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Keywords:

  • bilateral striatal necrosis;
  • mitochondrial DNA;
  • dystonia;
  • deep brain stimulation

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

Bilateral striatal necrosis (BSN) is relatively rare and has been related to a wide array of causes, including nuclear and mitochondrial DNA mutations. We report the clinical vignette of a patient with a 37 years-history of generalized dystonia secondary to BSN associated with multiple mitochondrial DNA deletions of undefined origin. Globus pallidus interna deep brain stimulation produced sustained benefit, with predominant improvements in disability. © 2007 Movement Disorder Society

Bilateral striatal necrosis (BSN) refers to a symmetrical degeneration of the caudate nucleus and putamen, involving at times the globus pallidus, substantia nigra, and tegmental nuclei.1 BSN may be caused by acute infectious or postinfectious inflammatory illness,1 nuclear or mitochondrial DNA (mtDNA) mutations,2–4 hypoxic–ischemic damage,5 metabolic defects,6 or exposure to carbon monoxide,5 methanol or cyanide.7 Genetic forms generally present in early childhood, as a progressive, disabling illness which may manifest with dystonia, choreoathetosis, eye movement abnormalities, myoclonus, seizures, and sometimes psychomotor retardation.2–4 Pharmacological treatment and rehabilitative strategies are of limited efficacy. We present here the case of a 43-year-old patient having BSN since childhood in association with multiple mtDNA deletions. The patient underwent globus pallidus interna (GPi) deep brain stimulation (DBS) with relevant gain in his functional capacities.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

This 41-year-old right-handed man was referred in November 2004 to the Department of Neurological and Psychiatric Sciences, Policlinico Hospital, Bari, Italy for a slowly progressive illness manifesting with severe generalized dystonia involving face, limbs, trunk, and bulbar muscles. He was born at term following uncomplicated pregnancy and delivery. Developmental milestones during preschool years were normally achieved. At age 6, in the absence of clear precipitants, he gradually developed postural abnormalities of the trunk and left foot inversion. At age 7, he noticed difficulties running while playing with his peers, and dysarthric speech. His gait worsened the following year, with bilateral foot inversion, inward rotation, and tremor of both legs (left > right) up to the point he needed support for long-distance walking. He did not show any visual or auditory deficits, nor suffered from other medical illnesses. He completed compulsory school at age 14 without difficulties. His condition was reported as “stable” for the following 20 years, but at age 30 years he became unable to walk unaided and dependent in daily activities, such as dressing, shaving, writing, and hygiene. At age 36, bilateral support became necessary. Throughout the whole duration of his illness, he received different diagnoses, among which “scoliosis,” “spinocerebellar ataxia,” and “spastic tetraparesis,” and treatment attempts based on vitamins, neurotrophic agents, and physical rehabilitation had not been effective. Family history was unremarkable.

At referral, he could barely walk with bilateral support, and was almost constantly wheelchair-bound. There was lower facial dystonia, a dystonic flexed posture of the right forearm and fingers of both hands, a flexed dystonic posture of legs bilaterally, inward rotation of legs, bilateral foot inversion, and striatal toe (see Video, Segment 1). He exhibited a moderately strain-strangled voice, but no respiratory difficulties, and was dysarthric. He scored 59 at the Burke–Fahn–Marsden (BFM)8 movement scale, and 23 at the disability scale score; scores were assigned by three movement disorders specialists (M.S.A, D.M., G.D.), and the mean score was recorded. During admission, he appeared cognitively preserved, and behavioral abnormalities were not observed; neuropsychometry was normal, including Mini-Mental State Examination (all of 30), and tests for abstract reasoning (Raven's progressive matrices), verbal memory (story recall task, forward and backward digit span), visuospatial memory (Corsi blocks test), and attention (Attentional matrices). Serum blood routine examinations, including ammonia, copper, ceruloplasmin, ferritin, full autoantibody screening (including anti-phospholipid and anti-basal ganglia antibodies) were all normal, whereas serum lactate/pyruvate ratio was above normal range. Urinary organic acids were normal. Search for peripheral blood acanthocytes was repeatedly negative. Brain magnetic resonance imaging revealed bilateral putaminal hypointense lesions on T1-weighted images (Fig. 1 a), which appeared hyperintense on T2-weighted images (Fig. 1b). Neither mutations in DYT-1 nor abnormal expansion in HD1 were identified in peripheral blood DNA. Histochemistry on skeletal muscle biopsy showed a few ragged red fibers and fibers staining negative to cytochrome c oxidase (complex IV) activity. Activities of mitochondrial respiratory chain complexes I and IV were markedly reduced in the patient's muscle extract. These findings prompted us to perform mutational screening of mitochondrial genes (Table 1). Southern blot and long polymerase chain reaction analysis of muscle DNA evidenced the presence of multiple deletions of mtDNA (Fig. 1c). Screening of ANT-1, Twinkle, and POLG1 and POLG2 genes, the known genes associated with mtDNA multiple deletions, did not reveal any mutation. Unfortunately, no tissues or DNA samples were available from the other family members, making linkage studies impossible.

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Figure 1. (A) T1-weighted magnetic resonance imaging of the brain of the patient presents symmetrical reduced signal on the putamen bilaterally. (B) T2-weighted magnetic resonance imaging of the brain of the patient presents symmetrical increased signal on the putamen bilaterally. (C) Analysis of muscle mitochondrial DNA from the patient. Left panel: Southern blot of PvuI and BamHI digested total DNA hybridised with a probe obtained by polymerase chain reaction of the entire molecule of mitochondrial DNA. Right panel: Polymerase chain reaction of mitochondrial DNA was performed with primers amplifying the entire mitochondrial molecule. Positions of wild-type (Wt mtDNA) and deleted (Δ mtDNA) molecules are indicated by arrows.

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Table 1. Mitochondrial genes sequenced in the patient
GenesNucleotide positionNucleotide changeAmino acid change
  1. mtDNA genes, nucleotide position, and type of nucleotide changes according to Cambridge sequence9 are indicated. The 4,216 mutation in ND1 gene is recognized as haplogroup J marker.10

  2. syn, synonimous aminoacid change; rCRS, human mtDNA revised Cambridge Sequence (rCRS).

ND14,216C>TY-H
ND411,719G>Asyn
 11,335CrCRS correction
 11,242C>Gsyn
 11,251A>Gsyn
ND513,368G>Asyn
ND614,233G>Asyn
ATPase 68,697A>Gsyn
 8,860G>Asyn
tRNAleu(UUR) 
tRNAlys 

The patient underwent unsuccessful trials of L-dopa (up to 600 mg/day), baclofen (up to 50 mg/day), and trihexyphenidyl (up to 16 mg/day); higher dosages of L-dopa and trihexyphenidyl were not tolerated. He was therefore referred elsewhere for DBS surgery. In February 2005, a frame-based stereotactic implantation of quadripolar DBS electrodes (DBS-3389, Medtronic) was performed into the posteroventral GPi bilaterally, under assisted local anesthesia. Intraoperative single-cell microelectrode recording was used for target localization, and proper positioning of the leads was confirmed with postoperative MRI the day after surgery. The extension cables and pulse generators (Kinetra, Medtronic) were implanted in the subclavicular area under general anesthesia 1 week after the lead implants. There were no surgical complications. The device was activated 2 days after the second surgery. Symmetric unipolar stimulation was used at the following initial settings: amplitude, 1 V; pulse width, 120 μs; frequency, 130 Hz. These parameters were adjusted during the first year of follow-up to obtain the best clinical response without side effects. Amplitude was increased in 0.5-V steps. Objective and subjective clinical improvement of dystonia was reached within 2 months after surgery at a stimulation amplitude of 1.65 V. Further increases of amplitude up to 3.5 V during the first 4 months did not produce additional clinical improvement in the absence of adverse effects; hence, amplitude was finally set at 1.65 V, the lowest value at which the patient manifested clinical benefit. At latest follow-up (April 2007) stimulation parameters were the following: amplitude, 1.65 V; pulse width, 120 μs; frequency, 130 Hz.

Subjective and objective improvement of dystonia increased slowly during the first 12 months. Face, axial, and limb dystonic postures responded to a greater extent than the dysarthria and the voice abnormality. Importantly, there was significant gain in ambulatory performance and in daily activities, mainly feeding, writing, and hygiene, though moderate postural abnormalities in the four limbs persisted, probably in relationship to coexisting skeletal deformities. After stabilization of stimulation parameters (1 year after surgery), BFM movement and disability scale scores (mean values of the scores assigned by the same raters of first evaluation) increased to 37 and 13, respectively, with a 36 and 44% improvement compared to baseline. At 2-year follow-up, BFM scores were unchanged; the patient was able to stand up from a chair on his own and walk using a roller, and no longer requiring the wheelchair (see Video Segment 2). Both patient and relatives felt that overall disability significantly diminished after stimulation, and that improvement persisted over time.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

Our patient presented an unusual association of generalized dystonia secondary to BSN and multiple mtDNA deletions of undefined cause. BSN has already been reported in patients carrying mutations in genes coding for complex I subunits (MTND1-6), tRNALeu(UUR) gene mutations (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and mutations of the mitochondrial ATPase 6 gene.3, 4, 11 We excluded MTND1-6 and tRNALeu(UUR) gene mutations, whereas ATPase 6 gene involvement was unlikely owing to the normal complex V activity. The presence of multiple mtDNA deletions suggested gene defects altering the stability of mtDNA.12 Despite a thorough diagnostic work-up, however, we failed to identify any known causative mutation for the multiple mtDNA deletions. Mitochondriopathies associated with multiple mtDNA deletions of undefined origin have been previously reported and presented with movement disorders other than dystonia (mainly, Parkinsonism of Mendelian inheritance).13, 14

The overall response of our patient to GPi-DBS was significant, clearly perceived by the patient and family, and long-standing, as supported by the relatively long follow-up duration (2 years). Moreover, our patient underwent surgery 37 years following disease onset, whereas disease duration of most patients with primary or secondary dystonia treated with DBS is considerably shorter, exceptionally exceeding 30 years.15, 16 The patient improved more on the disability score than on the movement score, possibly in relation to the presence of fixed limb postures, secondary to the long disease duration. This is in line with the observation of Vidailhet et al. that fixed postures may limit improvement of dystonia following GPi-DBS15 and, as underscored by Alterman and Tagliati, require additional orthopedic surgery.17 These reflections raise the issue of earlier intervention in dystonic patients eligible for surgery.

The response observed in our patient was not as satisfactory as that reported by the majority of patients with primary generalized dystonia, in whom 50–60% longstanding motor improvement has been reported in a large prospective study.15 As a group, secondary dystonias respond less robustly to GPi-DBS than primary dystonias, with results ranging from no benefit to partial amelioration.18 However, available case series suggest that some patients with secondary dystonia may respond favorably to DBS. Among these, patients with panthotenate-kinase associated neurodegeneration exhibited major improvement in dystonia and functional autonomy in a single case series, although the duration of the response may vary.19, 20 In another series of childhood-onset dystonia cases, a better response of secondary dystonia to DBS was recorded in patients with generalized dystonia, preserved cognition, nonprogressive course, and absence of other neurological features; most of these characteristics were found also in our patient, supporting a possible relationship between clinical phenotype and response to GPi-DBS.21 It needs to be remarked, however, that the factors predicting a favorable outcome of DBS in secondary dystonias remain undetermined.

Potential limitations of our study are the low dosage of the L-dopa trial (600 mg/day) and the rather low stimulation amplitude. Although sporadically patients with dopa-responsive dystonia (DRD) require higher doses of L-dopa (up to 1,000 mg) to gain benefit,22 our patient could not tolerate a higher dose of the drug; moreover, MRI and genetic findings do not favor a diagnosis of DRD for this patient. The choice of a relatively low stimulation amplitude was dictated by the lack of significant improvement at higher amplitudes, which the patient, in any case, tolerated without adverse effects. The significant gain in the disability burden achieved by our patient suggests that GPi-DBS could be considered as a treatment option also in those patients with long-standing secondary dystonia not manageable with the medications commonly used in this condition.

LEGENDS TO THE VIDEO

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

Segment 1. The patient exhibits facial dystonia, flexed dystonic posture of both upper limbs, a flexed dystonic posture of legs bilaterally, inward rotation of legs, and bilateral foot inversion. He appears wheelchair-bound, and deambulation is possible only for a few steps with bilateral support.

Segment 2. After pallidal DBS, the patient was able to stand up from a chair on his own and walk using a roller, and he no longer required the wheelchair.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. LEGENDS TO THE VIDEO
  6. REFERENCES
  7. Supporting Information

This article includes supplementary video clips, available online at http://www.interscience.wiley.com/jpages/0885-3185/suppmat .

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.