In this retrospective study of patients successfully treated with bilateral pallidal DBS for idiopathic cranial and cranial-cervical dystonia, we found that novel motor impairment occurred quite frequently. The motor impairments were largely bradykinetic in nature, with patients frequently reporting a moderate to severe worsening in a number of activities involving both upper and lower extremities that were previously unaffected by dystonia and felt to be normal at baseline. All patients experienced a major reduction in their cervical or cranial-cervical dystonia, but the motor impairments could not be completely dissociated from the beneficial effects on dystonia by programming changes.
During intraoperative testing and programming of GPi stimulators, the most common stimulation-induced adverse motor effects are dysarthria and tonic contraction of contralateral muscle groups in the face and arm [1
]. These effects occur immediately following programming, are reversible with a modest decrease in stimulation settings or adjustment in electrode choice, and are thought to result from spread of stimulation to the corticobulbar tract or corticospinal tract. In contrast, the motor changes we report here were primarily bradykinetic in nature. There are several reasons to believe the effects were not caused by spread of stimulation to the corticobulbar tract or corticospinal tract. First, in some of our patients the symptoms developed insidiously, in 1 case after 3 years of stimulation, rather than immediately following device activation (online supplementary video
, www.karger.com/doi/10.1159/000195718). Also, based on our measurements of electrode location, stimulation-induced bradykinesia is not explained by aberrant DBS lead location outside of the GPi and did not significantly correlate with distance of the lead from the internal capsule. The DBS lead tips were all placed in the posterior ventral portion of the GPi such that the corticobulbar tract fibers running medially are closest to the lead, followed more posteriorly by the corticospinal tract fibers to the arm, and even more posteriorly by the corticospinal tract fibers to the leg. As such, if the stimulation-induced bradykinesia were due to current spread to the pyramidal tracts, the first symptoms experienced would more likely anatomically correspond to the face, and in fact dysarthria is almost always the first symptom to occur acutely with spread of stimulation to the internal capsule. The patients in this study, however, were deliberately programmed at a voltage level lower than the threshold for dysarthria or tonic facial contraction, and patients who complained of lower extremity symptoms did not report facial symptoms.
Further, patients with the most benefit in dystonic symptoms tended to have the most difficulty with stimulation-induced bradykinesia suggesting that stimulation-induced bradykinesia may arise from the same neural circuit mediating the antidystonic effect rather than from a neighboring structure. Finally, using a current diffusion model to evaluate the effect of extracellular stimulation on the activation of neurons, McIntyre et al. [14
] found that at 3.0 V, 100 μs and 150 Hz, neurons greater than about 2.5 mm from the active electrode contact do not depolarize. Although our stimulation parameters on average were slightly higher than those used in the model by McIntyre, spread of current sufficient to cause widespread capsular activation at the mean distance of 3.6 mm between active contact and the border of the internal capsule seems unlikely.
Others have reported isolated cases of hypokinetic motor affects following GPi stimulation in nonparkinsonian disorders, including worsening of bradykinesia in a patient with Huntington's disease at high stimulation frequencies [15
] and the unilateral impairment of rapidly alternating movements in a patient treated with unilateral GPi DBS for severe Gilles de la Tourette syndrome [16
]. Tisch et al. [8
] reported the development of delayed-onset akinesia with gait slowing, difficulty rising from a chair, and turning in bed in 2 patients treated with bilateral GPi DBS for primary generalized dystonia. Inactivation of the GPi in normal nonhuman primates has been shown to decrease the amplitude and speed of arm movements [17
Recently, several small series and a few case reports have reported subthalamic DBS as a possible treatment for primary and some secondary forms of dystonia [20
]. Based on animal studies, surgical alteration of the indirect pathway alone would be expected to have fewer bradykinetic side effects than alteration of the direct and indirect pathways combined, but this remains to be demonstrated in humans [24
In patients with juvenile-onset primary generalized dystonia, Alterman et al. [26
] found that 60-Hz stimulation effectively treated dystonia symptoms. In our group of patients with adult-onset cervical and cranial-cervical dystonia, reducing stimulation frequency to 60 Hz eliminated bradykinetic adverse effects, but in almost all our patients this was associated with an unacceptable worsening of dystonia symptoms. Interestingly, as the frequency was slowly titrated up to 100–110 Hz, many of our patients had partial relief of dystonia without a significant induction of bradykinesia, possibly reflecting a frequency range where a compromise between improvement in dystonia and induction of bradykinetic effects could be achieved. Further study of a frequency-dependent relationship between improvement in dystonia and adverse motor effects in this patient population may contribute to our understanding of the mechanism of DBS that has already been revealed by stimulation frequency changes in other movement disorders [27
This study has a number of limitations, including our use of a subjective, nonvalidated questionnaire, which sought patient information in a retrospective manner and is therefore subject to recall bias. Moreover, although patients’ descriptions of symptoms generally suggested bradykinesia, some of the induced motor symptoms may not be purely from bradykinesia and instead could be the result of other induced motor effects such as rigidity, micrographia, or incoordination. Given the overall general satisfaction and dystonia improvement with GPi DBS, there also exists a potential for patients to underreport side effects. Objective measures of bradykinetic symptoms (such as comparing performances on specified motor tasks) are critical to better characterize and quantify changes. In future studies, it would be interesting to see if a relationship exists between degree of motor impairment and the time point a patient develops stimulation-induced symptoms. Rater- and subject-blinded testing would also greatly improve the validity of any future studies.
In conclusion, GPi DBS appears to be a safe and effective therapy for focal and segmental forms of dystonia, including cervical and cranial-cervical dystonias. However, GPi stimulation in these patients may induce bradykinetic symptoms in previously unaffected limbs leading to difficulty with important motor tasks such as writing, getting up from a chair or in/out of a car, and walking. Although these symptoms may be somewhat improved with alteration of stimulation parameters (frequency), they usually cannot be entirely eliminated without worsening of dystonia.