Chronic MCS has been used not only in relieving refractory pain but also in improving a variety of movement disorders including PD, tremor, and poststroke dystonia [2
]. Single case reports, multicenter retrospective clinical review and small case series of advanced PD patients treated with EMCS have been reported with variable clinical results [1
]. There are only three prospective case series [6
]. Arle ana Shils [9
] reported a significant effect on overall motor performance as assessed by UPDRS while Cilia et al. [8
] found that extradural MCS produced no motor benefit but subjective improvement involving mainly axial symptoms as well as reduction in daily off time and dyskinesias. Gutiérrez et al. [6
] confirmed the absence of significant modification of UPDRS III scores with only mild daily life activities improvement and slightly reduction of LEDD. The methodology of these prospective studies was fairly consistent with a evident degree of intra-cohort variability. Anyway, all these previous studies were open label. In 2011, Moro et al. [10
] reported the double-blinded outcomes at 3 months and unblinded outcomes at 1 year from unilateral subdural MCS in five patients with advanced PD. The authors concluded that no significant clinical benefits were evident on parkinsonian symptoms in both outcomes, but five patients represent a very restricted sample for drawing significant conclusions. Nevertheless, some items of the UPDRS, such as gait and balance, during off medication showed a slight improvement in on-MCS in Moro's PD patients (−17,4% and −5,3%, resp.).
Our study is a single-center prospective observational study, and the results suggest that extradural MCS can modulate the cardinal symptoms in advanced PD patients. The improvement concerned mainly axial symptoms, L-dopa-induced dyskinesias and dystonia, quality of life, and global condition (). The benefit on limbs tremor, rigidity and bradykinesia were bilateral but not significant, with a slight prevalence in the hemibody opposite to the stimulated side. EMCS proved to be safe as no complications or adverse effects were reported.
Changes of quality of clinical assessment in ten patients with advanced Parkinson's disease performed before motor cortex stimulation and after surgery at 6, 12, 24, and 36 months in off-medication/on-stimulation states.
Many previous data highlighted the strong involvement of motor cortex in PD [3
]. Functional neuroimaging studies showed that primary motor cortex (M1) is hypohyperactive in both early and late stages of PD. In patients with early untreated PD, fMRI showed M1 hypoactivation [18
]; conversely in advanced parkinsonism, M1 and lateral premotor cortex (L-PMC) were found to be hyperactive [19
]. M1 hyperactivity has been attributed to cortical reorganization resulting from drug-induced reafferentation of the deficient subcortical motor system [20
Increasing of the corticospinal projections at rest resulting from a reduced intracortical inhibition could be implicated in rigidity [21
], while intracortical or thalamocortical facilitatory inputs may not correctly activate all the cortical area involved in movement preparation and execution leading to bradykinesia [22
Motor cortex can be stimulated either not invasively using transcranial magnetic stimulation (TMS) or invasively using surgically positioned stimulating plate electrode like in extradural or subdural cortical stimulation (MCS).
It has been showed that both repetitive TMS and MCS improve motor performances in PD [23
The motor cortex region is the final common link between deeper circuitry coordinating movement and the spinal cord itself. It is one of the few areas in which the pyramidal and extrapyramidal systems interact. Movement disorders may therefore, respond to some type of stimulation of cells in this region. The motor cortex is connected to the basal ganglia indirectly via a corticostriatal pathway and directly via a corticosubthalamic circuit. MCS may exert its effect modulating the subthalamic nucleus (STN) directly or through the loop cortex-striatum-lateral globus pallidus-STN [6
]. Chronic MCS may alter not only the firing patterns in the basal ganglia, but also, due to its location, the interactions between the pyramidal and extrapyramidal systems [9
]. MCS may also modulate the activity of supplementary motor area (SMA) or modulate the “suppressor cortical system” [5
The topography and extension of the somatotopic representations within the motor cortex showed modification in advanced PD with progressive enlargement and displacement of hand motor map; this can explain the improvement of axial symptoms with plate electrode implanted over the motor strip at the hand knob [5
Bilateral effects of unilateral MCS are due to bi-directional interconnectivity between motor cortex and other neural structures located in the cortex, basal ganglia, and thalamus. Transcallosal pathways are the most responsible for these bilateral effects; interhemispheric conduction pathways exist between the hand representations of motor cortex but also weaker transcallosal connection for body parts exists outside hand areas which explains why the hand area should be targeted for MCS in PD [26
The clinical changes induced by MCS are usually delayed; time consuming process of synaptic plasticity, long-term potentiation or depression, expression of secondary messengers, or polarization of brain tissue may consequently also hypothesised as possible reasons for this delay [1
]. Also the observed benefit persisting for some days after IPG failures might be due to a plastic modification of the central neural circuits.
The choice of stimulation parameters is made on an empirical basis. The amplitude of stimulation is always subthreshold for movements and sensations, while both low and high frequency are used with positive results [5
]. We utilized low frequency stimulation (40–60
Hz) with 180 microsec pulse width according with Canavero's works [12
Long-term L-dopa syndrome symptoms, dyskinesia, and dystonia are significantly reduced in most of reported patients treated with MCS; the explanation might be that the doses of dopaminergic drugs are reduced besides a direct effect of cortical stimulation on symptoms [13
Clinical effects of MCS cannot be compared with STN DBS because of the different inclusion criteria and the small number of patients treated by MCS. However, STN DBS appears to be more effective on motor symptoms while MCS on axial symptoms [4
Complication rate and adverse events are low for extradural MCS [31
]. Occurrence of sporadic epileptic seizures has been reported during test stimulation in a minority of patients while epilepsy evoked by chronic MCS has not been reported. Indeed, stimulation parameters used in human series are either clinically or electroencephalographically epileptogenic [32
]. The most serious complication is epidural hematoma which is very rare making the risk of perioperative hemorrhage much lower compared to DBS in which most reported series suggest a intracerebral hemorrhagic risk <2%, with a range of 0.2% to 9.5% [34
]. Local pain in the site of plate electrode implant is also reported during the stimulation; it may be relieved by superficial denervation of the dura performed with its incision and resuturing around the electrode or with bipolar coagulation on its surface [33
Several authors suggested that MCS has a long standing effectiveness [5
], while other authors reported short lasting benefits within the first 12 months [9
]. In our patients, there was a reduction of effects after 12 months of stimulation documented by total UPDRS and UPDRS III total evaluations, despite increases of stimulation amplitude and changes in the other stimulation parameters. This reduction may be due to habituation of the cortex to stimulation, but also the progression of PD may be considered. Conversely benefits on axial symptoms, L-dopa induced dyskinesias, and activities of daily living were more long-lasting.
Our study have some limitation. First, evaluations were conducted in an open-label fashion, and this does not allow to exclude a placebo effect. Furthermore, assessment in off-stimulation condition performed 2 weeks after IPG switch-off may be too early to determine the true MCS effectiveness since the effect of stimulation could outlast 3-4 weeks. Finally, clinical features as axial symptoms and dyskinesias can be better evaluated using specific scales rather than UPDRS.