Volumetrics and Proteomics in Shunted Normal Pressure Hydrocephalus

BACKGROUND & SUMMARY DESCRIPTION OF THE PROJECT

Idiopathic normal pressure hydrocephalus (=iNPH) is a condition with disturbed cerebral dynamics causing symptoms in the form of balance and gait disorders, incontinence and cognitive impairment in patients with cerebral ventricular dilation. The condition is much more common than is generally known with a prevalence that increases sharply with age, from 2.1% in the age of 70 to 8.9% in ages over 80 years. Adams and Hakim described the disease as early as 1965 based on symptomatology and reversibility of symptoms after CSF tapping. However, it was not until 2005 that a compilation of evidence-based guidelines for the diagnosis and treatment of the disease came out, the iNPH International Guidelines. It was stated that at present, in addition to the CSF tap-test there is no reliable predictive test for a patient's likelihood to respond to shunting . There are several different scales for assessing the severity of the disease, one of which is the iNPH scale, with the subscales of gait, balance, neuropsychology and continence.

At the Department of Neurosurgery (NK) and Neurological (NL), Linköping University Hospital, there has been a well-functioning multi-professional team since 2004. The team investigates and treats iNPH with referrals coming from the Southeastern healthcare region of Sweden. Annually approximately 250 referrals are received, 70-80 patients are evaluated and at least 40 patients are operated with ventriculoperitoneal shunting. The evaluation consists in the first stage of radiological examinations, a clinical assessment by a neurologist, followed by motor assessment by a physiotherapist and cognitive assessment by an occupational therapist. CSF tap-tests are usually performed in which up to 50 ml of cerebrospinal fluid is drained by lumbar puncture, which in iNPH usually relieves the symptoms. Assessment also includes video recording of the movement pattern of a qualitative assessment. The results, together with the radiology, are weighed together and then the team if the patient should be offered treatment. The patients are operated with ventriculoperitoneal shunting at NK and followed up at NL with the same motor and cognitive tests three months after the operation, after which the results are evaluated. In larger studies, approximately 70 % of iNPH-patients receiving a shunt improve postoperatively.

Shunt therapy is the only treatment of iNPH and has been available since the 1950s. The goal of treatment is to reduce the amount of cerebrospinal fluid in the ventricular system and thereby normalize the volume in the ventricular system. Since the early 1990s adjustable shunt valves are increasingly used. This means that the valve if necessary can be adjusted after implantation with an external magnet applied to the site of the valve. The disadvantage of most adjustable valves is that the valve setting can be adjusted inadvertently when exposed to strong magnetic fields, for example if the patient undergoes a magnetic camera examination. Adjustable valves, however, bring many advantages as the resistance can be adapted to the patient's needs even after the operation. For example, one of the most common complications after shunting (subdural hematoma) can often be treated by raising the valve resistance. In 2015 the company Codman Johnson & Johnson introduced a novel shunt valve, Certas Plus, which is an adjustable shunt with eight different settings. The valve is established in clinical practice. Special features are the highest setting (8) which is 40 cm H20, which is a very high resistance which in theory should be equivalent to a turned off shunt and is called by the company "virtual off". It is also designed to be MR-resistant and thus does not change setting when exposed to a MRI magnetic field. These features have so far been tested in vitro but no clinical studies have yet been performed. The advantages of these functions are potentially fewer surgical procedures and inpatient care and also enables patients in the Southeastern healthcare region to carry out planned and acute MRI examinations in their home hospital without having to go to the Neurosurgical department in Linköping for valve readjustment.

Ventricular dilatation is a radiological diagnosis. Since the 1940s, the largest diameter between the lateral boundaries of the lateral ventricles and the largest biparietal diameter on the inside of the skull have been measured to obtain the so-called Evans index by dividing the two and obtaining the ratio. It is easy to measure but is a method with many sources of error and poor sensitivity to volume changes in the ventricular system. There is a need for a more reliable method in both clinical practice and research. Volumetry, i e measuring the volume of the ventricles, has become an increasingly used method which, however, has not yet taken place in clinical practice due to time-consuming manual calculation. With MRI images that are converted in a special software (ITK-SNAP), the volume may be calculated and a three-dimensional image of the ventricular system can be plotted. A few studies in the literature have studied the relationship between shunt valves resistance and reduction in ventricular volume. There are no prospective blinded studies studying the change in ventricular volume related to shunt therapy, shunt resistance, nor are there any studies on whether there is a correlation between ventricular volume reduction and postoperative clinical outcome. A study group in Uppsala has recently published a study on shunted iNPH-patients where a novel MRI-technology developed in Linköping (SyntheticMR) clearly can show how ventricular volume decreases after treatment without changing Evans' index. In the same study, it was also possible to show how another parameter in the ventricles, the so-called callosal angle, clearly changes after shunting. This is part of a radiological assessment scale, Radscale, which can be applied to this patient group. The same research group has previously also been able to show with SyntheticMR how the ventricular volume decreases after tap tests on iNPH patients to be restored to the original within 24 hours. CMIV (=Center for Medical Imaging and Visualization) at US Linköping has several of the University Hospital's 3-Tesla MR cameras and a good technological and scientific knowledge of SyntheticMR as the method is developed there. Using a short MRI protocol (6 minutes), it produces quantitative data of the condition of the brain tissue, which makes it easy to ascertain what is gray and white brain matter, the brain cells' support protein myelin as well as cerebrospinal fluid and calculates the volume of each component. Sequences with standard protocols for hydrocephalus, including DTI (=Diffusion Tensor Imaging) sequences, require an additional 15-20 minutes in the MRI camera. SyntheticMR can also as the hitherto only method easily calculate the volume of CSF that is located outside of the ventricles in the basal cisterns and brain sulci. However, no one has so far studied the volumes of extracerebral CSF in the healthy brain or in iNPH. In addition, no one has studied how this volume extracerebral CSF changes in response to shunting.