Introduction
Overview
Sydenham chorea is the prototype of chorea resulting from immune mechanisms. Although its incidence has steadily declined in the last decades, it remains the most common cause of acute chorea in childhood worldwide and is still an endemic condition in developing areas of the world. There is still interest related to the possibility that a similar pathogenic mechanism may be responsible for a subset of patients with tics and other movement disorders as well as behavioral abnormalities. The author reviews the clinical features, pathogenesis, and management of this condition.
Key points
|
• Sydenham chorea is the most common cause of acute chorea in children worldwide, although its incidence is declining. |
|
• Vascular chorea is the most important differential diagnosis of Sydenham chorea. |
|
• Evidence suggests that Sydenham chorea results from Streptococcus-induced antibodies that cross-react with central nervous system antigens. |
|
• Neuropsychiatric symptoms, such as obsessions, compulsions, hyperactivity, attention disorder, and depression, are often present in patients with Sydenham chorea. |
|
• Genetic conditions such as mutations of ACDY5, NKX2-1, PDE10A, and PDE2A may mimic Sydenham chorea. |
Historical note and terminology
The term chorea (from the Greek word for “dance”) was used since the Middle Ages to describe both organic and psychological disorders of motor control. Epidemics of a psychosomatic "dancing mania" (or "choreomania” from choros [dance] and mania [madness]) erupted in central Europe coincident with the Black Death, with St. Vitus among the various saints called onto intercede, leading to the terms chorea Sancti Viti and Saint Vitus’ dance (116; 76; 91; 120).
-
La Danse de Saint-Guy (St. Vitus dance)
(Source: Aubry C. Album Comique de Pathologie Pittoresque, Recueil de Vingt Caricatures Médicales. Paris: Huzard-Courcier for Ambroise Tardieu, 1823. Artist Antoine Chazal (French, 1793-1854). Lithography by Langlumé (French, a...
-
Dance of Saint Guy (St. Vitus dance) by Flemish artist Peter Paul Rubens (1577-1640)
(Source: Wellcome Collection, London, UK. Public Domain Mark.)
-
"Epileptics Walking to the Left” engraving
Three epileptic women each supported by two men. The artwork is widely interpreted as showing the dancing mania of the Middle Ages, referred to as St. John's dance, St. Vitus dance, or La Danse de Saint-Guy. Engraving by Dutch ...
For many years, chorea was the term applied to any hyperkinetic syndrome (91; 120). The itinerant German-Swiss physician, alchemist, astrologer, and philosopher Paracelsus (1493-1541; born Philippus Aureolus Theophrastus Bombastus von Hohenheim) divided chorea into three types: (1) chorea imaginativa (imagination), (2) chorea lasciva (sexual desires), and (3) chorea naturalis (organic disorders) (91; 120).
Swiss physician, alchemist, lay theologian, and philosopher Paracelsus (Theophrastus von Hohenheim; d. 1541)
(Source: Guerini V. A history of dentistry from the most ancient times until the end of the eighteenth century. Philadelphia & New York: Lea & Febiger, 1909.)
Historical reviews are available concerning the various choreic disorders (100; 118; 119; 120; 91; 123; 149) and the “dancing mania” (16; 116; 07; 90; 120; 122; 62).
English physician Thomas Sydenham (1624-1689), “The English Hippocrates," achieved fame during his own lifetime because he emphasized bedside observation, provided vivid clinical descriptions of diseases and their natural history, and adopted a moderate approach to treatment (181; 92; 120; 121).
-
English physician Thomas Sydenham (1624-1689) as a young man
Oil on canvas. (Courtesy of the Wellcome Collection, London, England. Public domain. Illustration restored, edited, and rematted by Dr. Douglas J Lanska.)
-
English physician Thomas Sydenham (1624-1689) as an old man
Print. Dutch engraver and printmaker Jacob Houbraken (1698-1780), Amsterdam, after Sir Peter Lely (1618-1680). Lely was a painter of Dutch origin whose career was nearly all spent in England, where he became the dominant portra...
In 1686, Sydenham confusingly applied the term “Saint Vitus’ dance” to his classic description of childhood chorea. After Sydenham, “Saint Vitus dance” could mean either organic chorea (Sydenham chorea, chorea minor, or chorea anglorum) or psychogenic chorea (chorea major or chorea germanorum) (76; 92; 120; 121). Nevertheless, in 1686 Sydenham did provide a clear and succinct description of some of the clinical features of postinfectious chorea:
|
There is a kind of convulsion, which attacks boys and girls from the tenth year to the time of puberty. It first shows itself by limping or unsteadiness in one of the legs, which the patient drags. The hand cannot be steady for a moment. It passes from one position to another by a convulsive movement, however much the patient may strive to the contrary. Before he can raise a cup to his lips, he makes as many gesticulations as a mountebank; because he does not move it in a straight line, but has his hand drawn aside by spasms, until by some good fortune he brings it at last to his mouth. He then gulps it off at once, so suddenly and so greedily as to look as if he were trying to amuse the lookers-on (185). |
Few illustrations exist of Syndenham chorea before the late 19th century.
La Danse de Saint-Guy (boys with Sydenham chorea)
(Source: La Médecine Illustrée 1880 [December 10.] Public domain. Edited by Dr. Douglas J Lanska.)
Sydenham's description of the irregular nature of choreic movements in children was well captured when sequential photographic images became possible.
Sequential photographs of a girl with Sydenham's chorea ("chorea minor") who was told to "stand still"
Photographs by German internist Friedrich Pineles (1868-1936) at the Medical Clinic in Heidelberg, c 1915. (Source: Pineles F. Hyperkinetic diseases: Infectious chorea. In: Burr CW, editor. Text-Book on Nervous Diseases. Philad...
As early as the 1860s, British neurologists John Hughlings Jackson (1835-1911) and (later Sir) William Henry Broadbent (1835-1907) implicated striatal dysfunction in childhood chorea, a fortuitous conclusion based largely on the longstanding but erroneous assumption that the striatum was the seat of movement. Jackson concluded, "It has long seemed to me that embolism ... of parts in the region of the corpus striatum gives a most satisfactory explanation of the physiology and pathology of cases of chorea" (105). Broadbent agreed that chorea was typically caused by embolism but claimed that some cases may be caused by "a morbid condition of the blood," resulting in a "delirium of the sensori-motor ganglia" (29).
-
English neurologist John Hughlings Jackson (1835-1911)
Photogravure after Lance Calkin (1859-1936), 1895. (Source: Wellcome Collection, London, UK. Public Domain Mark.)
-
English neurologist William Henry Broadbent (1835-1907)
Photograph by Elliott & Fry, a Victorian photography studio in London. Published in 1909 in LIFE. (Source: Wellcome Collection, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creati...
-
William Henry Broadbent as caricatured by "Spy" (Leslie Ward; 1851-1922)
From Vanity Fair, October 1902. (Source: Wikimedia Commons. Public domain.)
A review of clinical notes of inpatients seen by Sir William Gowers at the National Hospital of London from 1878 to 1911 showed that almost all chorea cases were caused by (or at least attributed to) Sydenham chorea (202).
British Neurologist Sir William Gowers
(Source: Courtesy of the U.S. National Library of Medicine. Public domain.)
In the nineteenth century, some observers recognized a relationship between childhood chorea, rheumatic arthritis, and valvular heart disease. In 1887, Canadian internist William Osler (1849-1919) studied 410 cases of Sydenham chorea and rheumatic heart disease treated at the Infirmary for Nervous Diseases since 1876. In Osler's On Chorea and Choreiform Affections (1887), based in large measure on his studies in the late 1880s in Philadelphia, he provided a new classification of chorea: (1) chorea minor (Sydenham); (2) chorea major (hysterical); (3) pseudo-chorea (eg, tics); and (4) secondary or symptomatic (eg, post-hemiplegic and Huntington) (123). He made the fundamental deduction that Sydenham chorea is an “infectious disorder” frequently associated with endocarditis, particularly affecting the mitral valve.
Canadian internist William Osler (1849-1919) in 1890
Osler was Professor of Clinical Medicine at the University of Pennsylvania from 1884 to 1888 before becoming the first Chairperson and Physician-in-Chief of the Johns Hopkins Department of Medicine in Baltimore. (Source: Collec...
In 1899, a diplococcus was isolated from the cerebrospinal and pericardial fluids of a child who died with chorea and carditis, suggesting that these disorders were bacterial infection complications. From 1901 to 1903, Frederic John Poynton (1869-1943) and Alexander Paine produced irregular movements, arthritis, and carditis in rabbits injected intravenously with diplococci from affected patients (160; 161; 162; 163).
Development of the antistreptolysin O titer as a marker of antecedent streptococcal pharyngitis in the early 1930s made it possible to demonstrate that all manifestations of rheumatic fever, including Sydenham chorea, which is a sequel to group A streptococcal pharyngitis. The causal relationship of Sydenham chorea with streptococcal infection was firmly established by the mid-20th century (186).
Acute rheumatic fever was quite common in the 19th and early 20th centuries. My own grandmother died in her 20s (in 1939) from cardiac complications of rheumatic fever sustained as a teenager, leaving my mother and her three siblings to be orphans.
Persistent Sydenham chorea has been suggested for the neurologic and medical illness of Austro-Bohemian Romantic composer Gustav Mahler (1860-1911) (45).
Gustav Mahler in the foyer of Vienna's Opera House
(Source: Specht R. Gustav Mahler. Berlin and Leipzig: Schuster and Loeffler, 1913, plate 12. Public domain.)
Mahler had a movement disorder with facial dyskinesia and a gait disorder consistent with chorea. As a conductor, Mahler was notorious for obsessive attention to details of staging and musical production. He was diagnosed with a valvulopathy in 1907 and died of subacute bacterial endocarditis in 1911. Cardoso and Lee suggested that the composer's valvulopathy, obsessive-compulsive disorder, and persistent chorea resulted from rheumatic fever in childhood with carditis and Sydenham chorea (45).
By the late 1930s, sulfonamides were demonstrated to prevent recurrences of rheumatic fever; in the 1940s, prompt administration of penicillin for group A streptococcal pharyngitis was shown to prevent primary (initial) attacks of rheumatic fever. Antibiotic prophylaxis for its prevention led to a marked drop in the incidence of rheumatic fever and its manifestations, including Sydenham chorea. In particular, the incidence of Sydenham chorea dropped drastically in North America and Western Europe after World War II, in part due to the increasing availability of antibiotics and the ability to diagnose and treat streptococcal infections early (146). Nevertheless, Sydenham chorea and acute rheumatic fever have persisted as important health problems in developing countries. (The cases of Sydenham chorea that I have observed were at hospitals in India and Jamaica in the 1980s and in Ecuador in the 2010s). Since the 1990s, Sydenham chorea has been recognized with increasing frequency in Brazil, Australia, and the United States, and there have more recent outbreaks in Central Europe (08; 169; 147; 113).
In the early twentieth century, the embolic theory was abandoned, and bacterial meningoencephalitis was proposed as an etiological explanation, but bacteria were not consistently cultured from brain tissue or cerebrospinal fluid of affected cases, and the process by which infection would selectively target the corpus striatum was never satisfactorily explained. Sydenham chorea is now understood to result from an antibody cross-reaction to basal ganglia epitopes following infection with group A β-hemolytic streptococci.
Because of the postinfectious immunological basis for Sydenham chorea, multiple studies have attempted to relate other movement disorders (eg, tics) and childhood behavioral abnormalities with Streptococcus-induced autoantibodies targeted at basal ganglia neurons (169; 35; 46; 50), albeit without convincing success.
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.
-
Throat appearance in Streptococcal pharyngitis
(Source: Somers LS. The diagnosis and treatment of membranous tonsillitis. Int Clin 1906;1[16th series]:41-56.)
-
Streptococci from Streptococcal pharyngitis
(Source: Somers LS. The diagnosis and treatment of membranous tonsillitis. Int Clin 1906;1[16th series]:41-56.)
These early artistic depictions of streptococcal pharyngitis from over a century ago compare favorably to modern color photography.
-
-
Intraoral view of Streptococcal pharyngitis (group A streptococci)
(Source: James Heilman MD. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativeco mmons.org/licenses/by-sa/3.0/deed.en.)
-
Intraoral view of culture-positive strep throat with typical tonsillar exudate in an 8-year-old child
(Source: James Heilman MD. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativeco mmons.org/licenses/by-sa/3.0/deed.en.)
-
Intraoral view of strep throat, caused by group A streptococci (1)
The patient exhibited redness and edema of the oropharynx and petechiae on the soft palate. Group A streptococci are spread through direct contact with mucus from the nose or throat of persons who are infected or through contac...
-
Intraoral view of strep throat, caused by group A streptococci (2)
The patient exhibited redness and edema of the oropharynx and petechiae on the soft palate. Group A streptococci are spread through direct contact with mucus from the nose or throat of persons who are infected or through contac...
-
Intraoral view of strep throat, caused by group A streptococci (3)
The patient exhibited redness and edema of the oropharynx and petechiae on the soft palate. Group A streptococci are spread through direct contact with mucus from the nose or throat of persons who are infected or through contac...
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.
-
Specimen revealing numbers of chain-linked Streptococcus pyogenes (Group A Streptococcus) bacteria (photomicrograph)
(Courtesy of the Centers for Disease Control and Prevention Public Health Image Library. Image 2109. 1979. Public domain.)
-
Pus specimen revealing numbers of chain-linked Streptococcus pyogenes (Group A Streptococcus) bacteria (photomicrograph)
(Pappenheim's stain, 900x) (Courtesy of the Centers for Disease Control and Prevention Public Health Image Library. Image 2110. 1954. Public domain.)
-
Group A Streptococcus, Streptococcus pyogenes bacteria atop the surface of neutrophil
Digitally colorized scanning electron microscopic (SEM) image depicts four yellow-colored Group A Streptococcus (GAS), Streptococcus pyogenes bacteria, which were atop the surface of neutrophil. (Produced by t...
-
Group of Gram-positive, Streptococcus pyogenes (group A Streptococcus) bacteria
The three-dimensional, computer-generated artistic recreation was based on scanning electron microscopic (SEM) imagery. (Courtesy of the Centers for Disease Control and Prevention Public Health Image Library. Image 22884. Image...
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.
Culture of Streptococcus pyogenes (Group A beta-hemolytic Streptococcus) bacteria on soy agar containing 5% defibrinated sheep's blood
Petri dish with Streptococcus pyogenes-inoculated trypticase soy agar containing 5% defibrinated sheep's blood that had been streaked and stabbed with a wire loop, which had been dipped into primary culture medium. The...
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, when grown on blood agar, alpha-hemolytic organisms 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 (55).
English pediatrician William Butler Cheadle (1836-1910) in 1881
Photograph by G Jerrard. (Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution [CC-BY 4.0] License, https://creativecommons.org/licenses/by/4.0.)
It was not until World War II that criteria rheumatic fever diagnosis were established by American cardiologist Thomas Duckett Jones (1899-1954) (108). 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 (165), so the disorder achieved national and international importance.
Rheumatic fever diagnosis continues to be based on the Jones criteria, developed in 1944 and then revised twice by the American Heart Association in 1992 and 2015 (108; 179; 86). 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.
Revised Jones Criteria for diagnosing acute rheumatic fever
(Source: Centers for Disease Control and Prevention, https://www.cdc.gov/groupastrep/diseases-hcp/acute-rheumatic-fever.html. Accessed June 5, 2022. Public domain.)
Although qualifying features now differ somewhat in low-risk 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 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, before 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 (211). 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 (123); Cheadle provided an overall synthesis of the most important clinical features of acute rheumatic fever, including the carditis (55).
Section of aortic valve in ulcerative endocarditis in a child with acute rheumatic fever
Proliferation and cell infiltration of subendothelial fibrous tissue, resembling the histologic features of subcutaneous nodules. (Source: Cheadle WB. The acute rheumatism of childhood. In: Albutt TC, editor. A System of Medici...
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.
-
Chronic mitral and tricuspid endocarditis
BS, 21-year-old black woman. Philadelphia Hospital Autopsy. Volume 18, page 154. Physician: Dr. Hughes. Pathologist: Dr. McConnell. The woman had acute rheumatic fever 4 years previously and again 2 years later. Beginn...
-
Mitral stenosis, with history of "chorea," since resolved
LF, 35-year-old white man. Philadelphia Hospital Autopsy. Volume 23, page 1. Physician: Dr. FP Henry. Pathologist: Dr. Karsner. Clinical note: At one time chorea. ... Cyanosis, dyspnea, edema, arrhythmia (extrasystolic...
-
Mitral stenosis with a "button-hole" mitral orifice
Jefferson Hospital Laboratories. (Source: DaCosta JC Jr. Principles and Practice of Physical Diagnosis. Third edition. Philadelphia and London: W.B. Saunders Company, 1915. Illustration edited by Dr. Douglas J Lanska.)
-
Mitral stenosis, showing stenotic mitral orifice
Jefferson Hospital Laboratories. (Source: DaCosta JC Jr. Principles and Practice of Physical Diagnosis. Third edition. Philadelphia and London: W.B. Saunders Company, 1915. Illustration edited by Dr. Douglas J Lanska.)
-
Rheumatic heart disease (1)
Sectioned human heart, extracted during a patient’s autopsy, reveals severe thickening of the mitral valve, thickened chordae tendineae, and the hypertrophic left ventricular myocardium, all due to a case of rheumatic heart dis...
-
Rheumatic heart disease (2)
This image of a sectioned human heart, extracted at the time of this patient’s autopsy, depicts a superior view of the aortic valve, which had been damaged due to a case of rheumatic heart disease. Note the thickened, fused val...
Experimental studies attempting to reproduce carditis in an animal model led to greater scrutiny of the pathologic features of human cases (160; 161; 162; 163). Sections of vegetations in simple rheumatic endocarditis often showed much necrotic tissue but no diplococci, sometimes with evidence of reparative changes, but in other cases, the necrotic tissue contained diplococci.
-
Section through a vegetation in simple rheumatic endocarditis (1)
In this photograph, there is much necrotic tissue but no diplococci, and at the base, reparative changes are commencing. (Source: Poynton FJ. Clinical lectures on rheumatic fever. I. Endocarditis in childhood considered as a sy...
-
Section through a vegetation in malignant rheumatic endocarditis (2)
In this photograph, the necrotic tissue contains myriads of diplococci. (Source: Poynton FJ. Clinical lectures on rheumatic fever. I. Endocarditis in childhood considered as a symptom of infective diseases. Int Clin 1903;3[13th...
Sections through affected valves could demonstrate separate identifiable zones of swollen connective tissue of the valve, cellular exudation, and necrosis in the vegetation.
Rheumatic endocarditis (section through the mitral valve)
(A) Zone of swollen connective tissue of the valve. (B) Zone of cellular exudation. (C) Area of necrosis in the vegetation. (Source: Poynton FJ. Clinical lectures on rheumatic fever. III. The parallelism between the clinical sy...
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.
-
Section through the left ventricle of a case of rheumatic carditis to show fatty change in the muscular fibers in the neighborhood of a capillary
(Source: Poynton FJ. Clinical lectures on rheumatic fever. II. Clinical evidences of myocardial damage in rheumatic fever. Int Clin 1903;3[13th series]:226-41.)
-
Section through the left ventricle of a case of rheumatic carditis to show cellular exudation in the interstitial tissues
(A) Cellular exudation. (Source: Poynton FJ. Clinical lectures on rheumatic fever. II. Clinical evidences of myocardial damage in rheumatic fever. Int Clin 1903;3[13th series]:226-41.)
-
Section through the left ventricle of a case of chronic rheumatic carditis
(A) A blood vessel with much perivascular fibrosis. (Source: Poynton FJ. Clinical lectures on rheumatic fever. II. Clinical evidences of myocardial damage in rheumatic fever. Int Clin 1903;3[13th series]:226-41.)
-
Section though the left ventricle of a case of chronic rheumatic carditis showing interstitial fibrosis
(A) The fibrous tissue. (Source: Poynton FJ. Clinical lectures on rheumatic fever. II. Clinical evidences of myocardial damage in rheumatic fever. Int Clin 1903;3[13th series]:226-41.)
With rheumatic pericarditis, there were identifiable zones of swollen connective tissue, cellular exudation, and necrosis with fibrino-cellular exudation.
Rheumatic pericarditis (section through the pericardium)
(A) Zone of swollen connective tissue. (B) Zone of cellular exudation. (C) Zone of necrosis and fibrino-cellular exudation. (D) Cardiac muscle. (Source: Poynton FJ. Clinical lectures on rheumatic fever. III. The parallelism bet...
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) (208). The arthritis is typically polyarticular, but monoarthritis may serve as sufficient to meet the criteria for a major manifestation according to the 2015 revision of the Jones criteria. Histologic sections through affected joint capsules may show separate identifiable zones of swollen connective tissue, cellular exudate, and necrosis and plastic exudation, which may take the form of very irregular granulations.
Rheumatic arthritis (section through knee joint capsule)
(A) Zone of swollen connective tissue. (B) Zone of cellular exudation. (C) Zone of necrosis and plastic exudation. (D) Muscle fibers. (Source: Poynton FJ. Clinical lectures on rheumatic fever. III. The parallelism between the c...
Tenosynovitis is common in adults and may suggest a diagnosis of disseminated gonococcal disease (208). The polyarthritis evolves over weeks but overlaps across individual joints, so it is not strictly migratory (208). Arthritis due to acute rheumatic fever generally subsides within 4 to 6 weeks without residual damage (208). 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 (51; 78). 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 lesions at the onset of the rheumatic fever (154). Sydenham chorea may be associated with other autoimmune disorders such as Takayasu arteritis (203; 12).
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 the arm, generally on the trunk and extremities and typically more prominent in a warm bath.
-
Erythema marginatum: serpiginous nonpruritic rash of arm, more prominent in bath
(Source: Wikimedia Commons. User:Adsie on September 11, 2020. Creative Commons Attribution [CC-BY 4.0] License, https://creativecommons.org/licenses/by/4.0.)
-
Erythema marginatum (detailed view)
(Source: Wikimedia Commons. User:Adsie on September 11, 2020. Creative Commons Attribution [CC-BY 4.0] License, https://creativecommons.org/licenses/by/4.0.)
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 (25). Other major criteria associated with subcutaneous nodules were carditis in 90%, arthritis in 79%, and chorea in 5% (25). The average number of nodules found in the group in which nodules were present was 18 (range four to 49); 31% had less than 10 nodules, and 12% had only four to five nodules (25). Subcutaneous nodules disappeared within 4 weeks in 69%, within 5 to 8 weeks in 19%, and within 9 to 12 weeks in 7% (25). In two cases (5%), multiple nodules were observed 12 weeks later when all other evidence of activity had disappeared (25).
Nineteenth-century artistic renderings graphically show the appearance and extent of these subcutaneous or "rheumatoid" nodules.
-
Subcutaneous "rheumatic" nodules in a boy with rheumatic fever
(Source: Sinkler W. Choreiform affections. In: Dercum FX, editor. A textbook on nervous diseases by American authors. Philadelphia: Lea Brothers, 1895:227-69.)
-
Subcutaneous nodules on the pinna of the ear of a female patient
Watercolor drawing by Thomas Godart (1821-1887). Godart was employed as Medical Artist at the medical school at St Bartholomew's Hospital. (Source: St. Bartholomew's Hospital and Museum, commonly known as "Barts," a teaching ho...
-
Subcutaneous nodules on the knee of a female patient
Watercolor drawing by Thomas Godart (1821-1887). Godart was employed as Medical Artist at the medical school at St Bartholomew's Hospital. (Source: St. Bartholomew's Hospital and Museum, commonly known as "Barts," a teaching ho...
-
Subcutaneous nodules on the hand
Watercolor drawing by Thomas Godart (1821-1887). Godart was employed as Medical Artist at the medical school at St Bartholomew's Hospital. (Source: St. Bartholomew's Hospital and Museum, commonly known as "Barts," a teaching ho...
-
Acute rheumatic fever, grave form, with numerous large subcutaneous nodules, fatal
Boy, aged 4 years and 3 months. Clinical features included rheumatic nodules, erythema marginatum, chorea, a "double mitral murmur," and arthritis. From the Hospital for Sick Children, Great Ormond St., London. Under the care o...
The histology of these lesions was recorded from the late 19th century as showing active proliferation and infiltration of fibrous tissues.
Section of subcutaneous tendinous nodule in acute rheumatic fever
Active proliferation and cell infiltration of fibrous tissue in a 7.5-year-old boy with acute rheumatic fever. Clinical features included chorea, arthritis, endocarditis, pericarditis, pleurisy, and subcutaneous nodules. Hospit...
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 (101).
Subcutaneous nodules on the left anterior shoulder and chest with faint overlying erythema in an 18-year-old man with Sydenham chorea
(Source: Heard MA, Green MC, Royer M. Acute rheumatic fever: a review of essential cutaneous and histological findings. Cureus 2021;13[1]:e12577. Creative Commons Attribution [CC-BY 4.0] License, https://creativecommons.org/lic...
Histologically, these may show mixed acute and chronic, superficial and deep, perivascular lymphohistiocytic inflammation, extending into the subcutis.
-
Subcutaneous nodule with superficial and deep perivascular lymphohistiocytic inflammation, extending into the subcutis from an 18-year-old man with Sy...
Hematoxylin and eosin, 2x magnification. (Source: Heard MA, Green MC, Royer M. Acute rheumatic fever: a review of essential cutaneous and histological findings. Cureus 2021;13[1]:e12577. Creative Commons Attribution [CC-BY 4.0]...
-
Subcutaneous nodule with subcutaneous mixed acute and chronic inflammation from an 18-year-old man with Sydenham chorea
Hematoxylin and eosin, 10x magnification. (Source: Heard MA, Green MC, Royer M. Acute rheumatic fever: a review of essential cutaneous and histological findings. Cureus 2021;13[1]:e12577. Creative Commons Attribution [CC-BY 4.0...
There were poorly formed granulomas with central coagulative necrosis and peripheral acute inflammation with conspicuous leukocytoclastic vasculitis (101).
Poorly formed perieccrine granuloma with peripheral leukocytoclasis from an 18-year-old man with Sydenham chorea
Hematoxylin and eosin, 10x magnification. (Source: Heard MA, Green MC, Royer M. Acute rheumatic fever: a review of essential cutaneous and histological findings. Cureus 2021;13[1]:e12577. Creative Commons Attribution [CC-BY 4.0...
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.
Pleural rheumatoid nodule
This necrotic lesion surrounded by palisaded histiocytes is present on the pleural surface. (Source: Yale Rosen on June 30, 2012. Creative Commons Attribution-Share Alike 2.0 Generic License, https://creativecommons.org/license...
Rheumatoid nodules can also occur in rheumatoid arthritis and systemic lupus erythematosus, and the histologic appearance is identical.
-
Rheumatoid nodule (low magnification)
(Source: Wikimedia Commons. Photomicrograph by User: Nephron. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)
-
Rheumatoid nodule (high magnification)
(Source: Wikimedia Commons. Photomicrograph by User: Nephron. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)
-
Rheumatoid nodule (very high magnification)
(Source: Wikimedia Commons. Photomicrograph by User: Nephron. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)
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 (51; 174). 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 (146; 51). This movement disorder is characterized by random, brief contractions, particularly affecting distal muscles, and it produces an odd dance-like character to the 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 (17).
-
Chorea (hemichorea) in Sydenham chorea
This boy has a 2-month history of left hemichorea, which developed after acute sore throat and was associated with elevated ASO titers. He displays prominent "piano-playing" movements of his left hand. (Contributed by Dr. Joseph J...
-
Sydenham chorea: Saint Vitus dance
This 11-year-old boy presented with acute onset generalized chorea and difficulty walking. (Contributed by Dr. Ravindra Kumar Garg.)
-
Sydenham chorea: chorea paralytica
This 13-year-old boy presented with 15 days history of generalized chorea, hypotonia, and marked disability. Chorea paralytica is an uncommon manifestation of Sydenham chorea. (Contributed by Dr. Ravindra Kumar Garg.)
Other neurologic and neuropsychiatric symptoms and signs.
Among a cohort of 48 subjects with acute rheumatic fever, subjects with Sydenham chorea experienced neuropsychiatric symptoms other than choreic movements at diagnosis significantly more frequently than did those without Sydenham chorea (152).
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) (194).
Speech disorders. Various speech alterations 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 (146). A case-control study of patients described a pattern of decreased verbal fluency that reflected reduced phonetic but not semantic output (65). Sydenham chorea also affects prosody: speech as a decreased range of fundamental frequency, higher intensity, and decreased speed (48; 49; 150).
Attention and executive function. A subset of patients with a history of Sydenham chorea has persistent attention impairment and executive function (44; 19; 53).
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 (158). Even vocal tics, found in 70% or more of patients with Sydenham chorea in one study, may be difficult to diagnose in patients with hyperkinesias (137). Involuntary vocalizations may result from chorea or dystonia of the pharynx and larynx (106). 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 (191).
Behavior abnormalities (obsessive-compulsive behavior and attention deficit or hyperactivity). Various behavioral abnormalities have been associated with Sydenham chorea, but the data are generally of poor quality to establish a causal relationship (158). Osier mentioned the lability, irritability, and "bizarre behaviors" of the children with Sydenham chorea (123). Obsessive-compulsive behavior was reported to be common in patients with Sydenham chorea (06; 184; 136; 129; 21; 158), although patients with rheumatic fever without chorea also have more obsessive-compulsive behavior and attention deficit or hyperactivity than healthy controls (136; 129). 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%) (129). Attention deficit/hyperactivity was reportedly significantly more common in the persistent than acute chorea (50% vs. 16%) (129), 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 (05). 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 (05). Obsessive-compulsive behavior in subjects with Sydenham chorea produced little interference in the performance of activities of daily living (129).
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 (103).
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 (183). 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) (184). 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 (184). The same study noted “significant psychiatric comorbidity”: emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, and oppositional behaviors (184). 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 (125).
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 (38). 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 (157). In fact, a population-based epidemiological survey performed in London failed to demonstrate a significant relationship between streptococcal infection and motor or behavioral syndromes (89; 171). A subsequent study similarly failed to find immunologic abnormalities that distinguish controls from patients with Tourette syndrome who meet criteriathe for PANDAS (142). However, a systematic review reiterates that no compelling evidence supports the association of auto-immune disorders with obsessive-compulsive and tic disorders (158).
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%) (141); 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 of nonacute Sydenham chorea and age- and gender-matched asymptomatic controls, depressive and anxiety symptoms were not more common in cases than controls (188).
There are rare r