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Deep Brain Stimulation in a Case of Mitochondrial Disease

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Video 1

DBS response in a myoclonus and dystonia syndrome secondary to a mitochondrial disorder and cerebral hypoxia. Segment 1: Pre-DBS. Baseline evaluation pre-DBS. We can observe myoclonic movements distributed mainly to the arms and head, which are activated during postures and actions. Myoclonic truncal movements can also be observed. Cervical and truncal dystonia are present and exacerbated during arm movements.

Segment 2: 4 months post-DBS. ON DBS stimulation evaluation at 4-month follow-up. A decrease in intensity and frequency of axial myoclonic movements can be observed.

Segment 3: 1-year post-DBS. Myoclonic movements are still predominant on actions localized to arms and head with a decrease in intensity and frequency compared to previous clinical evaluations. Dystonic posturing of neck and right arm seemed to remain the same when compared to baseline evaluation.

Daniel Martinez-Ramirez MD, Nawaz Hack MD, Matthew L. Vasquez BSc, Hokuto Morita MD, Juan C. Giugni MD, Janine M. Wolf BS, Janet Romrell PA, Pamela R. Zeilman MSN, ANP-BC, Christopher W. Hess MD, Kelly D. Foote MD, Michael S. Okun MD and Aparna Wagle Shukla MD

Article first published online:  29 SEP 2015 |DOI: 10.1002/mdc3.12241



DBS has proven to be an effective therapy for Parkinson's disease, essential tremor, and primary dystonia. Mixed results have been reported in case series for other hyperkinetic disorders, and sparse data are available regarding secondary movement disorders. We report on the clinical effects of bilateral globus pallidus internus (GPi) DBS, a progressive mitochondrial cytopathy.


A single patient with myoclonus and dystonia syndrome secondary to a mitochondrial cytopathy with history of perinatal hypoxia was identified from our University of Florida DBS database. Demographics, clinical, surgical, and DBS data were documented.


At 6 months post-DBS, we observed a 32% (361 to 527) improvement on quality of life (36-item Medical Outcome Study Short-Form Health Survey; SF-36). Objective clinical scales revealed a 33% (143 to 96) improvement in the Unified Myoclonus Rating Scale (UMRS) total score. The UMRS action myoclonus subsection revealed a 29% (69 to 46) improvement. No significant changes were observed in the Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS). After 1-year follow-up, a worsening of 59% (527 to 215) was observed in the SF-36 scale, of 19% (28.5 to 35) in the BFMDRS, and of 23% (96 to 124) in the UMRS. However, the frequency and intensity of action myoclonus scores remained lower when compared to baseline scores.


Although we observed a loss of benefit in the long term for most quality-of-life and clinical outcomes, the DBS effects on action myoclonus seemed to remain stable. Longer follow-up studies are necessary to confirm our short-term and unblinded findings.

DBS has evolved as an important surgical treatment for select patients with Parkinson's disease, essential tremor, and primary dystonia.[1] A recent rise in its application has been observed for neuropsychiatric disorders[2] and for other hyperkinetic disorders, such as chorea, ballism, and complex tremors.[3] Few case reports and small series have suggested that DBS may be helpful for secondary movement disorders.[4] In addition, results greatly vary across cases of DBS applied for secondary myoclonus or dystonia syndromes. A single optimal surgical target has yet to be been defined, and it is likely a variety of targets may be beneficial.[5-7]

Because the literature is sparse regarding DBS in mitochondrial disorders, we report on a case with a myoclonus and dystonia syndrome secondary to a progressive mitochondrial disease and brain hypoxia who underwent bilateral globus pallidus internus (GPi) DBS. We also provide a literature review of DBS in mitochondrial and postanoxic disorders.



Patients and Methods

Written informed consent from the study participant was obtained through the University of Florida (UF) Institutional Review Board.

Patient Selection and Outcome Measurements

A single subject was identified from the UF INFORM database with a myoclonus and dystonia syndrome and a pathologically confirmed diagnosis of a mitochondriopathy. The UF INFORM system is a clinical research database, which provides information on patient demographic, clinical, and functional characteristics of patients. The database currently has over 8,000 patients. Review of the electronic medical record was performed to obtain the patient's demographic, clinical, and surgical data, as well as DBS settings. The following scales were obtained preoperatively, at 6 months, and at 12 months post-DBS surgery, the Clinical Global Impression Scale (CGIS),[8] the quality of life 36-item Medical Outcome Study Short-Form Health Survey (SF-36).[9] the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS),[10] and the Unified Myoclonus Rating Scale (UMRS).[11] The CGIS is a 7-point scale that requires the clinician or patient to rate the severity of the illness in relation to previous evaluation, where 1 stands for “very much improved” and 7 for “very much worse.” The SF-36 is a measure of health status consisting of 8-scaled scores. Each scale is transformed into a 0 to 100 scale. The lower the score, the more disability.

Literature Search

An extensive PubMed search was performed to identify published reports involving DBS patients with secondary myoclonus or dystonia syndromes. The following search terms were used: (1) “Myoclonus”[Mesh] AND “Deep Brain Stimulation”[Mesh], (2) “Dystonia”[Mesh] OR “Dystonic Disorders”[Mesh] AND “Deep Brain Stimulation”[Mesh], (3) “Mitochondrial Diseases”[Mesh] AND “Deep Brain Stimulation”[Mesh], and (4) “Neurosurgical Procedures”[Mesh] AND “Mitochondrial Diseases”[Mesh]. The search yielded a total of 495 abstracts (Term 1: 11, Term 2: 469, Term 3: 3, Term 4: 13). All abstracts were reviewed. Three were identified reporting any movement disorder secondary to a mitochondrial disease and 3 reporting a postanoxic myoclonus syndrome, all treated with DBS implantation, which are discussed below.

Case Report

A 16-year-old woman presented for evaluation of jerky movements associated with abnormal postures. Notably, she had a birth history that included maternal diabetes, toxemia, and hypoglycemia. There was also a history of sepsis at birth. These complications required her to be resuscitated and ventilated for 48 hours postbirth. After, a developmental motor delay was noticed at 6 months, being able to walk at 24 months. Her movement disorder originally presented at the age of 3 years with jerky head movements, which spread downward, including the upper extremities. Over the subsequent 4 years, slow evolution of abnormal postures appeared in her neck, arms, and legs. The symptoms gradually progressed to include violent movements as well as painful postures interfering with writing, eating, and walking. Ultimately, the syndrome was reported to result in balance problems and falling. At age 7, after being hospitalized for an episode of generalized weakness triggered by an oral abscess, she was diagnosed by muscle biopsy with a mitochondrial encephalomyopathy possessing a complex I defect. Diagnosis was confirmed by enzymology for oxidative phosphorylation.

Owing to the fact that her movements became increasingly disabling despite an aggressive medical management with maximally tolerated doses of multiple medications, such as levetiracetam, oxcarbazepine, clonazepam, risperidone, and levodopa, other drugs, such as tetrabenazine or baclofen, were not tried and the patient was considered for DBS screening. Maximally tolerated dosages of trihexyphenidyl were only mildly helpful for her dystonia. Other drugs, such as tetrabenazine or baclofen, were not considered because of side effects. At her first visit to our center, she arrived in a wheelchair and the neurological exam showed a moderate dysarthria with mild generalized weakness. A myoclonus and dystonia syndrome was identified per movement disorders examination (see Video 1). We further analyzed the myoclonic movements with an electromyography (EMG) of splenius capitis bilaterally and deltoid muscles observing a mean duration of jerks of 75 ms while at rest, 150 ms when arms were in an outstretched posture, 55 ms when writing, and 165 ms when performing spirals. Electrophysiological characteristics of myoclonic movements are shown in Figure 1. Brain MRI with intravenous contrast at the time of evaluation in our center resulted within normal limits for age without intracranial abnormalities. After a complete interdisciplinary evaluation and discussion of the risk-benefit profile, bilateral GPi DBS was performed.

Electrophysiological characteristics

Figure 1. Electrophysiological characteristics of myoclonic movements. We recorded the muscle jerks from arms and neck. Surface EMG electrodes were applied to bilateral splenius capitis and deltoid muscles. Muscle jerks were recorded during rest, postural elevation of arms, writing, finger pointing task, and spiral drawing task. For each of these states, we analyzed the mean duration of jerks for five trials. The mean duration of jerks were 75 ms at rest, 150 ms at posture, 55 ms at action writing, 165 ms at action-performing spirals, and 200 ms at intention. (A and B) Recorded from left and right spenius capitis muscles when writing with right dominant hand. (C) Movements recorded from left deltoid muscle and from left and right splenius capitis muscles when arms at rest.



Surgical Planning and Stimulation Testing

An indirect stereotactic targeting plan was established through the use of a 3T volumetric contrast-enhanced brain MRI scan, obtained 1 day before surgery. Cosman-Robert-Wells head frame was applied under local anesthesia, and a stereotactic head CT scan was then obtained. The CT scan was fused to the previous MRI scan to map all the subcortical brain structures using a Cartesian coordinate system. Starting from default GPi target coordinates (X = ±21 mm; Y = +1 mm; Z = −6 mm), a following direct targeting was carried out using our UF modified Schaltenbrand-Bailey Sudhyadhom atlas. Bilateral GPi leads (Medtronic model 3387; Medtronic, Inc., Minneapolis, MN) were implanted in a single surgical session and the neurostimulators were placed and activated 1 month later. Detailed microelectrode mapping and macrotest stimulation were performed in the operating room to verify lead placement. Regarding the right lead, the maximum voltage used for having motor side effects (tongue pulling) across all contacts were as follows: contact 0: 4 to 6 V; contacts 1 to 3: 8 V. For the left lead, the maximum voltage used was 6 V for contact 0 with the same motor side effects. For the rest of the contacts, no side effects were observed. A CT-MRI fusion sequence along with detailed testing of programming thresholds for benefit and side effect at each contact were performed in the clinic to further confirm lead location. The DBS lead location coordinates were obtained from the CT-MRI images and were fused to a three-dimensional morphable atlas using the UF Schaltenbrand-Bailey Sudhyadhom atlas.[12] The leads were located in the GPi bilaterally and were intentionally placed slightly anterior and lateral in the GPi (Fig. 2) to allow for the possibility of higher current densities during programming. During the first DBS programming visit, the observed stimulation-induced side effects were hand pulling in contacts 0 and 1, bilaterally, at 2.5 to 3.0 V, and no side effects were observed in contacts 2 and 3, bilaterally.

Lead location on postoperative imaging

Figure 2. Lead location on postoperative imaging. Brain MRI T1-inverted sequence coronal views of right GPi lead location (A) and left GPi lead location (B). Red dotted line indicate lead trajectory. Outlines: blue, caudate; red, indicates GPi, lateral green, globus pallidus externus; internal green, thalamic structures; yellow, optic tract. Schaltenbrand-Bailey Sudhyadhom technique was used to measure lead location.


Both the patient and the family noticed an immediate and dramatic improvement in both the frequency and intensity of “violent jerks” after activation (1 month after lead implantation). At this point, she was able to hold objects, feed herself, and had developed some postural control. These were all reported as new abilities not present before DBS. The improvement persisted, and more gains were documented at subsequent monthly follow-up visits. She reported being able to drink from a glass and to apply makeup.

At 6 months post-DBS, she reported “very much improved” on both the myoclonus and dystonia symptoms according to the Patient-Global Impression Scale (PGIS), which is the highest possible rating achievable. The patient and family estimated an 80% overall improvement and also reported a daily dose reduction of 25% in anticholinergic therapy. Regarding the quality-of-life measured by the SF-36, a 32% improvement was reported. Objective clinical scales revealed a 33% improvement in the total UMRS score. UMRS section evaluating action myoclonus revealed an improvement 29%. The BFMDRS revealed no significant changes in scores.

After 1-year follow-up, the family reported a worsening of her jerky symptoms when compared to previous evaluation. Movements were described by the patient as “coming back as before surgery” and reported a “minimally to moderate worse” in the PGIS. A decline of 59% was observed in the SF-36 scale when compared to 6 months post-DBS evaluation. Clinically, the general neurological exam revealed no additional abnormalities. Although the total UMRS score showed a 19% worsening, the frequency and intensity of action myoclonus scores remained lower when compared to baseline scores. The BFMDRS also showed a worsening of 23%. Detailed clinical scale scores before and after surgery are shown in Table 1.

Table 1. Comparison between baseline and postoperative scores
  Baseline 6 months post-DBS 12 months post-DBS
CGIS 1 5
Total SF-36 361 527 215
Physical functioning 75 25 20
Role-physical 0 50 0
Bodily Pain 41 62 41
General Health 57 72 25
Vitality 45 55 40
Social Functioning 75 75 25
Role-Emotion 0 100 0
Mental Health 68 88 64
Total BFMDRS 30.5 28.5 35
Movement scale 13.5 13.5 18
Disability scale 17 15 17
Total UMRS 143 96 124
Action myoclonus 69 46 48

The lead coordinates and optimization of DBS settings during subsequent follow-ups are summarized in Table 2. Settings controlling her symptoms were obtained at 4 months post-DBS follow-up and remained constant at her 12-month appointment. However, we were required to provide her with new settings because of her worsening of symptoms trying to achieve better symptomatic control.

Table 2. Coordinates of lead contacts and follow-up DBS settings
Right Left
Contact 0 21.18 5.22 –9.03 –20.4 4.19 –8.46
Contact 1 21.24 6.10 –5.16 –20.4 5.37 –5.70
Contact 2 21.29 6.97 –2.29 –20.3 6.54 –2.94
Contact 3 21.34 7.85 0.57 –20.3 7.71 –0.18
  Post-DBS follow-up visits
Right Left
(−) (+) V PW Hz Imp. (−) (+) V PW Hz Imp.
  1. X, mediolateral; Y, anteroposterior; Z, axial; V, voltage; PW, pulse width; Hz, Hertz; Imp., impedance.

1 month 2 C 1.5 150 60 1,046 2 C 1.5 150 60 1,271
2 months 2 C 1.8 150 60 1,114 2 C 1.8 150 60 1,283
3 months 2 C 2.2 150 60 2 C 2.2 150 60
4 months 2 C 2.6 150 60 1,003 2 C 2.6 150 60 1,192
5 months 2 C 2.6 150 60 974 2 C 2.6 150 60 1,160
6 months 2 C 2.6 150 60 1,018 2 C 2.6 150 60 1,182
1 year 2 C 3.0 150 120 945 3.0 C 2.6 150 120 1,258


We present a single case of a progressive myoclonus and dystonia syndrome in a patient with a biopsy-proven complex I mitochondrial deficiency and a previous history of perinatal hypoxia. This patient initially reported a clinical improvement and this was supported by the objective myoclonus benefits post-DBS therapy. Whether the worsening of symptoms at the 12-month visit is owing to a limited DBS response, disease progression, or the need of higher DBS settings is still unknown.

DBS in Mitochondrial Disorders

Our extensive PubMed search yielded three mitochondrial disorder DBS-related case reports, and all revealed positive benefits. In the first, a 41-year-old male with bilateral striatal necrosis since childhood had generalized dystonia owing to multiple mitochondrial (mtDNA) deletions.[13] This patient underwent bilateral GPi DBS. At 1-year follow-up, BFMDRS movement and disability scores improved 36% and 44%, respectively, persisting at 2-year follow-up. The stimulation parameters were: 1.65 V, 120 μs pulse width, and 130 Hz. Noteworthy, the subject had significant benefit from DBS even though his time from symptom onset to DBS was 37 years. In the second report, a 49-year-old male with a rapidly progressive parkinson-dystonia syndrome associated with multiple mtDNA deletions initially responded well to bilateral GPi DBS; however, he required an additional implant of bilateral ventralis oralis anterior thalamic leads to help control worsening hyperkinetic symptoms.[14] The third reported a case of a patient with a biopsy-proven mitochondrial disorder with uncontrollable bilateral postural-kinetic tremor after several stroke-like episodes, who underwent staged left thalamotomy and right ventralis intermedius (VIM) DBS implantation.[15] An immediate improvement in the Fahn-Tolosa-Marin Tremor Rating Scale Parts A-B-C of 69-19-22 points to 6-3-2 points, respectively, was observed using the following parameters: 1.4 V, 60 μs pulse width, and 130 Hz. The patient was reported to remain stable at 3-year follow-up.

The present case represents only the fourth reporting benefit in mitochondrial associated movement disorders from DBS, specifically in myoclonus. Although the cases mentioned previously had different clinical presentation, making it difficult to compare with, the 2 patients with a dystonia syndrome reported clinical improvement from DBS. We hypothesize that the nondystonia improvement in our case was possibly owing to the additional contribution of the hypoxic brain injury to the symptoms, and that higher DBS settings need to be tried before considering them unresponsive to DBS and yet to be evaluated. However, we observed a fast clinical response of the myoclonus symptoms to DBS. An improvement of 33% regarding UMRS at 6 months postsurgery was observed, which was her most disabling symptom.

DBS in Postanoxic Myoclonus

Reports of DBS for secondary myoclonus syndromes have been limited with promising results. In one such report, a 36-year-old male, who developed action myoclonus as a result of perinatal anoxia, was treated with VIM DBS and there was an observed a reduction of 10 points (83.3%) for the left arm and of 7 points (77.8%) for the right arm in action myoclonus using the UMRS at a 24-month follow-up visit.[16] In a second report, a 71-year-old man developed posthypoxic myoclonus after recovering from a cardiopulmonary arrest resulting from a pulmonary embolism.[6] The subject underwent left GPi implantation, and there was an observed decrease of UMRS sections 2 and 4 scores of 28 (75%) and 37 (71.2%) points, respectively. However, in this case, the patient continued receiving high doses of multiple antiepileptic drugs. Last, a 54-year-old man with Lance-Adams syndrome treated with bilateral GPi DBS was recently reported. Changes in UMRS scores at 6 months were reported, noting an 80% in action myoclonus.[17] The smaller clinical improvement in the UMRS scores and specifically in action myoclonus (29%) observed in our patient might be explained by the possible additional contribution of the mitochondrial disorder to her movement disorders and the possible need of higher DBS settings, as explained above.

Mitochondriopathy and Cerebral Hypoxia as Possible Triggers

How hypoxic brain injury and mitochondrial abnormalities may contribute to the pathogenesis of movement disorders, such as in our case, remains unknown. It is important to note that her abnormal movements occurred after birth and they were progressive. Reported secondary etiologies of a myoclonus and dystonia syndrome have included storage disorders, neurodegenerative diseases, drug-induced, toxic-metabolic conditions, inflammatory disorders, and traumatic or hypoxic insults to the brain.[18, 19] Our patient had multiple perinatal comorbidities (gestational toxemia, hypoglycemia, and postnatal sepsis) that resulted in resuscitation and likely brain hypoxia from the incident. It has been hypothesized that anoxic injury to the thalamus may underpin the abnormalities delaying the presentation of the movement disorders, such as in our case.[20] Though she had a genetic confirmation of a complex I mitochondrial defect, which hypothetically could have contributed to the manifested syndrome, we cannot completely be sure that this is the underlying etiology. Whereas movement disorders reported in mitochondriopathies can be myoclonic and have been associated with seizures, our patient had only one of these known manifestations. Impaired mitochondrial function is known to impact biological processes that depend on energy and metabolism in structures with high metabolic activity, such as putamen, globus pallidus, and thalamus,[21] and these have been reported in many neurological disorders,[22] inclusive of both dystonia and myoclonus. Though we cannot be certain, we hypothesize the mitochondrial dysfunction in addition to the hypoxic brain injury were large contributors to the hyperkinetic movements in our case.

The mechanism of action of DBS in mitochondrial disorders remains uncertain, and the optimal stimulation target for similar syndromes continues to be debated. Described reports suggest benefits for movement disorders secondary to mitochondrial disease may occur even if surgery is not considered until long after symptom onset. The clear loss of the DBS benefit initially observed in our case suggests both a loss of DBS benefit and somewhat of a disease progression, at least for dystonia. Higher DBS settings need to be tried before considering dystonia to be unresponsive. Longer follow-up and blinded evaluations are required to confirm our short-term results and unblinded results and allow stronger conclusions. Although promising, DBS outcomes for secondary myoclonus and dystonia will require more study to better understand reasonable approaches to the application of this technology.

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