Subthalamotomy in the treatment of Parkinson's disease: clinical aspects and mechanisms of action

A review

Full access

Parkinson's disease (PD) is a neurodegenerative condition that can be pharmacologically treated with levodopa. However, important motor and nonmotor symptoms appear with its long-term use. The subthalamic nucleus (STN) is known to be involved in the pathophysiology of PD and to contribute to levodopa-induced complications. Surgery is considered in patients who have advanced PD that is refractory to pharmacotherapy and who display disabling dyskinesia. Deep brain stimulation of the STN is currently the main surgical procedure for PD, but lesioning is still performed. This review covers the clinical aspects and complications of subthalamotomy as one of the lesion-based options for PD patients with levodopa-induced dyskinesias. Moreover, the authors discuss the possible effects of subthalamic lesioning.

Abbreviations used in this paper:DBS = deep brain stimulation; GAD67 = glutamic acid decarboxylase; GPe = globus pallidus externus; GPi = GP internus; LEDD = levodopa equivalency daily dose; LID = levodopa-induced dyskinesia; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA = N-methyl-d-aspartate; PD = Parkinson's disease; PPN = pedunculopontine nucleus; RCT = randomized controlled trial; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; STN = subthalamic nucleus; UPDRS = Unified Parkinson's Disease Rating Scale; Zi = zona incerta; 6-OHDA = 6-hydroxydopamine.

Abstract

Parkinson's disease (PD) is a neurodegenerative condition that can be pharmacologically treated with levodopa. However, important motor and nonmotor symptoms appear with its long-term use. The subthalamic nucleus (STN) is known to be involved in the pathophysiology of PD and to contribute to levodopa-induced complications. Surgery is considered in patients who have advanced PD that is refractory to pharmacotherapy and who display disabling dyskinesia. Deep brain stimulation of the STN is currently the main surgical procedure for PD, but lesioning is still performed. This review covers the clinical aspects and complications of subthalamotomy as one of the lesion-based options for PD patients with levodopa-induced dyskinesias. Moreover, the authors discuss the possible effects of subthalamic lesioning.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its frequency is expected to increase as the population ages. Levodopa tremendously improves the cardinal symptoms of PD.52 However, its chronic administration leads to major motor complications, where patients may encounter motor fluctuations, wearing off, and dyskinesias.178 Dyskinesia describes aimless, involuntary movements for which no pharmacological treatments are currently approved.107 Around 40% of patients will develop levodopa-induced dyskinesias (LIDs) after 4–6 years of treatment, and this percentage increases to 90% after 9–15 years.3 This information led clinicians and surgeons to explore new ways to reduce these severe motor complications without affecting the beneficial effects of levodopa. The subthalamic nucleus (STN) is considered to play a pivotal role in the pathophysiology of PD and LID. Some patients with PD have seen their parkinsonian symptoms alleviated after a coincidental infarction in the STN.147,174,190 Subthalamic lesioning (subthalamotomy) performed in parkinsonian monkeys demonstrated promising results.17,18,23,64 Nowadays, the STN is one of the major targets of stereotactic lesioning and deep brain stimulation (DBS) for the treatment of movement disorders.53 Despite surgical interest in the STN, few reviews cover subthalamotomy as a treatment of PD.59,65,121 The present study reviews the clinical aspects and complications of subthalamotomy in the treatment of PD. Subthalamotomy is compared with other surgical treatments, and a discussion is provided on the possible mechanisms involved in the beneficial motor effects of subthalamic lesions.

History of Subthalamotomy

Historically, lesioning the STN has been avoided for fear of inducing hemiballismus. In fact, it has been known since the end of the 19th century that STN lesions provoked hemiballismus as observed in patients with PD who have suffered a stroke.34 It was demonstrated that lesions confined to the STN in normal monkeys were at high risk for hemiballismus,35,184 and destruction of 20% of the STN's volume was enough to provoke this involuntary movement.35 The development of hemiballismus in normal monkeys was confirmed in nonparkinsonian patients following lesioning restricted to the STN.46,104,108,118 Nevertheless, several authors performed so-called subthalamotomies for PD, giving rise to a great wealth of publications in the 1960s and 1970s.13,74,102,146 During the lesioning era, the target for subthalamotomy was not the STN as it is today. In fact, authors performed their lesioning in the zona incerta (Zi),14,112,113 the subventrolateral thalamus,116 the posterior subthalamic area, and the Raprl (prelemniscal radiations)24,75,82,173 or H2 Field of Forel (lenticular fasciculus),14,76,77,106,113,154,155 all under the term “subthalamotomy,” while others coined the term “campotomy.”152 However, none of these authors targeted the STN itself. Instead, lesions were made in the subthalamic area, mainly in the fiber bundles. As pointed out by Spiegel et al.,152 the advantage of targeting the pallidothalamic fibers is that a smaller lesion is needed to obtain clinical results than when targeting the globus pallidus internus (GPi). On the other hand, since precise imaging and electrophysiological data were scarce, if not completely lacking at that time, it is difficult to compare these publications with current subthalamotomy knowledge. In the 1960s and 1970s, lesioning in the subthalamic area was not restricted to PD treatment, but was also used for the treatment of tremor,82,173 cerebral palsy,82,94 and hyperkinetic movements,116 including dystonia,155 intractable spasms,82,155 athetosis,119,155 hemiballismus,11,12 and dyskinesia.183

Clinical Outcome of Subthalamotomy

Parkinsonian Symptoms

The last 2 decades have seen many studies addressing the motor5,16,20,47,57,58,99,109,120,129,168,176 and cognitive7,25,105 effects of subthalamotomy for PD (Table 1); there have also been several case reports.38,45,72,87,122 A recollection of studies indicates that subthalamotomies have beneficial effects on the motor symptoms in both off- and on-medication states with better results from bilateral lesions. The surgery significantly reduces contralateral cardinal symptoms (tremor, bradykinesia, and rigidity).8,130 The improvements obtained with unilateral lesions seemed to increase in the first 12 months and to decrease in the 2nd year after surgery (see the averages in Table 1). Small benefits were also observed ipsilateral to STN lesions but did not last for more than 1 year.8,130,161

TABLE 1:

Review of published literature on motor and dyskinesia evaluations, and on levodopa equivalency daily doses after subthalamotomy

Authors & YearNo. of PatientsFollow-Up in Mos (no. of patients)*% UPDRS Part III Score Improvement% UPDRS Part IV Score Improvement% LEDD
Off MedicationOn Medication
unilateral lesions
 Alvarez et al., 20011112 (n = 10)503959 (n = 5, >12 mos)
 Alvarez et al., 200988912 (n = 68)506045
24 (n = 36)303936
36 (n = 25)181528
 Coban et al., 20095625235027
 Hanağası et al., 2011111449434023
 Parkin et al., 2001115.4 (n = 8)824
 Patel et al., 2003266 (n = 16)19958§47
12 (n = 15)13552§45
24 (n = 18)15−6 (deterioration)64§34
 Rodriguez et al., 19981421112 (n = 7)60
 Su & Tseng, 2002; Su et al., 2002160136 (n = 12)303382§49
12 (n = 12)323085§43
 Vilela Filho & da Silva, 20022313.5 (n = 21)7443
 Witjas et al., 2009312 (n = 2)10040
 overall mean ± SD
  6 mos20.8 ± 3.420.4 ± 3.065.5 ± 14.944.7 ± 10.9
  12 mos44.2 ± 9.146.4 ± 12.065.5 ± 9.443.7 ± 7.0
  24 mos16.7 ± 3.06.3 ± 7.964 (—)30.5 ± 1.5
bilateral lesions
 Alvarez et al., 20057 staged>4850385040
11 simultaneous>36493353
 Alvarez et al., 20099**323647
 Merello et al., 2008564727††79
125291††76
 Tseng et al., 2007103445496§34
12526697§38
24424967§28
36404267§29

The number of patients is given only if the number of patients differs from the number of patients who underwent surgery.

Calculated based on the cardinal scores.

UPDRS Part IV items 32–33.

UPDRS Part IV items 32–35.

Dyskinesia rating scale.

Some of the patients may have been presented in Alvarez et al., 2005.

UPDRS Part IV items 32–39.

Effects on Levodopa Needs and LID

Dyskinesias, assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, are highly improved by both unilateral and bilateral STN lesions (Table 1). A striking feature is the consistency of improvement in LID over the first 2 years, where a steady 65% reduction is observed (see the averages in Table 1). Contralateral diphasic dyskinesias and off-medication dystonia seem to respond best to subthalamotomy, whereas peak-dose dyskinesias remain unchanged.8 Furthermore, ipsilateral LIDs are unresponsive to STN lesions.8 It is usually assumed that the reduction of LIDs is the result of reduced levodopa equivalency daily doses (LEDDs) after altering STN activity.91 One and 2 years after subthalamotomy, the LEDD was reduced by approximately 45% and 30%, respectively. The progression of the disease may, in part, explain the diminishing improvements in motor and levodopa needs.8 Nevertheless, the reduction in LEDD cannot be the sole explanation of the improvements in LIDs for 2 main reasons. First, the mean reduction in LIDs remained constant despite LEDD changes over a 2-year period. Second, ipsilateral LIDs continued to increase even if levodopa was greatly reduced. Another interesting feature of subthalamotomy is the potentiation of response to levodopa. It was reported that the on-time duration without significant dyskinesia increased 4-fold when the medication was halved.130 Daily off-time periods were reduced from 50% to near abolition in the 1st year.6,68,130,160

Lesions created by the insertion of microelectrode probes or DBS electrodes were found to have positive effects on parkinsonian symptoms peri- and postoperatively.100,101,135,152,189 This observation provided evidence to the knowledge that small and confined STN inactivation can be sufficient to produce an improvement of PD, as replicated in animal models.21 These so-called microlesions appear to have similar effects on the metabolic activity of the globus pallidus, the striatum, the thalamus, and the cortex as those measured after subthalamotomy, but to a lesser extent.135,157,168

Cognitive Outcome

Surgical procedures in the basal ganglia can potentially induce neuropsychological impairments, as observed after bilateral pallidotomy or subthalamic DBS.43,156 Contrary to this, subthalamotomy has not been shown to cause major cognitive impairment.105,130 In fact, no studies using a cognitive test (mini–mental state examination) observed a decline after unilateral or bilateral lesions.7,8,25,110,170 Slight improvements in verbal fluency, as well as decreases in dementia, apathy, and depression were seen in patients.7,8 A recent study demonstrated decreased attention, inhibition, and verbal learning in up to 30% of the patients, but these did not affect patients globally.105 Finally, executive functions and memory remained unaffected by STN lesions.41,105

Subthalamotomy Versus Other Surgical Treatments

According to the recent review of evidence-based medicine for the treatment of the motor symptoms of PD by the Movement Disorders Society,54 unilateral pallidotomy and bilateral GPi or STN DBS were found effective for motor complications of PD. Unilateral posteroventral pallidotomy is known to result in 20%–35% improvement in off-medication motor symptoms during the first 2 years after surgery.69 In a randomized controlled trial (RCT) comparing unilateral pallidotomy with medical therapy, contralateral dyskinesias were reduced by 75% and 78% at 6 and 24 months postpallidotomy, respectively, and remained unchanged with medical therapy.177 In the same study by Vitek et al., ipsilateral dyskinesias were also improved significantly. However, levodopa needs remained the same after 6 months (0.4% decrease in pallidotomy and 7.1% increase with the medical therapy only).

Bilateral subthalamic DBS is assumed to be the most widely used surgical procedure for PD treatment.1,85,145 In a recent 6-month RCT, bilateral STN DBS was compared with the best medical therapy.182 It was demonstrated that off-medication motor symptoms were improved by 28.6% and remained unchanged with medical therapy. Similar results were obtained for motor complications (36.9% vs 5.4% for STN DBS and medical therapy, respectively). Levodopa equivalencies were reduced by 23.1% after 6 months of STN DBS, whereas they increased insignificantly (1.1%) with the best medical therapy.

Subthalamotomy is still regarded as an experimental procedure for PD.54,165 Paradoxically, a recent study demonstrated that neurosurgeons performed subthalamotomies as often as pallidotomies or thalamotomies in most or all of their cases.85,145 It was shown that lesioning was more often offered to patients in countries with lower economical development or when patients financed their own surgeries. Subthalamotomy was not included in the recommended procedures for motor complications because of insufficient evidence. Two studies41,110 met Level I criteria, depicted by at least 1 high-quality RCT, but these studies were not included in the review because of their small sample sizes. In the first study,41 unilateral subthalamotomy was compared with unilateral pallidotomy and bilateral STN DBS. The authors concluded that both procedures offered major motor improvement and that these 2 surgeries were equally effective for the motor treatment of PD. Also, they observed that unilateral subthalamotomy had the advantage of reducing levodopa needs, whereas the needs remained unchanged with unilateral pallidotomy.41 In the second RCT comparing bilateral subthalamotomy and bilateral STN DBS, the 2 surgical procedures had similar benefits on motor symptoms in patients with PD and the results were comparable to previous literature.110 Although these 2 RCTs provided evidence on the positive effects of STN lesions, larger RCTs are warranted to fully assess the cost-effectiveness and the role of subthalamotomy in the treatment of PD.

The tremendous improvements and low complications profile observed in patients treated with DBS are obvious reasons for its vast use worldwide.22 However, STN lesioning may be an alternative when DBS is not a possible treatment for certain reasons, such as access to care and health status.73 Lesion therapies are much less expensive than DBS.50 In fact, the direct and indirect costs of a DBS system153 outrun lesion-based costs. Moreover, patients have shorter hospital stays after lesioning than those who receive DBS implants.50 Subthalamotomy also presents advantages that are not seen with other lesioning treatments. Patients undergoing unilateral subthalamotomy seem to respond as well as those undergoing unilateral pallidotomy when considering motor and dyskinesia improvements.41 Bilateral subthalamotomy does not seem to induce severe cognitive decline as seen in bilateral pallidotomy.55 Subthalamic nucleus lesions allow for a reduction in levodopa, whereas levodopa remains practically unchanged after pallidotomy.88 This advantage is valuable when patients have levodopa-induced hallucinations. Although there are no studies on this matter, STN DBS was recently shown to reduce hallucinations after medication adjustments172 and could be achieved with STN lesions.

Cellular and Biochemical Effects of Subthalamotomy

Neuroprotection

There is evidence suggesting that dopaminergic cells are sensitive to excitatory glutamatergic input implicated in neurotoxicity in PD.62 Dopaminergic cells present both N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors,125 and antagonizing the former receptor was shown to protect substantia nigra pars compacta (SNc) cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity.31,192 The STN is the main excitatory structure of the basal ganglia151 and has efferences in the SNc.150 It was originally hypothesized that STN overactivity in PD could contribute to progression of the disease4,150 and its inactivation may slow or prevent it.

In rats, most of the studies failed to demonstrate a neuroprotective effect of previous STN lesions before large exposure to the neurotoxin 6-hydroxydopamine (6-OHDA) on dopaminergic cells survival.115,131,140 I t w as, however, shown that the phenotype, measured by tyrosine hydroxylase immunohistochemistry, the rate-limiting enzyme in the production of dopamine synthesis, was preserved in the surviving cells in the first weeks after exposure to 6-OHDA.36,131,187 On the contrary, some authors observed neuroprotection in rats with small dopamine depletion,133 but its effectiveness decreased in a time-dependent manner and was no longer detected after 1 week.40

In primates, a recent study showed the neuroprotective effects of dopaminergic cells, when subthalamotomy is performed 2 weeks before or 1 week after MPTP insult.181 More recently, we observed no changes in tyrosine hydroxylase–positive immunohistochemistry or in dopamine or its metabolite concentrations after unilateral subthalamotomy.86 This discrepancy might be explained by the same 3 main factors seen in rodents: the extent of dopamine depletion, the extent of the STN lesion, and the time between the 2 insults. The dopaminergic denervation was much more profound in our monkeys than it was in the study by Wallace and colleagues.181 Monkeys in that study had 50% dopaminergic loss in the SNc, whereas monkeys in our study had a near complete loss. Neuroprotective effects of STN alteration are inversely proportional to the extent of the MPTP insult. A study in MPTP-injected monkeys failed to show neuroprotection with 85% of dopaminergic loss.98 The survival time between MPTP administration and subthalamotomy is also likely to explain the difference. In the study by Wallace et al., monkeys received a subthalamotomy only 6 days after MPTP and were killed roughly 14 days after lesioning,181 whereas the monkeys in our previous study were rendered parkinsonian many years before the STN lesion and were killed several weeks after surgery. Lastly, the STN is not the only glutamatergic source to the SNc. In fact, the latter receives excitatory input from the pedunculopontine nucleus (PPN) and the cortex93,95 and may also contribute to the glutamate-mediated excitotoxicity.164

Clinically, PD cardinal symptoms appear after 80% of striatal dopaminergic loss,167 and patients with PD undergo surgery when their disease becomes pharmacologically refractive to levodopa or when LIDs are disabling.8 Thus, neuroprotective studies do not reflect surgical practices in a clinical perspective and clearly cannot be applied in a clinical context.

Neurophysiology

Subthalamic nucleus activity in PD is known to increase in frequency and to increase burst firing.137 In humans and primates, similar changes were observed in the STN output nuclei, that is, the GPi and substantia nigra pars reticulata (SNr). Globus pallidus internus neuronal activity increases from 60–70 Hz in the normal state163,186 to 70–85 Hz in PD78,97 and from 60 to 70 Hz in the SNr.79,186 The administration of levodopa not only reverses these increases but also tends to further reduce the basal activity of the GPi and SNr.30,60,70,78,97,124 exerts comparable effects by restoring normal electrophysiological activity. Subthalamic nucleus lesions decreased the GPi firing rate in normal monkeys66 and reversed the increased GPi neuronal activity induced by 6-OHDA in rats.117 Some authors observed only that the GPi firing pattern returned to normal, resulting mainly in reduced burst firing without any change in firing rate.144 However, the MPTP-induced GPi oscillations persisted in parkinsonian monkeys.185 Similarly, SNr electrical activity was also decreased after subthalamotomy in normal191 and 6 -OHDA rats32,127,144 with reduced burst firing.114,171 Moreover, the 6-OHDA-induced increase in the PPN firing rate was prevented with STN lesions in rats, but no change was observed in normal rats after STN destruction.84 On the contrary, subthalamotomy in normal rats increased the number of PPN neurons that displayed bursting activity by more than 30%, whereas 6-OHDA lesions with or without STN lesions increased the number by only 8%–12%.84 These last 2 observations indicate that the changes in PPN activity following STN lesioning are not due to a direct subthalamo-pedunculopontine connection. Lastly, SNc neurons were also observed to reduce their firing rate and their burst activity after STN lesioning,26,148,149 but those findings were not replicated by others.191 Thus, it is generally agreed that subthalamotomy decreases neuronal activities in GPi, SNr, and SNc, which is consistent with the fact that STN exerts an excitatory input on these structures.

Neurochemistry

The consequences of these physiological changes in STN output translate into measurable biochemical modifications (Table 2). Reductions in cytochrome oxidase and succinate hydrogenase, both markers of cellular activities, were found in the GPi and SNr after STN lesioning in normal and 6-OHDA rats,27,28,132 corroborating the decrease in firing rates and patterns. Messenger RNA of enzyme glutamic acid decarboxylase (GAD67)—which is needed for the conversion of glutamate to γ-aminobutyric acid present in the globus pallidus externus (GPe), GPi, and SNr—also decreases with subthalamotomy in MPTP monkeys and 6-OHDA rats.44,132 This indicates that these cells are less active and consume less energy after subthalamotomy.111 However, increases in GAD67 levels were observed in the GPi and GPe of normal monkeys after STN lesions.10 As for the changes in the SNc electrophysiology, some studies reported increased striatal dopamine and tyrosine hydroxylase positivity,10,80 and others reported a reduction.148

TABLE 2:

Neurochemical changes after unilateral subthalamotomy in normal and parkinsonian animals*

Authors & YearTreatment% DA Denervation% STN LesionEffect of STN Lesion
studies in rats
 Blandini et al., 1995normalnonenear complete↓ mitochondrial complex I activity in EN & SNr; ↓ SNr NMDA receptor binding; no effect on AMPA receptor binding
 Blandini & Greenamyre, 1995normalnonenear complete↓ SDH & CO mitochondrial activities in striatum, SNc, & GP
 Price et al., 1993normalnonecomplete↓ AMPA & kainate receptor binding in ipsilateral SNr; ↓ NMDA receptor binding in ipsilat GP
 Aristieta et al., 20126-OHDAcomplete loss≈60%↑ striatal FosB/DFosB ipsilat to STN lesion in 6-OHDA rats treated w/ levodopa; ↑ striatal pDARPP32/DARPP32; reverses the increased D2/D1 ratio in 6-OHDA rats treated w/ levodopa
 Bacci et al., 20046-OHDAcomplete lossnear completereverses the increased striatal enkephalin mRNA levels in 6-OHDA rats; reverses the increased GAD67 mRNA levels in 6-OHDA rats in the EN & SNr; no effect on the decreased levels of substance P mRNA in 6-OHDA rats
 Blandini et al., 19976-OHDAcomplete losspartial (20%–70%) completepartial lesion: ↓ CO in EN & SDH in GP, EN; complete lesion: ↓ CO & SDH in EN, GP; both partial & complete STN lesions prevented the increase in CO & SDH in SNr
 Centonze et al., 20056-OHDAcomplete lossnear completereverses the 6-OHDA-induced overactive frequency & amplitude of striatal glutamate-mediated spontaneous excitatory postsynaptic currents
 Delfs et al., 19956-OHDA>90% loss of DA uptakenear complete↓ the increase in GAD67 mRNA in the GP induced by 6-OHDA; no effect in ipsilat EN; no effect on encephalin & substance P
 Hwang et al., 20066-OHDA66% loss of striatal DA; 50% loss of GPe DANA↑ striatal & pallidal content of DA & HVA in normal & 6-OHDA rats
 Levandis et al., 20086-OHDA>97% loss of striatal DA; >93% loss of SNc DA>50% loss↑ striatal FosB/ΔFosB ipsilat to STN lesion in 6-OHDA rats treated w/ levodopa
 Périer et al., 20036-OHDA98% loss of DATnear complete↓ the increase in CO subunit I & GAD67 mRNA in the striatum induced by 6-OHDA when combined w/ levodopa
 Touchon et al., 20046-OHDA80-85% loss of striatal THNA↓ striatal glutamate in 6-OHDA, STN lesion, or the combination of both lesions associated w/ an increase in glutamate immunolabeling in nerve terminals
 Walker et al., 20091806-OHDA90% loss of SNc TH>50% loss↑ striatal glutamate in normal rats; ↓ the striatal increase of glutamate in 6-OHDA rats
 Walker et al., 20091796-OHDA90% loss of SNc TH>50% loss↓ striatal DA & DA metabolites, ↑ in the HVA/DA ratio in normal rats; ↓ striatal DA, ↑ DA metabolites, DA metabolites/DA ratio unchanged in 6-OHDA rats
studies in primates
 Andrén et al., 1995normalnoneNA↑ GAD67 in bilateral caudate nucleus, GPi, GPe, VA/VL & ipsilat putamen; ↑ GABA in CM/Pf; ↑ DA in dorsal contralat putamen; ↑ TH in bilat GPi & contralat striatum
 Guridi et al., 1996MPTPnear complete80–90% loss↓ GAD67 mRNA in GPi, GPe, SNr; ↑ GAD67 mRNA in reticular thalamic nucleus
 Mitchell et al., 1985normalnonebicuculline injection↓ 2-deoxyglucose activity in GPe & GPi
 Shimo & Wichmann, 2009normalnone>50% loss↓ striatal dopamine

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CM/Pf = centromedian and parafascicular thalamic nuclei; CO = cytochrome oxidase; DA = dopamine; DAT = dopamine transporter; EN = entopeduncular nucleus, rat homolog of the primate GPe; GABA = γ-aminobutyric acid; GP = rat globus pallidus, homolog of the primate GPi; HVA = homovanillic acid; NA: not available; SDH = succinate dehydrogenase; TH = tyrosine hydroxylase; VA/VL = ventroanterior and ventrolateral thalamic nuclei; ↑ = increases; ↓ = decreases.

Subthalamotomy Complications

Hemiballismus

Subthalamic nucleus lesions have been known to induce hemiballismus, which is the violent, irregular, and involuntary movement of one half of the body.134 Hemiballismus is usually observed contralateral to STN lesions in patients with PD (Table 3), but ipsilateral hemiballismus was also described secondary to STN infarct or hemorrhage in nonparkinsonian patients.42,92,138 Hemiballismus has many causes and may be caused by lesions in the STN, but also by lesions in other structures of the basal ganglia.46,56,61,139,174 In patients with PD who undergo subthalamotomy, transient hemiballismus (< 1 year) was observed in 13.2% (40 of 303 patients enrolled in studies or case reports) with spontaneous recovery or with successful pharmacological treatment, whereas it remained permanent in 9.9% (includes 2 patients receiving ipsilateral thalamotomy during the same surgical procedure since they presented with hemiballismus/hemichorea by the end of STN surgery175,176). It has been suggested that smaller lesions would allow for compensatory mechanisms within the basal ganglia, tending to reestablish equilibrium and cease hemiballismus. Conversely, in larger STN lesions, a persistent decrease in GPi and SNr activities was observed.169 Recently, 2 cases were described in which transient hemiballismus was the result of a small hemorrhage or an infarct in the STN.118 Both patients recovered within 4 weeks after the symptoms appeared, without any pharmacological or surgical treatment, supporting this hypothesis. Other authors have suggested that lesions confined to the nucleus were more prone to induce hemiballismus and lesions extending its boundaries could prevent the development of hemiballismus by reducing pallidothalamic outflow.39,49 This hypothesis is supported by the fact that pallidotomies can completely abolish hemiballismus in patients with PD.162 Finally, hemiballismus is not strictly caused by STN lesions. It was also observed in patients with PD after thalamotomy48 and subthalamic DBS.90,123 Although these 2 hypotheses (size and location of the lesion) neither exclude nor invalidate one another,184 the underlying mechanisms of hemiballismus after subthalamotomy have yet to be clarified.

TABLE 3:

Hemiballismus after subthalamotomy or STN lesion in patients with PD*

Authors & YearNo. of Patients w/ HB (total no. of patients)Lesion LocationOnsetPersistenceTreatment
unilateral lesions
 Alvarez et al., 2009814 (89)NAimmediately (n = 13); 7 days (n = 1)persistentpallidotomy
 Barlas et al., 20011 (9)STNimmediately2 wksvalproate
 Chen et al., 20022 (2)1 STNimmediatelypersistentunsuccessful pharmacological treatment
1 STN + Zi3 days2 moshaloperidol & clonazepam
 Coban et al., 20091 (4)NA3 days1 movalproate
 Doshi & Bhatt, 20023 (3)NANAtransientnone
 Inzelberg & Korczyn, 19941 (1)NA1 yr (hemorrhage)persistentunsuccessful pharmacological treatment
 Mamo et al., 196516 (50)9 posterior STN, Zi, Raprl; 3 posterior STN, Zi, Raprl+ thalamus; 4 thalamusimmediatelyup to 10 daysnone
 Merello et al., 20063 (3)NAimmediately1 monone
 Obeso et al., 19971 (5)NA7 daysNANA
 Patel et al., 20032 (26)STNimmediatelypersistentZi DBS
 Rodriguez et al., 19981411 (7)subthalamic region5 daysNANA
 Su et al., 20033 (13)1 STN + Zi3 days4 wksnone
1 lat & anterior STN3 days2 mos
1 medial & lat STN35 days5 mos (died)
 Tseng et al., 20031 (1)STN + Zi + H2 FoF35 days3 wks (died)NA
 Vilela Filho & da Silva, 20022 (23)STN + ZiimmediatelyNAthalamotomy
bilateral lesions
 Alvarez et al., 200516 (18)extending dorsally, medially, & caudally to the STNw/in 48 hrsup to 3 mos (n = 7); up to 1 yr (n = 5); persistent (n = 4)NA
 Merello et al., 20081 (5)NAimmediatelypersistentpallidotomy
 Tseng et al., 20072 (10)STN + Zi + H2 FoF3 wks2 mosnone

FoF = Field of Forel; HB = hemiballismus; Raprl = prelemniscal radiations.

One of these 2 patients was presented in Su et al., 2002.160

Postural Disturbance

Patients with PD may present with postural abnormalities such as neck flexion and camptocormia.83 Patients with postural asymmetry show lateral curvature of the spine with an inclination of the trunk toward the ipsilateral side that is more depleted in dopamine. This instability of posture responds poorly to levodopa.103 Similar postural asymmetry was observed after STN lesioning in nonparkinsonian104 and PD patients.102,159 These patients displayed a body tilt contralateral to the lesion accompanied by head rotation. Head rotations were seen in normal and parkinsonian monkeys in which the STN was lesioned.10,33,67,71 It was proposed that an imbalance of the dopaminergic influence between the lesioned and nonlesioned hemispheres159 and/or the glutamatergic imbalance between the STN and the SNr may occur.86 Finally, transient postural disturbance was also reported after unilateral and bilateral subthalamotomy.110,175

Other Complications

In the series by Alvarez and colleagues8 consisting of 89 patients undergoing unilateral subthalamotomy, some patients presented with transient dysarthria, infection of the scalp, asymptomatic bleeding, and seizures. All of these complications were observed in less than 5% of patients. Speech and dysarthria complications were seen in 3 patients undergoing bilateral STN lesioning. Two of these patients also displayed trunk and gait ataxia.8 Ataxia was associated with larger lesions in those patients.7 Subthalamic nucleus lesions were also shown to induce blepharospasm or ptosis in healthy individuals,126 as well as in PD143 or dystonic patients89 undergoing subthalamotomy to alleviate their symptoms. Finally, neuropsychiatric side effects were also associated with STN alterations, such as hyperphagia,51 hypersexuality,2 and impulse behavior.2,126

Conclusions

The STN plays a pivotal role in the basal ganglia, since it is connected to many other structures within the basal ganglia and to nuclei outside of it. It is widely accepted that its overactivity in patients with PD is one of the pathophysiological causes underlying the cardinal symptoms of PD and dyskinesias. Despite the fact that the STN is the main target for DBS in patients with PD, subthalamotomy remains an alternative surgical option for patients whose conditions are refractory to pharmacological treatment or those who are unable to receive DBS implants due to medical reasons or access limitations. Several studies demonstrated the effectiveness of subthalamotomy in the treatment of PD. It reduces daily levodopa needs and was associated with few, mainly transient, complications. Nevertheless, more clinical evidence is needed to warrant its use as a treatment option for PD.

Acknowledgment

We thank Mrs. Josie Ledford for providing language revision.

Disclosure

V.A.J. received a studentship from the Fonds d'Enseignement et de Recherche (FER) of the Faculté de Pharmacie de l'Université Laval and currently holds a studentship from the Centre de recherche en endocrinologie moléculaire et oncologique et en génomique humaine. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Analysis and interpretation of data: Jourdain. Drafting the article: Jourdain, Schechtmann. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Di Paolo.

References

  • 1

    Abosch ATimmermann LBartley SRietkerk HGWhiting DConnolly PJ: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1112013

  • 2

    Absher JRVogt BAClark DGFlowers DLGorman DGKeyes JW: Hypersexuality and hemiballism due to subthalamic infarction. Neuropsychiatry Neuropsychol Behav Neurol 13:2202292000

  • 3

    Ahlskog JEMuenter MD: Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:4484582001

  • 4

    Albin RLGreenamyre JT: Alternative excitotoxic hypotheses. Neurology 42:7337381992

  • 5

    Alvarez Gonzalez LMacias RGuridi JLopez GMaragoto CTeijeiro J: Dorsal subthalamotomy for Parkinson's disease. Ann Neurol 46:4924931999

  • 6

    Alvarez LMacias RGuridi JLopez GAlvarez EMaragoto C: Dorsal subthalamotomy for Parkinson's disease. Mov Disord 16:72782001

  • 7

    Alvarez LMacias RLopez GAlvarez EPavon NRodriguez-Oroz MC: Bilateral subthalamotomy in Parkinson's disease: initial and long-term response. Brain 128:5705832005

  • 8

    Alvarez LMacias RPavón NLópez GRodríguez-Oroz MCRodríguez R: Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: results in 89 patients followed for up to 36 months. J Neurol Neurosurg Psychiatry 80:9799852009

  • 9

    Alvarez LMacias RPavon NRodriguez MCOObeso JA: Motor and cognitive effects of subthalamic nucleotomy in one hundred patients with Parkinson's disease. Mov Disord 24:Suppl 1S4572009. (Abstract)

  • 10

    Andrén PELevin EDLiminga UGunne L: Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset. Brain Res Bull 36:3013071995

  • 11

    Andy OJ: Diencephalic coagulation in the treatment of hemiballismus. Confin Neurol 22:3463501962

  • 12

    Andy OJBrowne JS: Diencephalic coagulation in the treatment of hemiballismus. Surg Forum 10:7957991960

  • 13

    Andy OJJurko MF: Alteration in Parkinson tremor during electrode insertion. Confin Neurol 26:3783811965

  • 14

    Andy OJJurko MFSias FR Jr: Subthalamotomy in treatment of Parkinsonian tremor. J Neurosurg 20:8608701963

  • 15

    Aristieta AAzkona GSagarduy AMiguelez CRuiz-Ortega JASanchez-Pernaute R: The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats. PLoS ONE 7:e426522012

  • 16

    Aziz TZNandi DParkin SLiu XGiladi NBain P: Targeting the subthalamic nucleus. Stereotact Funct Neurosurg 77:87902001

  • 17

    Aziz TZPeggs DAgarwal ESambrook MACrossman AR: Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg 6:5755821992

  • 18

    Aziz TZPeggs DSambrook MACrossman AR: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 6:2882921991

  • 19

    Bacci JJAbsi HManrique CBaunez CSalin PKerkerian-Le Goff L: Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus. Eur J Neurosci 20:333133412004

  • 20

    Barlas OHanağasi HAImer MSahin HASencer SEmre M: Do unilateral ablative lesions of the subthalamic nucleu in parkinsonian patients lead to hemiballism?. Mov Disord 16:3063102001

  • 21

    Baron MSWichmann TMa DDeLong MR: Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J Neurosci 22:5925992002

  • 22

    Benabid ALChabardes SMitrofanis JPollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 8:67812009

  • 23

    Bergman HWichmann TDeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:143614381990

  • 24

    Bertrand CHardy JMolina-Negro PMartinez NOptimum physiological target for the arrest of tremor. Gillingham FJDonaldson IML: Third Symposium on Parkinson's Disease EdinburghLivingstone1969. 251259

  • 25

    Bickel SAlvarez LMacias RPavon NLeon MFernandez C: Cognitive and neuropsychiatric effects of subthalamotomy for Parkinson's disease. Parkinsonism Relat Disord 16:5355392010

  • 26

    Bilbao GRuiz-Ortega JAMiguens NUlibarri ILinazasoro GGómez-Urquijo S: Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment. Brain Res 1084:1751842006

  • 27

    Blandini FGarcia-Osuna MGreenamyre JT: Subthalamic ablation reverses changes in basal ganglia oxidative metabolism and motor response to apomorphine induced by nigrostriatal lesion in rats. Eur J Neurosci 9:140714131997

  • 28

    Blandini FGreenamyre JT: Effect of subthalamic nucleus lesion on mitochondrial enzyme activity in rat basal ganglia. Brain Res 669:59661995

  • 29

    Blandini FPorter RHGreenamyre JT: Autoradiographic study of mitochondrial complex I and glutamate receptors in the basal ganglia of rats after unilateral subthalamic lesion. Neurosci Lett 186:991021995

  • 30

    Boraud TBezard EGuehl DBioulac BGross C: Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res 787:1571601998

  • 31

    Brouillet EBeal MF: NMDA antagonists partially protect against MPTP induced neurotoxicity in mice. Neuroreport 4:3873901993

  • 32

    Burbaud PGross CBenazzouz ACoussemacq MBioulac B: Reduction of apomorphine-induced rotational behaviour by subthalamic lesion in 6-OHDA lesioned rats is associated with a normalization of firing rate and discharge pattern of pars reticulata neurons. Exp Brain Res 105:48581995

  • 33

    Butler EGBourke DWFinkelstein DIHorne MK: The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys. J Clin Neurosci 4:2182271997

  • 34

    Carpenter MB: Ballism associated with partial destruction of the subthalamic nucleus of luys. Neurology 5:4794891955

  • 35

    Carpenter MBWhittier JRMettler FA: Analysis of choreoid hyperkinesia in the Rhesus monkey; surgical and pharmacological analysis of hyperkinesia resulting from lesions in the subthalamic nucleus of Luys. J Comp Neurol 92:2933311950

  • 36

    Carvalho GANikkhah G: Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions. Exp Neurol 171:4054172001

  • 37

    Centonze DGubellini PRossi SPicconi BPisani ABernardi G: Subthalamic nucleus lesion reverses motor abnormalities and striatal glutamatergic overactivity in experimental parkinsonism. Neuroscience 133:8318402005

  • 38

    Cerquetti DObeso JAMerello M: Neuronal discharge patterns in the globus pallidus pars interna in a patient with Parkinson's disease and hemiballismus secondary to subthalamotomy. Exp Brain Res 213:4474552011

  • 39

    Chen CCLee STWu TChen CJHuang CCLu CS: Hemiballism after subthalamotomy in patients with Parkinson's disease: report of 2 cases. Mov Disord 17:136713712002

  • 40

    Chen LLiu ZTian ZWang YLi S: Prevention of neurotoxin damage of 6-OHDA to dopaminergic nigral neuron by subthalamic nucleus lesions. Stereotact Funct Neurosurg 75:66752000

  • 41

    Coban AHanagasi HAKaramursel SBarlas O: Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease. Br J Neurosurg 23:23292009

  • 42

    Crozier SLehéricy SVerstichel PMasson CMasson M: Transient hemiballism/hemichorea due to an ipsilateral subthalamic nucleus infarction. Neurology 46:2672681996

  • 43

    De Bie RMSchuurman PREsselink RAJBosch DASpeelman JD: Bilateral pallidotomy in Parkinson's disease: a retrospective study. Mov Disord 17:5335382002

  • 44

    Delfs JMCiaramitaro VMParry TJChesselet MF: Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats. J Neurosci 15:656265751995

  • 45

    Deligny CDrapier SVerin MLajat YRaoul SDamier P: Bilateral subthalamotomy through DBS electrodes: a rescue option for device-related infection. Neurology 73:124312442009

  • 46

    Dewey RB JrJankovic J: Hemiballism-hemichorea. Clinical and pharmacologic findings in 21 patients. Arch Neurol 46:8628671989

  • 47

    Diederich NGoetz CGStebbins GTKlawans HLNittner KKoulosakis A: Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson's disease. Neurology 42:131113141992

  • 48

    Dierssen GGioino GGCooper IS: Participation of ipsilateral hemisphere lesions in the pathology of hemichorea and hemiballismus. Neurology 11:8948981961

  • 49

    Doshi PBhatt M: Hemiballism during subthalamic nucleus lesioning. Mov Disord 17:8488492002

  • 50

    Eskandar ENFlaherty ACosgrove GRShinobu LABarker FG II: Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, short-term outcomes, and hospital charges in a nationwide sample. J Neurosurg 99:8638712003

  • 51

    Etemadifar MAbtahi SHAbtahi SMMirdamadi MSajjadi SGolabbakhsh A: Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med 2012:7685802012

  • 52

    Fahn SOakes DShoulson IKieburtz KRudolph ALang A: Levodopa and the progression of Parkinson's disease. N Engl J Med 351:249825082004

  • 53

    Fasano ADaniele AAlbanese A: Treatment of motor and non-motor features of Parkinson's disease with deep brain stimulation. Lancet Neurol 11:4294422012

  • 54

    Fox SHKatzenschlager RLim SYRavina BSeppi KCoelho M: The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the motor symptoms of Parkinson's disease. Mov Disord 26:Suppl 3S2S412011

  • 55

    Ghika JGhika-Schmid FFankhauser HAssal GVingerhoets FAlbanese A: Bilateral contemporaneous posteroventral pallidotomy for the treatment of Parkinson's disease: neuropsychological and neurological side effects. Report of four cases and review of the literature. J Neurosurg 91:3133211999

  • 56

    Ghika-Schmid FGhika JRegli FBogousslavsky J: Hyperkinetic movement disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol Sci 146:1091161997

  • 57

    Gill SSHeywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson's disease. Lancet 350:12241997

  • 58

    Gill SSHeywood P: Bilateral subthalamic nucleotomy can be accomplished safely. Mov Disord 13:Suppl 22011998

  • 59

    Gill SSHeywood PSubthalamic nucleus lesions. Lozano AM: Movement Disorder Surgery BaselKarger2000. 15:188195

  • 60

    Gilmour TPLieu CANolt MJPiallat BDeogaonkar MSubramanian T: The effects of chronic levodopa treatments on the neuronal firing properties of the subthalamic nucleus and substantia nigra reticulata in hemiparkinsonian rhesus monkeys. Exp Neurol 228:53582011

  • 61

    Grandas FHemiballismus. Weiner WJTolosa E: Handbook of Clinical Neurology: Hyperkinetic Movement Disorders AmsterdamElsevier2011. 100:249260

  • 62

    Greene JGGreenamyre JT: Bioenergetics and glutamate excitotoxicity. Prog Neurobiol 48:6136341996

  • 63

    Guridi JHerrero MTLuquin MRGuillén JRuberg MLaguna J: Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. Brain 119:171717271996

  • 64

    Guridi JHerrero MTLuquin RGuillen JObeso JA: Subthalamotomy improves MPTP-induced parkinsonism in monkeys. Stereotact Funct Neurosurg 62:981021994

  • 65

    Guridi JObeso JA: The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma. Brain 124:5192001

  • 66

    Hamada IDeLong MR: Excitotoxic acid lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding. J Neurophysiol 68:185918661992

  • 67

    Hammond CFeger JBioulac BSouteyrand JP: Experimental hemiballism in the monkey produced by unilateral kainic acid lesion in corpus Luysii. Brain Res 171:5775801979

  • 68

    Hanağası HABarlas O: Unilateral ablative lesions of the subthalamic nucleus in moderate-to-advanced Parkinson's disease. Arch Neuropsychiatry 48:1141182011

  • 69

    Hariz MIPallidotomy for Parkinson's disease. Lozano AMGildenberg PLTasker RR: Textbook of Stereotactic and Functional Neurosurgery ed 2BerlinSpringer-Verlag2009. 15391548

  • 70

    Heimer GBar-Gad IGoldberg JABergman H: Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of parkinsonism. J Neurosci 22:785078552002

  • 71

    Henderson JMAnnett LETorres EMDunnett SB: Behavioural effects of subthalamic nucleus lesions in the hemiparkinsonian marmoset (Callithrix jacchus). Eur J Neurosci 10:6896981998

  • 72

    Hirashima YIkeda HAsahi TShibata TNoguchi KShima F: Mechanical injury of the subthalamic area during stereotactic surgery followed by improvement of trunk, neck, and face tremor—case report. Neurol Med Chir (Tokyo) 45:4844862005

  • 73

    Hooper AKOkun MSFoote KDFernandez HHJacobson CZeilman P: Clinical cases where lesion therapy was chosen over deep brain stimulation. Stereotact Funct Neurosurg 86:1471522008

  • 74

    Houdart RCophignon JDondey M: [Comparison of the effects of limited thalamic and sub-thalamic stereotaxic lesions.]. Confin Neurol 27:2462501966. (Fr)

  • 75

    Houdart RMamo HDondey MCophignon J: [Results of subthalamic coagulations in Parkinson's disease (apropos of 50 cases).]. Rev Neurol (Paris) 112:5215291965. (Fr)

  • 76

    Hughes BEvaluation of the subthalamic lesion in parkinsonism. Gillingham FJDonaldson IML: Third Symposium on Parkinson's Disease EdinburghLivingstone1969. 260261

  • 77

    Hullay JVelok JGombi RBoczàn G: Subthalamotomy in Parkinson's disease. Confin Neurol 32:3453481970

  • 78

    Hutchinson WDLevy RDostrovsky JOLozano AMLang AE: Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol 42:7677751997

  • 79

    Hutchison WDAllan RJOpitz HLevy RDostrovsky JOLang AE: Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol 44:6226281998

  • 80

    Hwang YSShim ILee BBChang JW: Effect of subthalamic nucleus lesions in a 6-hydroxydopamine-induced rat parkinsonian model: behavioral and biochemical studies. J Neurosurg 105:2842872006

  • 81

    Inzelberg RKorczyn AD: Persistent hemiballism in Parkinson's disease. J Neurol Neurosurg Psychiatry 57:101310141994

  • 82

    Ito Z: Stimulation and destruction of the prelemniscal radiation or its adjacent area in various extrapyramidal disorders. Confin Neurol 37:41481975

  • 83

    Jankovic J: Camptocormia, head drop and other bent spine syndromes: heterogeneous etiology and pathogenesis of Parkinsonian deformities. Mov Disord 25:5275282010

  • 84

    Jeon MFHa YCho YHLee BHPark YGChang JW: Effect of ipsilateral subthalamic nucleus lesioning in a rat parkinsonian model: study of behavior correlated with neuronal activity in the pedunculopontine nucleus. J Neurosurg 99:7627672003

  • 85

    Jourdain VSchechtmann G: Stereotactic neurosurgery for movement disorders in a world perspective. Results from the WSSFN-supported survey. Mov Disord 27:S1672012

  • 86

    Jourdain VAGrégoire LMorissette MMorin NParent MDi Paolo T: Potentiation of response to low doses of levodopa in MPTP-injected monkeys by chemical unilateral subthalamotomy. Laboratory investigation. J Neurosurg 118:1801912013

  • 87

    Keep MFMastrofrancesco LErdman DMurphy BAshby LS: Gamma knife subthalamotomy for Parkinson disease: the subthalamic nucleus as a new radiosurgical target. Case report. J Neurosurg 97:5 Suppl5925992002

  • 88

    Kishore ATurnbull IMSnow BJde la Fuente-Fernandez RSchulzer MMak E: Efficacy, stability and predictors of outcome of pallidotomy for Parkinson's disease. Six-month follow-up with additional 1-year observations. Brain 120:7297371997

  • 89

    Klostermann WVieregge PKörtke DKömpf D: [Apraxia in eyelid opening after stereotactic sub-thalmotomy. Case report and review of the literature.]. Nervenarzt 64:6636671993. (Ger)

  • 90

    Krack PBatir AVan Blercom NChabardes SFraix VArdouin C: Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 349:192519342003

  • 91

    Krack PLimousin PBenabid ALPollak P: Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson's disease. Lancet 350:16761997

  • 92

    Krauss JKPohle TBorremans JJ: Hemichorea and hemiballism associated with contralateral hemiparesis and ipsilateral basal ganglia lesions. Mov Disord 14:4975011999

  • 93

    Künzle H: An autoradiographic analysis of the efferent connections from premotor and adjacent prefrontal regions (areas 6 and 9) in Macaca fascicularis. Brain Behav Evol 15:1852341978

  • 94

    Laitinen LV: Short-term results of stereotaxic treatment for infantile cerebral palsy. Confin Neurol 26:2582631965

  • 95

    Lavoie BParent A: Pedunculopontine nucleus in the squirrel monkey: cholinergic and glutamatergic projections to the substantia nigra. J Comp Neurol 344:2322411994

  • 96

    Levandis GBazzini EArmentero MTNappi GBlandini F: Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease. Neurobiol Dis 29:1611682008

  • 97

    Levy RDostrovsky JOLang AESime EHutchison WDLozano AM: Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease. J Neurophysiol 86:2492602001

  • 98

    Luquin MRSaldise LGuillén JBelzunegui SSan Sebastián WIzal A: Does increased excitatory drive from the subthalamic nucleus contribute to dopaminergic neuronal death in Parkinson's disease?. Exp Neurol 201:4074152006

  • 99

    Macias RAlvarez EAlvarez LPavon NRodriguez-Oroz MCGuridi J: The evolution of dyskinesias after bilateral subthalamotomy for Parkinson's disease. Mov Disord 19:S2592004

  • 100

    Maltête DChastan NDerrey SDebono BGérardin ELefaucheur R: Microsubthalamotomy effect at day 3: screening for determinants. Mov Disord 24:2862892009

  • 101

    Maltête DDerrey SChastan NDebono BGérardin EFréger P: Microsubthalamotomy: an immediate predictor of long-term subthalamic stimulation efficacy in Parkinson disease. Mov Disord 23:104710502008

  • 102

    Mamo HDondey MCophignon JPialoux PFontelle PHoudart R: Latéro-pulsion transitoire au décours de coagulations sous-thalamiques et thalamiques chez des parkinsoniens. Rev Neurol (Paris) 112:5095201965

  • 103

    Marsden CD: Problems with long-term levodopa therapy for Parkinson's disease. Clin Neuropharmacol 17:Suppl 2S32S441994

  • 104

    Martin JP: Hemichorea resulting from a local lesion of the brain (the syndrome of the body of Luys). Brain 50:6376501927

  • 105

    McCarter RJWalton NHRowan AFGill SSPalomo M: Cognitive functioning after subthalamic nucleotomy for refractory Parkinson's disease. J Neurol Neurosurg Psychiatry 69:60662000

  • 106

    Meier MJStory JFrench LAChou SN: Quantitative assessment of behavioral changes following subthalamotomy in the treatment of Parkinson's disease. Confin Neurol 27:1541611966

  • 107

    Meissner WGFrasier MGasser TGoetz CGLozano APiccini P: Priorities in Parkinson's disease research. Nat Rev Drug Discov 10:3773932011

  • 108

    Melamed EKorn-Lubetzki IReches ASiew F: Hemiballismus: detection of focal hemorrhage in subthalamic nucleus by CT scan. Ann Neurol 4:5821978

  • 109

    Merello MPerez-Lloret SAntico JObeso JA: Dyskinesias induced by subthalamotomy in Parkinson's disease are unresponsive to amantadine. J Neurol Neurosurg Psychiatry 77:1721742006

  • 110

    Merello MTenca EPérez Lloret SMartín MEBruno VCavanagh S: Prospective randomized 1-year follow-up comparison of bilateral subthalamotomy versus bilateral subthalamic stimulation and the combination of both in Parkinson's disease patients: a pilot study. Br J Neurosurg 22:4154222008

  • 111

    Mitchell IJSambrook MACrossman AR: Subcortical changes in the regional uptake of [3H]-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus. Brain 108:4054221985

  • 112

    Mundinger FResults of 500 subthalamotomies in the region of the zona incerta. Gillingham FJDonaldson IML: Third Symposium on Parkinson's Disease EdinburghLivingstone1969. 261265

  • 113

    Mundinger F: Stereotaxic interventions on the zona incerta area for treatment of extrapyramidal motor disturbances and their results. Confin Neurol 26:2222301965

  • 114

    Murer MGRiquelme LATseng KYPazo JH: Substantia nigra pars reticulata single unit activity in normal and 60HDA-lesioned rats: effects of intrastriatal apomorphine and subthalamic lesions. Synapse 27:2782931997

  • 115

    Nakao NNakai ENakai KItakura T: Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3-nitropropionic acid. Ann Neurol 45:6406511999

  • 116

    Narabayashi HKubota K: Reconsideration of ventrolateral thalamotomy for hyperkinesis. Prog Brain Res 21:3393491966

  • 117

    Ni ZBouali-Benazzouz RGao DBenabid ALBenazzouz A: Changes in the firing pattern of globus pallidus neurons after the degeneration of nigrostriatal pathway are mediated by the subthalamic nucleus in the rat. Eur J Neurosci 12:433843442000

  • 118

    Nishioka HTaguchi TNanri KIkeda Y: Transient hemiballism caused by a small lesion of the subthalamic nucleus. J Clin Neurosci 15:141614182008

  • 119

    Nittner K: The combined thalamo-subthalamotomy. Confin Neurol 32:93991970

  • 120

    Obeso JAAlvarez LGuridi JTeijeiro JJuncos JLRodriguez MC: Lesion of the subthalamic nucleus (STN) in Parkinson's disease. Neurology 48:A1381997

  • 121

    Obeso JAAlvarez LMacias RPavon NLopez GRodriguez-Rojas R: Subthalamotomy for Parkinson's disease. Lozano AMGildenberg PLTasker RR: Textbook of Stereotactic and Functional Neurosurgery ed 2BerlinSpringer-Verlag2011. 15691576

  • 122

    Obeso JAJahanshahi MAlvarez LMacias RPedroso IWilkinson L: What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease. Exp Neurol 220:2832922009

  • 123

    Pahwa RWilkinson SBOverman JLyons KE: Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up. J Neurosurg 99:71772003

  • 124

    Papa SMDesimone RFiorani MOldfield EH: Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias. Ann Neurol 46:7327381999

  • 125

    Paquet MTremblay MSoghomonian JJSmith Y: AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study. J Neurosci 17:137713961997

  • 126

    Park HKKim HJKim SJKim JSShin HWKim JS: From Jekyll to Hyde after limbic subthalamic nucleus infarction. Neurology 77:82842011

  • 127

    Park YSJeon MFLee BHChang JW: Lesion of subthalamic nucleus in parkinsonian rats: effects of dopamine d(1) and d(2) receptor agonists on the neuronal activities of the substantia nigra pars reticulata. J Korean Neurosurg Soc 42:4554612007

  • 128

    Parkin SNandi DGiladi NJoint CGregory RBain P: Lesioning the subthalamic nucleus in the treatment of Parkinson's disease. Stereotact Funct Neurosurg 77:68722001

  • 129

    Patel NKHeywood PO'Sullivan KLove SGill SS: MRI-directed subthalamic nucleus surgery for Parkinson's disease. Stereotact Funct Neurosurg 78:1321452002

  • 130

    Patel NKHeywood PO'Sullivan KMcCarter RLove SGill SS: Unilateral subthalamotomy in the treatment of Parkinson's disease. Brain 126:113611452003

  • 131

    Paul GMeissner WRein SHarnack DWinter CHosmann K: Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease. Exp Neurol 185:2722802004

  • 132

    Périer CMarin CJimenez ABonastre MTolosa EHirsch EC: Effect of subthalamic nucleus or entopeduncular nucleus lesion on levodopa-induced neurochemical changes within the basal ganglia and on levodopa-induced motor alterations in 6-hydroxydopamine-lesioned rats. J Neurochem 86:132813372003

  • 133

    Piallat BBenazzouz ABenabid AL: Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci 8:140814141996

  • 134

    Postuma RBLang AE: Hemiballism: revisiting a classic disorder. Lancet Neurol 2:6616682003

  • 135

    Pourfar MTang CLin TDhawan VKaplitt MGEidelberg D: Assessing the microlesion effect of subthalamic deep brain stimulation surgery with FDG PET. Clinical article. J Neurosurg 110:127812822009

  • 136

    Price RH JrHollingsworth ZYoung ABPenney JB Jr: Excitatory amino acid receptor regulation after subthalamic nucleus lesions in the rat. Brain Res 602:1571601993

  • 137

    Remple MSBradenham CHKao CCCharles PDNeimat JSKonrad PE: Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression. Mov Disord 26:165716622011

  • 138

    Renard DLe Floch ACastelnovo GCollombier LKotzki POLabauge P: Hemiballism due to an ipsilateral subthalamic nucleus lesion. J Neurol 258:5075092011

  • 139

    Ristic AMarinkovic JDragasevic NStanisavljevic DKostić V: Long-term prognosis of vascular hemiballismus. Stroke 33:210921112002

  • 140

    Rizelio VSzawka REXavier LLAchaval MRigon PSaur L: Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease. Braz J Med Biol Res 43:85952010

  • 141

    Rodriguez MCGuridi OJAlvarez LMewes KMacias RVitek J: The subthalamic nucleus and tremor in Parkinson's disease. Mov Disord 13:Suppl 31111181998

  • 142

    Rodriguez MCObeso JAOlanow CW: Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 44:3 Suppl 1S175S1881998

  • 143

    Rogano LAAssis MTeixeira MJ: [Horner syndrome after stereotactic Parkinson disease surgery.]. Arq Neuropsiquiatr 61:2A2482492003. (Portugese)

  • 144

    Ryan LJSanders DJ: Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats. Brain Res 626:3273311993

  • 145

    Schechtmann GJourdain V: Health economics and surgical treatment for Parkinson's disease in a world perspective. Mov Disord 28:Suppl 112992013. (Abstract)

  • 146

    Selby G: Stereotactic surgery for the relief of Parkinson's disease. 1. A critical review. J Neurol Sci 5:3153421967

  • 147

    Sellal FHirsch ELisovoski FMutschler VCollard MMarescaux C: Contralateral disappearance of parkinsonian signs after subthalamic hematoma. Neurology 42:2552561992

  • 148

    Shimo YWichmann T: Neuronal activity in the subthalamic nucleus modulates the release of dopamine in the monkey striatum. Eur J Neurosci 29:1041132009

  • 149

    Smith IDGrace AA: Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity. Synapse 12:2873031992

  • 150

    Smith YCharara AParent A: Synaptic innervation of midbrain dopaminergic neurons by glutamate-enriched terminals in the squirrel monkey. J Comp Neurol 364:2312531996

  • 151

    Smith YParent A: Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity. Brain Res 453:3533561988

  • 152

    Spiegel EAWycis HTSzekely EGAdams DJFlanagan MBaird HW III: Campotomy in various extrapyramidal disorders. J Neurosurg 20:8718841963

  • 153

    Spottke EAVolkmann JLorenz DKrack PSmala AMSturm V: Evaluation of healthcare utilization and health status of patients with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus. J Neurol 249:7597662002

  • 154

    Story JLFrench LAChou SNMeier MJ: Experiences with subthalamic lesions in patients with movement disorders. Confin Neurol 26:2182211965

  • 155

    Struppler ABurg DLücking CHVelho F: The mode of innervation following thalamotomy and subthalamotomy. Confin Neurol 36:3473541974

  • 156

    Strutt AMSimpson RJankovic JYork MK: Changes in cognitive-emotional and physiological symptoms of depression following STN-DBS for the treatment of Parkinson's disease. Eur J Neurol 19:1211272012

  • 157

    Su PCMa YFukuda MMentis MJTseng HMYen RF: Metabolic changes following subthalamotomy for advanced Parkinson's disease. Ann Neurol 50:5145202001

  • 158

    Su PCTseng HM: Subthalamotomy for end-stage severe Parkinson's disease. Mov Disord 17:6256272002. (Letter)

  • 159

    Su PCTseng HMLiou HH: Postural asymmetries following unilateral subthalomotomy for advanced Parkinson's disease. Mov Disord 17:1911942002

  • 160

    Su PCTseng HMLiu HMYen RFLiou HH: Subthalamotomy for advanced Parkinson disease. J Neurosurg 97:5986062002

  • 161

    Su PCTseng HMLiu HMYen RFLiou HH: Treatment of advanced Parkinson's disease by subthalamotomy: one-year results. Mov Disord 18:5315382003

  • 162

    Suarez JIMetman LVReich SGDougherty PMHallett MLenz FA: Pallidotomy for hemiballismus: efficacy and characteristics of neuronal activity. Ann Neurol 42:8078111997

  • 163

    Tachibana YIwamuro HKita HTakada MNambu A: Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia. Eur J Neurosci 34:147014842011

  • 164

    Takada MMatsumura MKojima JYamaji YInase MTokuno H: Protection against dopaminergic nigrostriatal cell death by excitatory input ablation. Eur J Neurosci 12:177117802000

  • 165

    Tarsy D: Does subthalamotomy have a place in the treatment of Parkinson's disease?. J Neurol Neurosurg Psychiatry 80:9399402009

  • 166

    Touchon JCMoore CFrederickson JMeshul CK: Lesion of subthalamic or motor thalamic nucleus in 6-hydroxydopamine-treated rats: effects on striatal glutamate and apomorphine-induced contralateral rotations. Synapse 51:2872982004

  • 167

    Toulouse ASullivan AM: Progress in Parkinson's disease—where do we stand?. Prog Neurobiol 85:3763922008

  • 168

    Trost MSu PCBarnes ASu SLYen RFTseng HM: Evolving metabolic changes during the first postoperative year after subthalamotomy. J Neurosurg 99:8728782003

  • 169

    Tseng HMSu PCLiu HM: Persistent hemiballism after subthalamotomy: the size of the lesion matters more than the location. Mov Disord 18:120912112003

  • 170

    Tseng HMSu PCLiu HMLiou HHYen RF: Bilateral subthalamotomy for advanced Parkinson disease. Surg Neurol 68:Suppl 1S43S512007

  • 171

    Tseng KYKasanetz FKargieman LPazo JHMurer MGRiquelme LA: Subthalamic nucleus lesions reduce low frequency oscillatory firing of substantia nigra pars reticulata neurons in a rat model of Parkinson's disease. Brain Res 904:931032001

  • 172

    Umemura AOka YOkita KMatsukawa NYamada K: Subthalamic nucleus stimulation for Parkinson disease with severe medication-induced hallucinations or delusions. Clinical article. J Neurosurg 114:170117052011

  • 173

    Velasco FCMolina-Negro PBertrand CHardy J: Further definition of the subthalamic target for arrest of tremor. J Neurosurg 36:1841911972

  • 174

    Vidaković ADragasević NKostić VS: Hemiballism: report of 25 cases. J Neurol Neurosurg Psychiatry 57:9459491994

  • 175

    Vilela Filho Oda Silva DJ: Unilateral subthalamic nucleus lesioning: a safe and effective treatment for Parkinson's disease. Arq Neuropsiquiatr 60:9359482002

  • 176

    Vilela Filho OSilva DJSouza HACavalcante JESousa JTFerraz FP: Stereotactic subthalamic nucleus lesioning for the treatment of Parkinson's disease. Stereotact Funct Neurosurg 77:79862001

  • 177

    Vitek JLBakay RAEFreeman AEvatt MGreen JMcDonald W: Randomized trial of pallidotomy versus medical therapy for Parkinson's disease. Ann Neurol 53:5585692003

  • 178

    Voon VFernagut POWickens JBaunez CRodriguez MPavon N: Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders. Lancet Neurol 8:114011492009

  • 179

    Walker RHKoch RJMoore CMeshul CK: Subthalamic nucleus stimulation and lesioning have distinct state-dependent effects upon striatal dopamine metabolism. Synapse 63:1361462009

  • 180

    Walker RHKoch RJSweeney JEMoore CMeshul CK: Effects of subthalamic nucleus lesions and stimulation upon glutamate levels in the dopamine-depleted rat striatum. Neuroreport 20:7707752009

  • 181

    Wallace BAAshkan KHeise CEFoote KDTorres NMitrofanis J: Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain 130:212921452007

  • 182

    Weaver FMFollett KStern MHur KHarris CMarks WJ Jr: Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 301:63732009

  • 183

    Wertheimer PBourret JLapraz C: [Apropos of a case of volitional postural dyskinesia treated with thalamic subthalamic leucotomy.]. Rev Prat 102:4814861960. (Fr)

  • 184

    Whittier JRMettler FA: Studies on the subthalamus of the rhesus monkey; hyperkinesia and other physiologic effects of subthalamic lesions; with special reference to the subthalamic nucleus of Luys. J Comp Neurol 90:3193721949

  • 185

    Wichmann TBergman HDeLong MR: The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 72:5215301994

  • 186

    Wichmann TBergman HStarr PASubramanian TWatts RLDeLong MR: Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 125:3974091999

  • 187

    Winter CHosmann KHarnack DMeissner WPaul GMorgenstern R: Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease. Synapse 60:69802006

  • 188

    Witjas TAzulay JPEusebio APergut JCRégis J: Gamma knife subthalamotomy in Parkinson's disease: long-term follow-up. Mov Disord 24:Suppl 1S4772009. (Abstract)

  • 189

    Wong SHEldridge PRDuffy AFox SHVarma TRKFletcher NA: Two cases of unexpected long-term improvement of Parkinson's disease after subthalamic nucleus deep brain stimulation removal. Br J Neurosurg 25:2812832011

  • 190

    Yamada ATakeuchi HMiki H: [Unilateral abolition of parkinsonian rigidity after subthalamic nucleus hemorrhage.]. Rinsho Shinkeigaku 32:8878891992. (Jpn)

  • 191

    Zahr NMMartin LPWaszczak BL: Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia. Synapse 54:1191282004

  • 192

    Zuddas AOberto GVaglini FFascetti FFornai FCorsini GU: MK-801 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in primates. J Neurochem 59:7337391992

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Thérèse Di Paolo, Ph.D., Neurosciences Research Center, Centre de Recherche du CHU de Québec, CHUL, 2705 Laurier Blvd., Quebec City, QC, Canada, G1V 4G2. email: therese.dipaolo@crchul.ulaval.ca.

Please include this information when citing this paper: published online November 8, 2013; DOI: 10.3171/2013.10.JNS13332.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Abosch ATimmermann LBartley SRietkerk HGWhiting DConnolly PJ: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1112013

2

Absher JRVogt BAClark DGFlowers DLGorman DGKeyes JW: Hypersexuality and hemiballism due to subthalamic infarction. Neuropsychiatry Neuropsychol Behav Neurol 13:2202292000

3

Ahlskog JEMuenter MD: Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:4484582001

4

Albin RLGreenamyre JT: Alternative excitotoxic hypotheses. Neurology 42:7337381992

5

Alvarez Gonzalez LMacias RGuridi JLopez GMaragoto CTeijeiro J: Dorsal subthalamotomy for Parkinson's disease. Ann Neurol 46:4924931999

6

Alvarez LMacias RGuridi JLopez GAlvarez EMaragoto C: Dorsal subthalamotomy for Parkinson's disease. Mov Disord 16:72782001

7

Alvarez LMacias RLopez GAlvarez EPavon NRodriguez-Oroz MC: Bilateral subthalamotomy in Parkinson's disease: initial and long-term response. Brain 128:5705832005

8

Alvarez LMacias RPavón NLópez GRodríguez-Oroz MCRodríguez R: Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: results in 89 patients followed for up to 36 months. J Neurol Neurosurg Psychiatry 80:9799852009

9

Alvarez LMacias RPavon NRodriguez MCOObeso JA: Motor and cognitive effects of subthalamic nucleotomy in one hundred patients with Parkinson's disease. Mov Disord 24:Suppl 1S4572009. (Abstract)

10

Andrén PELevin EDLiminga UGunne L: Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset. Brain Res Bull 36:3013071995

11

Andy OJ: Diencephalic coagulation in the treatment of hemiballismus. Confin Neurol 22:3463501962

12

Andy OJBrowne JS: Diencephalic coagulation in the treatment of hemiballismus. Surg Forum 10:7957991960

13

Andy OJJurko MF: Alteration in Parkinson tremor during electrode insertion. Confin Neurol 26:3783811965

14

Andy OJJurko MFSias FR Jr: Subthalamotomy in treatment of Parkinsonian tremor. J Neurosurg 20:8608701963

15

Aristieta AAzkona GSagarduy AMiguelez CRuiz-Ortega JASanchez-Pernaute R: The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats. PLoS ONE 7:e426522012

16

Aziz TZNandi DParkin SLiu XGiladi NBain P: Targeting the subthalamic nucleus. Stereotact Funct Neurosurg 77:87902001

17

Aziz TZPeggs DAgarwal ESambrook MACrossman AR: Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg 6:5755821992

18

Aziz TZPeggs DSambrook MACrossman AR: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 6:2882921991

19

Bacci JJAbsi HManrique CBaunez CSalin PKerkerian-Le Goff L: Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus. Eur J Neurosci 20:333133412004

20

Barlas OHanağasi HAImer MSahin HASencer SEmre M: Do unilateral ablative lesions of the subthalamic nucleu in parkinsonian patients lead to hemiballism?. Mov Disord 16:3063102001

21

Baron MSWichmann TMa DDeLong MR: Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J Neurosci 22:5925992002

22

Benabid ALChabardes SMitrofanis JPollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 8:67812009

23

Bergman HWichmann TDeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:143614381990

24

Bertrand CHardy JMolina-Negro PMartinez NOptimum physiological target for the arrest of tremor. Gillingham FJDonaldson IML: Third Symposium on Parkinson's Disease EdinburghLivingstone1969. 251259

25

Bickel SAlvarez LMacias RPavon NLeon MFernandez C: Cognitive and neuropsychiatric effects of subthalamotomy for Parkinson's disease. Parkinsonism Relat Disord 16:5355392010

26

Bilbao GRuiz-Ortega JAMiguens NUlibarri ILinazasoro GGómez-Urquijo S: Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment. Brain Res 1084:1751842006

27

Blandini FGarcia-Osuna MGreenamyre JT: Subthalamic ablation reverses changes in basal ganglia oxidative metabolism and motor response to apomorphine induced by nigrostriatal lesion in rats. Eur J Neurosci 9:140714131997

28

Blandini FGreenamyre JT: Effect of subthalamic nucleus lesion on mitochondrial enzyme activity in rat basal ganglia. Brain Res 669:59661995

29

Blandini FPorter RHGreenamyre JT: Autoradiographic study of mitochondrial complex I and glutamate receptors in the basal ganglia of rats after unilateral subthalamic lesion. Neurosci Lett 186:991021995

30

Boraud TBezard EGuehl DBioulac BGross C: Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res 787:1571601998

31

Brouillet EBeal MF: NMDA antagonists partially protect against MPTP induced neurotoxicity in mice. Neuroreport 4:3873901993

32

Burbaud PGross CBenazzouz ACoussemacq MBioulac B: Reduction of apomorphine-induced rotational behaviour by subthalamic lesion in 6-OHDA lesioned rats is associated with a normalization of firing rate and discharge pattern of pars reticulata neurons. Exp Brain Res 105:48581995

33

Butler EGBourke DWFinkelstein DIHorne MK: The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys. J Clin Neurosci 4:2182271997

34

Carpenter MB: Ballism associated with partial destruction of the subthalamic nucleus of luys. Neurology 5:4794891955

35

Carpenter MBWhittier JRMettler FA: Analysis of choreoid hyperkinesia in the Rhesus monkey; surgical and pharmacological analysis of hyperkinesia resulting from lesions in the subthalamic nucleus of Luys. J Comp Neurol 92:2933311950

36

Carvalho GANikkhah G: Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions. Exp Neurol 171:4054172001

37

Centonze DGubellini PRossi SPicconi BPisani ABernardi G: Subthalamic nucleus lesion reverses motor abnormalities and striatal glutamatergic overactivity in experimental parkinsonism. Neuroscience 133:8318402005

38

Cerquetti DObeso JAMerello M: Neuronal discharge patterns in the globus pallidus pars interna in a patient with Parkinson's disease and hemiballismus secondary to subthalamotomy. Exp Brain Res 213:4474552011

39

Chen CCLee STWu TChen CJHuang CCLu CS: Hemiballism after subthalamotomy in patients with Parkinson's disease: report of 2 cases. Mov Disord 17:136713712002

40

Chen LLiu ZTian ZWang YLi S: Prevention of neurotoxin damage of 6-OHDA to dopaminergic nigral neuron by subthalamic nucleus lesions. Stereotact Funct Neurosurg 75:66752000

41

Coban AHanagasi HAKaramursel SBarlas O: Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease. Br J Neurosurg 23:23292009

42

Crozier SLehéricy SVerstichel PMasson CMasson M: Transient hemiballism/hemichorea due to an ipsilateral subthalamic nucleus infarction. Neurology 46:2672681996

43

De Bie RMSchuurman PREsselink RAJBosch DASpeelman JD: Bilateral pallidotomy in Parkinson's disease: a retrospective study. Mov Disord 17:5335382002

44

Delfs JMCiaramitaro VMParry TJChesselet MF: Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats. J Neurosci 15:656265751995

45

Deligny CDrapier SVerin MLajat YRaoul SDamier P: Bilateral subthalamotomy through DBS electrodes: a rescue option for device-related infection. Neurology 73:124312442009

46

Dewey RB JrJankovic J: Hemiballism-hemichorea. Clinical and pharmacologic findings in 21 patients. Arch Neurol 46:8628671989

47

Diederich NGoetz CGStebbins GTKlawans HLNittner KKoulosakis A: Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson's disease. Neurology 42:131113141992

48

Dierssen GGioino GGCooper IS: Participation of ipsilateral hemisphere lesions in the pathology of hemichorea and hemiballismus. Neurology 11:8948981961

49

Doshi PBhatt M: Hemiballism during subthalamic nucleus lesioning. Mov Disord 17:8488492002

50

Eskandar ENFlaherty ACosgrove GRShinobu LABarker FG II: Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, short-term outcomes, and hospital charges in a nationwide sample. J Neurosurg 99:8638712003

51

Etemadifar MAbtahi SHAbtahi SMMirdamadi MSajjadi SGolabbakhsh A: Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med 2012:7685802012

52

Fahn SOakes DShoulson IKieburtz KRudolph ALang A: Levodopa and the progression of Parkinson's disease. N Engl J Med 351:249825082004

53

Fasano ADaniele AAlbanese A: Treatment of motor and non-motor features of Parkinson's disease with deep brain stimulation. Lancet Neurol 11:4294422012

54

Fox SHKatzenschlager RLim SYRavina BSeppi KCoelho M: The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the motor symptoms of Parkinson's disease. Mov Disord 26:Suppl 3S2S412011

55

Ghika JGhika-Schmid FFankhauser HAssal GVingerhoets FAlbanese A: Bilateral contemporaneous posteroventral pallidotomy for the treatment of Parkinson's disease: neuropsychological and neurological side effects. Report of four cases and review of the literature. J Neurosurg 91:3133211999

56

Ghika-Schmid FGhika JRegli FBogousslavsky J: Hyperkinetic movement disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol Sci 146:1091161997

57

Gill SSHeywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson's disease. Lancet 350:12241997

58

Gill SSHeywood P: Bilateral subthalamic nucleotomy can be accomplished safely. Mov Disord 13:Suppl 22011998

59

Gill SSHeywood PSubthalamic nucleus lesions. Lozano AM: Movement Disorder Surgery BaselKarger2000. 15:188195

60

Gilmour TPLieu CANolt MJPiallat BDeogaonkar MSubramanian T: The effects of chronic levodopa treatments on the neuronal firing properties of the subthalamic nucleus and substantia nigra reticulata in hemiparkinsonian rhesus monkeys. Exp Neurol 228:53582011

61

Grandas FHemiballismus. Weiner WJTolosa E: Handbook of Clinical Neurology: Hyperkinetic Movement Disorders AmsterdamElsevier2011. 100:249260

62

Greene JGGreenamyre JT: Bioenergetics and glutamate excitotoxicity. Prog Neurobiol 48:6136341996

63

Guridi JHerrero MTLuquin MRGuillén JRuberg MLaguna J: Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. Brain 119:171717271996

64

Guridi JHerrero MTLuquin RGuillen JObeso JA: Subthalamotomy improves MPTP-induced parkinsonism in monkeys. Stereotact Funct Neurosurg 62:981021994

65

Guridi JObeso JA: The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma. Brain 124:5192001

66

Hamada IDeLong MR: Excitotoxic acid lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding. J Neurophysiol 68:185918661992

67

Hammond CFeger JBioulac BSouteyrand JP: Experimental hemiballism in the monkey produced by unilateral kainic acid lesion in corpus Luysii. Brain Res 171:5775801979

68

Hanağası HABarlas O: Unilateral ablative lesions of the subthalamic nucleus in moderate-to-advanced Parkinson's disease. Arch Neuropsychiatry 48:1141182011

69

Hariz MIPallidotomy for Parkinson's disease. Lozano AMGildenberg PLTasker RR: Textbook of Stereotactic and Functional Neurosurgery ed 2BerlinSpringer-Verlag2009. 15391548

70

Heimer GBar-Gad IGoldberg JABergman H: Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of parkinsonism. J Neurosci 22:785078552002

71

Henderson JMAnnett LETorres EMDunnett SB: Behavioural effects of subthalamic nucleus lesions in the hemiparkinsonian marmoset (Callithrix jacchus). Eur J Neurosci 10:6896981998

72

Hirashima YIkeda HAsahi TShibata TNoguchi KShima F: Mechanical injury of the subthalamic area during stereotactic surgery followed by improvement of trunk, neck, and face tremor—case report. Neurol Med Chir (Tokyo) 45:4844862005

73

Hooper AKOkun MSFoote KDFernandez HHJacobson CZeilman P: Clinical cases where lesion therapy was chosen over deep brain stimulation. Stereotact Funct Neurosurg 86:1471522008

74

Houdart RCophignon JDondey M: [Comparison of the effects of limited thalamic and sub-thalamic stereotaxic lesions.]. Confin Neurol 27:2462501966. (Fr)

75

Houdart RMamo HDondey MCophignon J: [Results of subthalamic coagulations in Parkinson's disease (apropos of 50 cases).]. Rev Neurol (Paris) 112:5215291965. (Fr)

76

Hughes BEvaluation of the subthalamic lesion in parkinsonism. Gillingham FJDonaldson IML: Third Symposium on Parkinson's Disease EdinburghLivingstone1969. 260261

77

Hullay JVelok JGombi RBoczàn G: Subthalamotomy in Parkinson's disease. Confin Neurol 32:3453481970

78

Hutchinson WDLevy RDostrovsky JOLozano AMLang AE: Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol 42:7677751997

79