A Controlled Comparison of Two DBS Targets for Upper Extremity Action Tremor
Condition: Action Tremor
MeSH terms: Tremor
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Deep Brain Stimulation
Intervention type(s): Device
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized allocation of half the patients to be stimulated the first 3 months in the VIM-nucleus of the thalamus (VIM) and then 3 months in the posterior subthalamic area (PSA), and for the other half the first 3 months in the PSA and the next 3 months in the VIM
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Treatment; Deep Brain Stimulation; VIM Nucleus of the Thalamus; Posterior Subthalamic Area; Zona Incerta; Efficacy; Safety