure hydrocephalus from Parkinson disease. Moreover, the gait of patients with normal pressure hydrocephalus does not improve with external cues that are beneficial in patients with Parkinson disease (98). Baseline postural instability of patients with suspected normal pressure hydrocephalus suggests an alternative diagnosis and, if shunted, their outcome tends to be poor (58). Other causes of gait difficulties simulating normal pressure hydrocephalus (eg, spinocerebellar degenerations or cerebellar degeneration due to chronic alcoholism) have more ataxic character (31). Congenital hydrocephalus may become symptomatic with aging and may mimic normal pressure hydrocephalus. Head circumference at or greater than the 98th percentile suggests congenital etiology. Thus, head circumference measurement should be part of an examination in suspected normal pressure hydrocephalus. Furthermore, patients with normal pressure hydrocephalus had bigger head circumference when compared with normal sex-matched and age-matched controls. This suggests that a considerable fraction of these patients actually have a congenital hydrocephalus that became symptomatic in late adulthood (62).

Diagnostic workup

In general, the laboratory evaluation of normal pressure hydrocephalus is difficult. Adhering to a specific protocol for each patient improves the outcomes of diagnostic evaluations of normal pressure hydrocephalus (01). The diagnosis of normal pressure hydrocephalus is supported by the presence of the triad of dementia, gait impairment, and urinary incontinence, together with hydrocephalus seen on CT or MRI with white matter changes, aqueductal CSF flow void sign on MRI, normal pressure of CSF during lumbar puncture, and improvement of clinical symptoms after removal of CSF. Unclear cases may benefit from invasive studies of intracranial pressure monitoring or cerebral compliance. The only premortem definitive confirmation of the diagnosis is improvement after shunt surgery.

Because the clinical picture of normal pressure hydrocephalus is not specific, several diagnostic tests have a crucial role in the diagnosis. The most important diagnostic procedure is CT or MRI scan of the brain to establish the presence of hydrocephalus. The diagnosis of normal pressure hydrocephalus is supported when the width of the anterior ventricular horns is greater than 30% of the cranial cavity (Evan ratio) and inferior horns are wider than 2 mm. These two horns are typically disproportionally enlarged compared to other parts of the ventricular system. However, ventricular dilatation appears to be insufficient for the diagnosis of normal pressure hydrocephalus because the ventricular size does not predict intraventricular pressures (56). Linear measurements of caudocranial alterations of the ventricular geometry such as vertical frontal horn diameters, rather than laterolateral changes of ventricular size, are more sensitive to predict normal pressure hydrocephalus (93). A new index for assessing the total ventricular volume compared to the anteroposterior diameter of the lateral ventricle index has been suggested and the values higher than 0.50 are suggestive of hydrocephalus (43).

Patients with normal pressure hydrocephalus have a unique distribution of CSF with a high ratio between ventricular volume and total intracranial CSF volume; however, the total CSF volume is not different from normal controls (109). The degree of cortical atrophy is usually milder than the degree of ventricular atrophy, but the presence of prominent cortical atrophy does not rule out normal pressure hydrocephalus (119). Disproportional dilatation of the perihippocampal fissure is characteristic for atrophy seen in Alzheimer disease but not in normal pressure hydrocephalus. Voxel-based morphometry of a disproportionate distribution of CSF space between the ventricles and subarachnoid space may help to distinguish normal pressure hydrocephalus from Alzheimer disease or other neurodegenerative processes with global brain atrophy (119). The degree of enlargement of the perihippocampal fissure was a specific and sensitive marker for differentiating normal pressure hydrocephalus (enlarged ventricles and normal or slightly dilated perihippocampal fissure) from hydrocephalus ex vacuo due to Alzheimer disease (enlarged ventricles and perihippocampal fissure) (119). Tight brain convexity with crowding of sulci, resulting in narrowing of subarachnoid spaces in the frontal and parietal lobes, and disproportionate widening of the Sylvian fissure (mismatch sign), which are best assessed on coronal MRI sections, a small callosal angle, and wide temporal horns have been suggested as positive predictors of good shunting outcome (41; 113). Additionally, a small callosal angle, together with the Sylvian fissure dilatation, and absence of narrowing of superior parietal sulci can discriminate the idiopathic normal pressure hydrocephalus from the hydrocephalus ex vacuo (57).

Normal size of the fourth ventricle with dilated third and lateral ventricles is suggestive of aqueductal stenosis. This can be corroborated by metrizamide cisternography showing lack of filling above the level of the fourth ventricle. MRI has higher sensitivity to white matter changes than CT, and increased signal in the periventricular area supports the diagnosis of normal pressure hydrocephalus due to transependymal exudation of CSF. However, MRI appearance and the distribution of the white matter changes alone do not have sufficient sensitivity to differentiate normal pressure hydrocephalus from brain pathology due to hypertension (110). Measurement of T1 and T2 water proton relaxation times in the periventricular white matter can distinguish edema in normal pressure hydrocephalus from nonspecific white matter changes (113). Diffusion tensor imaging is more suitable to assess the integrity of white matter, and reduced axonal density of the white matter, representing irreversible changes, is associated with worse prognosis after the shunting (55).

A more specific MRI sign is decreased signal from the aqueduct compared to signal from the ventricles (CSF flow void sign).

Flow velocity in the aqueduct is increased because of reduced compliance of the brain. The presence of CSF flow void sign is not specific for normal pressure hydrocephalus, but its absence may suggest a diagnosis other than normal pressure hydrocephalus (113). Prominent CSF flow void on proton-density weighted images and increased CSF stroke volume have been found in patients with normal pressure hydrocephalus who favorably responded to ventriculoperitoneal shunt (113). However, other studies did not replicate high positive predictive value of CSF flow void or the quantification of the aqueductal stroke volume for shunting outcome (29; 52). Net retrograde aqueductal flow is also a characteristic feature for normal pressure hydrocephalus (92). Overall, MR imaging measurement of intracranial hydrodynamics and brain compliance are abnormal in patients with normal pressure hydrocephalus but cannot reliably predict shunting responders (11).

The Normal Pressure Hydrocephalus Radscale has been proposed as a useful diagnostic tool using radiologic features of normal pressure hydrocephalus. It is a combined scoring of seven different structural imaging markers on preoperative brain CT or MR imaging in patients with idiopathic normal pressure hydrocephalus: callosal angle, Evans Index, Sylvian fissure dilation, apical sulcal narrowing, mean temporal horn diameter, periventricular white matter lesions, and focal sulcal dilation (23). However, a meta-analysis of published radiologic papers found that callosal angle and periventricular changes were the only diagnostically effective radiological predictors of patients with shunt-responsive idiopathic normal pressure hydrocephalus (104).

Drainage of 20 to 50 cc of CSF may transiently improve gait and cognitive abilities, thus, supporting the diagnosis of normal pressure hydrocephalus; however, the test can also give false-negative results (71). A delayed assessment of cognition and mobility 24 hours and especially 48 hours after large volume CSF removal may increase sensitivity to predict a good outcome to shunting (108). Measurement of cerebral blood flow before and after lumbar puncture can be helpful in preoperative selection of patients. The patients with increased blood flow after a large volume CSF removal have better postoperative prognosis (44; 115). Temporary external lumbar drainage can provide more affirmative information and has a high positive predictive value for improvement after shunt surgery (70). Patients whose clinical picture is highly suggestive of normal pressure hydrocephalus and who did not respond to external continuous lumbar drainage should be further evaluated using more invasive procedures (84). However, some authors have suggested that a high rate of false negative results occur using external lumbar drainage (114). Several centers use invasive measurements of intracranial pressure and CSF infusion tests, which have a high positive predictive value and a relatively low complication rate (87). Cerebral compliance can also be assessed by measuring pressure-volume relationships, which requires intraventricular or lumbar injections with intracranial pressure monitoring. Detection of decreased CSF outflow conductance, which is reciprocal to resistance R(out), has been suggested to be specific for normal pressure hydrocephalus (18). Abnormal cerebral compliance is also useful in differentiation of normal pressure hydrocephalus from cerebral atrophy (76). The Dutch normal pressure hydrocephalus study prospectively assessed the usefulness of measurement of resistance to outflow of CSF in 101 patients. The most reliable results with 92% positive predictive value for good outcome were seen in patients with cut-off levels of 18 mmHg/ml per minute (normal levels are below 10 mmHg/ml per minute) (15). Analysis of 80 patients who were diagnosed during the early stages of normal pressure hydrocephalus and did not have any signs of cognitive deficit did not confirm the usefulness of increased resistance to the outflow of CSF for the prediction of a good outcome after shunting (77); however, other studies replicated a high positive predictive value for a good outcome of abnormal R(out) in patients with normal pressure hydrocephalus (97).

Abnormal circulation and absorption of CSF can be evaluated with radioisotope cisternography. In healthy subjects, intrathecally administered radioisotope accumulates around the brain convexity and is absorbed within 48 hours. Reflux of isotope to the ventricles with ventricular stasis after 48 hours and absence of radioisotope in cisterns has been claimed to be specific for normal pressure hydrocephalus; however, this abnormality seen on cisternography is not specific and has relatively low predictive accuracy (111). Some authors have even completely abandoned this test in the evaluation of normal pressure hydrocephalus (71; 74).

Studies of regional cerebral blood flow and cerebral metabolism in normal pressure hydrocephalus have reported controversial results with nonspecific patterns. Detection of impaired autoregulation with insufficient response to acetazolamide limited to the white matter has been associated with better outcome after surgery (101). PET study has shown globally reduced glucose uptake. This differs from biparietal and bitemporal reduction commonly found in Alzheimer disease (47). Computed tomography perfusion studies can distinguish between healthy controls and patients with hydrocephalus who have reduced perfusion in the white matter and basal ganglia; however, no difference between shunt responders and nonresponders could be demonstrated (122).

Impaired microcirculation and subsequent neuronal dysfunction may be reflected in the composition of cerebrospinal fluid. Total tau protein and hyperphosphorylated tau, beta-amyloid (1-42), vascular endothelial growth factor, glial fibrillary acidic protein, and neurofilament protein have been suggested as potential biomarkers of normal pressure hydrocephalus (30; 103). Meta-analysis of cerebrospinal fluid beta-amyloid (1-42), total tau, and hyperphosphorylated tau levels suggested that these markers are lower in patients with normal pressure hydrocephalus when compared to normal controls (25). Neurofilament light protein and amyloid precursor protein (APP) were reduced in patients with normal pressure hydrocephalus and their levels increased after a successful shunting, possibly reflecting improved axonal integrity (50). However, higher levels of neurofilament light chain and total tau protein were associated with a less favorable response to shunt surgery, suggesting a more active neurodegeneration in this group of patients (20). Similar results with reduced levels of amyloid precursor protein, total tau, and phosphorylated tau were observed in patients with normal pressure hydrocephalus when compared to patients with Alzheimer disease (80). However, a reduction of the interstitial space in hydrocephalus can impair amyloid precursor protein fragment drainage, resulting in low levels of all forms of amyloid and tau proteins and, thus, provide misleading information to distinguish normal pressure hydrocephalus from Alzheimer disease (36). Assay of Aβ42 toxic conformer may be more sensitive as a biomarker for Alzheimer disease pathology and a subgroup of patients with normal pressure hydrocephalus with increased Aβ42 toxic conformer showed cognitive decline 2 years postoperatively whereas the decreased-conformer subgroup maintained the improvement after the shunting procedure (03).

Management

The only established treatment of normal pressure hydrocephalus is a CSF-diverting operation. American Academy of Neurology practice guidelines state that shunting is possibly effective in idiopathic normal pressure hydrocephalus with a 96% chance of subjective improvement and an 83% chance of improvement on timed walk test at 6 months with three studies with Class 3 evidence (39). Results of a pilot study using a placebo-controlled design with the shunt valve closed in some patients showed a trend for gait improvement in patients who had their valve open for 4 months following surgery (69). Postoperative physical therapy with dynamic equilibrium gait training can facilitate gait recovery and reduce the number of falls (82).

The selection of patients to potentially benefit from a shunt is controversial. It varies from a rigorous approach to offering the benefit of the doubt. An operation should be considered in patients with a history of dementia for less than 2 years and prominent gait impairment; patients with isolated gait impairment are particularly good candidates for an operation (37). Concurrence of cerebrovascular disease predicts poor response to shunt placement (17). Patients who have a high risk of surgical complication may be treated by repeated high-volume lumbar punctures (67).

Marked cortical atrophy is not a contraindication for operation, as many patients with normal pressure hydrocephalus are older. Patients with amelioration of symptoms after lumbar puncture or temporary lumbar drainage are likely to respond positively to a shunt. Invasive monitoring can reduce uncertainty in atypical cases. Resistance to outflow higher than 18 mmHg/ml per minute has the highest positive predictive value for significant improvement (15). Quantitative MRI CSF flow measurement with a CSF stroke volume of more than 42 microliters has also been reported to be useful in predicting outcome of shunting (19).

Indication for the shunt procedure in patients without the typical clinical picture or with a long history of symptoms is difficult. However, patients should be monitored for new symptoms; in particular, demented patients who develop characteristic gait impairment should also be considered for shunt operation (89). There is no conclusive evidence that any type of shunting procedure or valve opening pressure has superior results. However, results of the Dutch normal pressure hydrocephalus study suggest that patients with low-pressure shunts have a tendency for better outcome than patients with medium-pressure valves (16).

Production of CSF can also be reduced by acetazolamide or digoxin. Patients with high perioperative risk may benefit from a pharmacological approach. Treatment with 125 to 375 mg per day of acetazolamide improved periventricular hyperintensities and gait parameters in a small group of patients with normal pressure hydrocephalus (04).

Outcomes

American Academy of Neurology practice guidelines predictors of successful outcome of shunting included elevated increased resistance to outflow (1 study Class 1, multiple Class 2), impaired cerebral blood flow reactivity to acetazolamide (by SPECT) (1 study Class 1), and positive response to either external lumbar drainage (1 Class 3) or repeated lumbar punctures (39).

Prognosis of patients who have had an operation depends on the selection of cases. The proportion of patients with long-term improvement varies from 25% to 80% and depends on indications for operation, experience of neurosurgeons, and preoperative conditions (112; 88). The clinical benefit from shunting may be sustained for a long-term period (more than 5 years), but these patients still need frequent follow-up visits because shunt complications requiring shunt revisions are relatively common (91). However, shunt-related mortality is negligible (79). Mortality in operated patients with normal pressure hydrocephalus is 1.8 times increased compared to the general population. However, the survival of patients who improve in gait and functional independence are similar to that of the general population, indicating that shunt surgery for idiopathic normal pressure hydrocephalus, besides improving symptoms and signs, can normalize survival (05). Furthermore, early shunt surgery improves the survival and surgery should not be delayed (07). The timing of shunting surgery after the diagnosis is established can also affect the outcomes. Early shunt surgery improves survival, and surgery should not be delayed (07). Patients who underwent a shunting procedure within the first 3 months of the diagnosis had a better outcome than those who delayed surgery (26). Similar results were observed in patients who were considered to have a prodromal stage of idiopathic normal pressure hydrocephalus, and an early intervention in these patients maintained good cognitive and mobility function and social participation ability in the long term (53).

Secondary normal pressure hydrocephalus has a higher rate of beneficial effect from an operation than idiopathic normal pressure hydrocephalus. Prominent gait impairment preceding cognitive impairment or as an isolated symptom is considered to be a good prognostic sign (31). The presence of widespread white matter lesions may reduce the degree of the gait improvement (21).

Best reversibility of dementia has been reported in patients whose verbal memory immediate recall impairment was less than one standard deviation from controls and who had relatively preserved frontal executive and visuospatial functions (105). Another study identified improvement in the Rey Auditory Verbal Learning Test-L after the lumbar CSF drainage as a predictor of cognitive improvement after shunting surgery (75). However, lower ventricular CSF Aβ42 and higher lumbar CSF tau levels did not predict the cognitive outcome after surgery even though these patients had biopsy proven accumulation of Aβ tau proteins (75).

Significant improvement of cognitive function was also seen in patients who had a higher mean value of intracranial pressure before the shunt surgery (33). However, patients who are traditionally considered poor candidates for shunting surgery, such as those with a longer history of dementia, cortical atrophy, and urinary incontinence, may also benefit from shunting and improvement of cognitive status; gait and sphincter incontinence is not uncommon (34; 89). Patients presenting with cognitive decline have a higher risk of developing Alzheimer disease or multiinfarct dementia, and the cognitive outcome of shunting of these patients is relatively poor (59). Definite gait improvement was present in 75% of shunted patients 3 to 6 months after the operation, but it was sustained in only one third of patients at 3 years; the 3-year benefit for cognitive improvement was noted only in one of eight patients, and for urinary continence, in one of six patients (58). Analysis of gait may be also helpful to identify patients with good outcomes and the improvement of speed, stride length, performance-oriented mobility assessment, Berg Balance Scale, and timed up and go times after a high-volume lumbar puncture were associated with good outcome after surgery (35; 85).

Decreased ventricular size does not predict a favorable outcome of shunting, and patients with no significant change of the ventricular size tend to have more significant clinical improvement than those with a significant reduction of the ventriculomegaly (78). Three-day external CSF drainage does not noticeably change the ventricular size in spite of observed clinical improvement (65). Patients without clinical improvement and persisting ventriculomegaly in spite of patent shunt and low intracranial pressure are considered to have shunt-nonresponsive hydrocephalus. Dramatic improvement after reduction of the ventricular size by external cerebrospinal fluid drainage with negative pressure (shunt siphoning) has been reported in four patients with shunt-nonresponsive hydrocephalus (12). Volumetric analysis of the caudate, thalamus, putamen, pallidum, hippocampus, and nucleus accumbens demonstrated significant reduction in patients with normal pressure hydrocephalus compared to controls. In the normal pressure hydrocephalus group, smaller caudate and nucleus accumbens volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms whereas reduced volume of the pallidum was associated with better performance on the Mini-Mental State Examination and reduced apathy (86). Analysis of morphometric changes after shunting showed that patients with good response had expansion of brain convexity subarachnoid space (117). Overall, volumetric analysis with fine segmentation could reliably differentiate CSF drainage responders from other normal pressure hydrocephalus-like patients, and it could accurately predict the neurologic outcomes after shunting (116).

Complications of CSF-diverting operations are the main concern. Vanneste and colleagues reviewed results from several hospitals and found the total incidence of complications to reach 30%, but only 5% were serious with long-term sequelae (112). The ratio of substantial benefit to serious harm was approximately three to one, and the strictness of shunt indication did not significantly alter this ratio (112). Subdural hematomas, intracranial infections, stroke, and shunt failure were among the most common complications. Ventriculoatrial shunts may cause cardiac tamponade or pulmonary embolism, and ventriculoperitoneal shunt may cause ascites or injury to abdominal organs. Prophylactic therapy with aspirin increases the risk of subdural hematoma (13).

The majority of untreated cases, or those with a failed shunt, progress with deterioration of dementia, development of akinetic state, and urine and stool incontinence (107). Progression can be fast, and the follow-up of surgical candidates for shunting showed a significant progression even within a 3-month period, further supporting a timely surgery when indicated (06). Patients are at risk for fractures and other injuries, including subdural hematoma, from falls. Immobilization can be complicated by pneumonia, pulmonary embolism, decubiti, urinary tract infections, and sepsis.

Special considerations

Pregnancy

No information is available, as normal pressure hydrocephalus is rare in patients under 65 years of age.

Anesthesia

Two commonly used anesthetics can influence absorption of CSF and level of intracranial pressure. This must be considered in the interpretation of intracranial pressure monitoring and measurements of resistance to outflow of CSF ROUT. Fentanyl decreases resistance to reabsorption of CSF and halothane increases resistance to reabsorption of CSF and secondarily increases intracranial pressure, especially after prolonged use of anesthesia (08).