Cognitive Investigation clinical trials

Normal Pressure Hydrocephalus Treatment by Acetazolamide

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.