Normal Pressure Hydrocephalus Treatment by Acetazolamide
Status:
Terminated
Trial end date:
2017-01-01
Target enrollment:
Participant gender:
Summary
Normal pressure hydrocephalus (NPH) is an uncommon cause of dementia possibly reversible with
treatment. First described in 1965 it consists of a triad of gait disturbance, cognitive
deterioration, and urinary incontinence together with enlarged cerebral ventricles and normal
cerebrospinal fluid (CSF) pressure. Foregoing trauma and hemorrhage, infection, mass lesions,
or aqueductal stenosis can contribute to hydrocephalus. These symptomatic or secondary forms
of NPH are not considered here and the focus lies on the idiopathic type (iNPH). Prevalence
of iNPH increases significantly with age. General estimates range from 21.9 per 100,000 in
total population surveys but increase up to 181.7 per 100,000 for people 70 to 79 years of
age. The clinical presentation varies significantly in severity and progression of symptoms.
For diagnosis the entire triad does not have to be present. In typical cases gait and balance
disturbances appear either before or concurrently with urinary incontinence or the onset of
dementia. Current treatment recommendations are based on surgical diversion of CSF , with
shunts placed either into the ventricular system or the lumbar subarachnoid space to a distal
site, such as the peritoneal or the pleural cavity or the venous system, where the CSF can be
reabsorbed . Even though immediate response rate to shunt treatment might be favorable and
rates of 80% responders have been reported , the perioperative and long-term morbidity and
mortality of CSF shunting procedures are significant. A meta-analysis of 44 articles found
that the pooled, mean rate of shunt complication was 38% . Even though acute surgical
complication rates are low, shunt dysfunctions and long-term complications are relatively
common. Shunt malfunction (20%), subdural hematoma (2-17%), seizure (3-11%), shunt infection
(3-6%) and intracerebral hematoma (3%) are the most common complications . In those with good
long-term survival, sustained improvement is possible, with a rate of 39% documented after 5
years .In view of the complication rates, the lack of alternative treatment options and
clinical studies is surprising. Even though iNPH per definition lacks raised intracranial
pressure on spinal tap, monitoring of ICP prior to surgery reveals an increased amount of
brief (usually 30 seconds to 1 minute) increases in the static ICP, called Lundberg B waves,
in patients which improve by shunt placements . When patients are scheduled for shunt
treatment there is a waiting period of several weeks between diagnosis and operation due to
congested waiting list.
Acetazolamide (Diamox) has been shown to reduce the production of CSF in clinical cases of
raised intracranial pressure . It is considered the drug of choice for the treatment of
idiopathic intracranial pressure (pseudotumor cerebri). Intuitively a connection between
Acetazolamide as a treatment option in iNPH seems logical. Encouraging case studies have been
published previously showing a fascinating improvement and success of treating iNPH with
Acetazolamide. A systematic placebo controlled study concerning the use of Acetazolamide in
iNPH is missing and would possibly pave the way to an alternative treatment option avoiding
surgery and its complications.