Dystonia in Parhnson’s Disease: Clinical and Pharmacological Features W. H. Poewe, MD,” A. J. Lees, MD,t and G. M. Stern, M D t We studied the features of dystonia in 9 patients with untreated idiopathic Parkinson’s disease and in 56 patients on sustained treatment with L-dopa Dystonia was seen as an initial symptom in patients with both early- and late-onset Parkinson’s disease and included action dystonia of the limbs and cranial dystonia Although the coexistence of parkinsonism and dystonia suggests a common pathophysiology, antiparkinsonian drugs did not consistently influence dystonic spasms. L-dopa-induced dystonia was seen as an off-period, biphasic, or peak-dose phenomenon. Each type showed a distinctive pattern of localization of dystonic spasms, possibly reflecting neurochemical aspects of basal ganglia somatotopy. Neuropharmacological studies performed in 12 patients suggest that off-period dystonia is genuinely induced by L-dopa and best relieved by antiparkinsonian agents. Poewe WH, Lees AJ, Stern GM. Dystonia in Parkinson’s disease: clinical and pharmacological features. Ann Neurol 1988;23:73-78 Dystonia as both an initial and a late feature of Parlunson’s disease was recognized almost a century ago E3, 7, 271. It is now most frequently encountered as a drug-induced phenomenon appearing in the course of sustained L-dopa treatment [ 151. In this study the clinical characteristics of dystonia in Parkinson’s disease have been analyzed in 65 patients. Short-term intravenous pharmacological studies were performed in 12 patients with L-dopa-induced foot dystonia to clarify the underlying neuropharmacological mechanism. Patients and Methods All patients with Parkinson’s disease and symptoms of dystonia who attended the Movement Disorder Clinic of University College Hospital between 1983 and 1985 were studied. There were 9 patients in whom dystonia had been an initial symptom and 56 in whom dystonia had developed during L-dopa treatment. In the latter group the average age at onset of Parkinson’s disease was 48.7 years (range, 24 to 71 years); duration of disease, 9.7 years (range, 2 to 20 years); duration of L-dopa treatment, 8.9 years (range 0.25 to 17 years); and daily dose of L-dopa 654 mg (range, 300 to 2,000 mg). Concomitant drugs were anticholinergics in 22 patients, bromocriptine in 4, and selegiline in 4; 3 had undergone thalamotomy. Twelve patients were selected for admission to hospital for short-term pharmacological studies; 10 had L-dopa-induced early morning foot dystonia, 1 had biphasic hemidystonia with prominent foot involvement, and 1 showed consistent exercise-induced foot dystonia (dystonic claudication) unrelated to L-dopa administration. In all patients with foot dystonia, each episode persisted From the “University Clinic for Neurology, Innsbruck, Austria, and the ?Department of Neurology, The Middlesex Hospital, London, England. for at least 45 minutes with clear-cut, marked, and painful dystonic postures. This allowed the immediate responses to intravenous medications to be assessed reliably. In those with early morning dystonia, the first daily dose of L-dopa was withheld for up to 2 hours to ensure reproducible effects; in the patient with dystonic claudication, tests were carried out during treadmill exercises. After baseline observations, the following drugs were given intravenously at a time when dystonic spasms had reached maximum severity: 75 mg Ldopa, 0.1 mg lisuride (a synthetic ergoline with dopamine receptor agonist properties), 1 mg haloperidol (a dopamine receptor antagonist), 5 mg procyclidine (a centrally active anticholinergic drug), and 1 mg physostigmine (a central inhibitor of acetylcholinesterase). The minimum “washout” period between injections was 24 hours; lisuride challenges were preceded by 20 mg of domperidone orally 2 hours before injection. All challenges were performed under single-blind conditions. Responses were assessed by one of us (W. P.) according to the following scale: (1) complete cessation of dystonia within 30 minutes; (2) marked improvement of dystonic posturing and pain within 30 minutes; or ( 3 ) marked deterioration of dystonic posturing andor severity of pain within 30 minutes or increase in duration of the episode. Mild or equivocal responses were recorded as no effect. Speed of response onset was noted, as were changes in parkinsonian symptoms and the patients self-evaluation. Results Dystonia as an Initial Feature of Untreated Parkinson’s Disease Of the 9 patients who developed patterns of focal or segmental dystonia as an initial symptom, in 6 the on- Received Mar 3, 1987, and in revised form July 15. Accepted for publication July 15, 1987. Address correspondence to Dr Poewe, University Clinic for Neurology, Anichstr. 35, A-6020 Innsbruck, Austria. Copyright 0 1988 by the American Neurological Association 73 set of dystonia preceded other symptoms by up to 13 years; in 3 it concurred with other parkinsonian symptoms. Writer’s cramp was an initial symptom in 4 patients, and in 3, exercise-induced painful foot dystonia led to a distinctive gait disturbance (dystonic claudication); 1 patient with hemiparlunsonism had ipsilateral dystonic posturing and 2 others had cranial dystonia. In all but 1 of the patients with limb dystonia, Parkinson’s disease began on the same side. The one exception was a patient who had dystonia of both hands when left-sided disease appeared. PATIENT 1. The patient was well until the age of 37, when she developed dystonic writer’s cramp. Action dystonia of the right hand soon progressed to involve a variety of manual tasks, and at the age of 44 blepharospasm and oromandibular dystonia (Meige syndrome) also became apparent. L-Dopa (300 mg/day with peripheral decarboxylase inhibitor) led to worsening of the cranial dystonia and also induced involuntary choreic movements of the right arm. It was replaced by benthexol (10 mdday), producing modest improvement of Meige syndrome. The writer’s cramp was replaced by dystonic spasms of the proximal right arm consisting of adduction and pronation, usually triggered by walking. The patient has been without any medication for the past 3 years and has gradually developed Parkinson’s disease with right-sided resting tremor, rigidity, and bradykinesia. Dystonic spasms of her right arm have stopped but there are still occasional bouts of cranial dystonia. Dystonia in L-Dopa-Treated Parkinson’s Disease Fifty-six patients developed dystonia during sustained L-dopa treatment; preliminary observations in 42 have previously been published C261. This group includes 3 in whom dystonia had been an initial symptom, but in whom the pattern or type of dystonia had markedly altered after L-dopa had been commenced. Within the group, in all but 3 recurrence of dystonia was related to the periodicity of clinical effects of L-dopa and could be classified as off-period, biphasic, or peak-dose dystonia. Onset of dystonia was related neither to the duration of Parkinson’s disease nor to the duration of L-dopa treatment. Earb Morning and Off-PeriodDystonia Forty-six of the 56 patients showed dystonia clearly linked to the L-dopa wearing-off phase. In all but 3, dystonia tended to occur in the morning before the first dose of L-dopa had been taken. In 16, it was succeeded by one or more identical dystonic phases during wearing-off episodes throughout the day and night, whereas in 27 it tended to be restricted to the morning predose phase. In 3, dystonia appeared only in wearing-off periods in the second half of the day and 74 Annals of Neurology Vol 23 No 1 January 1988 Painful bilateral dystonicfoot spasms (early morning dystoniaj in Patient 2. Note bilaterd toe curling with arching of the sole and inversion at the ankle. during the night. The clinical pattern was similar in all 46 with off-period dystonia. PATIENT 2. The patient developed signs of Parkinson’s disease in his right arm at the age of 44 and a year later began taking 500 mg L-dopa daily with a peripheral decarboxylase inhibitor. After 6 good years he began to experience end-ofdose effects and predominantly right-sided peak dose chorea; after 8 years of treatment he developed painful dystonic spasms of his feet occurring regularly between 6 and 7 AM before his first dose of L-dopa. During hospital observation, dystonic cramps were confirmed to begin while the patient was still in bed with extreme plantar flexion of all toes, arching and inversion of the feet, and marked stiffening and pain in the calf muscles. Spasms usually started on the left but gradually became bilateral (Figure). Dystonia could last for more than an hour while the patient remained severely bradykinetic and rigid and frequently uttered paranoid ideas in a barely audible voice. The switch to the on phase about 30 minutes after L-dopa administration was sudden: in less than a minute his mood would brighten, and dystonic foot posture resolved to be replaced by right-sided chorea. He was then able to leave his bed, move freely, and speak clearly. For the rest of the day he showed wearing-off effects after each dose of L-dopa, but usually without further dystonic spasms. Early morning dystonia, however, could be prevented only if he took his first dose of L-dopa at 5 AM. In the 46 patients with this pattern of dystonia, abnormal postures and painful dystonia primarily affected the feet and toes with equinovarus deformities and curling under of toes or extension of the great toe. Boardlike painful stiffening of the calf muscles on the affected side was also frequent, but extension of dystonia to involve flexion of the whole leg occurred in only 5 patients. Involvement of other body segments in off-period dystonia was also uncommon and when present it usually affected the homolateral upper limb. Off-period dystonia was unilateral in 22 patients and bilateral in 24, of whom 13 showed unilateral predominance. Off-period foot dystonia tended to involve the side initially or more severely affected by Parkinson’s disease and was more often present on the same side as peak-dose chorea. The duration of individual episodes of off-period dystonia varied considerably, from iess than 5 minutes to longer than 2 hours. Wallung or other forms of exercise involving the lower limbs as well as nervous tension were triggering factors in 38 patients; rest and relaxation were generally beneficial. Twenty-three of 43 patients with early morning dystonia experienced symptoms only after rising. Biphasic Dystonia In 7 patients, L-dopa-induced dystonia followed a biphasic pattern with the appearance of dystonic symptoms both during the onset and end-of-dose phases of an individual dose. In 5 , dystonia was of comparable severity in both phases; in 2 it was more evident during the onset-of-dose than in the wearing-off phase. For all affected patients, onset of dystonia proved to be a reliable indicator that L-dopa peak-dose benefit effects were imminent. In all patients, biphasic dystonia was predominantly unilateral, always involving the foot in an identical manner to that seen in off-period dystonia. In the majority, dystonia also involved the homolateral arm and leg; in some there were also signs of cranial dystonia. The side more affected by biphasic dystonia was identical to that initially or more severely affected by Parkinson’s disease in all 7 patients. 3 . The patient developed Parkinson’s disease at the age of 55 with tremor of the left hand. Four years later she began L-dopa treatment (4 gm daily) with excellent improvement for 5 years. Response fluctuations then appeared together with spasm affecting the left lower limb. When the patient was examined in hospital the following pattern was seen: upon awaking there was profound early morning akinesia and bilateral resting tremor of aU limbs. Within 20 minutes of the first dose of L-dopa (500 mg without a decarboxylase inhibitor), her left foot plantar flexed and inverted, all toes curled under, and the left leg went into painful flexion at the hip and knee for as long as 30 minutes. This subsided as soon as L-dopa-induced mobility supervened, permitting movement for the next 90 minutes, after which identical episodes of limb spasms caused immobility and violent limb tremor to recur. The second dystonic episode also lasted about 30 minutes until the next L-dopa dose had taken effect. The rest of the day was dominated by further sequences of biphasic dystonia with a gradual decrease in the duration of the intervening symptom-free phase. PATIENT Three of the patients also had early morning foot dystonia, but the distribution of biphasic dystonia was distinct from off-period dystonia, with more widespread involvement of the lower h b and trunk. Peak-Dose-Dystonia Nine patients had L-dopa-induced dystonic posturing as peak-dose phenomena. In 2, dystonia was the only manifestation of L-dopa-induced involuntary movements and both had peak-dose cranial dystonia with disabling blepharospasm and dystonic jaw spasm. Six patients with peak-dose dystonic phenomena also had early morning off-period dystonia; whereas the latter was always restricted to the lower limb, peak-dose dystonia seemed to be confined to the face and neck in these patients. In 5, peak-dose involuntary movements included both facial dystonia and limb chorea. Pharmacological Observations Dystonia in Untreated Patients Six of the 9 patients with dystonia as an initial symptom of Parkinson’s disease were treated with benzhexol at a mean daily dose of 8.6 mg (range, 8 to 12 mg) and 7 with L-dopa (mean dose 400 mg daily in combination with a decarboxylase inhibitor); only one patient had taken bromocriptine (total daily dose of 70 mg). Benzhexol treatment led to modest improvement of cranial dystonia and hemidystonia in 2 patients taking 10 and 12 mg, respectively, but there was worsening of cranial dystonia in 1 patient taking 6 mg, and 6 to 8 mg had no effect on dystonic symptoms in 3. In contrast to this inconsistent response of dystonia, parkinsonian symptoms showed modest improvement with anticholinergic therapy in all patients. Of the 7 patients treated with L-dopa there was an unequivocal effect on dystonia in 4 leading to marked deterioration in cranial dystonia (Meige syndrome, 2 patients) and a notable improvement of dystonic claudication and writer’s cramp (1 patient each). In 3, L-dopa produced no evident effect on dystonia. Bromocriptine monotherapy was given to only 1 of the 9 patients; both dystonia (writer’s cramp) and parlunsonian symptoms improved. L-Dopa Withdrawal and Off-PeriodDystonia In 7 of 46 patients with L-dopa-induced off-period dystonia, medication was discontinued or reduced by 50% for up to 7 days. All 5 patients who abstained developed frequent bouts of foot dystonia of increased duration and severity during the first day of L-dopa withdrawal; parkinsonian features showed only modest deterioration. By the end of the second drug-free day, parkinsonian disabilities had reappeared; foot dystonia had completely subsided and did not recur until Ldopa was recommenced. Two had been able to estab- Poewe et al: Dystonia in PD 75 Table I. Foot Dystonia: Pharmacological Challenges ( n = 12) No. of Patients Responding Drug Dopamiqergic L-dopa 75 mg IV (n = 110) Lisuride 0.1 mg IV (n = 10) Anticholinergic Procyclidine 5 mg IV (n = 9) Antidopaminergic Haloperidol 1 mg IV (n = 10) Cholinergic Physostigmine 1 mg IV (n = 9) Abolition Improvement No Effect Exacerbation 9 6 ... ... 6 ... 2" ... ... 7" "Parkinsonian symptoms aggravated. IV = intravenous. lish independently a critical dosage of L-dopa below which they did not experience off-period dystonia (400 and 500 mg L-dopa per day, respectively). lntravenotls Challenges in Patients with L-Dopa-lndzlced Foot Dystonia The results of challenges with drugs influencing dopaminergic and cholinergic systems in 12 patients with L-dopa-induced foot dystonia are summarized in Table 1. Both dopaminergic agents were effective in improving foot dystonia. L-dopa was more potent than lisuride, which had no effect in 2 patients with offperiod foot dystonia and a longer latency before the onset of benefit (20 to 30 minutes versus 5 to 10 minutes for L-dopa). Procyclidine was also beneficial in most patients; 2 nonresponders both had off-period dystonia. Physostigmine exacerbated tremor, rigidity, and foot dystonia in all but 2 patients. Haloperidol did not influence dystonia in most patients, but abolished foot dystonia in 1 patient with early morning symptoms and also in 1 with dose-unrelated dystonic claudication. Some worsening of parkinsonian symptoms followed haloperidol injection in all patients and 2 experienced impairment of L-dopa responsiveness for more than 48 hours when L-dopa failed to produce the usual mobility and did not lead to peak-dose chorea. Discussion Kmesigenic foot dystonia as an early symptom of Parkinson's disease was described by Purves Stewart E27) almost a century ago, and there have been a number of confirmatory recent reports [lo, 12, 14, 183. This might suggest a shared pathophysiology for dystonia and bradykinesia, rigidity and tremor. However, in some patients dystonia becomes less pronounced or even resolves despite progressive parkinsonism. The response of dystonia in untreated Parkinson's disease to antiparhnsonian therapy is inconsistent [10, 12, 181. In this study L-dopa and anticholinergics al76 Annals of Neurology Vol 23 No 1 January 1988 ways improved parkinsonian features, but had unpredictable effects on the dystonic symptoms. The poor response to L-dopa is an important feature distinguishing idiopathic Parkinson's disease with dystonia from dystonia-parkinsonism of juvenile onset [2, 331. The latter frequently shows familial occurrence [2,32} and diurnal variation of symptoms [22,3 1, 321, suggesting a close relationship to the childhood condition of hereditary progressive dystonia with diurnal fluctuation (Segawa syndrome) [23, 29, 301. Whether the difference between dystonia in adult-onset idiopathic Parkinson's disease and the juvenile dystoniaparkinsonism syndromes is due to age-related changes in the neurochemical organization of the striatum 1247 or reflects a maturational defect of nigral compacta neurons unique to juvenile dystonia-parkinsonism 1333 is unclear. Drug-induced dystonia can be classified into offperiod, biphasic, and peak-dose types. Off-period dystonia is by far the most common type of drug-induced dystonia encountered in Parkinson's disease, with an overall incidence varying from 20 to 33% of patients receiving treatment for longer than 3 years [4,213. It can be regarded as a drug-provoked phenomenon, as it usually resolves completely when L-dopa is stopped or the dosage is appreciably reduced, as seen in this and other studies [9, 193. Furthermore, off-period dystonia has not yet been observed in patients receiving sustained bromocriptine monotherapy [161. The mean age at onset of Parkinson's disease in all three groups with L-dopa-induced dystonia was below 50; in the 7 patients with biphasic dystonia it was below 40. This accords with observations that both offperiod dystonia and biphasic dyskinesia are more common in patients who are younger at onset 11, 9, 20). One of the most intriguing features of L-dopainduced off-period dystonia is an almost exclusive involvement of the feet-often ipsilateral to the side most affected by Parkinson's disease-whereas peak- Table 2. Topography of t-Dopa-Induced Dystonia in Parkinson’s Disease (n = 56) Body Area Involved Foot Proximal leg Ipsilateral arm Trunk Facetneck Off-Period (n = 46) Biphasic (n = 7 ) 46 5 6 7 5 5 Peak-Dose 9) (n = 1 1 1 0 1 0 1 4 9 dose dystonia shows a marked predilection for the orofacial region, platysma, and neck. This contrast was striking in several patients in this study who had dystonic foot postures in the off period and orofacial dystonia when L-dopa had taken effect. Biphasic dystonia seemed to lie between these poles with marked foot involvement in all patients but with a tendency to become more widespread (Table 2). Although extension of off-period dystonia to proximal parts of the limbs has been seen by others 191, this was only observed in minor degree in 5 of our 46 patients. Such distinctions may reflect somatotopic organization within the basal ganglia, as has been observed in autoradiographic studies of frontoputaminal projections (131 and single cell recording studies in the putamen and pallidum [ 5 ] of primates. The changes in dopaminergic input into the striatum in Parkinson’s disease have also been shown to affect the caudate and putamen in a topographically distinct fashion; the degree of dopamine depletion shows a rostrocaudal gradient IS}. On the basis of such findings it is conceivable that involuntary movements triggered by increased dopaminergic function, i.e., peak-dose dyskinesias in L-dopa-treated patients, could affect different body areas from those associated with decreased dopaminergic activity, i.e., off-period dystonia. It is generally assumed that striatal dopaminergic receptor supersensitivity plays a major role in the genesis of L-dopa-induced peak-dose dyskinesias [6, 117 and may also be important in peak-dose dystonia. The pharmacological mechanism underlying L-dopainduced off-period dystonia, however, is more difficult to understand. In this study dopamine agonists produced consistent benefit as did the anticholinergic agent procyclidine; the cholinergic agent physostigmine usually aggravated dystonic symptoms. Accordingly, it has been suggested that dystonic spasms occurring during off periods merely reflect an integral part of reappearing parkinsonism [lo]. In this study, however, L-dopa withdrawal for more than 24 hours, while causing reemergence of fully developed parkinsonism, also led to complete relief from foot dystonia. Similarly, haloperidol aggravated parkinsonism in all patients but did not increase foot spasms and even improved dystonic symptoms in some patients. Secondary striad cholinergic hyperfunction developing with sustained L-dopa treatment might be an important factor in L-dopa-induced off-period dystonia and could explain the pharmacological findings of this study (251. 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