Normal Pressure Hydrocephalus (NPH)

Lawrence S. Honig
Normal pressure hydrocephalus (NPH) is a potentially reversible cause of dementia,
which is often amenable to surgical therapy. NPH is a progressive subacute or
chronic disorder with a triad of clinical manifestations: cognitive impairment, gait
change, and urinary incontinence. The syndrome was recognized by Adams, Hakim
and colleagues in 1965, and they described the benefit accrued by shunting CSF to
enhance absorption in some patients. However, ventricular enlargement is common
in a variety of dementing disorders, and because urinary and gait abnormalities are
also common in the elderly, the diagnosis of hydrocephalus in the elderly is often
challenging. It is also controversial because, without careful selection criteria,
reversal of dementia by surgery is more often a hope than an accomplished feat.
NPH is a communicating hydrocephalus without evident obstruction of the normal
pathway of CSF flow. Nonetheless, communicating chronic hydrocephalus
commonly involves either decreased flow of CSF through the aqueduct or relatively
inadequate CSF resorption (which can be considered obstructive). Impaired CSF
resorption in chronic hydrocephalus usually occurs at the arachnoid granulations
over the convexity, where CSF resorption normally occurs. NPH is often idiopathic
and may relate simply to an abnormal brain aging process, while in some cases it
may follow subarachnoid hemorrhage from trauma or aneurysm, meningitis, tumor,
or surgery. Irrespective of the underlying etiology, the ventricles expand at the
expense of brain volume, causing both brain compression and periventricular white
matter changes. These changes are thought to arise from brain edema caused by
transependymal flow of fluid, or to ischemic demyelination caused by compression of
brain tissue. There may also be neuronal dysfunction from the compression.
However, the overall effect is sufficiently chronic, or compensated, so that the CSF
pressure is normal.

CLINICAL SYNDROME
Gait change is usually the first symptom, as well as the most frequent symptom, of
NPH. This change may be subacute, fluctuating, or more chronic, but most often
worsens over weeks or months, or at the most several years. The gait disturbance is
often inconsistent and variable but has parkinsonian features, with shuffling,
shortened stride length, imbalance, and often initial slowness. Frequently, the gait is
wide-based (not commonly a feature of Parkinson disease), often with external
rotation of the legs. The gait is classically described as magnetic, with inability to lift
the feet off the floor. It is also described as a gait apraxia, since it appears that
motor program involved in starting to move the legs is impaired, without evident
impairment of strength. In addition to difficulty with the initiation of gait, there may

also be difficulty maintaining gait, and there may be freezing,with problems

reinitiating movement. Tremor is uncommon, but falls are common.
Urinary symptoms are also frequent in NPH, although they usually are not the first
symptom, and may go unrecognized, consisting only of urinary urgency or frequency.
Urinary incontinence itself is common, presumably due to loss of descending control
mechanisms, with consequent unsuppressed bladder contractions, together with
decreased voluntary ability to control the bladder outlet. A characteristic feature is
said to be incontinence sans gne in which there is little evident concern regarding
the incontinence.
Impaired cognition, ranging from subtle to severe, occurs in NPH, usually following
after the onset of gait and urinary dysfunction. The characteristics of dementia
associated with hydrocephalus include subcortical features. Symptoms may include
not only forgetfulness, but slowness in mental processing, inertia, apathy, and
impaired executive function, including decisionmaking and task-switching. Memory
impairment in hydrocephalus may differ from that seen in cortical dementias such as
Alzheimer disease (AD). As in AD, there may be preservation of long-term
knowledge, although the memory deficits may more clearly involve poor learning.
Impairment in delayed recall of learned material may relate to deficits in learning but
may also involve initiation and speed of retrieval. For example, with simple cues,
recall may be much better than free recall, indicating a dominant deficit in retrieval,
rather than defective encoding of learned material. Advanced hydrocephalus may
result in severe slowing of mentation, and an akinetic mute state.
The triad of gait disorder, incontinence, and dementia may be caused by brain
disorders other than hydrocephalus, including subcortical arteriosclerotic
encephalopathy (Binswanger disease). Furthermore, elderly individuals may suffer
from multiple neurologic conditions including a primary degenerative dementia such
as AD (which itself can be associated with incontinence), with superimposed effects
of multiple brain infarcts, spinal cord compression, or lumbar polyradicular disease.
Nonneurologic causes of incontinence due to urologic dysfunction at the level of the
prostate in men or bladder neck in women are also common.

EVALUATION OF HYDROCEPHALUS
The first test to be performed in suspected hydrocephalus is CT or MRI. While CT
can essentially exclude hydrocephalus, MRI is required for accurate assessment.
The characteristic feature of hydrocephalus is ventricular enlargement out of
proportion to sulcal enlargement. In general, brain atrophy due to degenerative
disease or aging involves both central (ventricular) and peripheral (sulcal) spaces.
But judging whether the ventricular enlargement is disproportionate can be difficult,
and is often fraught with interobserver disagreement. Thus, auxiliary features can be
useful in assessing the likelihood of hydrocephalus. Abnormal periventricular white
matter, with low attenuation by CT or increased T2-weighted or FLAIR signal by MRI,
suggests transependymal fluid flow, consistent with hydrocephalus, but

periventricular white matter signal change is nonspecific and may arise from
microvascular ischemic
P.357
disease. Other allied structural changes suggesting hydrocephalus may include
ballooning of the frontal horns of the ventricles, markedly dilated temporal horns,
and bowing and thinning of the corpus callosum. Rapid longitudinal change can be
diagnostically useful, but multiple CT or MRI studies over several years may not be
available. There are no laboratory tests of blood or CSF that are informative
regarding hydrocephalus.
Confirmatory tests are often sought in hydrocephalus because of these uncertainties
in clinical diagnosis and neuroimaging. The additional tests may be useful for
diagnosis and to determine the likelihood of response to CSF shunting. Tests include
the tap test (a single large volume removal of CSF), repeated taps, or a trial of
continuous external CSF drainage. The best tolerated test is the tap test in which 25
to 40 cc of CSF are removed through lumbar puncture, with recording of opening
and closing pressures, and subjective and objective observation of gait
postprocedure. Objective measurement is best made by videotaped recording of the
patient prior to the procedure and at intervals of hours and days after the tap. Gait
typically improves during the hours after the tap, with gradual loss of benefit over the
next days to week. Cognition or urination may also improve, although this is usually
less evident, and more difficult to assess objectively. Lack of benefit from the tap
points to likely lack of likelihood of benefit from CSF shunting. The opening pressure
on lumbar puncture in normal pressure hydrocephalus may be in the upper range of
normal (14-20 cm H2O), and such relatively higher normal pressures may also be
indicative of a greater likelihood of benefit from CSF shunting. Other tests are more
invasive, including multiple lumbar punctures over 3 to 5 days, or insertion of a
continuous lumbar CSF drain for 3 to 5 days, with serial videotape recordings and
sometimes serial neuropsychologic testing. Radionuclide cisternogram to assess
CSF flow does not appear to be prognostically useful.

TREATMENT
Treatment for NPH is neurosurgical and involves shunting CSF from the ventricle to
either the peritoneum or atrium, thereby relieving the compressive symptoms.
Ventriculoperitoneal shunts involve a tube that is usually placed in the right lateral
ventricle and connected via a valve under the scalp to subcutaneous tubing,
terminating in the peritoneum. Overall, shunting is well tolerated although
overshunting may occur, with headache, orthostatic symptoms, or development of
subdural hematoma or hygroma. Present standards of care include use of
programmable valves that allow adjustment of flow (through alterations in the setting
for the pressure required to trigger CSF drainage through the shunt tube), without
shunt revision. Shunt infections are rare but require removal of inserted hardware.

Shunting is most likely to be effective in those patients whose symptoms initially

involved only gait, and in those with milder cognitive dysfunction. It may also be
more effective in those with a history of meningitis, subarachnoid hemorrhage, or
other identifiable secondary cause of hydrocephalus. It is more likely to be effective
in patients with positive spinal tap test, and persons whose measured ICP is higher.
Patients with more severe dementia, more evident marked sulcal atrophy, or those
whose first symptom is dementia, with subsequent gait and urinary involvement, are
less likely to respond favorably to CSF shunting. This may relate to irreversibility of
symptoms, or may relate to a greater likelihood of underlying AD.

SUGGESTED READING
Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with normal cerebrospinal
fluid pressure: a treatable syndrome. N Engl J Med. 1965;273:117-126.
Chang S, Agarwal S, Williams MA, et al. Demographic factors influence cognitive recovery after shunt
for normal-pressure hydrocephalus. Neurologist. 2006;12:39-42.
Devito EE, Pickard JD, Salmond CH, et al. The neuropsychology of normal pressure hydrocephalus
(NPH). Br J Neurosurg. 2005;19:217-224.
Gallia GL, Rigamonti D, Williams MA. The diagnosis and treatment of idiopathic normal pressure
hydrocephalus. Nat Clin Pract Neurol. 2006;2: 375-381.
Graff-Radford NR. Normal pressure hydrocephalus. Neurol Clin. 2007;25: 809-832.
Jack CR, Mokri B, Laws ER, et al. MR findings in normal-pressure hydrocephalus: significance and
comparison with other forms of dementia. J Comput Assist Tomogr. 1987;11:923-931.
Klinge P, Marmarou A, Bergsneider M, et al. Outcome of shunting in idiopathic normal-pressure
hydrocephalus and the value of outcome assessment in shunted patients. Neurosurgery.
2005;57(suppl 3):S40-S52.

NORMAL PRESSURE HYDROCEPHALUS

The gait disorder in normal pressure hydrocephalus (see Chapter 54) resembles that
of parkinsonism, with shuffling short steps and loss of postural reflexes and
sometimes freezing. Features of urinary incontinence and dementia occur later.
Tremor is rare. The grossly enlarged ventricles lead to the correct diagnosis, with the
symptoms often improving on removal or shunting of CSF. The gait disorder is in
striking contrast to the lack of parkinsonism in the upper part of the body. The major
differential diagnoses for lower body parkinsonism include vascular parkinsonism
and the idiopathic gait disorder of the elderly.

DRUG-INDUCED PARKINSONISM
Drugs that block striatal dopamine D2 receptors (e.g., phenothiazines,
butyrophenones, thioxanthenes, and other centrally acting dopamine receptor
blockers) or deplete striatal dopamine (e.g., reserpine, tetrabenazine) can induce a
parkinsonian state. This condition is reversible when the offending agent is
withdrawn, but it may require several weeks. Parkinsonism that persists longer than
6 months is attributed to underlying PD that becomes evident during exposure to
these antidopaminergic drugs. Anticholinergic drugs can ameliorate the parkinsonian
signs and symptoms. The atypical antipsychotic agents, clonazapine and quetiapine,
are the antipsychotics least likely to induce or worsen parkinsonism.

POSTENCEPHALITIC PARKINSONISM
Although rarely encountered today, postencephalitic parkinsonism was common in
the first half of the 20th century. Parkinsonism was the most prominent sequel of the
pandemics of encephalitis lethargica (von Economo encephalitis) that occurred
between 1919 and 1926. Although the causative agent was never established, it
affected mainly the midbrain, thus destroying the substantia nigra. The pathology is
distinctive because of the presence of NFTs in the remaining nigral neurons and
absence of Lewy bodies. In addition to slowly progressive parkinsonism, with
features similar to those of PD, oculogyric crises often occur in which the eyes
deviate to a fixed position for minutes to hours. Dystonia, tics, behavioral disorders,
and ocular palsies may be present. Patients with postencephalitic parkinsonism are
more sensitive to levodopa, with limited tolerance because of the development of
dyskinesias, mania, or hypersexuality at low dosages. Anticholinergics are tolerated
well, however, and are also effective against oculogyria.

1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-INDUCED
PARKINSONISM
Although rare, this disorder is important because this toxin selectively destroys the
dopamine nigrostriatal neurons, and the mechanism has been investigated
intensively for possible clues to the etiology and pathogenesis of PD. 1-Methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a protoxin, being converted to MPP + by
the action of the enzyme monoamine oxidase type B. MPP + is taken up selectively
by dopamine neurons and terminals via the dopamine transporter system. MPP +
inhibits complex I in the mitochondria, depletes ATP, and increases the content of

superoxide ion radicals. Superoxide in turn can react with nitric oxide to form the
oxyradical peroxynitrite. MPTP-induced parkinsonism has occurred in drug abusers
who used it intravenously and possibly also in some laboratory workers exposed to
the toxin. The clinical syndrome is indistinguishable from PD and responds to
levodopa. PET indicates that a subclinical exposure to MPTP results in a reduction of
fluorodopa uptake in the striatum, thereby making the person liable to future
development of parkinsonism.

VASCULAR PARKINSONISM
Vascular parkinsonism resulting from lacunar disease is not common but can be
diagnosed by neuroimaging, with MRI evidence of hyperintense T2-weighted signals
compatible with small infarcts. Hypertension is usually required for the development
of this disorder. The onset of symptoms, usually with a gait disorder, is insidious, and
the course is progressive. A history of a major stroke preceding the onset of
parkinsonism is rare, although a stepwise course is sometimes seen. Gait is
profoundly affected (lower body parkinsonism) with freezing and loss of postural
reflexes. Tremor is rare. Response to the typical antiparkinsonian agents is poor.