Sydenham Chorea

Etiology

Sydenham chorea is believed to be an autoimmune disorder typically occurring after a group A β-Hemolytic streptococcal infection. The immune system is stimulated to produce antibodies against streptococcal bacterial infection. These antibodies cross-react with basal ganglia cells, especially striatum cells, which are important in controlling motor movements. Death and damage to these cells are considered responsible for the disease's manifestations.

Epidemiology

The disease typically is delayed 6 to 8 weeks after group A β-hemolytic streptococcal pharyngitis; it does not occur after skin infections. Sydenham chorea is more prevalent in females than males (3:1). Sydenham chorea is primarily a childhood disease, with most affected patients aged 5 to 18. The disease is rarely reported in children younger than 5; the peak age is 8 to 9. Sydenham chorea affects children of all ethnicities and races. Sydenham chorea is a major Jones criterion for rheumatic fever. Around 25% of patients with rheumatic fever develop Sydenham chorea, the incidence of which has declined steadily over the past few decades in North America due to the steady decline in the incidence of rheumatic fever and the more widespread use of antibiotics.[5]   

Adult onset of Sydenham chorea is uncommon, and most adult cases are usually secondary to recurrence following childhood illness. The incidence is higher in developing countries due to β-hemolytic Streptococci infection and inadequate treatment of streptococci infection, exacerbated by overcrowding and poor hygienic conditions. Chorea gravidarum is a pregnancy-related variant. Most cases are a recurrence of SC and are considered to be due to the hormonal changes of pregnancy, but it also can be precipitated by the use of oral contraceptives. Symptoms often resolve quickly immediately after delivery.

Pathophysiology

Most authorities believe Sydenham chorea to be an autoimmune disease that is triggered by a group A β-hemolytic streptococcal infection, subsequently resulting in a hypersensitivity humoral reaction to the infection and cross-reactivity of streptococcal antigens and human tissue antigens through molecular mimicry.[6]The stimulated antibodies target the basal ganglia brain cells in the host and cause a diffuse inflammatory process in the dorsal corpus striatum, mainly the caudate nucleus and putamen. The ventral striatum, especially the nucleus accumbens, is also affected, resulting in Sydenham chorea's frequently associated cognitive and behavioral symptoms. The symptoms of Sydenham chorea are caused by an imbalance between the dopaminergic system, intrastriatal cholinergic system, and the inhibitory gamma-aminobutyric acid (GABA) system. Sydenham chorea is often considered the model for pediatric autoimmune neuropsychiatric disorders.[7]

Histopathology

Sydenham chorea is caused by a hypersensitivity humoral response triggered by an infection with group A β-hemolytic Streptococcus. The subsequent immune inflammatory response attacks and destroys cells of the basal ganglia.

History and Physical

Sydenham chorea often presents following other symptoms and signs of rheumatic fever, but it can occur alone. Isolated attacks, without other rheumatic fever symptoms, are common in recurrent chorea attacks. Typically, the first episode occurs 6 to 8 weeks after an episode of group A β-hemolytic Streptococcus (GABHS) pharyngitis. The features of the chorea include involuntary movements, poor tone and muscular weakness, and psychological features. The involuntary movements are the cardinal signs of Sydenham chorea and are characterized by the abrupt onset of symptoms that usually affect all 4 limbs. Other motor symptoms include gait disturbances, loss of motor control, deterioration of handwriting, and development of cognitive or emotional disorders. Facial grimacing or tongue chorea may develop. The patients may demonstrate the "milkmaid sign," a relapsing grip similar to the handgrip while milking a cow. Tics are common in Sydenham chorea. Vocal tics occur in 70% of patients and are believed to be related to the chorea of the pharynx and larynx. Dysarthria is common, as well as decreased verbal fluency due to the involvement of bulbar muscles. Overall, around 70% of patients have generalized chorea, 30 to 35% have hemichorea, and 60% have other neurological symptoms, including dysarthria and dysgraphia.[8]

Behavioral problems are common. The most common was anxiety disorder/depression (77%).[8] Obsessions and compulsions are present in up to 70% of patients, and 16.7% meet the criteria for obsessive-compulsive disorder. Hyperactivity and attention deficit disorder has been found in up to 45% of patients. Psychosis has been reported in the acute phase of the illness. Carditis occurs in up to 80% of patients.[9] Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a controversial diagnosis in which patients develop a rather acute onset of OCD and tics that persist despite treatment.[10]

Chorea gravidarum is a syndrome describing the onset of chorea during pregnancy. It is not a specific disease. Rheumatic fever, or a history of rheumatic fever, was the most typical cause, indicating that it is the same as Sydenham's chorea. These patients also have similar pathological changes in the brain.[11] Due to the decline in the incidence of rheumatic fever, it is not a significant cause of chorea gravidarum nowadays. The primary pathophysiological mechanism remains immune-mediated, frequently linked to underlying autoimmune conditions like antiphospholipid antibody syndromes.[12] The other etiological hypothesis is hormonal changes, especially estrogen, during pregnancy and the use of oral contraceptives. 

Evaluation

There are no specific ancillary tests to provide a definitive diagnosis of the illness. All patients with chorea need a detailed neurologic and cardiac evaluation. Routine blood tests should include a complete blood count (CBC), complete metabolic panel (CMP), liver function test (LFT), B12 (deficiency in children can lead to chorea), thyroid-stimulating hormone (TSH), and drug screens. Antistreptolysin-O titer (ASOT) and anti-DNAse B titers are important tests to request. Anti-DNAse B titers may be elevated up to one year after group A streptococcal pharyngitis. Due to the latency between the initial pharyngeal infection and the onset of the chorea, acute phase reactants such as C-reactive protein and erythrocyte sedimentation rates have limited utility. Echocardiograms are indicated to evaluate for carditis, as up to 80% of patients with Sydenham chorea have a concurrent cardiac disease.[13][14]

Brain MRI and CT scans typically are normal, although occasional reversible hyperintensity may occur in the basal ganglia. In children, obtaining an MRI is of questionable use, given the requirements for sedation, and careful consideration should be made on a case-by-case basis. The new onset of chorea in adults may indicate a structural basal ganglia pathology, especially in the striatum. A brain MRI in such cases will be strongly indicated. PET scans and SPECT imaging have demonstrated hypermetabolism and hyperperfusion of the basal ganglia in case reports, whereas other chorea disorders are associated with hypometabolism. These tests are rarely indicated except in research.

Treatment / Management

In the past, the illness was considered benign and typically would remit after a few months. More recent studies have found that up to half of the patients have chorea lasting up to 2 years. Recurrences of movement disorders occur in up to 50% of patients regardless of prophylaxis. Many of these recurrences have not been associated with Streptococcus infection or anti-basal ganglia antibodies. A significant concern for patients with the illness is the development of valvular heart disease as a component of rheumatic fever. There is a strong correlation between Sydenham chorea and the development of carditis and valvular heart disease.[15][16]

The treatment modalities of Sydenham chorea can be considered in 3 parts: prophylactic penicillin therapy, symptomatic treatments with antipsychotics or anticonvulsants, and immunomodulating therapy with steroids, intravenous immunoglobulin (IVIg), and plasma exchange.[17]

Prevention of the SD by aggressively treating Group A B-hemolytic streptococcal pharyngeal infection and reducing the likelihood of rheumatic heart disease is effective. Once Sydenham chorea is diagnosed, secondary antibiotic prophylaxis is indicated to decrease the risk of neurologic and cardiac problems with future streptococcal infections. The World Health Organization (WHO) recommends secondary prophylaxis for those younger than 21.

Symptomatic treatment of the illness has not been well-studied. Typically, valproic acid has been used in escalating doses, starting at 250 mg per day and rapidly increasing to 1500 mg per day or until symptoms abate. Valproic acid does have a slow onset of action; thus, at least 2 weeks should be allowed before abandoning it as ineffective. The second-line treatment if valproic acid fails is neuroleptics. Risperidone 1 mg to 2 mg per day has been found effective in controlling the chorea.[18] However, they increase the risk of tardive dyskinesia. More recently, tetrabenazine, a dopamine-depleting agent with fewer potential side effects, has been suggested. Its effectiveness is not well studied. Immunosuppression is ineffective in the management of the illness.

Immunomodulating therapy is generally reserved for more resistant and refractory Sydenham chorea. Steroids are generally beneficial. Data on IVIg and plasma exchange are more limited.[17]

Differential Diagnosis

Sydenham chorea should be differentiated from other causes of chorea, including autoimmune, toxic, vascular, and genetic causes. The acuity of onset can assist in diagnosis. The toxic and vascular causes are more acute to subacute, and the genetic causes are more gradual. Family is typically, but not always, present in the latter. Acute onset of chorea in a child is most commonly due to Sydenham chorea as a manifestation of acute rheumatic fever and systemic lupus erythematosus (SLE) in the presence of antiphospholipid antibody.

The following list of differential diagnoses also needs to be considered:

• Huntington disease
• Acute stroke affecting the basal ganglia
• Medications, including dopaminergic and dopamine antagonists
• Hypoglycemia and nonketotic hyperglycemia
• Lyme disease
• Multiple system atrophy
• Neuroacanthocytosis
• Neuronal ceroid Lipofuscinoses
• Olivopontocerebellar atrophy [19][20]

Complications

Most make a full recovery in 3 to 6 months. A small number of children continue experiencing symptoms for up to 2 years. Symptoms can also return later in life, especially in people AFAB who take estrogen or birth control pills or get pregnant.