Clinical Approach to the Diagnostic Evaluation of Chorea

Chorea is a presenting symptom of various diseases that affect patients across different age groups. The term “chorea” was derived from the Greek word “χορεια,” which was used to characterize “dance-like” movements.¹ Chorea is defined as an involuntary hyperkinetic movement disorder consistent with spontaneous, purposeless, and irregular movements that flow from one body part to the next. Its severity can range from mild restlessness to a continuous flow of disabling and violent movements.

A prominent feature of chorea is motor impersistence, characterized by the inability to sustain a voluntary action or posture. For example, individuals with chorea may have difficulty keeping their tongue protruded or sustaining a consistent grip, often referred to as the “milkmaid’s grip.” Anosognosia, the lack of awareness of symptoms, is another notable feature observed in certain etiologies of chorea, notably in Huntington disease (HD), the most common cause of hereditary chorea in adults. In addition, affected individuals may unconsciously incorporate choreiform movements into voluntary actions, masking the presence of symptomatic movements. As a consequence, the recognition of chorea in neurodegenerative disease may be delayed.²

Although the pathophysiology of chorea may vary depending on the underlying cause, it is commonly associated with disruptions in signaling within the cortical-basal ganglia-thalamo-cortical loop.^3,4 Various genetic and acquired conditions can lead to cortical-basal ganglia-thalamo-cortical circuitry dysfunction, including neurodegeneration, structural damage, autoimmune conditions, metabolic dysregulation, and others. This article provides an overview of the etiologies of chorea and outlines the essential clinical steps for its examination and differential diagnosis.

Clinical Examination and History

Differentiating chorea from other hyperkinetic movement disorders which may coexist can be challenging and necessitates careful observation of the entire body throughout the clinical encounter. Table 1 includes the hyperkinetic movement disorders which are most important to distinguish from chorea.

A complete medication and family history are required to investigate for acquired or hereditary causes of chorea. However, a genetic cause cannot be dismissed solely on the basis of a negative family history. An unknown or negative family history may be due to missed diagnoses in relatives, incomplete penetrance in triplet repeat disorders, or sporadic cases, which should be considered.⁷ Figure 1 presents a classification of various chorea etiologies categorized by inheritance pattern and age at onset based on the most common forms of the disease.

The time course and onset of chorea can offer valuable clues for diagnosis.⁸ In general, genetic etiologies are associated with chronic chorea, whereas acquired causes commonly result in acute or subacute chorea (Figure 1). For example, Sydenham chorea is an acute pediatric etiology of chorea, whereas HD is a chronic cause of chorea that most commonly manifests in adulthood.

Chorea is often generalized (ie, affecting multiple body regions). However, focal chorea can have diagnostic significance. Chorea in the forehead is commonly seen in HD. Orobuccolingual chorea is common in tardive syndromes, paraneoplastic syndromes, VPS13A disease (chorea-acanthocytosis), Lesch-Nyhan syndrome, Wilson disease, and pantothenate kinase–associated neurodegeneration. Hemichorea, or choreiform movements on 1 side of the body, is typically caused by vascular or structural brain etiologies, such as infections and nonketotic hyperglycemia. Autoimmune conditions, such as Sydenham chorea and paraneoplastic syndromes, are also linked to asymmetric or hemichorea.^2,9

Rating Scales

Several rating scales have been developed to quantify the severity of chorea.¹⁰ One of the most widely used scales in this context is the Total Maximal Chorea score within the motor section of the Unified Huntington’s Disease Rating Scale which rates the maximal chorea in HD in 7 different body regions.¹¹ The Universidade Federal de Minas Gerais Sydenham’s Chorea Rating Scale is another example that provides an overview of the patient’s motor function, performance in activities of daily living, and behavioral abnormalities.¹² Although chorea rating scales provide a more precise means of measuring chorea, they are not required; documentation of chorea can be achieved by describing the severity and location of the movements.

Genetic Testing

In chronic chorea, particularly in the presence of a positive family history, targeted genetic testing is a pivotal primary step, which should be directed by the age at onset and the possible form of inheritance (Figure 1).⁸ HD is the most common genetic cause of chorea resulting from a CAG repeat expansion in the HTT gene located on chromosome 4.¹³ If the genetic test for HD is negative, various HD phenocopies should be considered. Among the most common HD phenocopies are C9orf72 disease, HD-like (HDL) syndrome type 2 (HDL2), and spinocerebellar ataxia 17 (HDL4).^8,14C9orf72-related disease is more prevalent in White individuals, whereas HDL2 is more common in those of African ancestry. In children, benign hereditary chorea is a common genetic cause of chorea, and should be considered. Detailed information on affected genes and updates on the genetics of chorea have been published.^2,15,16

Genetic counseling should precede genetic testing to ensure that patients are well informed regarding the implications for family members and insurability. In addition, genetic counseling can address the ethical and emotional considerations associated with the process.¹⁷ Genetic testing can provoke anxiety, and a skilled multidisciplinary team is essential to provide appropriate supportive services for symptomatic patients as well as at-risk individuals undergoing predictive testing.

Laboratory Studies and Neuroimaging

The neurologic examination and history are important in narrowing the differential diagnosis of chorea. When chorea onset is acute or subacute, a broad spectrum of reversible or treatable causes should be considered.⁸ Laboratory tests and neuroimaging should be used when necessary particularly in cases of acute or subacute chorea. Figure 2 highlights the key laboratory studies essential for diagnosing chorea. When evaluating acquired causes of chorea, laboratory tests are crucial for identifying underlying conditions, particularly metabolic or endocrine etiologies,¹⁸ infectious causes,¹⁹ and autoimmune or paraneoplastic chorea.²⁰ Genetic causes of chorea can also be associated with abnormal laboratory values, most importantly in neuroferritinopathy, aceruloplasminemia, ataxia telangiectasia, Wilson disease, VPS13A disease, and XK disease (McLeod syndrome) (Figure 2).

Neuroimaging modalities, especially MRI, can be used to detect structural lesions. Neuroimaging can detect focal lesions (eg, neoplasm, abscess) and other abnormalities in the basal ganglia (eg, demyelinating disorders, ischemic or hemorrhagic stroke). Table 2 provides an overview of the most important neuroimaging signs in cases of hereditary chorea.

Conclusion

The burden of chorea extends beyond physical symptoms, affecting various aspects of everyday living as well as the emotional and financial well-being of patients and their support networks. The primary focus in managing new-onset chorea is identifying and diagnosing any reversible causes. The clinical examination and family history play crucial roles in narrowing the differential diagnosis. Targeted genetic testing is essential for patients with a supportive family history and compatible clinical findings but should be preceded by genetic counseling or an in-depth discussion about the risk–benefit ratio of genetic testing. In cases of acute or subacute chorea, laboratory studies and neuroimaging are particularly important.

Effective management of chorea requires a comprehensive approach that includes ongoing monitoring and supportive care to address the multifaceted challenges posed by the condition. A multidisciplinary care team involving a neurologist; genetic counselor; psychiatrist; physical, occupational, and speech therapist; social worker; and neuropsychologist can provide tailored interventions to improve patient outcomes. Educating patients and their families about the nature of chorea and available treatment options can empower them to participate actively in care decisions and coping strategies. Early intervention and continuous support are key to enhancing quality of life for people with chorea.