Clinical manifestations

Presentation and course

Streptococcal pharyngitis. Acute rheumatic fever (and its major clinical manifestations of carditis, arthritis, and Sydenham chorea) are the result of an autoimmune process triggered by streptococcal pharyngitis (or scarlet fever) with Group A beta-hemolytic Streptococci (GAS). Even before color photography was available, artistic renditions of streptococcal pharyngitis and the microscopic appearance of the responsible organism were fairly accurate in medical textbooks.

These early artistic depictions of streptococcal pharyngitis from over a century ago compare favorably to modern color photography.

Common features include erythema and edema of the oropharynx, a typical tonsillar exudate, and petechiae on the soft palate.

Group A Streptococcus (group A strep, Streptococcus pyogenes) can cause both noninvasive and invasive disease, as well as nonsuppurative sequelae. The wide range of clinical disorders caused by Streptococcus pyogenes includes, in addition to acute rheumatic fever, pharyngitis (Strep throat), cellulitis, impetigo, type II necrotizing fasciitis, scarlet fever, streptococcal toxic shock syndrome, and post-streptococcal glomerulonephritis.

Streptococcus pyogenes is a species of Gram-positive, aerotolerant bacteria in the genus Streptococcus. These bacteria are extracellular and are comprised of nonmotile and non-sporing cocci (round cells) that tend to link in chains.

Streptococcus pyogenes is the predominant streptococcal species harboring the Lancefield group A antigen and is often called Group A Streptococcus (GAS). Group A streptococci, when grown on blood agar, typically produce small (2 to 3 mm) zones of beta-hemolysis, a complete destruction of red blood cells.

Because of this feature, the name Group A beta-hemolytic Streptococcus (GABHS) is also used. The characteristic color changes, including a light-colored halo surrounding each colony in which the red blood cells in the blood agar medium had been destroyed, or hemolyzed, indicate that the bacteria are indeed beta-hemolytic in nature. In contrast, alpha-hemolytic organisms, when grown on blood agar, are surrounded by a hazy, indistinct zone of partial red blood cell hemolysis.

Jones criteria. The entire clinical spectrum of acute rheumatic fever (from tonsillitis to carditis) was first described by English pediatrician William Butler Cheadle (1836-1910) in "Harveian lectures on the various manifestations of the rheumatic state as exemplified in childhood and early life" in 1889 (52).

It was not until World War II that criteria for the diagnosis of rheumatic were established by American cardiologist Thomas Duckett Jones (1899-1954) (101). During World War II, rheumatic fever was one of the major causes of lost man days due to sickness in the Navy and Marine Corps (152), so the disorder achieved national, and indeed international, importance.

Rheumatic fever diagnosis continues to be based on the Jones criteria, which was developed in 1944, then revised twice by the American Heart Association in 1992 and 2015 (101; 163; 81). The Jones criteria divide clinical manifestations into major and minor categories, and then set a minimum threshold for features that must be present for a diagnosis of rheumatic fever. The last revision of the Jones criteria supplements the major criteria with echocardiographic examination; introduces a concept of subclinical carditis; and specifies low-, medium-, and high-risk populations.

Although qualifying features differ somewhat now in low-risk populations and moderate-to-high-risk populations, the conditions specified as major manifestations have not changed: carditis, arthritis, (Sydenham) chorea, erythema marginatum, and subcutaneous nodules. The American Heart Association recommends that all the patients with suspected rheumatic fever have Doppler echocardiography after the Jones criteria have been verified, even if no clinical signs of carditis are present.

In an investigation from New Zealand, prior to the 2015 revision of the criteria, the authors employed slightly modified Jones criteria, allowing as major criteria subclinical carditis (ie, solely based on echocardiography), carditis, and monoarthritis if the patient is on anti-inflammatory drugs; this led to a 16% increase of the number of diagnoses of acute rheumatic fever (192). These issues were in large measure incorporated into the 2015 revision.

One feature of the Jones criteria, even in the most recent 2015 incarnation, is the absence of any criteria for clinical or laboratory evidence of antecedent streptococcal pharyngitis (acute pustular pharyngitis, rapid antigen testing or culture-positive throat culture for Group A beta-hemolytic Streptococci (GAS), antistreptolysin O antibody titers).

Carditis. By the end of the 19th century, Osler, based on his clinicopathologic studies in Philadelphia in the late 1880s, made the fundamental deduction that Sydenham chorea is an “infectious disorder,” frequently associated with endocarditis, particularly affecting the mitral valve (115), and Cheadle had provided an overall synthesis of the most important clinical features of acute rheumatic fever, including the carditis (52).

Indeed, Cheadle illustrated a photomicrograph of a section of the aortic valve from a child with ulcerative endocarditis due to acute rheumatic fever; this showed proliferation and cell infiltration of the subendothelial fibrous tissue, which he noted resembled the histologic features of subcutaneous nodules. But as Osler had recognized, the cardiac valvulopathy most commonly affected the mitral valve, sometimes in conjunction with involvement of other valves, findings that are generally evident on gross examination.

Experimental studies attempting to reproduce the carditis in an animal model led to greater scrutiny of the pathologic features of the human cases (147; 148; 149; 150). Sections of vegetations in simple rheumatic endocarditis often showed much necrotic tissue, but no diplococci, with sometimes evidence of reparative changes, but in other cases, the necrotic tissue contained diplococci.

Sections through affected valves could demonstrate separate identifiable zones of swollen connective tissue of the valve, cellular exudation, and necrosis in the vegetation.

Sections through the left ventricle showed a range of findings including fatty change in the cardiac muscle fibers, cellular exudates, and in more chronic cases fibrosis.

With rheumatic pericarditis, there were identifiable zones of swollen connective tissue, cellular exudation, and necrosis with fibrino-cellular exudation.

Arthritis. Symptoms of acute rheumatic fever can include arthritis, which is usually symmetrical and involves large joints (eg, knees, ankles, elbows, and wrists). Arthritis occurs in approximately 75% of first attacks of acute rheumatic fever, but the likelihood increases with the age of the patient. Arthritis is a major manifestation of acute rheumatic fever in 92% of adults meeting the Jones criteria (in a prior incarnation of the criteria) (189). The arthritis is typically polyarticular, but monoarthritis may serve as sufficient to meet criteria for a major manifestation according to the 2015 revision of the Jones criteria. Histologic sections through affected joint capsules may show separate identifiable zone of swollen connective tissue, cellular exudate, and necrosis and plastic exudation, which may take the form of very irregular granulations.

Tenosynovitis is common in adults and may suggest a diagnosis of disseminated gonococcal disease (189). The polyarthritis evolves over weeks but overlaps across individual joints, so it is not strictly migratory (189). Arthritis due to acute rheumatic fever generally subsides within 4 to 6 weeks without residual damage (189). If the arthritis does not resolve over this period, an alternate diagnosis should be considered.

Sydenham chorea. Sydenham chorea is a major manifestation of rheumatic fever. Sixty percent to 80% of patients display cardiac involvement, particularly mitral valve dysfunction, in Sydenham chorea, whereas the association with arthritis is less common, seen in 30% of patients; however, in approximately 20% of patients, chorea is the sole finding (48; 74). A prospective follow up of patients with Sydenham chorea with and without cardiac involvement in the first episode of chorea suggests that the heart remains spared in those without lesion at the onset of the rheumatic fever (141). Sydenham chorea may be associated with other autoimmune disorders such as Takayasu arteritis (184; 11).

Please see further discussion of the clinical features of Sydenham chorea in a separate section below. This material was separated because its inclusion here would have overwhelmed the discussion of the Jones criteria and the various components.

Erythema marginatum. Although a "major" manifestation of rheumatic fever, erythema marginatum is uncommonly reported in some modern series, so it cannot be considered a sensitive sign of the disorder, only one that is fairly specific if present after streptococcal pharyngitis, especially when other manifestations of rheumatic fever are present. The very low frequency reported in some modern series of rheumatic fever may reflect limitations of observation and reporting.

Erythema marginatum is an evanescent, serpiginous, non-pruritic rash of arm generally on the trunk and extremities, and typically more prominent in a warm bath.

Subcutaneous nodules. Although a "major" manifestation of rheumatic fever, subcutaneous nodules are uncommonly reported in some modern series, so they cannot be considered a sensitive sign of the disorder, only one that is fairly specific if present after streptococcal pharyngitis, especially when other manifestations of rheumatic fever are present. The very low frequency reported in some modern series of rheumatic fever may reflect limitations of observation and reporting.

It has often been assumed that subcutaneous nodules are rare, evanescent, and invariably associated with carditis. In a prospective study of acute rheumatic fever, 42 cases (13%) with subcutaneous nodules occurred among a series of 336 consecutive cases (24). Other major criteria associated with subcutaneous nodules were carditis in 90%, arthritis in 79%, and chorea in 5% (24). The average number of nodules found in the group in which nodules were present was 18 (range 4 to 49): 31% had less than 10 nodules, and 12% had only 4 to 5 nodules (24). Subcutaneous nodules disappeared within 4 weeks in 69%, within 5 to 8 weeks in 19%, and within 9 to 12 weeks in 7% (24). In two cases (5%), multiple nodules were observed 12 weeks later when all other evidence of activity had disappeared (24).

Nineteenth century artistic renderings graphically show the appearance and extent of these subcutaneous or "rheumatoid" nodules.

The histology of these lesions was recorded from the late 19th century as showing active proliferation and infiltration of fibrous tissues.

In most modern reports, such lesions are present in only a minority of cases, are few in number when present, and are often somewhat subtle (95).

Histologically, these may show mixed acute and chronic, superficial and deep, perivascular lymphohistiocytic inflammation, extending into the subcutis.

There were poorly formed granulomas with central coagulative necrosis and peripheral acute inflammation with conspicuous leukocytoclastic vasculitis (95).

Subcutaneous nodules are found in approximately one third of patients with rheumatic fever (markedly lower rates in some series may reflect the adequacy of assessment). Typical subcutaneous nodules are firm or hard, usually mobile (ie, not attached to overlying skin or underlying bony structures), and nontender. They may be solitary or multiple, may change in size over time, and may persist for months to years. The lesions are generally small (varying from millimeters to several centimeters in size) and have a tendency to occur over bony prominences such as knuckles, olecranon processes, and humoral epicondyles. The overlying skin may be erythematous. Histologically similar lesions may involve the pleura.

Rheumatoid nodules can also occur in rheumatoid arthritis and systemic lupus erythematosus, and the histologic appearance is identical.

Sydenham chorea. Sydenham chorea is the most common movement disorder associated with bacterial infection. The usual age at onset of Sydenham chorea is 8 to 9 years, but there are reports on patients who developed chorea during the third decade of life. In most series, there is a female preponderance (48; 160). Typically, patients develop this disease 4 to 8 weeks after an episode of group A beta-hemolytic streptococcal pharyngitis. It does not occur after streptococcal infection of the skin.

The chorea spreads rapidly and typically becomes generalized, but 20% of patients remain with hemichorea (135; 48). This movement disorder is characterized by random, brief contractions, particularly affecting distal muscles, and it produces an odd dance-like character to movements of affected individuals. Patients display motor impersistence, which is particularly noticeable during tongue protrusion and ocular fixation. The muscle tone is usually decreased; in severe and rare cases, this is so pronounced that the patient may become bedridden (chorea paralytica). Some adult patients with a history of Sydenham chorea have residual bradykinesia, which may explain the proclivity of these patients to develop drug-induced parkinsonism when treated with neuroleptics (16).

Other neurologic and neuropsychiatric symptoms and signs.

Rating scale. The Universidade Federal de Minas Gerais Sydenham Chorea Rating Scale was designed to provide a detailed quantitative description of the performance of activities of daily living, behavioral abnormalities, and motor function of patients with Sydenham chorea; it comprises 27 items, and each is scored from 0 (no symptom or sign) to 4 (severe disability or finding) (177).

Speech disorders. Various alterations of speech have been observed in Sydenham chorea; during the 19th century, Gowers had already recognized that Sydenham chorea patients present with a “disinclination to speak.” Dysarthria is common, probably of extrapyramidal origin (135). A case-control study of patients described a pattern of decreased verbal fluency that reflected reduced phonetic, but not semantic output (61). Prosody is also affected in Sydenham chorea: speech as a decreased range of fundamental frequency, higher intensity, and decreased speed (45; 46; 139).

Attention and executive function. A subset of patients with a history of Sydenham chorea has persistent impairment attention and executive function (41; 18; 50).

Tics. Although there are reports of the common occurrence of tics in Sydenham chorea, it can be extremely difficult to distinguish simple motor tics (sudden, repetitive, nonrhythmic motor movement or vocalization involving discrete muscle groups) from chorea, and available studies are of low methodological quality (145). Even vocal tics, found in 70% or more of patients with Sydenham chorea in 1 study, may be difficult to diagnose in patients with hyperkinesias (128). Involuntary vocalizations may result from chorea or dystonia of the pharynx and larynx (99). Under these circumstances the vocalization lacks the subjective feeling (premonitory urge or sensory tic) so characteristic of idiopathic tic disorders such as Tourette syndrome. Involuntary sounds present in occasional patients with Sydenham chorea probably result from choreic contractions of the upper respiratory tract muscles rather than true tics (174).

Behavior abnormalities (obsessive-compulsive behavior and attention deficit/hyperactivity). Various behavioral abnormalities have been associated with Sydenham chorea, but the data are generally of poor quality to establish a causal relationship (145). Osier mentioned the lability, irritability, and "bizarre behaviors" of the children with Sydenham chorea (115). Obsessive-compulsive behavior was reported to be common in patients with Sydenham chorea (05; 168; 127; 121; 20; 145), although patients with rheumatic fever without chorea also have more obsessive-compulsive behavior and attention deficit/hyperactivity than healthy controls (127; 121). Nevertheless, in a study of behavioral abnormalities in 50 healthy subjects, 50 patients with rheumatic fever without chorea, and 56 patients with Sydenham chorea, the authors found that obsessive-compulsive behavior, obsessive-compulsive disorder, and attention deficit and hyperactivity disorder were significantly more frequent in subjects with Sydenham chorea (19%, 23%, 30%) than in subjects with rheumatic fever without chorea (14%, 6%, 8%) (121). Attention deficit/hyperactivity was reportedly significantly more common in the persistent than acute chorea (50% vs. 16%) (121), but it is not always easy to differentiate restlessness associated with chorea from true hyperactivity of hyperactivity attention deficit disorder.

A study comparing the phenomenology of obsessions and compulsions in subjects with Sydenham chorea and subjects with tic disorders found that the symptoms observed in those with Sydenham chorea differed from those with tic disorders but were similar to those previously reported in pediatric patients with primary obsessive-compulsive disorder (04). The most frequent symptoms observed among subjects with comorbid Sydenham chorea and obsessive-compulsive symptoms were aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions (04). Obsessive-compulsive behavior in subjects with Sydenham chorea produced little interference in the performance of activities of daily living (121).

There may be a genetic-environment interaction in the development of behavioral problems in Sydenham chorea; obsessive-compulsive spectrum disorders in rheumatic fever probands were associated with an increased risk of obsessive-compulsive spectrum disorders in first-degree relatives (96).

The finding that behavioral problems are common in patients with rheumatic fever and chorea contributed to the notion that Sydenham chorea is a model for childhood autoimmune neuropsychiatric disorders (167). A controversial hypothesis proposes that infection with group A beta-hemolytic streptococci may induce tics, obsessive-compulsive behavior, and other neuropsychiatric disturbances, purported causing "PANDAS" (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus) (168). The following working diagnostic criteria for this condition have been proposed: (1) presence of obsessive-compulsive disorder or a tic disorder; (2) prepubertal symptom onset; (3) episodic course of symptom severity; (4) association with group A beta-hemolytic streptococci infections; and (5) association with neurologic abnormalities (168). The same study noted “significant psychiatric comorbidity”: emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, and oppositional behaviors (168). Nevertheless, most had a benign course with mild, if any, persistent motor or behavioral findings, which is better than those previously reported for childhood-onset obsessive-compulsive disorders (117).

A growing list of neurologic symptoms and signs are purportedly associated with streptococcus infection: dementia, dystonia, encephalitis lethargica-like syndrome, motor stereotypies, myoclonus, opsoclonus, parkinsonism, paroxysmal dyskinesia, restless leg syndrome, and tremor (36). At the present time, however, there is no conclusive evidence that antibasal ganglia antibodies (ABGA) induced by streptococcus play a significant role in the pathogenesis of tic disorders, although ABGA seropositivity are increased fivefold in primary obsessive-compulsive disorders compared with controls (144). In fact, a population-based epidemiological survey performed in London failed to demonstrate a significant relationship between streptococcal infection and motor or behavioral syndromes (83; 157). A subsequent study similarly failed to find immunologic abnormalities that distinguish controls from patients with Tourette syndrome who meet criteria for PANDAS (132). However, a systematic review reiterates that there is no compelling evidence supporting the association of auto-immune disorders with obsessive-compulsive and tic disorders (145).

Psychiatric disorders. Among 50 patients with Sydenham chorea, the most frequent psychiatric disorders observed were major depression (14%), generalized anxiety disorder (16%), social phobia (24%), and obsessive-compulsive disorder (24%) (131); the frequency of psychiatric disorders did not differ between cases with acute chorea in remission and persistent chorea, except for depressive disorders, which were more frequent in the latter. In another study of 32 cases nonacute Sydenham chorea and age- and gender-matched asymptomatic controls, depressive and anxiety symptoms were not more common in cases than controls (171).

There are rare reports of trichotillomania (109) and psychosis during the acute phase of the illness in cases of Sydenham chorea (179).

Other. Many patients with active chorea have hypometric saccades, and a few of them also show oculogyric crisis.

Migraine is reportedly more frequent in Sydenham chorea than in normal controls (180).

The peripheral nervous system is not targeted in Sydenham chorea (36; 185).

Prognosis and complications

The older literature describes Sydenham chorea as a rather benign, self-limited condition that remits after several months (135). However, prospective follow-up of patients shows that chorea persists 2 years after its onset in a substantial proportion of cases. Moreover, despite regular use of secondary prophylaxis, recurrences are frequently observed (49; 107), although many of the recurrences are not associated with either streptococcal infections or antibasal ganglia antibodies (92; 107; 187). A Turkish study reviewed the outcome of 90 patients with Sydenham chorea (89): 16% experienced recurrence associated with persistence of the first episode for more than 1 year well as irregular use of antibiotics prophylaxis.

The most worrisome problem in patients with Sydenham chorea is the occurrence of cardiac valvular disease and other cardiac complications. In areas where rheumatic fever is endemic, 70% of cardiac surgeries are performed to treat its complications (33). A Slovenian study emphasized the association of Sydenham chorea with carditis, which was found in all patients with chorea (106). A similar outcome was found in a retrospective review of 375 Turkish patients seen at an academic center over 25 years (74).

Clinical vignette

An 8-year-old girl suddenly developed pain and swelling of right wrist, knee, and ankles associated with movement disorder in all limbs. One week later, the patient was unable to speak and became bedridden due to worsening of the involuntary movements. Twenty days after onset, she was admitted to a hospital. Examination revealed anarthria, severe generalized chorea, and decreased muscle tone, as well as inability to walk or even sit without assistance. Her medical history was remarkable for repeated episodes of pharyngitis, and an episode of rheumatic fever 2 years before the current admission with carditis, arthritis, and Sydenham chorea; the latter was controlled with haloperidol, but the family did not comply with penicillin prophylaxis.

During the admission to treat the episode of chorea paralytica, echocardiography showed mild mitral insufficiency. Lab work-up included antistreptolysin titers 336 UI/mL (normal range less than 250), C-reactive protein 7.45 mg/mL (normal range less than 8), and sedimentation rate 35 mm. One week of valproic acid 30 mg/kg per day failed to improve the chorea. Valproic acid was discontinued, and she was started on pimozide 4 mg twice a day. She was discharged 15 days after admission, with persistent anarthria, mild chorea, and severely decreased muscle tone, but was able to sit and walk with assistance. On a follow-up visit 3 weeks later, she could sit and walk unassisted and no evident chorea but had continued dysarthria, decreased verbal output, moderately decreased muscle tone. After several additional weeks of pimozide therapy, the pimozide was gradually tapered until it was discontinued 4 months after discharge.

Forty-two months after the episode of chorea paralytica, the patient had no evident neurologic abnormalities and continued on penicillin prophylaxis.

Biological basis

Etiology and pathogenesis

Group A beta-hemolytic streptococci are the causative agents of Sydenham chorea and related disorders.

Italian-American internist Angelo Taranta (1927-2016) and American internist Gene H Stollerman (1920-2014) established the casual relationship between infection with group A beta-hemolytic streptococci and the occurrence of Sydenham chorea (170). Based on the assumption of molecular mimicry between streptococcal and CNS antigens, they proposed that the bacterial infection in genetically predisposed subjects leads to formation of cross-reactive antibodies that disrupt the basal ganglia function. Multiple studies have since demonstrated the presence of such circulating antibasal ganglia antibodies (ABGA) in 50% to 90% of patients with Sydenham chorea (97; 33). A specific epitope of streptococcal M proteins that cross-reacts with basal ganglia has been identified (29). In 1 study all patients with active Sydenham chorea had ABGA by ELISA and Western Blot, whereas ABGA positivity in subjects with persistent Sydenham chorea (duration of disease greater than 2 years despite best medical treatment) was about 60% (54).

Although several groups have since reported binding and other effects of ABGA from Sydenham chorea patients when applied to various cell cultures, the pathological significance of ABGA in vivo still remains to be determined.

Despite the suggestive findings in cell culture studies, an in vivo study failed to demonstrate that antibodies from Sydenham chorea patients infused in the basal ganglia of rodents induce behavioral changes, although they were found to bind to a ∼50-kDa molecule in the striatum extract (21). One possible explanation is that a low titer of the antibodies prevented the occurrence of detectable behavioral manifestations.

There is growing evidence that the pathogenesis of Sydenham chorea involves changes of dopamine transmission (71):

Despite the accumulating evidence for the so-called “dopamine hypothesis” of the pathogenesis of Sydenham chorea, other groups have failed to replicate some of the findings described above (39).

It remains unclear why up to 50% of patients with Sydenham chorea develop persistent chorea (39). In this subset of individuals, the titers of ABGA are low, whereas serum brain-derived neurotrophic factor (BDNF) levels are high, so it is possible that the acute immune process causes structural brain lesions resulting in permanent dysfunction of the basal ganglia (172).

Although some investigations suggest that susceptibility to rheumatic chorea is linked to human leukocyte antigen (HLA) expression (08), other studies failed to identify any relationship between Sydenham chorea and HLA class I and II alleles (70). A subsequent investigation has shown, however, an association between HLA-DRB1*07 and recurrent streptococcal pharyngitis and rheumatic heart disease (93).

A proposed genetic marker for rheumatic fever and related conditions is the B-cell alloantigen D8/17 (76). However, despite repeated reports of the group that developed the assay claiming its high specificity and sensitivity (73; 91), other authors report that the D8/17 marker lacks specificity and sensitivity. For instance, the discriminating power of monoclonal antibody against D8/17 was relatively low among patients of North Indian ethnic origin (103). In a study from the United States, 66% of Caucasian patients with obsessive-compulsive disorder or chronic tic disorder and 8% of controls tested positive for D8/17 (134). In the Netherlands, only a minority of patients with post-group A beta-hemolytic streptococcal arthritis had an elevation of D8/17-positive lymphocytes (100).

Another suggested genetic risk factor for development of acute rheumatic fever but not Sydenham chorea is polymorphisms within the promoter region of the tumor necrosis factor-alpha gene (154).

Due to the difficulties with the molecular mimicry hypothesis to fully account for the pathogenesis of Sydenham chorea, studies have further explored immunologic mechanisms to either support or refute the autoantibody hypothesis.

Some authors have suggested that streptococcal infection induces vasculitis of medium-sized vessels, leading to neuronal dysfunction (an idea that originated in the 1860s). Rheumatic fever does share similar cardiac and neurologic pathologies with the antiphospholipid syndrome, but antiphospholipid antibodies are almost invariably absent in Sydenham chorea. Nevertheless, considerable overlap of humoral immunity in rheumatic fever and antiphospholipid syndrome suggest that some common pathogenic mechanisms may underlie the development of cardiac valve lesions and CNS abnormalities in both diseases (25).

Currently, the weight of evidence suggests that the pathogenesis of Sydenham chorea is related to circulating cross-reactive antibodies. Streptococcus-induced antibodies can also be associated with a form of acute disseminated encephalomyelitis characterized by a high frequency of dystonia and other movement disorders as well as basal ganglia lesions on neuroimaging (65). Antineural and antinuclear antibodies have also been found in patients with Tourette syndrome, but their relationship with prior streptococcus infection remains doubtful (133).

It has long been suspected that choreas in general, including Sydenham chorea, are characterized by increased excitability of the motor cortex. However, a study of 16 patients with Sydenham chorea demonstrated that there is reduced excitability of corticospinal output similarly to what is found in Huntington disease (104); the reasons for this finding remain to be determined (90; 104).

Epidemiology

Nineteenth-century studies in England identified a clear seasonal pattern to rheumatic fever and Sydenham chorea, although the significance of this was not understood at the time. Beginning in the second half of the 19th century, large clinical series at the newly founded pediatric hospitals (the Hospital for Sick Children, Great Ormond Street, London) provided detailed demographic and clinical features of patients (122). English physician Sir William Selby Church, 1st Baronet, KCB (1837-1928) presented graphs of cases of rheumatic fever in the London Hospital from 1873-1881, and St. Bartholomew's Hospital, London, from 1882-1893.

Church's graph of rheumatic fever cases at the London Hospital was based on the earlier work of British pathologist Henry Singer Gabbett (1851-1926), and in particular used the summary data from Gabbett's table in his 1883 article in Lancet (77; 78).

The incidence of rheumatic fever and Sydenham chorea in the United States and Western Europe has declined since World War II as result of improved health care, increased antibiotic usage, and lower virulence of streptococcal strains (153).

This fall is demonstrated by the finding that the annual age-adjusted incidence rate of initial attacks of rheumatic fever per 100,000 children declined from 3.0 in 1970 to 0.5 in 1980 in Fairfax County Virginia, United States (158). Sydenham chorea accounted for 0.9% of children admissions to hospitals in Chicago before 1940, whereas this number dropped to 0.2% during the period between 1950 and 1980 (135).

Despite the fall in the incidence, Sydenham chorea remains the most common cause of acute chorea in children. Since the 1990s, outbreaks of rheumatic fever with occurrence of chorea have been identified in the United States and Australia (07; 155). A study performed in the pediatrics unit of a university hospital in Pennsylvania that showed Sydenham chorea accounted for of 96% of all patients with chorea seen during the 1980 to 2004 period (196).

Studies from Australia confirm that Sydenham chorea is a relatively common cause of acute chorea in children (66; 161). Australian aboriginals are reported to be at high risk of developing rheumatic fever (31). In the Northern Territory of Australia, an area predominantly inhabited by Aboriginal people, the point prevalence of rheumatic fever was 9.6 per 1000 people aged 5 to 14 years in 1995 (32). A national survey of all cases of rheumatic fever in Australia identified 151 children with this condition in a 3-year period. Not surprisingly, most (87%) were in Indigenous Australians. Sydenham chorea was diagnosed in 19%. However, the authors identified 10 cases in non-Indigenous Australians, of whom 3 had atypical presentations. The authors concluded that rheumatic fever may be more common than previously thought among low-risk children (136).

The incidence of acute rheumatic fever in Slovenia has increased more recently, with an annual incidence of 1.25 cases per 100,000 children during the period from 2008 through 2014 (106); carditis was present in all patients, arthritis in 37%, and Sydenham chorea in 32%.

Retrospective analysis of the medical records of 377 patients with acute rheumatic fever admitted to the pediatric cardiology department at a university hospital in southern Turkey suggested that admissions for this disorder decreased significantly over the interval from 1993 to 2017, presumably reflecting a corresponding decline in the population incidence of rheumatic fever (74). The most common manifestations were carditis 84%, arthritis 74%, and Sydenham chorea at 14%; only two patients (0.5%) had erythema marginatum and two patients (0.5%) had subcutaneous nodules. Of the patients with carditis, 49% had mild or subclinical carditis, 20% had moderate carditis, and 32% had severe carditis. The cardiac valves most commonly affected were the mitral valve alone (55%), followed by both mitral and aortic valves (34%), and the aortic valve alone (6%).

Although, population-based studies are lacking, rheumatic fever has remained a significant public health problem in developing areas, such as Brazil, particularly within the low-income population.

Prevention

Prompt treatment of streptococcal pharyngitis with appropriate antibiotics has lowered the incidence of Sydenham chorea. Once the diagnosis of rheumatic chorea is established, the patient must receive secondary prophylaxis with penicillin, or for patients with an allergy to penicillin, sulpha drugs. This has been shown to effectively decrease the risk of neurologic or cardiac problems with additional streptococcal infections (123). Patients with a history of Sydenham chorea should be informed of the possible reemergence of chorea during pregnancy or with use of oral contraceptives.

Differential diagnosis

Confusing conditions

Sydenham chorea is the most common cause of acute chorea in children worldwide, but several other conditions can cause present with chorea in this age range (10). Several conditions may present with clinical manifestations similar to Sydenham chorea (Table 1) (35).

The most important differential diagnosis is systemic lupus erythematosus (SLE), where up to 2% of patients may develop chorea. Most subjects with systemic lupus erythematosus have other nonneurologic manifestations such as arthritis, pericarditis, and other serositis as well as skin abnormalities. Moreover, the neurologic picture of systemic lupus erythematosus tends to be more complex and may include psychosis, seizures, other movement disorders, and even changes in mental status and level of consciousness (09). Only in rare instances will chorea, with a tendency for spontaneous remissions and recurrences, be an isolated manifestation of systemic lupus erythematosus. The difficulty in distinguishing these 2 conditions is increased by the finding that up to 20% of patients with Sydenham chorea display recurrence of the movement disorder. Eventually, patients with isolated chorea due to systemic lupus erythematosus develop other features, meeting diagnostic criteria for this condition (13).

Primary antiphospholipid antibody syndrome is differentiated from Sydenham chorea by the absence of other clinical and laboratory features of rheumatic fever as well as the usual association with repeated spontaneous abortions, venous thrombosis, other vascular events, and the presence of typical laboratory abnormalities.

In children and adolescents, anti-NMDA receptor encephalitis is usually a paraneoplastic disorder related to ovarian teratoma. Patients present with a combination of psychiatric problems and a mixed movement disorder that may include chorea. However, the severe and proteiform clinical presentation readily distinguishes this condition from Sydenham chorea (12).

Encephalitides, either as a result of direct viral invasion or by means of an immune-mediated postinfectious process, can cause chorea (151). This usually happens, however, in younger children; the clinical picture is more diverse (eg seizures, pyramidal signs, and impaired psychomotor development), and there are laboratory abnormalities suggestive of the underlying condition.

Drug-induced choreas are readily distinguished by careful history demonstrating a temporal relationship between onset of the movement disorder and exposure to the agent.

Although vascular disease is uncommon in the first 2 decades of life, it can occur and cause chorea (125). This may happen in 3% of patients with moyamoya disease (02).

Benign hereditary chorea (BHC) is a genetic syndrome associated with multiple mutations, most commonly a mutation of NKX2-1. It is an autosomal dominant disorder but may remain unrecognized due to the variable expression or possible de novo mutation. These patients display chorea, other movement disorders (ie, tics, myoclonus), as well as behavioral disorders (38). It usually starts in early childhood and progresses until the second decade, after which time it remains static or even spontaneously improves. Patients may have a slight hypotonia and motor delay because of chorea; they may also have mild gait ataxia, dystonia, tics, handwriting impairment, and drop attacks. However, the disorder is self-limiting after adolescence in most cases, although it may persist as a mild chorea beyond 60 years of age. Benign hereditary chorea has been linked to mutations in the NKX2-1 (previously called TITF1) gene on chromosome 14q13, coding for a protein called homeobox protein Nkx-2.1, which is a member of the homeobox protein family a transcription factors that are essential for organogenesis of the lung, thyroid, and basal ganglia (142). Benign hereditary chorea should be considered in children and adults with chorea, mental retardation, congenital hypothyroidism, and chronic lung disease; hence, the term brain-thyroid-lung syndrome has been proposed for this disease. About half of the patients spontaneously improve in adulthood, but levodopa can also be beneficial. There are reports suggesting that thyroid hormone replacement therapy and methylphenidate may be effective (79; 159).

Another form of “benign” chorea with relatively intact cognitive function is an autosomal dominant syndrome associated with ACDY5 mutation, but the phenotype of this disorder is expanding, and it may include dystonia, myoclonus, axial hypotonia, and episodic and fluctuating painful spasms associated with falls, sleep disturbance, and other manifestations (126).

More rare mutations of the genes PDE10A and PDE2A may also result in a clinical picture resembling benign hereditary chorea. However, these are autosomal recessive conditions, often associated with a seizure disorder and bilateral striatal necrosis (129; 156). Other genes to be considered in this scenario are FOXG1, GNAO1, GPR88, SLC2A1, SQSTM1, ATP8A2, or SYT-1. One review describes the differential diagnosis of autoimmune choreas in detail (39), and a more recent article addresses the differential diagnosis of chorea in children (10).

Table 1. Differential Diagnoses for Sydenham Chorea

Diagnostic workup

The aim of the diagnostic workup in patients suspected to have rheumatic chorea is 3-fold: (1) to identify evidence of recent streptococcal infection or acute phase reaction; (2) to search for cardiac injury associated with rheumatic fever; and (3) to rule out alternative causes.

In the absence of a clear diagnosis of rheumatic fever, children and young adults with chorea should undergo complete neurologic examination and diagnostic testing to assess the various causes of chorea because there is no specific biological marker of Sydenham chorea.

Supporting evidence of preceding streptococcal infection (eg, increased antistreptolysin-O, antiDNAse-B, or other antistreptococcal antibodies; positive throat culture for group A Streptococcus; or recent scarlet fever) and tests of the acute-phase response are often less helpful in Sydenham chorea than in other forms of rheumatic fever due to the usual long latency between the infection and onset of the movement disorder.

Antistreptolysin O titer. Elevated antistreptolysin O titer may be found in populations with a high prevalence of streptococcal infection. Furthermore, the antistreptolysin O titer declines if the interval between infection and rheumatic fever is greater than 2 months. Anti-DNase-B titers, however, may remain elevated up to 1 year after strep pharyngitis. Heart evaluation (ie, Doppler echocardiography) is mandatory because the association of Sydenham chorea with carditis is found in up to 80% of patients. Cardiac lesions are the main source of serious morbidity in Sydenham chorea. Serologic studies for systemic lupus erythematosus and primary antiphospholipid antibody syndrome must be ordered to rule out these conditions. EEG may show generalized slowing acutely or after clinical recovery. Spinal fluid analysis is usually normal, but it may show a slight increased lymphocyte count. It is important to highlight that although autoantibodies are important for the pathogenesis of Sydenham chorea, they have no role in establishing the diagnosis in clinical practice. This is related to their lack of specificity (40).

Acute phase reactants. The acute-phase response is considered part of the innate immune system, and acute phase reactants play a role in mediating such systemic effects as fever, leukocytosis, and increased cortisol. Acute phase reactants are inflammation markers that exhibit significant changes in serum concentration during inflammation. Acute phase reactants can be classified as positive or negative, depending on their serum concentrations during inflammation. Positive acute phase reactants are upregulated, and their concentrations increase during inflammation: examples include procalcitonin, C-reactive protein, ferritin, fibrinogen, hepcidin, and serum amyloid A. The erythrocyte sedimentation rate (ESR), an indirect acute phase reactant, reflects plasma viscosity and the presence of acute phase proteins, especially fibrinogen. Negative acute phase reactants are downregulated, and their concentrations decrease during inflammation; examples include albumin, prealbumin, transferrin, retinol-binding protein, and antithrombin.

Structural neuroimaging. CT scan of the brain invariably fails to display abnormalities in Sydenham chorea. Head MRI is also often normal, although there are case reports of reversible hyperintensity in the basal ganglia. In one study, increased signal intensity was noted in just 2 of 24 patients (82). Volumetric studies showed that the striatum and putamen are significantly enlarged in the acute phase of Sydenham chorea compared with controls, although extensive overlap between cases and controls makes this of little practical use for clinical diagnosis (82; 102). Very rarely, patients may develop necrotic lesions of the basal ganglia (30).

Functional neuroimaging. PET and SPECT imaging may prove to be useful tools in the evaluation, revealing transient alterations in striatal metabolism in some patients (88; 191; 116; 17; 57; 140; 19; 87). Most of these studies found transient increases in striatal metabolism, which contrasts with other choreic disorders (eg, Huntington disease) that are associated with hypometabolism; however, one study found hyperperfusion in 2 patients with Sydenham chorea, whereas the remaining 5 had hypometabolism (57). Subjects with acute generalized Sydenham chorea may have symmetric or asymmetric increases in basal ganglia perfusion, or may have normal basal ganglia perfusion, whereas subjects with acute hemichorea invariably have asymmetrically increased basal ganglia perfusion (87). Some subjects with Sydenham chorea in motor remission have persistent hyperperfusion of the left putamen on SPECT (19).

Management

Care for patients with Sydenham chorea should be targeted at primary treatment (penicillin, bed rest, aspirin), palliation (symptomatic medication), and prophylaxis.

Antibiotic treatment and prophylaxis. Even though most patients with Sydenham chorea do not have an active infection when chorea appears, most published treatment recommendations include a 10-day course of oral penicillin or a single intramuscular dose of penicillin (186; 68). Sulfa drugs are commonly used for individuals with a penicillin allergy.

The most important measure in the treatment of patients with Sydenham chorea is antibiotic prophylaxis with long-acting penicillin G or, if there is a penicillin allergy, with sulfa drugs. The purpose of this secondary prevention is to prevent colonization or infection of the upper respiratory tract with group A beta-hemolytic streptococci and the development of recurrent attacks of rheumatic fever (195). Monthly injections of a new long-acting formulation of penicillin, benzathine penicillin G, can prevent recurrences of rheumatic fever in children (166). Secondary prophylaxis is mandatory for all patients who have had an attack of rheumatic fever, regardless of whether they have residual rheumatic valvular heart disease (195). Penicillin prophylaxis appears to reduce the likelihood of further cardiac complications and the recurrence rate of chorea (Gebremariam 1999; 68).

Penicillin remains the antibiotic of choice (63; 195). Intramuscular injection of benzathine benzylpenicillin 1.2 million units every three weeks (every four weeks in low-risk areas or in low-risk patients) is the most effective strategy for preventing recurrent attacks of rheumatic fever (119; 194; 195). Oral penicillin is an alternative, but a serious concern with oral administration is noncompliance because patients often find it difficult to adhere to a daily regimen of antibiotics for many years (64; 195). Even for patients who strictly adhere to an oral penicillin regimen, serum penicillin levels are less predictable, and rheumatic fever recurs more frequently than in comparable patients receiving intramuscular benzathine benzylpenicillin (193; 195). For patients who are allergic to penicillin (or suspected to be allergic), oral sulfadiazine or oral sulfasoxazole represent optimal second choices (194; 195). Although the sulfa drugs should not be used for primary prophylaxis, they are acceptable for secondary prophylaxis (195). In the rare circumstances where patients are allergic both to penicillin and the sulfa drugs, or if these drugs are not available, oral erythromycin may be used (194; 195).

The duration of treatment depends on the severity of cardiac involvement. Patients with no carditis may stop prophylaxis after 5 years or age 18 (whichever is longer), those with mild carditis should continue for 10 years or age 21, and those with moderate to severe carditis should receive lifelong prophylaxis (195). In instances where the diagnosis of Sydenham chorea is made after age 21 years, the policy is less clear; because of the potential seriousness of causing or aggravating cardiac pathology, some have recommended maintaining prophylaxis indefinitely (34).

Unfortunately, there is significant diversity of antibiotic treatment and/or reporting across prior studies (68). Studies that reported penicillin use varied in terms of its method of administration (eg, either oral or intramuscular primary penicillin therapy preceding intramuscular prophylaxis) or in the substitution of amoxicillin followed by prophylaxis with feneticillin (68). Long-term compliance and logistical problems are also problems with protracted prophylaxis (67; 68).

Although secondary antibiotic prophylaxis has been shown to reduce the risk of new cardiac lesions associated with recurrent rheumatic fever, the effect of prophylaxis on the recurrence of chorea is less clear. Available data suggest that prophylaxis likely reduces the rate of recurrence, but it does not completely prevent it (23; 181; 107; 89; 68).

Symptomatic treatment of acute chorea. There are few controlled studies of the symptomatic treatment of Sydenham chorea, and available information is of limited methodological quality (37; 188; 68; 130). Treatment remains largely empirical and is less than optimal (188; 68). There are no large, well-conducted, randomized controlled trials. Consequently, recommendations for optimal management remain inconsistent and are hampered by the side effects from pharmacotherapy (188; 68). Treatment decisions are currently based on the treating physician’s clinical experience, the desire to avoid side effects, and the availability of only limited scientific evidence (68). Chorea often improves with symptomatic therapy using antiepileptic medications, dopamine-blocking neuroleptics, or dopamine-depleting agents (68). Immunotherapy is typically reserved for those who fail to respond (68); corticosteroids are beneficial, but data using intravenous immunoglobulins and plasmapheresis are very limited (68).

Antiepileptic medications. Open label trials and anecdotal experience have supported the use of antiepileptic medications for Sydenham chorea. Valproic acid has been used with an initial dosage of 250 mg per day that is increased during a 2-week period to 250 mg 3 times a day; if the response is not satisfactory, the dosage can be gradually increased to 1500 mg per day. As this drug has a rather slow onset of action, it is prudent to wait 2 weeks before concluding that a regimen is ineffective. Carbamazepine and levetiracetam have also been reported to be effective in controlling chorea in uncontrolled open-label studies (69). Based on a comparative trial, carbamazepine (15 mg/kg per day) and valproic acid (20 to 25 mg/kg per day) are equally effective and safe drugs in the treatment of choreiform movements in Sydenham chorea (80).

Neuroleptics. If the patient fails to respond to antiepileptic medications, the next option is to prescribe dopamine blocking or dopamine depleting therapies. However, dopamine D2 receptor blockers must be used with great caution in patients with Sydenham chorea, given the observation of development of parkinsonism, dystonia, or both in patients treated with neuroleptics, and the potential risk of developing tardive dyskinesia. In one case-control study comparing the response to neuroleptics in patients with Sydenham chorea and Tourette syndrome, 5% of 100 patients with chorea developed extrapyramidal complications, whereas such complications were not observed among patients with tics matched for age and neuroleptic dosage (173).

Risperidone, a relatively potent dopamine D2 receptor blocker, is usually effective in controlling the chorea. The usual initial regimen is 1 mg twice a day. If, 2 weeks later, the chorea is still troublesome, the dosage can be increased to 2 mg twice a day. Haloperidol and pimozide are also occasionally used in the management of chorea in Sydenham chorea, although they are less well tolerated.

Because neuroleptics act by blocking dopamine receptors and, therefore, may cause tardive dyskinesia, many clinicians use tetrabenazine, a dopamine-depleting drug, for the symptomatic treatment of Sydenham chorea as this drug has a very low risk of tardive dyskinesia.

Discontinuation of antichoreic agents. There are no published guidelines concerning the discontinuation of antichoreic agents. One approach is to attempt a gradual decrease of dosage (eg, 25% reduction every 2 weeks) after the patient remains free of chorea for at least 1 month.

Immunosuppressive therapies. Some controversy exists as to the role of immunosuppression in the management of Sydenham chorea due to the poor methodological quality of supporting data, potential complications, and high cost of some of the therapies.

Corticosteroids are generally reserved for cases with severe carditis, severe chorea (chorea paralytica), or persistent disabling chorea refractory to antichoreic agents. A placebo-controlled study showed that oral prednisone shortened the time to clinical remission of chorea but did not affect rates of remission and recurrence (143). An observational, retrospective, multicentric study involving 30 subjects with Sydenham chorea (of whom 15 were treated with prednisone, and 15 received symptomatic drugs or no treatment) reported that oral prednisone (2 mg/kg for 14 days followed by gradual tapering) shortened both the median time for improvement and the time to achieve clinical remission (75). Methylprednisolone 25 mg/kg per day in children and 1 g/day in adults of for 5 days followed by 1 mg/kg per day of prednisone appears to be an effective and well-tolerated treatment for patients with Sydenham chorea refractory to conventional treatment with antichoreic drugs and penicillin (44; 14; 178).

Few reports describe the usefulness of plasma exchange or intravenous immunoglobulin in Sydenham chorea; because of the efficacy of other therapeutic agents, potential complications, and the high cost of the latter treatment modalities, these options are not usually recommended. In a randomized open-label study, the authors compared outcomes for 10 children treated with standard management alone and 10 who received additional intravenous immunoglobulin (186); outcomes were better for the intravenous immunoglobulin group based on a clinical rating scale, brain single-photon emission computed tomography, and the duration of symptomatic treatment.

Recurrent chorea. In a significant subgroup of patients, recurrence of Sydenham chorea is not attributable to a true relapse of rheumatic fever (107); instead, apparent recurrences may represent either a primary underlying increased susceptibility or the outcome of permanent subclinical damage to the basal ganglia following the initial choreic episode (107). In a longitudinal study of 24 patients had Sydenham chorea, 10 patients (42%) developed 11 recurrent episodes of chorea from 3 months to 10 years after the initial episode (107). Association of recurrent chorea with rheumatic fever could be suspected in only 6 of the 11 episodes of recurrence (55%), due to cessation of prophylactic antibiotic treatment or poor compliance in 4 patients and rise in anti-streptolysin O titers in 2. In an 18-year-old woman, chorea recurred during her first pregnancy. At recurrence, chorea was the sole rheumatic sign in all 9 patients who had a single recurrent episode. In a patient with 2 recurrent episodes, mitral regurgitation developed into mitral stenosis. No statistical differences in previous rheumatic fever activity and rheumatic cardiac involvement were found between subjects with a single episode and those with recurrent episodes.

Special considerations

Pregnancy

Patients with previous history of Sydenham chorea may develop chorea gravidarum as manifest by a recurrence of the movement disorder during pregnancy (120), although it is important to emphasize that there are other causes of chorea gravidarum such as systemic lupus erythematosus (33). The onset of chorea gravidarum is usually in the first trimester with spontaneous improvement or even remission in the third semester. If the movement disorder is not severe, no treatment is advisable. However, if necessary, low doses of neuroleptics can be considered and are safe to mother and child (01; 190).