Deep brain stimulation of the subthalamic nucleus for essential tremor (2013)

Essential tremor (ET), characterized by a postural and/or kinetic tremor and primarily manifested in the upper extremities, head, and other parts of the body, is one of the most common neurological disorders.1 The traditional target for the neurosurgical treatment of ET, the ventral intermedius nucleus (Vim) of the thalamus, has confirmed that chronic deep brain stimulation (DBS) is an effective, standard, and primary procedure for ET.2 However, the loss of tremor suppression due to tolerance of chronic Vim stimulation, accompanied by other adverse effects, such as paresthesias, dysarthria, dysequilibrium, hyperhidrosis, and localized pain, has necessitated changes in the stimulation target in some patients. Therefore, an alternative target for ET stimulation is required. Although targeting the subthalamic nucleus (STN) also has complications, such as dyskinesia, dysarthria, paresthesias, diplopia, mood changes, depression, and restless leg syndrome, in view of the evidence that STN could be the target for patients with tremors associated with Parkinson's disease (PD), STN was elected in two ET patients in our study with positive effects. Our research is reported to have explored the possibilities of STN-DBS in the treatment of ET. Two patients with ET were included in this retrospective study. The STN-DBS patients underwent surgery at Beijing Tiantan Hospital between August 2010 and March 2012. The two patients underwent multi-medications but failed. Case I is a 47-year-old female with a 3-year history of tremors of the head and upper limbs. Case II is a 43-year-old male with a 6-year history of tremors of the left upper limbs. The surgical procedure for STN-DBS is the same as the procedure used for PD and has been described in detail elsewhere.2 Both subjects underwent stereotactically-guided DBS procedures utilizing an atlas of neuroanatomy, microelectrode recording, and intra-operative testing to locate the target. Microelectrode recordings (FHC Inc., USA) were used to confirm the location of the STN to assure the precise targeting of the STN surgery. Software provided by Medtronic (USA) was used for targeting and microelectrode recording. The electrophysiological characteristics of neuronal firing within the STN and substantia nigra zona were typical. We analyzed the discharge pattern, frequency, amplitude, and background noise of the electrical signals combined with the atlas of neuroanatomy to confirm the upper and lower bounds of the STN. The electrical signals of the STN were of high frequency and high amplitude with irregular interval burst discharges of single cells. The background noise of the substantia nigra zona exhibited a significant decline in the regular discharges and a lower background noise (Figure 1A).Figure 1. A:: Electrical signals of the STN were of high frequency and high amplitude with irregular interval bursting discharges of single cells in patients with essential tremor. B: The position of electrodes of bilateral STN-DBS (axial scan, arrows). C: The position of electrodes of unilateral STN-DBS (coronal scan, arrow).Bilateral (case I) or unilateral (case II) systems were chosen based on the patient's symptoms. The DBS electrode (model 3389; Medtronic, Inc.) was implanted under local anesthesia. The final position of the electrode was dictated by the response to macrostimulation. We locked the stimulating electrodes when precisely located. An extracorporal stimulator was used during the surgery to modulate the stimulus voltage, frequency, pulse width, and contact chosen so as to achieve the most pronounced effect on the tremor. Then, the generator was planted in the infraclavicular region one week after the first surgery. A post-operative CT was performed on the day of the surgical procedure. An MRI was performed one week later to confirm the location of each electrode (Figure 1B and 1C). The voltage was increased in steps until the most pronounced effect on tremor was achieved with no side effects. Patients were contacted for further consultation with a physician or by telephone for comprehensive evaluation of the therapeutic efficacy. The patients were evaluated using the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) after surgery with respect to the STN. Evaluation of the efficacy of the DBS was then presented as a result of on-stimulation in relation to the off-stimulation during the same evaluation. The settings for the stimulation parameters in case I are as follows: amplitude is 1.5 V (right) and 2.0 V (left), frequency is 130 Hz, and pulse width (PW) is 60 μs. The settings for the stimulation parameters in case II are as follows: amplitude is 3.0 V, frequency is 130 Hz, and pulse width is 60 μs. MRI showed that the electrodes were located in STN. The FTMTRS was used to assess the patients pre- and post-operatively. The total tremor score was improved by 66.7% after 24-month follow-up (case I) and 75.5% after 6-month follow-up (case II). No severe adverse events, such as infections, hemorrhage, paresthesias, dysarthria, cognitive deficits, imbalance, or diplopia, were noted in the patients after electrode implants for DBS. Since the initial presentation in 1987 of Vim-DBS for Parkinsonian tremors, the stereotactic community has followed Benabid and high-frequency stimulation of Vim is now the established target for ET.2 Nevertheless, there are some disadvantages with high-frequency stimulation that need further improvement. For example, the choice of the target position in the Vim varies slightly from surgeon to surgeon.2 The stimulation effects decrease over time, most noticeable of which is the tremor of action. There are no reported significant differences in gait or balance measures in the DBS “off” versus “on” conditions, and pre-existing restless legs syndrome is not improved. The optimal target should be the target that maximizes the likelihood of a good effect from stimulation, favourable long-term results, and minimize adverse effects. Because of the limitation of Vim-DBS, it is necessary to look for an optimal new target for ET. It is difficult to evaluate the outcome between different targets since the target differs somewhat between different groups. But it is helpful to evaluate the outcome between different targets in the same group. STN, posterior subthalamic area (PSA), and caudal zona incerta (cZi) is the potential new target for ET. The reasons for tolerance to Vim-DBS in the treatment of ET are as follows. First, disease progression could lead to an increase in tremors, and subsequently require increasing currents to reach satisfactory tremor suppression. Second, early tolerance could be due to a declining effect of microthalamotomy directly after surgery. Third, according to Benabid and coworkers, tolerance could be due to an adaptation of the biological response of the stimulated neuronal network. The application of STN-DBS in the treatment of ET has yielded positive results, and the reasons are as follows: STN-DBS is an effective treatment of tremor, whether caused by PD or unknown reasons; as a visible target in MRI, the target position of the STN is relatively consistent compared with Vim; and previous pre-clinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins.3 In the substantia nigra of rats, STN-DBS between 2 and 4 weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons.3 Although STN-DBS appears to have significant neuroprotective properties in PD patients, it is unknown whether or not STN-DBS in ET patients provides added neuroprotective benefits. We propose that STN and Vim stimulations may activate different remote targets and reconstruct different contact networks of structural connectivity, and this might be related to the tolerance of Vim-DBS and neuroprotective effect of STN-DBS in ET. Therefore, the long-term outcome of STN may be superior to Vim. Of course, it should be verified using further clinical trial or experiment research.