Normal-pressure hydrocephalus

Diagnostic workup
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By Peter Hedera MD and Robert P Friedland MD

In general, the laboratory evaluation of normal-pressure hydrocephalus is difficult. 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 2 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 (Kim et al 2015). 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 (Tsunoda et al 2001). 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 (Friedland 1989). 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 (Yamashita et al 2014). 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) (Holodni et al 1998). Tight brain convexity with 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 (Hashimoto et al 2010; Virhammar et al 2014).

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 a sufficient sensitivity to differentiate normal-pressure hydrocephalus from brain pathology due to hypertension (Tullberg et al 2002). 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 (Tamaki et al 1990). 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 (Jack et al 1987). 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 (Bradley et al 1996). 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 (Dixon et al 2002; Kahlon et al 2007). Overall, MR imaging measurement of intracranial hydrodynamics and brain compliance are abnormal in normal-pressure hydrocephalus patients but cannot reliably predict shunting responders (Bateman and Loiselle 2007).

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 (Wikkelso et al 1986). 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 (Hertel et al 2003; Walter et al 2005). Temporary external lumbar drainage can provide more affirmative information and has a high positive predictive value for improvement after shunt surgery (Marmarou et al 2005a). 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 (Panayiotopoulos et al 2005). However, some authors have suggested that a high rate of false negative results occur using external lumbar drainage (Walchenbach et al 2002). 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 (Pfisterer et al 2007). 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 (Borgesen and Gjerris 1987). Abnormal cerebral compliance is also useful in differentiation of normal-pressure hydrocephalus from cerebral atrophy (Meier and Bartels 2002). 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) (Boon et al 1997). 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 (Meier and Miethke 2003); however, other studies replicated a high positive predictive value for a good outcome of abnormal R(out) in normal-pressure hydrocephalus patients (Sorterberg et al 2004).

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 (Vanneste et al 1992a). Some authors have even completely abandoned this test in the evaluation of normal-pressure hydrocephalus (Marmarou et al 2005b; McGirt et al 2005).

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 (Tanaka et al 1997). PET study has shown globally reduced glucose uptake. This differs from biparietal and bitemporal reduction commonly found in Alzheimer disease (Jagust et al 1985).

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 (Eide and Stanisic 2010; Tarnaris et al 2011). 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 (Jeppsson et al 2013). Similar results with reduced levels of amyloid precursor protein, total tau, and phosphorylated tau were observed in normal-pressure hydrocephalus patients when compared to Alzheimer disease patients (Miyajima et al 2013). 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 (Graff-Radford 2014).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited