Dystonia-Parkinson syndrome: differential effects of levodopa and dopamine agonists

Eleven patients who presented with predystonic syndrome later developed pure dystonic syndromes and later developed parkinsonism. This suggests that dystonic syndromes can be the precursor to a mixed syndrome including both dystonia and parkinsonism. While the parkinsonian features in such patients respond to either levodopa or direct-acting agonists, levodopa often exacerbates the underlying dystonia. Direct acting agonists appear to be less liable to do this.     

Dystonia in multiple system atrophy

OBJECTIVE: To delineate the frequency and nature of dystonia in multiple system atrophy (MSA). METHODS: A cohort of 24 patients with clinically probable MSA over the past 10 years were prospectively followed up. Motor features were either dominated by parkinsonism (MSA-P subtype, n=18) or cerebellar ataxia (MSA-C, n=6). Classification of dystonic features and their changes with time was based on clinical observation during 6-12 monthly follow up visits. Parkinsonian features and complications of drug therapy were assessed. Most patients (22/24) died during the observation period. Neuropathological examination was confirmatory in all of the five necropsied patients. RESULTS: At first neurological visit dystonia was present in 11 (46%) patients all of whom had been levodopa naive at this time point. Six patients (25%) exhibited cervical dystonia (antecollis) (MSA-P n=4, MSA-C n=2), five patients (21%) showed unilateral limb dystonia (MSA-P n=4; MSA-C n=1). A definite initial response to levodopa treatment was seen in 15/18 patients with MSA-P, but in none of the six patients with MSA-C. A subgroup of 12 patients with MSA-P developed levodopa induced dyskinesias 2.3 years (range 0.5-4) after initiation of levodopa therapy. Most patients had peak dose craniocervical dystonia; however, some patients experienced limb or generalised dystonia. Isolated peak dose limb chorea occurred in only one patient. CONCLUSION: The prospective clinical study suggests that dystonia is common in untreated MSA-P. This finding may reflect younger age at disease onset and putaminal pathology in MSA-P. Levodopa induced dyskinesias were almost exclusively dystonic affecting predominantly craniocervical musculature. Future studies are required to elucidate the underlying pathophysiology of dystonia in MSA.     

Dystonia in progressive supranuclear palsy.

OBJECTIVES: To document the nature, distribution, and frequency of dystonic symptoms in progressive supranuclear palsy (PSP). METHODS: Charts and videotapes of all clinically diagnosed patients with PSP seen between 1983 and 1993 were reviewed and the occurrence, nature, and distribution of all dystonic symptoms were recorded. RESULTS: Of 83 identified cases 38 had some dystonic features. Twenty (24%) had blepharospasm (one was induced by levodopa), 22 (27%) had limb dystonia (one was induced by electroconvulsive therapy and another by levodopa), 14 (17%) had axial dystonia in extension, one had oromandibular dystonia induced by levodopa, and two had other cranial dystonias. Six patients had limb dystonia as an early or presenting feature, sometimes leading to misdiagnosis of cortical-basal ganglionic degeneration. All three patients who had postmortem confirmation of the diagnosis had other concurrent disease. One patient with bilateral limb dystonia and blepharospasm had evidence of previous hydrocephalus and severe arteriosclerotic changes. One with arm dystonia also had cerebrovascular disease and one with hemidystonia also had rare swollen chromatolytic neurons in the frontotemporal cortex. CONCLUSIONS: Dystonia is a common manifestation of PSP. Limb dystonia is particularly common and may indicate the presence of concurrent disease. When dystonia occurs in PSP, dopaminergic medication should be cautiously reduced or discontinued to rule out the possibility of treatment induced symptoms.     

Early-morning dystonia. A late side effect of long-term levodopa therapy in Parkinson's disease.

Four women with Parkinson's disease undergoing prolonged levodopa therapy had daily episodes of dystonic posturing, affecting one lower extremity, several years after initiation of treatment. The dystonia occurred only in the early morning, on awakening and before the first dose of levodopa, when the patients were in the akinetic-rigid state with no dyskinesias. It further interfered with gait, slowly subsided within one to two hours, and did not recur until next morning. This abnormal involuntary posture was unaffected by manipulations of daily levodopa dosage and schedule, completely disappeared after withdrawal of drug therapy, and recurred following its readministration. Additional adverse reactions including dyskinesias, "on-off" phenomena, and declining efficacy of levodopa were present in all patients. Early-morning dystonia may represent another late side effect secondary to long-term levodopa administration in parkinsonism.     

Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification

Autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF, syn. autosomal recessive juvenile parkinsonism, PARK2) is one of the hereditary parkinsonian syndromes. We examined subjects consisting of 43 patients from 22 families with AR-EPDF. The clinical features were relatively homogeneous, including the average age at onset of 26.1 years, beginning with dystonic gait disturbance, diurnal fluctuation of the symptoms (sleep benefit) unrelated to medication, dystonia (mainly foot dystonia), hyperactive tendon reflex, remarkable effect of levodopa and other antiparkinsonism drugs, susceptibility to dopa-induced dyskinesia, mild autonomic symptoms, absence of dementia, and slow progression of disease. Some patients had hysteric character or psychic symptoms provoked by medication. Pathologic study revealed neuronal loss in the substantia nigra pars compacta and locus coeruleus without Lewy body formation. We performed extensive molecular genetic analysis of the parkin gene in 16 families to identify a total of six different deletional mutations. In AR-EPDF loss of newly discovered 'Parkin' protein is responsible for selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus. Compared with autosomal dominant Parkinson's disease, AR-EPDF appears to be more prevalent and present in several ethnic groups.     

Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women

BACKGROUND: X-linked dystonia-parkinsonism (XDP) or "lubag" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.     

Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations.

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.     

Surgical targets for dystonic tremor: Considerations between the globus pallidus and ventral intermediate thalamic nucleus

Dystonic tremor (DT) is characterized by coexisting tremor and abnormal dystonic posturing in the same segment. DT is often medically refractory and DBS is an important therapeutic option. However, the optimal surgical target for DT remains uncertain with Vim, GPi and zona incerta previously reported as effective. We retrospectively reviewed the outcome data from all patients with DT involving at least one upper extremity who underwent DBS at Vanderbilt University from July 2006 to July 2010. We evaluated the improvement of tremor and dystonia after their response to DBS was judged to be maximal. Ten patients met the inclusion criteria. Vim was targeted in four patients and three had unilateral procedure and one bilateral Vim DBS. GPi was targeted in four patients with bilateral DBS procedure in every patient from this subgroup. A combined bilateral GPi and unilateral Vim DBS was performed in two patients. The best results for tremor control were observed in patients with Vim DBS but they had persisting mild dystonia. Patients with GPi DBS had average DT improvement by approximately 50% but their dystonia symptoms were markedly improved. We propose that the patients with DT with a mild dystonia should be considered for Vim DBS procedure and the coexistence of severe DT and dystonia may be successfully controlled by combined GPi and Vim DBS surgeries.     

The diagnosis of manganese-induced parkinsonism

Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance problems, in addition to various non-motor symptoms. There are many causes of parkinsonism such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive condition in which there is a dramatic and sustained responsiveness to levodopa therapy. Manganese is an essential trace element that can be associated with neurotoxicity. Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas can also be involved. MRI scans may show globus pallidus changes during (and for a short period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due to manganese may have some clinical features that occur less commonly in Parkinson's disease, such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of the body. Patients with manganese-induced parkinsonism may be younger at the onset of the disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa therapy in manganese-induced parkinsonism. In summary it may be possible to differentiate manganese-induced parkinsonism from Parkinson's disease using clinical and imaging studies.     

Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family

We examined 106 members of a family affected with dopa-responsive dystonia (DRD), a subset of idiopathic dystonia. Ten members had unequivocal dystonia; 8 of these had generalized dystonia and the other 2 had focal dystonias (writer's cramp and spastic dysphonia). Twenty members had lesser dystonic signs and symptoms suggestive of a diagnosis of dystonia. Five members, including 1 with dystonia, had prominent parkinsonism that became symptomatic in late adulthood. All members affected with dystonia or parkinsonism had increased muscle tone (rigidity), which may represent the minimal clinical expression of DRD. Gene penetrance in families with DRD may be greater than previously suspected.     

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

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 guided-stereotactic 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.     

Parkinsonism following dystonia in three patients

Three patients who presented initially with dystonia and subsequently developed typical idiopathic parkinsonism were evaluated. One patient presented with a writer's cramp, one with axial dystonia, and one with Meige syndrome. All three displayed amelioration of their dystonia with progression of their parkinsonism over a period of 2 to 15 years. Treatment with levodopa gave some relief of the parkinsonism symptoms in two patients but exacerbated or reactivated the dystonia. It is suggested that both the dystonia and the parkinsonism represent the changing clinical expression of the same disorder at different times in its evolution.     

Meige disease: striatal dopaminergic preponderance.

A dopamine agonist (apomorphine) and a cholinomimetic drug (physostigmine) were administered to five patients with blepharospasm and oromandibular dystonia (Meige disease). The effects of haloperidol and levodopa were also assessed. Apomorphine lessened and physostigmine aggravated the facial dyskinesias in all patients, while placebo injections had no consistent effect. Levodopa did not modify the symptoms, but haloperidol attentuated the facial dystonia. Dysfunction of the basal ganglia, characterized by a state of striatal dopamine preponderance, probably underlies the dystonic spasms in Meige disease. The prominent cholinergic enhancement of facial dyskinesias may distinguish this disorder pharmacologically from tardive dyskinesia, a differentiation which has practical therapeutic implications.     

Variability of clinical expression and evolution of spinal deformity in a family with late detection of dopa-responsive dystonia

This case report documents an unusual presentation of dopa-responsive dystonia (DRD) in three siblings (two females, one male) which simulated cerebral palsy (CP) and describes the evolution of their spinal deformity in relation to growth and responsiveness to levodopa therapy. The siblings were normal at birth with a negative history of neurological disease or spinal imbalance. They showed marked phenotypic variation but all developed progressive scoliosis and neurological impairment with mixed spastic dystonic features, leading to the misdiagnosis of spastic dystonic CP. Age at establishment of the diagnosis of DRD and levodopa trial for the three patients was 12 years, 9 years 6 months, and 3 years 6 months respectively. In patients 1 and 3, spinal deformity responded dramatically to levodopa treatment and neurological symptoms were ameliorated. Patient 2 developed a rigid scoliotic curve and, despite neurological improvement with levodopa, the spinal curvature remained unresponsive necessitating surgical correction. Spinal decompensation is a common manifestation of DRD, which with early diagnosis and initiation of levodopa treatment has an excellent prognosis. This report highlights the variability of clinical expression in DRD and the importance of an adequate trial of levodopa when unexplained dystonic features are documented.     

Paroxysmal non-kinesigenic dyskinesia caused by the mutation of MR-1 in a large Polish kindred

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a clinical syndrome of sudden involuntary movements, mostly of dystonic type, which may be triggered by alcohol or coffee intake, stress and fatigue. The attacks of PNKD may consist of various combinations of dystonia, chorea, athetosis and balism. They can be partial and unilateral, but mostly the hyperkinetic movements are bilateral and generalized. We present a large Polish family with 7 symptomatic members of the family in 6 generations. In all affected persons, the onset of clinical symptoms was in early childhood. All male cases showed an increase in severity and frequency of the attacks with ageing, while the only living female patient noticed an improvement of PNKD during both her pregnancies and also after menopause. In addition, at the age of 55 years, she developed symptoms of Parkinson's disease with good response to levodopa treatment.     

Comparison of dystonia between Parkinson's disease and atypical parkinsonism: The clinical usefulness of dystonia distribution and characteristics in the differential diagnosis of parkinsonism

Objective

Dystonia is occasionally found in patients with Parkinson's disease (PD) and atypical parkinsonisms. However, systematic comparative analysis of the association between dystonia and parkinsonism have seldom been reported. The goals of this study are to compare the clinical characteristics and distributions of dystonia between PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

Dopa-responsive dystonia and Tourette syndrome in a large Danish family

BACKGROUND: Guanosine triphosphate cyclohydrolase I (GTPCH) catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4). Autosomal dominantly inherited defects in the GTPCH gene (GCH1) cause a form of dystonia that is responsive to treatment with levodopa (dopa-responsive dystonia [DRD]). OBJECTIVE: To investigate molecular and clinical aspects of DRD in a large Danish family. METHODS: For analysis of the GCH1 gene, a mutation-scanning method based on denaturing gradient gel electrophoresis (DGGE) was used. A novel mutation, X251R, was identified in the GCH1 gene of 2 distantly related Danish patients with DRD, one of whom also had Tourette syndrome (TS). Thirty-five additional family members were investigated for this mutation, and 16 of them underwent clinical neurological examination. RESULTS: A total of 18 patients were heterozygous for the X251R allele, 16 of whom had neurological complaints spanning from very mild parkinsonism to severe invalidism due to dystonia. Of 13 symptomatic heterozygotes who had been neurologically examined, 10 had signs of dystonia or parkinsonism. Sixteen of the heterozygotes were treated with levodopa, and 13 reported a treatment benefit. Three of the symptomatic heterozygotes had signs of TS. CONCLUSIONS: This study confirms the large variability in DRD symptoms and emphasizes the usefulness of molecular analysis for diagnosis and treatment of DRD. The presence of TS is suggested to be coincidental, though the development of TS-like symptoms due to mutations in GCH1 cannot be excluded.     

Dystonia in Parkinson's disease: clinical and pharmacological features

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.     

Spinocerebellar ataxia type 3 presenting as an L-DOPA responsive dystonia phenotype in a Chinese family

The clinical spectrum of spinocerebellar ataxia 3 (SCA 3) disease is wide and varied. We describe a Chinese patient with a mutation at the SCA 3 locus with clinical features of levodopa-responsive dystonia. The family history was suggestive of being autosomally dominant. Levodopa responsiveness though rare has been described in families with features of parkinsonism. Noteworthy is the relatively late onset of disease (>40 years) possibly explained by the low number of affected alleles at 59, the usual range being from 62 to 86, with the lowest recorded number at 56. This expands the wide and varied phenotypic manifestations of SCA 3, and highlights the observation that features suggestive of levodopa-responsive dystonia (DRD) such as focal dystonia, gait difficulty with diurnal fluctuation of symptoms, and a marked response to low doses of levodopa can be presenting features of SCA 3. SCA 3 should be considered a differential diagnosis in adult patients who present with DRD phenotype and with a positive family history.     

Positron emission tomographic studies of dopa-responsive dystonia and early-onset idiopathic parkinsonism

There are two major syndromes presenting in the early decades of life with dystonia and parkinsonism: dopa-responsive dystonia (DRD) and early-onset idiopathic parkinsonism (EOIP). DRD presents predominantly in childhood with prominent dystonia and lesser degrees of parkinsonism. EOIP presents before age 40 with parkinsonism (often with associated dystonia). Both disorders are exquisitely sensitive to levodopa, although the long-term prognosis in each appears to be different. Some have suggested, however, that DRD is a form of EOIP. We performed positron emission tomography with 6-fluorodopa in 10 patients with DRD and 18 patients with EOIP to study the integrity of their nigrostriatal dopaminergic systems. In DRD, we found normal striatal FD uptake. In contrast, patients with EOIP had reduced striatal FD uptake. We conclude that the pathophysiologies of DRD and EOIP are distinct. Although both disorders presumably represent a deficiency of striatal dopamine, the results suggest that in DRD dopa uptake, decarboxylation, and storage mechanisms are intact. This may explain the sustained response of DRD to low doses of levodopa. 6-Fluorodopa positron emission tomography distinguishes DRD from EOIP.