Internal globus pallidotomy in dystonia secondary to Huntington\'s disease

Movement Disorders Vol. 15, No. 6, 2000, pp. 1248–1251 © 2000 Movement Disorder Society

Brief Report

Internal Globus Pallidotomy in Dystonia Secondary to Huntington’s Disease Esther Cubo, MD, Kathleen M. Shannon, MD, Richard D. Penn, MD, and Jeffrey S. Kroin, PhD Department of Neurological Sciences, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A.

Summary INTRODUCTION AND METHOD: The prototypic motor feature of Huntington’s disease (HD) is chorea, but parkinsonism and involuntary movements such as dystonia and myoclonus can also be present. Pallidotomy has been shown to be an effective treatment for medically refractory Parkinson’s disease (PD). We performed bilateral microelectrode guidedstereotactic pallidotomies targeted at globus pallidum internus (GPi) to treat a 13-year-old patient diagnosed with Westphal variant of HD with intractable generalized dystonia and parkinsonism. RESULTS: Intraoperative microelectrode recordings of GPi

cells showed a relatively low firing rate, 29 ± 14 Hz, with most neurons showing pauses. Acutely, after surgery, limb dystonia mildly improved but trunk dystonia persisted. Postoperative follow up 3 months later showed minimal clinical improvement in dystonic features with marked worsening of spasticity. CONCLUSION: In our case, bilateral pallidotomy produced modest palliative functional improvement in dystonic features. Cellular firing patterns were markedly different than in PD and were similar to those found in dystonia. Key Words: Pallidotomy—Huntington’s disease— Dystonia.

Huntington’s disease (HD) is a heredodegenerative disease of the central nervous system characterized by progressive motor, behavioral, and cognitive alterations. The prototypic motor feature of HD is the presence of chorea, but in the Westphal variant of HD (WHD), juvenile onset of parkinsonism, dystonia, and myoclonus usually predominate. Treatment of patients with HD is tailored to the treatable symptom complex. Pharmacologic therapy, including antidopaminergic drugs, has been reported to be of some use for chorea, but hypokinesia and gait can be worsened by the use of these drugs,1 and benefits wane with disease progression. In patients with WHD, parkinsonism may improve with dopaminergic therapy.2 Pallidotomy has been shown to be an effective treatment for medically refractory Parkinson’s disease (PD), and ameliorates not only parkinson-

ism, but also choreic dyskinesias and dystonia.3,4 In primary dystonia, pallidotomy can also be beneficial.5,6 We present the case of a patient with WHD with severe dystonia and parkinsonism who underwent bilateral pallidotomies. We studied the clinical effects of bilateral pallidotomies, and compared the pattern of neuronal activity from our patient with those previously published in dystonia and PD. CASE REPORT Clinical Description A 13-year-old girl with a 9-year history of WHD was followed at our Movement Disorder Clinic at RushPresbyterian-St. Luke’s Medical Center since 1995. She had a positive family history for HD (paternal side) with a positive genetic testing for HD (75 CAG repeats). Her disease was characterized by generalized dystonia and parkinsonism without chorea. She was able to walk with assistance only. She was living with her mother and attending a regular school with special aids. In January

Received November 30, 1999; revisions received March 9 and May 31, 2000. Accepted June 4, 2000. Address correspondence and reprint requests to Esther Cubo, MD, Department of Neurological Sciences, Rush-Presbyterian-St. Luke’s Medical Center, 1725 W. Harrison St., Chicago, IL 60612, U.S.A.

1248

PALLIDOTOMY IN HD 1999, she was admitted to the hospital as a result of a rapid worsening of her dystonia without any precipitant event such as infection or trauma. At presentation, she was alert but did not follow simple commands and had no useful speech. The patient’s pupils were equal and reactive to light. Her extraocular movements were significant for slow and interrupted saccades. She had generalized dystonia and rigidity, causing sustained twisting postures of the arms and legs, and severe arching of the back. Painful stimuli to all extremities and trunk produced withdrawal. The deep tendon reflexes were 3+ of 4 bilaterally with equivocal plantar responses. She was unable to walk or stand. The Burke-Fahn-Marsden Dystonia Rating Scale7 score was 56 (maximum score 120). Neurologic work-up for infection and toxic screening were normal. Magnetic resonance imaging of the brain, including T1- and T2-weighted images, revealed severe atrophy of both the caudate nuclei and globus pallidum (GP). No other lesions or focal abnormalities were seen. Because of the severity of the dystonia, she was started on midazolam and had to be intubated and ventilated. The patient received several pharmacologic therapies, including benzodiazepines, anticholinergics, baclofen, dantrolene, dopaminergic, and antidopaminergic drugs, without substantial improvement. Because of prior published reports on the efficacy of pallidotomy on parkinsonism and dystonia in other clinical settings, a neurosurgical consultation was obtained. Her medications at that time were 12 mg midazolam per day, 6 mg trihexyphenidyl per day, 0.1 mg clonidine per day, 30 mg baclofen per day, and 50 mg dantrolene per day. Surgical Procedure The decision to operate bilaterally was based on the rapid progression and the extent and distribution of the dystonia. Because of her severe dystonia, this patient required sedation using a propofol drip throughout the procedure, and she was therefore unable to assist in localization of lesion placement by means of her report to stimulation. Otherwise, the surgical procedure was identical to that in PD and described in detail elsewhere.3,8 Briefly, localization of the GP internus (GPi) was performed using a stereotactic head frame (CRW stereotactic system; Radionics, Inc, Burlington, MA, USA) and magnetic resonance imaging of the brain (1.5-T MR imager, Signa; General Electric Medical Systems, Milwaukee, WI, USA). The initial targets were calculated 2 mm anterior to the midcommissural point, 3 mm below the AC–PC line and 20 mm lateral to the midline. Singleunit extracellular recordings helped guide lesion placement. Three microelectrode tracks were explored on the right side and four on the left. The mean discharge rate

1249

was calculated as the average number of spikes of similar amplitude recorded over a 20-second period. The posteroventral border of GPi was identified by the cessation of neuronal firing for at least 2 mm. Although 20 to 30 cells were identified in each GPi, only eight cells (three cells from the left GPi and five cells from the right GPi) were held long enough to accurately determine their firing rate. Neuronal activity was relatively low with a firing rate of 29 ± 14 Hz and most neurons showing pauses (Fig. 2A). In the track of the last pass on each side, a radiofrequency lesion generator (Radionics, Inc) was used first to stimulate the area of activity and, if no movements were seen in the contralateral extremities, lesions were made at that level and also 3 mm higher along the path with the lesion generator set at 75°C for 1 minute each. Postoperative Course After surgery the patient remained stuporous and the propofol and midazolam were discontinued. Vigorous stimuli produced moaning. Pupils were midriatic (5 mm bilaterally, but she was on trihexyphenidyl) and reactive to light. She had preserved oculocephalic reflexes. Corneal reflexes were decreased. Painful stimuli to all extremities and the trunk produced withdrawal. The deep tendon reflexes were 3+ of 4 in her arms and 4 of 4 in her legs with bilateral clonus. She developed bilateral extensor plantar responses. Acutely, limb dystonia mildly improved but trunk dystonia persisted. Several days after the surgery, she had two generalized tonic–clonic seizures and severe limb spasticity developed. The patient was started on 300 mg phenytoin per day. She was also injected with botulinum toxin in her upper extremities. She continued taking trihexyphenidyl and baclofen for

FIG. 1. (A) GPi cells from the microelectrode track in this patient with WHD showing a bursting pattern with pauses. Mean firing rate 29 ± 14 Hz. (Time scale: 1 second between vertical bars.) (B) GPi cells from the microelectrode track in a patient with PD. Mean firing rate 82 ± 12 Hz. (Time scale: 1 second between vertical bars.)

Movement Disorders, Vol. 15, No. 6, 2000

1250

E. CUBO ET AL.

FIG. 2. Postoperative MRI of the brain (axial inversion recovery sequences) showing the bilateral pallidotomy and edema involving the internal capsule, mostly on the left side.

the dystonia. A postoperative computed tomography scan and magnetic resonance image of the brain showed that the lesions were largely placed in the GPi (Fig. 1) with significant edema involving the internal capsule, mostly on the left side. The patient was extubated and the muscle relaxants and anesthetics were discontinued. She was discharged to a long-term care hospital. Postoperative follow up 3 months later showed modest clinical improvement in limb dystonic features. The Burke-FahnMarsden Dystonia Rating Scale score was 49 at that time. The patient died 4 months later from a progressive worsening of her medical conditions, but no autopsy was obtained. DISCUSSION Although there are no data on patterns of neuronal activity in normal humans, microelectrode recordings from patients with generalized dystonia indicate that the mean discharge rates (21–48 Hz) in the GPi are lower than those in patients with PD (80–85 Hz; Fig. 2B)3,5 but slightly faster than that found in a patient with hemiballismus.6 In comparison to normal or parkinsonian primates, the GPi discharges in patients with dystonia are

Movement Disorders, Vol. 15, No. 6, 2000

also more irregular with more bursting and pauses.6 In this patient with WHD, the GPi microelectrode recordings showed a relatively low firing rate of 29 Hz ± 14 Hz with most neurons showing pauses. Although propofol has been associated with the development of dystonic and dyskinetic movements, and potentially could alter the GPi firing rates during surgery,5,9 the pattern of our patient resembles the firing rates of GPi neurons in patients with idiopathic dystonia as recently described.5,6 Previous studies have shown that pallidotomy significantly improves choreiform movements in HD and levodopa-induced dyskinesias in PD.3,4,9,10 Reduction of parkinsonian tremor, rigidity, and bradykinesia after pallidotomy are also seen but the extent is more variable and the duration shorter that for dyskinesias.11 In addition, pallidotomy may lessen the severity of dystonia, although the effect may be more dramatic in idiopathic than in secondary dystonia.12 The progressive course of improvement of dystonic symptoms is unlike the immediate response seen in PD. This pattern may imply that some physiological compensation, plasticity, or even relearning may be responsible for the reduction on motor tone and improved motor control after pallidotomy in dystonia.12 In our patient, dystonia and bradykinesia were the most disabling features. Over a 3-month follow-up period after pallidotomy, we did find modest palliative functional improvement in dystonic features with marked worsening of spasticity. Postoperative scores on the Burke-Fahn-Marsden Dystonia Rating Scale showed persistent high levels of impairment. In addition to the surgery, to enhance clinical function, we administered botulinum toxin injections and thereafter we could not evaluate surgically related improvement in isolation. The lack of major clinical improvement in dystonia and parkinsonian features in our case and subsequent spasticity may be the result of inadvertent involvement of the internal capsule. Because of the bilateral marked atrophy of the GPi of our patient, the lesion site was particularly difficult to determine by neuroimaging. Additionally, it is possible that her severe disability was related to the high degree of pallidal histopathologic disturbances13,14 before surgery, so that the lesions even though properly placed were not markedly therapeutic. This degree of degeneration is typically not seen in either PD or primary dystonia. In our case, the only usefulness of the procedure was that it permitted the patient to be managed without continuous intravenous muscle relaxants, which allowed nursing home placement. Acknowledgments: The authors thank Dr. Christopher G. Goetz and Dr. Jerrold L. Vitek for their advice and assistance.

PALLIDOTOMY IN HD REFERENCES 1. Jeroen P, van Vugt P, Hilter BJ, et al. Hypokinesia in Huntington’s disease. Mov Disord 1996;11:384–388. 2. Jongen PJ, Renier WP, Gabreels FJ. Seven cases of Huntington’s disease in childhood and levodopa induced improvement in the hypokinetic-rigid form. Clin Neurol Neurosurg 1980;82:257–261. 3. Shannon KM, Penn RD, Kroin JS, et al. Stereotactic pallidotomy for the treatment of Parkinson’s disease. Efficacy and adverse effects at 6 months in 26 patients. Neurology 1998;50:434–438. 4. Vitek JL, Bakay RA, Hashimoto T, et al. Microelectrode-guided pallidotomy: technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. 5. Lozano MA, Kumar R, Gross RE, et al. Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865– 870. 6. Vitek JL, Zhang J, Evatt M, et al. GPi pallidotomy for dystonia: clinical outcome and neuronal activity. Adv Neurol 1998;78:211– 219. 7. Burke RE, Fahn S, Marsden CD, et al. Validity and reliability of a

8.

9. 10. 11. 12. 13. 14.

1251

rating scale for primary torsion dystonias. Neurology 1985;35:73– 77. Krauss JK, Desalomos JM, Lai E, et al. Microelectrode-guided posteroventral pallidotomy for treatment of Parkinson’s disease: post-operative magnetic resonance imaging analysis. J Neurosurg 1997;87:358–367. Chodakiewitz JW. Localizing pallidotomy lesions. J Neurosurg 1998;88:1125. Spiegel EA. Development of stereoencephalotomy for extrapyramidal diseases. J Neurosurg 1966;24:433–439. Lozano AM, Lang AE, Galvez-Jimenez N, et al. Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Ondo WG, Desalomos M, Jankovic J, et al. Pallidotomy for generalized dystonia. Mov Disord 1998;13:693–698. Myers RH, Vonsattel JP, Stevens TJ, et al. Clinical and neuropathologic assessment of severity in Huntington’s disease. Neurology 1988;38:341–347. Vonsattel JP, DiFiglia M. Huntington’s disease. J Neuropathol Exp Neurol 1998;57:369–384.

Movement Disorders, Vol. 15, No. 6, 2000