Targeting thalamic tremor cells in deep brain stimulation for multiple sclerosis-induced complex tremor
The patient was a 37-year-old right handed woman who developed lower extremity weakness at the age of 26. Brain magnetic resonance imaging (MRI) showed periventricular demyelinating lesions. Cerebrospinal fluid (CSF) examination revealed oligoclonal band positivity leading to the diagnosis of MS according to Mc Donald's criteria.[] Despite immunomodulatory therapy, the patient suffered from relapsing and remitting episodes of pyramidal, sensory, and autonomous symptoms. In the past 5 years, she developed severe tremors in both upper extremities, more pronounced at the right side. This was substantially limiting her daily living activities. The patient's Expanded Disability Status Scale (EDSS) associated to tremor and ataxia increased up to 7.[] After an unsuccessful course of different drug treatments including high doses of propranolol, primidon, isoniazide, and pramipexole, patient was referred to our clinic for DBS.\nUpon examination, we found 7-10 Hz resting, action, and intention tremors, more pronounced at the right side. Furthermore, the patient suffered from mild postural-and truncal ataxia, but was still able to walk with bilateral support. In addition, the patient showed slight restriction of the horizontal movements in the left eye, and there were few beats of nystagmus in both eyes at horizontal sight. In addition, her speech showed mild dysarthria. Muscular strength was intact in four extremities.\nMore specific examination revealed that she was also unable to perform the 9-hole peg test with her right hand and scored 45.61 seconds with the left hand.[] The total score of the Fahn Tolosa Marin tremor scale (FTMTS) was 72.[] The patient failed the trail making test with the upper right extremity, and had very hard time performing the test with her left hand.\nMRI of the brain revealed lesions that were iso or hypointense on T1-weighted images and hyperintense on T2-weighted and fluid attenuated inversion recovery (FLAIR) images in the right cerebellum, both middle cerebellar peduncles, periventricular region, in both centrum semiovale and juxtacortical localizations representing demyelinating lesions. Cervical MRI also revealed hyperintense demyelinating lesions on T2-weighted images at the level of C3-4.\nA preoperative MRI was performed consisting of a double-dose contrast enhanced T1-weighted and T2-weighted 1 mm images. On the day of surgery, the stereotactic frame, Leksell G (Elekta Inc., Atlanta GA, USA) was mounted, while the patient received a local anesthetic. A stereotactic computed tomography (CT) was obtained with a slice thickness of 1 mm. We decided to perform 5 microelectrode-guided electrophysiology in the anatomically defined Vim/Vop region on fused CT/MRI-images (Framelink, Medtronic Inc. Minneapolis, MN, USA) with the following coordinates for the central electrode: 12 mm lateral to the AC–PC line, 1 mm posterior to the mid-commissural point, and 3 mm superior to the intercommissural line. Special attention was paid to the trajectory planning to avoid blood vessels during the insertion of the electrodes. After making a precoronally located burr hole, 5 microelectrodes (Leadpoint®, Medtronic) were introduced, 10 mm above the presumed target for electrophysiological recordings. Recordings were performed in steps of 0.5 mm till 7 mm below target. We found typical thalamic cells in all 5 electrode trajectories. Tremor cells were only found in the central trajectories at both sides. Tremor cells showed the same frequency as the tremor-induced potentials on the electromyogram (EMG) recorded from the upper extremities and did not show kineto-kinesthetic responses upon passive flexion/extension movements of the hands []. These cells were found at 1.5 and 1 mm above the presumed target at the right side and at 0.5 and 1 mm below the presumed target at the left side. We performed macrostimulation in all trajectories and assessed the effect on different types of tremor. While we found some therapeutic effects in the medial, lateral, posterior, and anterior trajectories, examination showed the best effects at the central trajectories at the level where we recorded tremor cells. We decided to implant the final electrodes (model 3389, Medtronic) in these trajectories with contact 1 at this anatomical point. The position of the final electrodes was verified with fluoroscopy. The electrodes were finally fixed in the burr hole with methyl metacrylate and connected to an extension cable, which was externalized at a distance of about 7 cm from the burr hole, and connected to an external pulse generator (Model 3625, Medtronic). On the second postoperative day, the patient underwent MRI to evaluate the relative position of the electrodes and to detect (a) symptomatic bleedings or other complications []. Two days later, the second operation was performed under general anesthesia, to implant the pulse generator infraclavicularly (Activa PC, Medtronic).\nThe patient underwent programming of the stimulation parameters in the next days after surgery. The most optimal stimulation parameters were 3.2 V for the left and 2.6 V for the right side. The contact combinations were bipolar for the right side with contact 1 negative and contact 2 positive, and monopolar for the left side, with contacts 4 and 5 negative, and the case positive. The stimulation frequency was 130 Hz and the pulse width was 90 μs for both sides. No side effects of stimulation were noted.\nAfter surgery the patient was able to eat and drink independently, which she could not perform preoperatively, and the tremor associated to posture in both upper extremities was substantially reduced. She was now able to stand without support and walk with unilateral support.\nSixth months later, the patient's EDSS was reduced from 7 to 6. The patient's 25-foot test score improved from 31.18 seconds with bilateral support to 20.2 seconds with unilateral support. Her performance with the 9-hole peg test improved substantially, scoring 127 seconds with her right and 23 seconds with her left hand in the. The FTMTS improved by 51%.