MOVEMENT DISORDERS

INTRODUCTION — Movement disorders are characterized by either reduced (bradykinetic) or excessive (hyperkinetic) activity. Bradykinetic movement disorders frequently are accompanied by rigidity, postural instability, and loss of automatic associated movements. Diagnosis of the specific condition depends primarily upon careful observation of the clinical features. Many such disorders, mostly rare, exist and only four are discussed here: Parkinson disease Wilson disease Huntington disease Hallervorden-Spatz disease (Neurodegeneration with brain iron accumulation)

ANATOMY OF THE BASAL GANGLIA — A brief review of the anatomy of the basal ganglia is appropriate because this site is involved in many of the bradykinetic disorders. The basal ganglia regulate the initiation, scaling, and control of the amplitude and direction of movement. Movement disorders can result from biochemical or structural abnormalities in these structures. The basal ganglia are a complex of deep nuclei that consist of the corpus striatum, globus pallidus, and substantia nigra. The corpus striatum, which includes the caudate nucleus and the putamen, receives input from the cerebral cortex and the thalamus and, in turn, projects to the globus pallidus.

The substantia nigra is divided into the dopamine-rich pars compacta and the less dense pars reticularis. The pars reticularis is similar histologically and chemically to the medial segment of the globus pallidus, and both project via the thalamus to the premotor and motor cortex. The substantia nigra pars compacta gives rise to the nigral-striatal pathway, which is the main dopaminergic tract.

The output of the basal ganglia projects by way of the thalamus to the cerebral cortex and then to the pyramidal system. Basal ganglia output is known as the extrapyramidal system because it was formerly thought to be in parallel with the pyramidal system. Integration of the basal ganglia with the cortex facilitates motor control.

PARKINSON DISEASE — Bradykinetic movement disorders consist predominantly of conditions with features of parkinsonism, of which Parkinson disease (PD) is the most prominent example. Characteristic findings include rigidity, akinesia, and gait disturbance.

Clinical features — PD typically presents in middle and late life. However, early-onset disease can occur before age 40 years, and a juvenile form presents before age 20. Most affected children have a rigid, akinetic disorder, although many have a typical resting tremor. Dystonia often involving the legs, levodopa-induced dyskinesias, and levodopa-related motor fluctuations (eg, "wearing off" and "on-off" responses several hours following a dose) are common in the juvenile form.

Genetics — Most cases of PD are sporadic, but genetic loci (PARK1 through PARK13) with causative mutations in six nuclear genes have been associated with autosomal dominant or recessive Parkinson disease or parkinsonism. These genes encode the following proteins: Alpha synuclein Ubiquitin carboxyl-terminal hydrolase-1 (UCHL1)Parkin DJ1  PTEN-induced putative kinase 1 (PINK1)  Leucine rich repeat kinase 2 (LRRK2), also called dardarin.

Most sporadic cases of PD do not show clear familial aggregation, but genetic factors likely contribute to PD susceptibility. One genetic locus (PARK10) on chromosome 1p has been associated with late onset idiopathic PD, and mutations in the glucocerebrosidase gene (GBA) in Ashkenazi Jews have been associated with a significantly increased risk of PD compared with healthy controls.

The pathogenesis of autosomal dominant or recessive Parkinson disease is not completely understood. A speculative unifying model suggested by genetic analysis proposes the following mechanisms: Abnormal aggregation and misfolding of alpha synuclein leads to Lewy body formation, triggering cellular oxidative stress and energy depletion. Mutations in parkin and UCHL1 may interfere with proteosome degradation of abnormal proteins such as alpha synuclein. Mutations in DJ1 may enhance misfolding and aggregation of alpha synuclein. Mutations in DJ1 and PINK1 may contribute to increased oxidative stress and decreased cellular resistance to stress imposed by misfolded and abnormally aggregated proteins. Mutations in GBA may lead to reduced lipid binding of alpha synuclein and thus an increased pool available for misfolding and aggregation.

Phenotypic variability — Some have argued that it is premature to claim that all of these gene mutations cause true Parkinson's disease, since Lewy bodies are not clearly associated with either DJ1 or PINK1 mutations. In addition, there is phenotypic variability between these different mutations. Alpha synuclein mutations (PARK1 and PARK4) are associated with an autosomal dominant inheritance mode; the phenotype varies from classic Parkinson's disease to dementia with Lewy bodies. Many patients with early-onset autosomal recessive familial PD and isolated juvenile-onset disease have mutations in the parkin gene (PARK2), located on chromosome 6q25.2-27. In one series, mutations occurred more frequently in patients with isolated disease when the age of onset was before 20 than after 30 years (77 versus 3 percent). In the patients who died, neuropathologic examination of the brains showed depigmentation of the substantia nigra pars compacta. However, the neurons did not contain the eosinophilic cytoplasmic inclusions (Lewy bodies) typically seen in PD.

However, the parkin-associated phenotype can be indistinguishable from idiopathic Parkinson's disease in some individuals, as evidenced by detailed evaluation of a large pedigree of parkin mutation carriers from northern Italy. Among the 77 parkin mutation carriers, 25 had levodopa-responsive parkinsonism, and five of them met criteria for definite Parkinson's disease. Neuropathologic examination of one 73 year old patient who carried two mutant parkin alleles demonstrated Lewy bodies in substantia nigra and locus ceruleus. Mutations of DJ1 (PARK7) are associated with autosomal recessive inheritance, age younger than 40 at onset, slow progression, and good response to levodopa. Mutations of PINK1 (PARK6) are associated with autosomal recessive inheritance, age younger than 50 at onset, slow progression, and excellent response to levodopa, similar to parkin and DJ1. PARK6 has been found worldwide. Although preliminary evidence suggested that PINK1 was not associated with sporadic forms of PD, a subsequent report from Italy found that PINK1 was responsible for some sporadic cases of early onset PD. The LRRK2 gene (PARK8 locus) maps to chromosome 12p11.2-q13.1 and codes for dardarin, a protein of unknown function whose structure suggests it may be a cytoplasmic protein kinase. Mutations in LRRK2 are associated with parkinsonism characterized by typical clinical features of PD, including levodopa responsiveness. However, the age of onset is highly variable (range 35 to 78 years). Furthermore, the neuropathologic features may be variable even within the same family; these include abnormalities consistent with Lewy body PD, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and tau pathology suggestive of progressive supranuclear palsy.

The LRRK2 gene may account for a significant proportion of PD cases. Genetic screening studies suggest that the Gly2019Ser mutation in the LRRK2 gene accounts for 3 to 13 percent of autosomal dominant PD in Europe, and 41 percent of autosomal dominant PD in families from North Africa. The Gly2019Ser mutation has been identified in asymptomatic carriers, suggesting reduced or age-dependent penetrance. LRRK2 mutations have been found in 0.4 to 1.6 percent of patients with idiopathic PD, although such cases could also be explained by reduced penetrance in familial disease.

Diagnosis — The diagnosis of juvenile parkinsonism is based on clinical signs. Patients have gradual onset of slowness of movement, tremors in the hands or legs (but not the head), rigidity of muscles, shuffling gait, and postural instability. Other signs include lack of facial expression (hypomimia), drooling, dysarthria, and dystonia (involuntary spasms and abnormal postures of hands and feet).

Treatment — Levodopa is the most effective drug in the treatment of PD. However, most patients develop abnormal involuntary movements (dyskinesias) and unpredictable fluctuations in motor functioning within three years of treatment. Patients with onset before age 20 years are most likely to be affected. As a result, therapy is initiated with other drugs that will control the symptoms and delay the need for levodopa. They include anticholinergic drugs (eg, trihexyphenidyl, amantadine) and dopamine agonists (eg, pramipexole, ropinirole, and pergolide).

Complications of levodopa are managed by adjusting the dosage and frequency of administration. If these changes do not alleviate symptoms, surgical treatment, such as high frequency stimulation of the subthalamic nucleus or globus pallidus, is considered.

WILSON DISEASE — Wilson disease (WD, hepatolenticular degeneration) is a treatable cause of juvenile parkinsonism, dystonia, and other movement disorders. This rare disorder has an estimated prevalence of 30 per million. WD is an autosomal recessive defect of cellular copper export. The major abnormality in WD is reduced biliary excretion of copper that leads to its accumulation, initially in the liver and then in other tissues, particularly the brain. Tissue copper deposition causes a multitude of signs and symptoms that reflect hepatic, neurologic, hematologic, and renal impairment. The incorporation of copper into ceruloplasmin is also impaired.

The pathogenesis, diagnosis and treatment of WD are discussed in detail separately in the appropriate topic reviews. (See "Pathogenesis and clinical manifestations of Wilson's disease", see "Diagnosis of Wilson's disease" and see "Treatment of Wilson's disease").

HUNTINGTON DISEASE — Huntington disease (HD) typically presents during the fourth and fifth decades of life; however, onset occurs during childhood or adolescence in approximately 5 to 7 percent of affected patients.

Genetics — The genetics and pathogenesis of HD are discussed in detail separately. (See "Genetics and pathogenesis of Huntington disease"). Reviewed briefly, HD is transmitted as an autosomal dominant trait with the affected gene being on the short arm of chromosome 4. Juvenile onset disease shows a major transmitting parent effect, as approximately 80 percent of symptomatic patients inherit the mutant HD gene from their father. The high number of cellular divisions that occur during spermatogenesis likely accounts for the pronounced paternal-repeat instability.

HD is one of a number of disorders that are associated with expansion of unstable trinucleotide (CAG) repeats that encode for polyglutamine tracts in the protein products. There is mounting evidence that fragments of the huntingtin protein containing expanded polyglutamine tracts may be neurotoxic. The greater the number of CAG repeats on expanded alleles, the earlier the age of onset and more severe the disease.

Demonstration of more than 36 CAG repeats in one of the alleles in the HD gene confirms the diagnosis of HD. Alleles with 27 to 35 CAG repeats are termed intermediate alleles. An individual with an allele in this range is not at risk of developing symptoms of HD, but may be at risk of having a child with an allele in the disease range. Juvenile forms are associated with alleles containing more than 60 to 70 repeats and, in some patients, more than 100 repeats.

The inverse relationship between age of onset and number of CAG repeats was confirmed in a Dutch cohort of 755 affected patients. The correlation was stronger for paternal than maternal inheritance.

Clinical features — Patients with juvenile-onset HD develop dystonia, ataxia, and seizures. Most of them have the akinetic-rigid syndrome termed the Westphal variant. Approximately one-fourth have the classic feature of chorea seen in adults. Children also have more rapidly progressive disease than adults.

Biochemical changes observed in the brains of adults with HD may explain the neurologic features. Glutamic acid decarboxylase activity is reduced, especially in the corpus striatum, substantia nigra, and other basal ganglia. In contrast, thyrotropin-releasing hormone, neurotensin, somatostatin, and neuropeptide Y are increased in the corpus striatum. The depletion of gamma-aminobutyric acid in the corpus striatum may result in disinhibition of the nigral-striatal pathway. Coupled with the accumulation of somatostatin, the net result may be the release of striatal dopamine, which results in chorea.

The pattern of brain abnormality depends upon the age of onset. The characteristic pathologic change in adults with HD is diffuse, marked atrophy of the neostriatum that may be worse in the caudate than in the putamen. The changes are more dramatic in early-onset HD. Affected patients typically show generalized brain atrophy and loss of cerebellar Purkinje cells.

Treatment — Dopamine-blocking drugs, such as haloperidol, and dopamine-depleting agents, including tetrabenazine, often are useful in controlling chorea. Tetrabenazine is available in Canada and several other countries.

A randomized controlled trial found that tetrabenazine at adjusted doses of up to 100 mg daily was effective for reducing chorea in ambulatory patients with HD compared with placebo. However, tetrabenazine treatment was associated with significantly more adverse events than placebo treatment. Dose-limiting symptoms with tetrabenazine included sedation, akathisia, parkinsonism, and depressed mood; these generally resolved with dosage adjustments. Two small randomized trials in adults found that the NMDA-receptor antagonist amantadine also decreases choreic dyskinesias, however a third small trial found no such benefit. Levodopa may provide symptomatic relief of the parkinsonian features of childhood HD.

Future directions — Many different potential therapies have shown some promise in animal models of Huntington disease. These include paroxetine, coenzyme Q10, minocycline, sodium butyrate, essential fatty acids, remacemide, creatine, cystamine, cysteamine and riluzole. Preliminary clinical trials of many of these agents are underway.

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION — Neurodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz disease, is a rare progressive neurodegenerative disorder that causes parkinsonism, dystonia, cognitive decline, and other neurologic deficits in children. The onset of NBIA typically is between 4 and 12 years, although it may present as parkinsonian dementia in adults.

Genetics — Most cases are inherited in an autosomal recessive pattern, but NBIA also occurs sporadically, and some phenotypically similar cases appear to be transmitted as an autosomal dominant. Many patients with NBIA have mutations in the gene encoding pantothenate kinase 2 (PANK2), localized to 20p12.3, and are said to have pantothenate kinase-associated neurodegeneration (PKAN). However, other gene mutations result in a similar phenotype.

The relationship between genotype and phenotype was evaluated in a study of 123 patients from 98 families with NBIA. The patients were classified as having classic disease with early onset and rapid progression or atypical disease with later onset and slow progression. All patients with classic disease and one-third of those with atypical disease had PANK2 mutations. These patients had the characteristic appearance of hyperintensity within the hypointense medial globus pallidus on T2 weighted magnetic resonance images, known as eye of the tiger, that was not seen in patients without mutations. Prominent speech-related and psychiatric symptoms were common in patients with atypical disease and PANK2 mutations and unusual in those with atypical disease without the mutations or in those with classic disease.

Clinical features — Children with NBIA have posture and gait abnormalities, bradykinesia, rigidity, and other parkinsonian features, including tremor. Affected patients also may have hyperkinetic movement disorders, such as dystonia and choreoathetosis, as well as progressive dysarthria, dementia, ataxia, spasticity, seizure disorder, optic atrophy, and retinitis pigmentosa. In the large series cited above, abnormalities in classic NBIA were noted with the following frequencies. Extrapyramidal signs including dystonia, dysarthria, rigidity, and choreoathetosis — 98 percent Retinopathy — 68 percent Cognitive decline — 29 percent Corticospinal tract involvement, including spasticity, hyperreflexia, and extensor toe signs — 25 percent. Few patients had optic atrophy (3 percent) and none had seizures.

The diagnosis of NBIA is based upon clinical features. Laboratory studies usually are not helpful. The disease may be suspected when a MRI scan shows a central focus of increased T2 signal intensity surrounded by a zone of decreased signal in the region of the globus pallidus (eye of the tiger sign). Scintillation counting after infusion of radioactive iron (⁵⁹ Fe) may demonstrate increased iron uptake in the basal ganglia.

Increased iron uptake is confirmed by postmortem examination, which reveals the characteristic pigmentary degeneration of the basal ganglia, particularly the internal segment of the globus pallidus and the zona reticularis of the substantia nigra. The pigmentary changes result from marked iron accumulation in these areas.

The mechanism by which basal ganglia iron uptake is increased in NBIA is not well understood. Systemic and cerebrospinal fluid iron levels, as well as plasma ferritin, transferrin, and ceruloplasmin, all are normal. Furthermore, disorders of systemic iron overload, such as hemochromatosis, are not associated with increased brain iron.

Marked neuroaxonal degeneration with the formation of spheroids is another distinctive pathologic feature of NBIA. These glycoprotein-containing axonal swellings have been attributed to abnormal lipid membrane peroxidation. It may result from chelation of ferrous iron caused by increased cysteine (demonstrated in one patient with NBIA), leading to the accelerated generation of free hydroxyl radicals in the presence of non-protein-bound iron.

Treatment — Treatment of NBIA, including iron chelation with deferoxamine and antioxidant therapy, is ineffective. Levodopa and anticholinergic drugs may provide modest relief of parkinsonian symptoms.