Movement disorders
SHORT REPORT
Effect of stimulation frequency on immediate freezing of gait in newly activated STN DBS in Parkinson’s disease Tao Xie,1 Un Jung Kang,1 Peter Warnke2 < Additional videos are
published online only. To view these files please visit the journal online (http://dx.doi.org/ 10.1136/jnnp-2011-302091). 1
Department of Neurology, University of Chicago Medical Center, Chicago, Illinois, USA 2 Department of Neurosurgery, University of Chicago Medical Center, Chicago, Illinois, USA Correspondence to Dr Tao Xie, Assistant Professor, Department of Neurology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637, USA;
[email protected] Received 21 December 2011 Revised 15 April 2012 Accepted 18 April 2012 Published Online First 13 June 2012
ABSTRACT Background Patients with Parkinson’s disease (PD) may develop freezing of gait (FOG) with chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) at the commonly used frequency of 130 Hz and FOG can be ameliorated by 60 Hz stimulation in some patients. It is not clear whether the development of FOG is due to the disease progression or the chronic stimulation at this 130 Hz frequency. Aims To investigate the effect of stimulation frequency on immediate FOG in newly activated STN DBS patient with PD and determine if stimulation frequency alone could affect the FOG. Methods Two cases of PD who developed FOG immediately upon activation of the newly placed STN DBS were studied for the effect of stimulation frequency on FOG in both ‘off’ and ‘on’ medication status. Results Both patients developed severe FOG with the commonly used 130 Hz stimulation. Switching the frequency to 60 Hz immediately alleviated the FOG, without change in contacts, voltages and pulse widths. This frequency effect on FOG was present in both ‘off’ and ‘on’ statuses and remained effective during the 10month follow-up period. Conclusion These two cases demonstrate that lower frequency stimulation of 60 Hz could improve FOG, while the commonly used 130 Hz stimulation could cause FOG or make it worse. In addition, the beneficial effect of low frequency DBS was additive to dopaminergic medication effect and included other axial symptoms. Patients with Parkinson’s disease (PD) may develop freezing of gait (FOG) after chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) at the commonly used stimulation frequency of 130 Hz.1e4 The FOG episodes have been shown to be ameliorated by 60 Hz stimulation in some of these patients.1e4 In these reports, FOG was noted several years after DBS and may have resulted from the disease progression or the chronic stimulation at 130 Hz frequency. Here, we report two cases of PD who developed FOG immediately upon activation of the newly placed STN DBS with the commonly used 130 Hz stimulation. Switching the frequency to 60 Hz immediately ameliorated FOG, demonstrating the effect of stimulation frequency on FOG without being confounded by the effect of chronic stimulation or disease progression. Furthermore, we show the effect of low frequency DBS in the ‘on’ medication state and on other axial symptoms.
J Neurol Neurosurg Psychiatry 2012;83:1015e1017. doi:10.1136/jnnp-2011-302091
Case 1 is a 61-year-old man with a 7-year history of PD, starting with resting tremor in hands, generalised rigidity and bradykinesia. His symptoms responded well to rasagiline, pramipexole and carbidopa/levodopa until 4 years later when he developed motor fluctuation and peak-dose dyskinesia. FOG and frequent falls were present more during ‘off ’ than on periods. All his off motor symptoms responded well to dopaminergic medications (total levodopa equivalent dose of more than 2000 mg daily) except that about 20% of FOG still persisted even when he was at his best on state. UPDRS-III Score (unified PD rating scale, motor section) reduced by 56% when he was on (score of 22) compared with his off state 12 h after his last dose of medications (score of 50). He developed medication side effects including excessive daytime sleepiness, tactile hallucination and orthostatic hypotension. He subsequently had a bilateral STN DBS placement (Medtronic 3389, Medtronic, Minneapolis, Minnesota, USA), with the bottom contact (contact 0 or 4) targeting the base of the STN at 12 mm lateral to the midline, 6 mm below the anterior commissureeposterior commissure line and 2 mm posterior to the midcommissural point. The electrode position was verified by postsurgical CT fused to the planning MRI with superimposed SchaltenbrandeWharen atlas (figure 1). He developed mild microlesion benefit after the surgery. His DBS was first activated 2 weeks postsurgically after he had been off the medications for 8 h, using contacts of case+/2with an amplitude of 2.2 volts, pulse width of 60 ms and frequency of 130 Hz on the left, and the same contact settings and parameters on the right except for an amplitude of 2.0 volts (Kinetra, Medtronic). His FOG immediately worsened once his DBS was turned on (online Case-1 Video segment, ‘Off Medications, On DBS 130 Hz’), which was immediately and dramatically improved after the frequency was switched to 60 Hz on both sides (online Case-1 Video segment, ‘Off Medications, On DBS 60 Hz’), without changing the rest of his DBS parameters. His UPDRS-III Scores were 33 in his off DBS state, 39 with 130 Hz and 27 with 60 Hz stimulation. The frequency effect on the gait was present in both off and on medication states, and remained stable at his 10-month follow-up visit. He had no FOG on medication and 60 Hz stimulation at his 10-month visit (online Case-1 Video segment ‘On Medications, On DBS 60 Hz’). 1015
Movement disorders
Figure 1 Postsurgical head CT fused with T2 brain MRI, with axial imaging showing the location of the bilateral deep brain stimulation leads at subthalamic nucleus, with superimposed SchaltenbrandeWharen atlas and trajectory, in case 1.
Figure 2 Postsurgical head CT fused with T2 brain MRI, with axial imaging showing the location of the bilateral deep brain stimulation leads at subthalamic nucleus, with superimposed SchaltenbrandeWharen atlas and trajectory, in case 2.
Case 2 is a 67-year-old woman with a 15-year history of PD, starting with resting tremor in hands, generalised rigidity and bradykinesia. She was treated with carbidopa/levodopa and pramipexole and responded well until 8 years later when she developed motor fluctuation and peak-dose dyskinesia. She also developed FOG and frequent falls during off periods. All her off symptoms, including FOG, responded well to dopaminergic medications (levodopa equivalent dose of 2000 mg per day), with medication-related visual hallucination and orthostatic hypotension. UPDRS-III Score was reduced by 76% when she was on (score of 14) compared with off medications for 12 h (score of 58). She subsequently had a successful bilateral STN DBS placement (Medtronic 3389, Medtronic), with the bottom contact targeting the base of the STN at 12 mm lateral to the midline, 5 mm below the anterior commissureeposterior commissure line and 5 mm posterior to the mid-commissural point. Her electrode position was verified by postsurgical CT fused to the planning MRI with superimposed SchaltenbrandeWharen atlas (figure 2). DBS was first activated 2 weeks postsurgically after she had been off the medications for 8 h, using contacts of case+/2- with an amplitude of 3.2 volts, pulse width of 60 ms and frequency of 130 Hz on the left, and the same contact settings and parameters on the right except for an amplitude of 2.3 volts. Her FOG immediately became much worse once the DBS was turned on, with difficulty in taking a step and dramatically improved immediately after the frequency was switched down to 60 Hz on both sides, with the rest of DBS parameters unchanged. Her UPDRS-III Scores were 37 at off DBS, 41 with 130 Hz and 24 with 60 Hz stimulation. The frequency effect on the gait was present in both off and on medication states, and remained stable in her 10-month followup visit (online Case-2 Video segments ‘On Medications, On DBS 130 Hz’ and ‘On Medications, On DBS 60 Hz’). In both cases, bradykinesia and other axial symptoms, including voice and ability to arise from chair with arms crossed, also worsened with 130 Hz and better with 60 Hz stimulation. On the other hand, the resting tremor was better controlled with 130 Hz than 60 Hz stimulation. There was no difference between 30 Hz and 60 Hz stimulation on FOG in both off and
on medication states. DBS voltage was gradually increased to 3.2 volts on the right electrode and to 2.8 volts on the left electrode in case 1 and to 2.8 volts on the right electrode and to 3.6 volts on the left electrode in case 2 to maintain good control of symptoms. The dopaminergic medications in both cases were gradually decreased from a month after the surgery, by 54% in case 1 and 34% in case 2 by their 10-month follow-up visit. Their motor fluctuation, dyskinesia and medication complications all improved postsurgically with DBS and reduced dose of dopaminergic medications. This is the first report demonstrating that the commonly used 130 Hz stimulation could cause or worsen the FOG in patients with PD with newly activated STN DBS, while 60 Hz stimulation improves FOG. These two cases demonstrate the important and immediate effect of DBS stimulation frequency on FOG, separate from possible effects of chronic stimulation or disease progression, which confounded the interpretation of the previous reports.1e4 The effect of low frequency DBS on FOG remained stable in the 10-month follow-up. The benefit of low frequency DBS on freezing was present in both off and on medication states. FOG that did not improve with dopaminergic medication before the surgery in case 1 resolved on medication with 60 Hz stimulation at his 10-month visit, demonstrating a synergistic effect of 60 Hz stimulation and dopaminergic medication. This also raises the potential non-dopaminergic mechanism of low frequency DBS to improve FOG. Interestingly, other axial symptoms also improved along with the FOG in association with frequency change to 60 Hz, while resting tremor worsened with low frequency DBS compared with high frequency. The mechanism of the low frequency effect on FOG is unclear. Low frequency 10e25 Hz stimulation of pedunculopontine nucleus (PPN) can improve FOG while stimulation frequencies higher than 80 Hz make it worse.5 6 Therefore, the effect of low frequency stimulation of STN on FOG could be mediated by activation of the PPN being only 5 mm apart between these two targets. However, other structures may be
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J Neurol Neurosurg Psychiatry 2012;83:1015e1017. doi:10.1136/jnnp-2011-302091
Movement disorders involved in mediating the effect of low frequency DBS. Combined STN and PPN stimulation was reported to be more effective than bilateral PPN for FOG.3 The location of the contact 2 in the Medtronic 3389 lead that we used is in the dorsal STN or bordering the zona incerta with lenticular fasciculus or postsubthalamic area, which have been reported to provide a better control of Parkinsonism than ventral STN and might have played a role in its benefit on FOG. Further study is needed to clarify the mechanism of this interesting phenomenon, which is important to better understand and treat FOG, a symptom often difficult to manage in advanced PD.7 Contributors TX: Drafting and revising the manuscript for intellectual content and editing the video. UJK: Revising the manuscript. PW: Revising the manuscript. Funding All three authors were partially supported by the American Parkinson Disease Association Center for Advanced Research at University of Chicago and UJK was supported in part by R01 NS064439. Competing interests None.
Patient consent Obtained. Ethics approval Case report. No need for IRB. Provenance and peer review Not commissioned; externally peer reviewed.
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Moreau C, Defebvre L, Destee A, et al. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008;71:80e4. Brozova H, Barnaure I, Alterman RL, et al. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2009;72:770. Moreau C, Defebvre L, Devos D, et al. STN versus PPN-DBS for alleviating freezing of gait: toward a frequency modulation approach? Mov Disord 2009;24:2164e6. Moreau C, Defebvre L, Destee A, et al. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease: reply from the authors. Neurology 2009;72:770e1. Plaha P, Gill S. Bilateral deep brain stimulation of the pedunculopontine nucleus for PD. Neuroreport 2005;16:1883e7. Mazzone P, Lozano A, Stanzione P, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in PD. Neuroreport 2006;16:1877e81. Ferraye MU, Debuˆ B, Fraix V, et al. Effects of subthalamic nucleus stimulation and levodopa on freezing of gait in Parkinson disease. Neurology 2008;70:1431e7.
Neurological picture Transient high-intensity signal of heterotopia on DWI in an epilepsy patient A 48-year-old woman was admitted for the evaluation of fluctuating alertness and severe headache lasting for 1 day. There was no family or patient history suggesting a risk of epilepsy, including febrile convulsion. Her daughter reported that the patient had intermittent bouts of staring and was unable to communicate properly. Her neurological examination was normal. Brain fluid attenuated inversion recovery, and diffusionweighted images (DWI) revealed linear, high-intensity signal in the subcortical white matter in the left superior frontal area (figure 1A,B). Our neuro-radiologist suggested that the heterotopia might be related to a malignant tumour, or acute infarction, and recommended a fluorine-18-fluorodeoxyglucose PET (18-FDG PET) scan to exclude malignancy. Initial EEG revealed evidence of two episodes of ictal events arising from the left frontal area, implying that she had a non-convulsive status epilepticus. Three days after admission, she experienced two brief tonicclonic seizures with loss of consciousness. The interval between the seizures was 3 h. On the same day, 18-FDG-PET showed intense hypermetabolism in the left frontal lobe (figure 1C). We suspected that the PET was performed in an ictal state because one ictal event was recorded on follow-up EEG, and she still complained of intermittent headache and eye deviation to the right side. Her seizures were ultimately controlled with oxcarbazepine and levetiracetam. One month later, follow-up MRI indicated the disappearance of the high-intensity signal heterotopias on DWI, and 18-FDG-PET revealed hypometabolism (figure 2). Transient signal changes on DWI in epilepsy are well known,1 but isolated signal changes of heterotopia have never been documented. Reported cases had broader cortical regions including the frontal, parietal and temporal cortices. The transient signal changes may reflect cytotoxic and vasogenic oedema J Neurol Neurosurg Psychiatry October 2012 Vol 83 No 10
Figure 1 On admission, fluid attenuated inversion recovery, and diffusion-weighted images MRI demonstrated high-intensity signal of the heterotopic gray matter in the left frontal lobe (A, B). Initial 18-FDG-PET showed hypermetabolic heterotopias in the ictal state (C). 1017
