Multicentre RCT of Awake Versus Asleep Tractography Based DBS for ET

INTRODUCTION AND RATIONALE

Essential tremor Essential tremor is the most common neurological movement disorder and often begins at an early age. In 20 to 30 years, the disorder develops to an advanced stage, in which patients are severely disabled by the tremor (trembling, shaking) of their hands in particular (and additional shaking of the head, legs and vocal cords may occur). In most severe cases, drug treatment only partially suppresses the tremor, and also loses effect over time. As a result, patients can no longer use their hands properly, for example, when eating and carrying out their activities of daily living. Patients become care-dependent. In addition, the involuntary tremor is socially disruptive and prevents patients from showing up in public places; they become socially isolated.

Because the tremor increases gradually in severity (over decades), patients and their immediate environment adapt their lives accordingly. For example, they drink with a straw, eat foods that are easy to scoop up and avoid social occasions because the trembling is perceived as disturbing. Often the possibility of treatment with DBS could have been considered years earlier, however this possibility is unknown to both patient and caregiver, or the DBS is seen as experimental.

Thalamic DBS is an effective surgical treatment for patients with disabling essential tremor who have severe limitations in their functioning despite pharmacological treatment. During the surgical placement of DBS brain electrodes, patients are awake so that the effect of the electrode implantation can be monitored. Awake DBS surgery is extremely burdensome and therefore prevents many patients from undergoing the treatment. To increase accessibility to DBS, we want to perform the surgery asleep.

Functional stereotactic neurosurgery Currently the standard DBS procedure is performed awake. Patients need to be awake during the surgery as the optimal placement of the stimulation electrodes into the brain is confirmed by intra-operative clinical testing. This procedure is extremely burdensome for patients: 1) cranial injections are needed for local anesthesia 2) a frame is fixed to their head with four bone-pins 3) they are secured to the operating table for the procedure 4) burr holes are drilled into their skull and 5) electrodes are implanted during which patients are hours continuously tested for DBS effect.

Due to advances in MRI tractography techniques (displaying connecting pathways between brain regions using magnetic resonance imaging) the target area for DBS can now be clearly visualized and therefore it may be possible to perform the entire procedure asleep without the need for intraoperative clinical testing. Several studies, including a recent randomized controlled DBS trial in Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS is safe. This trial also showed that Parkinson's patients experienced asleep DBS as less invasive, both psychologically and physically. Logically, asleep DBS also lowers the burden of surgery for essential tremor patients. This is expected to increase the accessibility for DBS. This would allow more people with essential tremor to be helped, as well as in an earlier stage of their disease; more patients will benefit for a longer time period from DBS. To determine whether asleep DBS for essential tremor suppresses tremor as well as awake DBS, a comparative study is warranted.

General anesthesia General anesthesia is routinely used in different types of surgery. In the Amsterdam UMC, all Parkinson's disease patients, patients with dystonia, obsessive-compulsive disorder, anorexia or epilepsia, where peri-operative testing is not necessary, the electrodes are placed asleep. The patients receiving electrode insertion under local anesthesia will receive general anesthesia to implant the pulse generator subcutaneously. The procedure is described in chapter 4- Treatment of subjects.

Asleep compared to awake thalamic DBS for essential tremor

Tremor suppression Since the 1980s, DBS for essential tremor was targeting the thalamus, a deep-seated grey matter brain nucleus. Current emphasis in the field of DBS is on neural networks rather than separate nuclei in the brain. Several studies showed essential tremor to arise from pathological network activity in cerebellar-cortical projections. In recent years the MRI techniques for visualisation of brain networks became widely available in DBS software modules. The 3-Tesla MRI diffusion deterministic tractography is a powerful tool to visualise structural connections between brain nuclei and different cortical areas. In recent years several DBS groups reported about using tractography to visualize the cerebellar-cortical projections, or dentato-rubro-thalamic-tract (DRT), in DBS for essential tremor. By visualizing the DRT, a direct target for DBS electrode placement was generated. In the Amsterdam UMC, we have been evaluating DRT for DBS in essential tremor from 2017. Since then, we published two major studies evaluating DRT based DBS in essential tremor. First, we studied the optimization of deterministic DRT tractography by applying a standardized technique for constructing the tract and using a newly developed MRI sequence; the fast grey matter acquisition T1 inversion recovery (FGATIR). This enabled us to construct an approximation of the DRT that strongly correlated with optimal tremor control for DBS. In the following prospective clinical study we implemented this DRT technique for all our DBS cases in essential tremor. We showed that during intraoperative testing the pre-determined trajectory based on DRT depiction showed complete tremor suppression in all cases. Intraoperative testing confirmed the optimal location for tremor suppression was accurately indicated by the (preoperative generated) DRT. These two studies show DRT based DBS provides a direct target area for DBS in essential tremor and possibly omits the need for intraoperative, awake, testing.

Adverse effects Several studies, including a recent randomized controlled DBS trial in Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS is safe. This trial also showed that people experience asleep DBS less invasive, both psychologically and physically.6 Multiple studies report on dysarthria and gait ataxia after thalamic/DRT DBS in essential tremor. When dysarthria occurs during awake test stimulation, it is usually not possible to differentiate between effects of intraoperative testing and edema due to electrode introduction. Moreover, in a third of patients stimulation-induced dysarthria during follow up was not preceded by dysarthria during test stimulation, indicating that this is not a reliable predictor for chronic effects. Gait ataxia cannot be tested during surgery, and usually occurs gradually during follow up, both with or without pre-existing balance difficulties. This shows awake intraoperative testing cannot be used to prevent these side effects from occurring during follow up. Another known side effect can be induced by co-stimulation of the corticospinal fibres, which are located (passing) near the thalamus. In our recent essential tremor studies we have shown that tractography can also be used to visualize the corticospinal fibres, ensuring sufficient distance to the DBS electrode trajectory for preventing co-stimulation (which would result in involuntary muscle contractions).

In sum, due to advancing insights in essential tremor pathophysiology and MRI tractography techniques, it is now possible to directly visualize part of the brain tremor network involved in the occurrence of tremor, the dentato-rubro-thalamic-tract. In awake DBS, this tract provided a direct target and showed high correlation with optimal tremor control, with a comparable side effect profile. DBS surgery could therefore now be performed asleep. To our knowledge, no randomized controlled trial has been done to compare the outcome between awake and asleep tractography guided DBS in essential tremor.