Chorea

Etiology

Chorea results from disruption of the basal ganglia's modulation of thalamocortical motor pathways. Multiple pathophysiologic mechanisms may be implicated. These include neuronal degeneration in selective regions, neurotransmitter receptor blockade, other metabolic factors within the basal ganglia, and exceedingly rarely a structural lesion. Chorea is classified into inherited, primarily Huntington disease (HD), immunologic Sydenham chorea, drug-related, structural, and various miscellaneous etiologies ( Table 32.1 ).

Pathophysiology

The putamen, globus pallidus, and subthalamic nuclei are the key pathologic sites related to the development of chorea. Normal movement patterns depend on the presence of a critical physiologic balance between the direct and indirect motor pathways, with the direct pathway promoting and the indirect pathway inhibiting movements. The direct pathway consists of inhibitory projections (gamma-aminobutyric acid [GABA] mediated) from the striatum to the internal portion of the globus pallidus and substantia nigra pars reticulata (GPi/SNr) and from the GPi/SNr to the thalamus, and excitatory projections (glutamate-mediate) from the thalamus to the cortex. In the indirect pathway, there are inhibitory GABA pathways from the striatum to the external portion of the globus pallidus (GPe) and from the GPe to the subthalamic nucleus (STN). This double inhibition causes stimulation of the STN that, in turn, through its excitatory glutaminergic projections, stimulates the GPi/SNr. These two structures once stimulated, produce inhibition (GABA mediated) of the thalamus and consequently inhibition of the excitatory thalamocortical pathway.

In HD, the major neurodegenerative pathology occurs within the caudate nuclei and the putamen (striatum). These changes primarily affect medium-sized “spiny” neurons that secrete the inhibitory neurotransmitter GABA. It has been proposed that in the earlier stages of HD the indirect pathway is mainly affected, resulting in loss of inhibition from the striatum to the external portion of the globus pallidus and consequent increase inhibition of the STN and decreased excitation of GPi/SNr, with overall decreased inhibition to the thalamus. This disinhibition of the thalamus allows for enhanced excitatory outflow to the cortex, resulting in the disorganized, excessive (hyperkinetic) movement patterns of chorea. As HD progresses into the later stages, the direct pathway also becomes affected causing a hypokinetic or akinetic stage.

Concomitantly, HD patients also have a prominent associated temporal and frontal lobe cerebral cortex neuronal degeneration.

With Sydenham chorea, various streptococcal proteins or antigens (streptococcal M proteins) induce the body's production of antineuronal immunoglobulin G (IgG) antibodies. These antibodies cross-react against the body's own cells that provide the neuronal antigens within the basal ganglia, such as the caudate nuclei and STN.

Clinical Presentation

The spectrum of clinical findings in chorea varies, presenting in isolation or with other involuntary movements. At the simplest level, chorea appears as semipurposeful movements resembling fidgetiness. This is exemplified by the flitting movements of the fingers, wrists, toes, and ankles so characteristic of HD. The movements can be focal, as in tardive dyskinesia (TD), where they are more repetitive and stereotypical. They may present as lip pouting or pursing, cheek puffing, lateral or forward jaw movements, or tongue rolling or protruding.

Asymmetric chorea, such as hemichorea, primarily affects the limbs on one side of the body. Sometimes, chorea affects only specific functional muscle groups, such as respiratory chorea. When there is a more diffuse basal ganglia dysfunction, chorea is often accompanied by parkinsonism, tics, and dystonia. Later, chorea can interfere with activities of daily living; for example, limb chorea can cause falls and interfere with dressing and eating. Chorea of the face, jaw, larynx, and respiratory muscles may eventually limit verbal communication.

On neurologic examination, there is altered finger-to-nose testing. Rapid alternating movements are executed with a jerky and interrupted performance. When patients with significant chorea grasp an examiner's fingers, a squeezing motion called milkmaid's grip is sometimes noted. This is a sign of motor impersistence. As with other adventitious movements, seen with the various movement disorders, chorea is frequently aggravated while walking. Various oculomotor abnormalities may be observed. These include slow and hypometric saccades and saccadic pursuit, convergence paresis, and gaze impersistence. Parkinsonian features, particularly bradykinesia and dystonia, are sometimes evidenced with more advanced disease.

Huntington Disease

This hereditary, progressive neurodegenerative disorder is the most common cause of chorea. The classic signs of HD include the development of chorea, neurobehavioral changes, and gradual dementia ( Fig. 32.1 ). Symptoms typically become evident during the fourth or fifth decade of life, although onset varies from early childhood to late adulthood. HD symptoms vary among patients in range and severity, as well as by age at onset, and in rate of clinical progression. An early onset is associated with increased severity and more rapid progression. For example, adult-onset HD typically lasts approximately 15–20 years, whereas the course of juvenile HD tends to last approximately 8–10 years.

The initial clinical presentation may be either neurologic or psychiatric. Characteristic early presentations include the gradual onset of subtle personality changes, forgetfulness, clumsiness, and development of choreiform, fidgeting movement of the fingers or toes. Neurobehavioral changes include both emotional and behavioral disturbance. Patients present with increased irritability, suspiciousness, impulsiveness, lack of self-control, and anhedonia. Sometimes anxiety, depression, mania, obsessive-compulsive behaviors, and agitation are seen early in the disease. Later, a severe distortion in thinking and occasionally hallucinations, such as the perception of sounds, sights, or other sensations without external stimuli, may develop. The juvenile form of HD more often presents with dystonia, rigidity, or cerebella ataxia than chorea per se.

Cognitive decline is characterized by progressive dementia or gradual impairment of the mental processes involved in comprehension, reasoning, judgment, and memory. Typical early signs include forgetfulness, inattention, increased difficulty in concentrating, and various forms of disinhibition manifested by emotional outbursts, financial irresponsibility, or sexual promiscuity. Communication difficulties develop, including problems expressing thoughts in words, initiating conversations, or comprehending others’ words and responding appropriately.

Motor disturbances are characterized by the gradual onset of clumsiness, balance difficulties, and fidgeting movements. Early chorea may be limited to the fingers and toes, later extending to the arms, legs, face, and trunk. Eventually, chorea tends to become widespread or generalized. Parkinsonism and dystonia are sometimes seen later in the disease. Many patients with HD develop a distinctive manner of walking that may be unsteady, disjointed, lurching, and dancelike. Eventually, postural instability, dysphagia, and dysarthria appear.

Later disease stages are characterized by severe dementia and progressive motor dysfunction; patients usually become unable to walk, have poor dietary intake, become unable to care for themselves, and eventually cease to talk, leading to a persistent vegetative state. Life-threatening complications may result from serious falls, sometimes even leading to subdural hematomas, poor nutrition, infection, choking, aspiration pneumonia, or heart failure.