A Controlled Comparison of Two DBS Targets for Upper Extremity Action Tremor
A Controlled Comparison of Two DBS Targets for Upper Extremity Action Tremor
Action tremor of the arms can be an invalidizing symptom of diseases such as Essential
 Tremor, Dystonic Tremor, Parkinson's disease and Multiple Sclerosis. In this study we compare
 the efficacy and safety of two different brain targets for deep brain stimulation (DBS) that
 both are known to reduce action tremor of the arms. These two targets are called the VIM
 nucleus of the thalamus (VIM) and the posterior subthalamic area (PSA), which includes the
 Zona Incerta. Both targets can be reached by one lead (wirh four electrode contact).

 Patients that are found eligible for DBS because of severe action tremor of the arms are
 invited to participate. After randomization, half of them are stimulated first in the VIM for
 3 months and then in the PSA for 3 months, and the other half first in the PSA and then VIM
 for 3 months each. Tremor severity is scored on a clinical quantitative scale at baseline and
 at the end of each of these two 3-month periods, and eventual side-effects are registered.
 The best target is then selected and after another 6 months scoring is repeated. We intend to
 provide robust data about whether one of the two targets is superior to the other both
 regarding ability to reduce tremor efficiently and to avoid or minimize side-effects, or if
 there is no significant difference between the two targets. We also carefully check the exact
 position of the active electrode contact in the brain and compare this with efficacy and
 safety evaluations. Long-term follow-up is planned after 3, 5, 7 and 10 years.
Tremor is defined as rhythmic and oscillating involuntary movements of a body part. Action
 tremor occurs when a body part is activated, and is clinically most frequently seen in
 Essential (idiopathic) Tremor (ET), with an overall prevalence of 0.9 %, and of 4.6 % in
 people over 65 years. But it can also be the most disabling symptom in many other
 neurological diseases such as dystonia, multiple sclerosis (MS), advanced Parkinson's disease
 (PD), and some spino-cerebellar ataxias/hereditary disorders with dysfunction of cerebellar
 connections. The cerebello-thalamo-cortical pathway is probably involved in all tremors. The
 exact mechanisms that disrupt these pathways and produce tremor remain, however, largely
 unknown. The cerebello-thalamic tract originates from the cerebellar nuclei (dentate,
 emboliform and globose), ascends and crosses in the pons and enters the red nucleus (RN) in
 the mesencephalon. Most fibers project further to the ventral thalamic nuclei - oralis (VO)
 and intermedius (VIM). The posterior subthalamic area (PSA) is the region inferior to VO and
 VIM, dorsal and posterior to the subthalmic nucleus (STN) , and lateral to RN. Its principal
 components are the nucleus called Zona Incerta (ZI) and the fiber bundle called the
 prelemniscal radiation (RaPrl). Whereas STN and RN are visible on standard T2-weighted
 MRI-scans, PSA is only indirectly defined by these surrounding structures. Classification and
 differential diagnosis of action tremor disorders can be difficult, since with rare
 exceptions there are no confirmative diagnostic tests or biomarkers for the primary tremor
 forms. Differential diagnosis of primary action tremor forms such as ET, Dystonic tremor (DT)
 and Cerebellar tremor (CbT), therefore relies mainly on clinical examination and the
 exclusion of underlying diseases causing secondary action tremors (such as PD and MS). Action
 tremor is divided into postural (when a position is maintained), or kinetic (when a movement
 is made). Other neurological findings (dystonia, cerebellar, pyramidal, parkinsonian,
 neuropathic signs), and systemic signs must be assessed. Supplementary diagnostic workup
 includes MRI in all cases to show/exclude tremor-causing lesions such as infarcts, MS plaques
 or other inflammatory diseases, cerebellar atrophy, or atrophy or pathological signal changes
 along the cerebello-thalamo-cortical circuits, including the basal ganglia. DAT-scan
 (131I-FP-CIT SPECT) of the DopAmine Transporter (DAT) shows reduced binding in the striatum
 in PD and other degenerative parkinsonian disorders, but not in ET, DT or CbT. It is
 performed in all patients who have rest tremor or other parkinsonian signs. Necessary
 laboratory tests of blood (+/- CSF and urine) are also performed. Medical treatment available
 for primary (and most secondary) action tremor disorders are only symptomatic. The two most
 commonly used drugs for ET, the non-selective beta-blocker propranolol and the anticonvulsant
 primidone both received a level A recommendation of efficacy by the American Academy of
 Neurology in 2005. This was based on mostly small and short-term studies (3-6 weeks), showing
 an average tremor reduction of about 50-60% in about 50% of patients. No controlled long-term
 studies have been done, but open-label studies indicate development of tolerance and reduced
 effect in 10-15%. Level B evidence of a probable effect has been given to other beta-blockers
 (atenolol, sotalol) and the antiepileptics alprazolam, topiramate and gabapentin. There have
 been no systematic studies for other tremors like dystonic or cerebellar tremors. Thus, for
 these patients no medications with established efficacy exist, except intramuscular botulinum
 toxin injections for dystonic head tremor.

 Deep brain stimulation (DBS) of the Nucleus Ventralis Intermedius of the thalamus (VIM) is
 still considered the target of choice for patients with disabling action tremor at most
 centers. Open-label, mostly short-term studies of VIM-DBS in ET have reported up to 80-90%
 reduction of action tremor, but long-term clinical experience and studies show that gradual
 loss of tremor control over months and years occurs in many patients. Masked raters were not
 used, except for one study. The problem termed "development of tolerance" to stimulation, is
 emphasized in recent reviews and clearly limits the functional long-term benefit of VIM-DBS.
 VIM-DBS also tends to be less effective on proximal tremor, which is often the most severe
 symptom. Because VIM cannot be clearly outlined on MRI or mapped using microelectrode
 recordings, targeting it employs the use of standard stereotaxic coordinates.The definition
 of these varies between centers. They are defined in relation to the inter-commissural line
 (ICL). Final placement of the electrode is decided after peroperative clinical testing of
 effect on tremor and side effects in the awake patient. Bilateral VIM-stimulation is
 associated with a relatively high rate of side effects. In a meta-analysis of 430 patients,
 19 % had paresthesias, 9 % dysarthria, 7 % headache and 6 % unsteadiness or gait
 difficulties. Therefore, many centers offer only unilateral stimulation to most patients even
 if they have bilateral tremor. The limitations of VIM-stimulation have led to a renewed
 interest in exploring the PSA as an alternative. Open label case series from several centers
 indicate better results from PSA-DBS than VIM-DBS, particularly in reducing kinetic tremor,
 including proximal arm tremor and intention tremor. The targeted area within the PSA varies
 among centers. Plaha et al reported results from blinded 1-year follow-up of bilateral
 stimulation of the caudal ZI in 5 patients with PD tremor, and 13 patients with action
 tremors from a range of diseases (ET, MS, CbT, DT, Holmes tremor). Average improvement of
 postural/action tremor was 88% and of rest tremor 95%. In the MS-patients, both severe
 proximal arm tremor, truncal ataxia and severe head-and-neck tremor improved. There was no
 significant decline of clinical efficacy or significant change in stimulation parameters
 during serial follow-ups, but some side-effects were seen in a few patients due to misplaced
 electrodes or edema. Blomstedt et al reported results of PSA-DBS in 21 patients with ET (most
 unilateral), achieving on average 95% tremor reduction and 87% functional improvement in the
 contralateral arm. Transient, mild expressive dysphasia was observed in eight patients. In
 summary, the most frequent side-effects reported in PSA-DBS series are paresthesias,
 dysarthria, dysequilibrium and blurred vision, and thus similar to those observed with
 VIM-DBS, but are consistently reported to be mild and transient in almost all patients. So
 far no controlled comparison of the efficacy and safety between stimulation of the two
 targets has been reported.With respect to the ICL, the targets for PSA used in the above
 studies were 10-14 mm lateral, 6-7.5 mm posterior to the midpoint of the ICL, and 2-4 mm
 inferior. Few authors have studied different targets in the same patients. Herzog et al
 compared stimulation with the upper electrode contacts the thalamic level, and with the lower
 contacts 1.5mm below the ICL in 21 patients with ET or MS-tremor. The results favoured the
 contacts below the ICL.

 To overcome the limitations of today´s standard method of treating severe action tremors with
 VIM-DBS, we are performing a double-blind, randomized, controlled and comparative study of
 VIM-DBS versus PSA-DBS in patients with disabling action tremor. We will implant one
 quadripolar electrode (each contact 1.5 mm, interspace 0.5 mm) so that it covers both targets
 on one side, unilaterally or bilaterally as indicated clinically. The efficacy of stimulating
 each target will be studied in individual patients and between patient groups in a cross-over
 design, in two consecutive randomized 3-month periods, by the use of validated tremor scores.
 Further continuous stimulation of the most effective target in each patient will be evaluated
 after another 6 months. This will provide unbiased efficacy-data about the two targets, both
 within each patient, and between patient groups. Stimulation efficacy will also be evaluated
 in relation to the exact target localization, defined by merging post-op helical CT scan
 (which shows the four electrode contacts), with pre-op MRI, including Diffusion Tensor
 Imaging/fiber tracking. Such high-resolution correlation data has to date only been published
 in a few action tremor patients world-wide, and will add important new data to aid DBS
 targeting in the future. Since little is known about whether cognitive functions are altered
 by the disease or the treatment, we will include neuropsychological testing before and after
 effective DBS treatment.

 Methods: i) Clinical evaluation and scoring. Before the patients are invited to participate,
 they have been thoroughly evaluated for correct diagnosis, including a complete clinical
 neurological examination, MRI of the head/brain (+/- spine/spinal cord), laboratory tests,
 etc. The inclusion examination ensures that inclusion criteria are fulfilled and that none of
 the exclusion criteria are met. The study examinations include clinical examination and
 scoring performed at baseline -end of 1. Random.per./3 mo. - end of 2. Random.per./6 mo.- 1
 year

 Performed at all study visits:

 -  The Fahn-Tolosa-Marin tremor scale contains 21 items scored 0-4, with 0 indicating no
 tremor/disability and 4 severe tremor (constant, high amplitude)/inability to perform a
 task due to tremor. Item 1-9 score tremor for face, tongue, voice, head, trunk and the
 four extremeties. For face only rest tremor is scored, for tongue, head and trunk rest
 and postural tremor, and for the extremities action/intention tremor is also scored.
 Items 10-13 test handwriting, and spiral drawing with right and left hand, and line
 drawing between defined points. Item 14 tests pouring of water from one plastic cup to
 the other, and Item 15-21 describe functional disability of speaking, feeding (not
 liquids), bringing liquids to mouth, hygiene, dressing, writing, working.

 -  Quality of life in Essential Tremor- scale (QUEST). A 30 item questionnaire developed
 specifically for tremor patients, evaluating quality of life, cognitive, and emotional
 aspects of the tremor.

 -  VAS of Global Disease Burden (patient evaluated). Visual analogue 0-10 centimeter
 continuous scale, on which the patient scores at which severity they assess the global
 tremor disease burden.

 -  The Hospital Anxiety and Depression Scale. A well-established and validated self-report
 questionnaire which contains 14 items expressing emotions, alternating between 7
 emotions of anxiety and 7 of depression. Scores for each item ranging from 0-3. Cut-off
 sum-scores exist for clinically significant symptoms of anxiety and depression,
 respectively.

 In addition,complete neurological exam. and neuropsychological testing is performed at
 baseline and at 1 year of DBS.

 ii) Operation. Preoperative axial MRI sequences (T2-weighted fast-spin-echo,
 diffusion-weighted spin-echo echo-planar imaging, and 3D inversion prepared T1-weighted
 gradient-echo) will be obtained on a 3 Tesla MRI-scanner the day before the operation. In
 local anaesthesia a CRW™ stereotactic frame, (Radionics, MA, USA) is mounted, placed
 parallell to the AC-PC line, before performing a stereotactic 3D CT scan. The MRI and CT
 scans are merged using the iPlan™ (version 3.0 or later) computer-aided neuronavigation
 system (BrainLAB, München, Germany), which is also used to plan the targets based on
 predefined stereotactic coordinates for VIM and PSA, refined according to relationship to the
 MRI-visible STN and RN. Trajectory angle will be chosen to cover VIM and to enter PSA
 slightly posterior and medial to STN, at the level of maximal diameter of RN. To ensure
 safety, trajectories are always planned to avoid vessels, sulci and ventricles.
 Microelectrode recordings (MER) will not be performed.

 Clinical test stimulation will be performed in the awake patient, at four 2 mm steps, from 8
 mm above the most caudal target in the PSA (Caudal Zona Incerta) using the permanent
 quadripolar electrode, and the placement accepted if good tremor suppression is confirmed and
 no unacceptable side effects observed. Electrode position is checked using perioperative
 radiography, and the electrodes fixed to the scull. After removal of the stereotactic frame,
 the electrodes are connected to a pulse generator implanted in the subclavicular or abdominal
 region.

 iii) Randomization periods/stimulation treatment. Half the patients are randomized to receive
 VIM-stimulation from 0-3 months after surgery and then switched to receive PSA-stimulation
 for the next 3 months, and the other half to receive PSA-stimulation the first three months
 and VIM-stimulation the next 3 months. During these two randomization periods the pulse width
 will be held constant at 60 microseconds and frequency 130 Hz, monopolar mode (bipolar mode
 only if monopolar leads to intolerable side effects). Current should not exceed 3 mA during
 the randomization periods. After scoring at the end of the last 3-month randomization period,
 the electrode contact yielding the best tremor reduction with no or only minor/possible side
 effects is chosen for further treatment. During follow-up to 1-yr post-op there may be 2
 additional visits for optimal adjustment of stimulation parameters. Randomization is
 performed through a web-based program provided by Faculty of Medicine, unit for Applied
 Clinical Research at the Norwegian University of Science and Technology, Trondheim.

 iv) Neuropsychological examinations. A standard set of well-known and validated
 neuropsychological tests will be performed pre-op and 1-yr post-op.
Inclusion Criteria:

 -  Min 5-yr duration chronic action tremor of upper limb(s), w/ or w/out tremor of
 head/neck, trunk, lower limbs, who have insufficient relief from adequate trials of
 recommended medications. The arm tremor must be so severe that it interferes with the
 patient's work performance or activities of daily living, such as drinking/eating,
 dressing/hygiene, and/or writing. Clinical diagnosis (according to criteria defined by
 the Consensus Statement of the Movement Disorders Society) include Essential Tremor,
 Dystonic Tremor, Cerebellar Tremor- idiopathic or secondary (to e.g.MS or SCA), or
 severe PD tremor (who are not eligible for DBS of the subthalamic nucleus).

 Exclusion Criteria:

 -  Brain MRI showing so marked general atrophy, or supra-tentorial white matter changes,
 that the safety of the procedure is affected. Co-morbidity of dementia or other severe
 neuropsychiatric disorder (major depression or anxiety disorder, active/recent
 psychosis, drug or other substance abuse). Increased risk of bleeding, cancer at
 advanced/not stabilized stage, other severe co-morbidity (e.g. With chronic pain,
 short life expectancy,). Other surgical contraindications.