• chorea
• multicentric study
• national
• retrospective
• Sydenham's chorea
• treatments

INTRODUCTION
Sydenham’s chorea (SC) is a widely recognized post-streptococcal autoimmune disorder of the central nervous system. According to Jones Criteria for diagnosis of acute rheumatic fever (ARF), it is one of the major clinical manifestations criteria.
The reported prevalence of SC in ARF is highly variable, with estimates ranging from 10 to 50%. While the incidence of SC has declined dramatically in the United States and Western Europe since the 1950s, SC remains prevalent in developing countries.
SC occurs most commonly in patients between 5 and 15 years of age, with the peak incidence at 8 to 9 years. A female predominance has been consistently reported.
Although SC is clearly related to group A beta-hemolytic streptococcal infection and it cannot occur without GAS pharyngitis, its pathogenesis is not completely understood. While GAS infections are common in childhood, SC is rare, suggesting that the host response to the GAS infection may be central to the pathogenic mechanisms of the disorder. There may be an inherited predisposition to respond to GAS infection with the production of autoantibodies directed at the brain.
The prevailing model of pathogenesis in SC involves a disordered immune response. A process, termed molecular mimicry, is hypothesized to be the result of host antibodies generated against extracellular GAS epitopes which then cross-react with endogenous antigens. In SC, studies have shown that antibodies induced by GAS cross-react with basal ganglia antigens.
A number of studies have implicated the involvement of the dopaminergic system in the expression of the SC movement disturbances. Successful control of the choreic symptoms using dopaminergic blockers, as Haloperidol, has provided evidence that increased dopaminergic activity is, at least in part, responsible for the involuntary movements.
SC is the most common acquired chorea in childhood worldwide and it is characterized by chorea (sudden, involuntary, brief, random and irregular movement of the limbs and face), hypotonia, emotional lability and other psychological symptoms, as well as difficulties of speech and gait.
SC could be associated with other manifestations of ARF include carditis and valvulitis, migratory polyarthritis, subcutaneous nodules, and erythema marginatum.
There is no definitive diagnostic test for SC. As a result, the diagnosis of SC is made clinically based on the characteristic and the absence of an underlying cause. Although other manifestations of rheumatic fever strongly support the diagnosis of SC, their presence is not mandatory, according to the modified Jones Criteria.
Electroencephalographic abnormalities in SC are nonspecific. Magnetic resonance imaging (MRI) is the preferred modality for neuroimaging but it is normal in many patients. Findings in SC are variable and there are no pathognomonic findings.
Nowadays, there is no consensus regarding SC treatment, except for antibiotic therapy to treat the underlying infection and chronic antibiotic therapy to prevent recurrence and minimize the risk of rheumatic heart disease.
Authors state that mild SC might not need treatment, while for severe disease, symptomatic treatment such as valproate, haloperidol, pimozide, tiapride, and carbamazepine, and immunosuppressive treatments such as corticosteroids, intravenous immunoglobulin and plasma exchange, could be used.
SC typically improves gradually, with symptoms typically lasting 12 to 15 weeks.
Full recovery occurs in almost all patients, but symptoms occasionally persist for two years or more. Although the initial bout remits with or without therapy, chorea can recur within two to three years and in some cases also as late as ten years.
SC is still an important health problem. Although it is known as a benign, self-limiting condition, it has high morbidity especially in those patients with recurrent and persistent SC. It is important to diagnose, principally because a regular use of penicillin prophylaxis can reduce the risk of recurrence of SC and also prevent rheumatic heart disease and morbidity from neuropsychiatric effects.

RATIONALE OFE THE STUDY
Given the large cohort of patients throughout the national territory, our multicentric retrospective study was conducted in order to describe Sydenham’s Chorea (SC) among children with rheumatic fever (RF) in a developed nation such as Italy.

The first objective of our study is to determine the demographic, clinical and laboratory characteristics of SC and the distribution of EEG and MRI findings in this national cohort of patients.
The second and more important objective is to assess the efficacy of current therapeutic approaches, describing the Italian experience.

MATERIALS AND METHODS
This is a five-year national study which has involved 169 patients with Sydenham’s Chorea diagnosed according to the revised Jones Criteria for acute rheumatic fever.
The efficacy of treatments was evaluated using the mRS (modified Rankin Scale), where available, a 7-point scale running from 0 to 6, measuring the degree of disability or dependence in patients’ daily activities.

RESULTS AND DISCUSSION
Most of the observations of our study are in accordance with the literature data. Some of them are the predominance of female gender, the mean age at the time of SC presentation and the prevalence of female patients over males during early childhood. The prevalence of the mitral valve involvement and the prevalence of generalized chorea over hemichorea are in accordance with the literature data too.
Although there are some interesting points that deserve to be noted which are in contrast to the literature data. Some of them are the lack of prevalence of female patients over males during early childhood, the irrelevance of familiarity, the high prevalence of carditis and the low prevalence of obsessive-compulsive symptoms.
Other noteworthy observations emerge from the comparison between female and male patients. Males have an earlier median age of SC onset and a longer latency than females. In the male group there is the same high prevalence of carditis as in the female group, but the ratio between subclinical and clinical carditis is less prominent. Another noteworthy observation is the lower prevalence of lesions of the mitral valve in the male group with subclinical endocarditis. More cases of combined lesions of the aortic and the mitral valves and of lesions of the aortic valve are reported in this group. A more prominent female prevalence is observed among hemichorea cases than among generalized chorea cases. Contrary to the general data and the female data, male patients less frequently present two or more other neurological manifestations. Female patients seem to present EEG abnormalities more commonly than male patients. Data about MRI are similar in the two groups. Both EEG and MRI abnormalities are more commonly reported in the male group than the female one.

Our multicenter study shows heterogeneity of treatment throughout the nation. Almost all patients in our cohort received rheumatic fever prophylaxis with benzathine G penicillin every 21 days. An additional therapy to penicillin was recorded in 88.17% of cases. A smaller group of patients received a symptomatic treatment. While larger groups received an immunemodulant treatment or a combination of symptomatic and immunemodulant treatments. These types of therapies were recorded in similar percentage. The most commonly used symptomatic drug and immunemodulant drug in our cohort are Valproic Acid and corticosteroids respectively.

Italian current therapeutic approaches are consistent with growing evidence for the efficacy of immunemodulant treatment which is leading to a shift in the treatment of SC all over the world.

In our study we compared the conventional therapy (only symptomatic drugs) with the immunemodulant therapy either alone or in association with symptomatic drugs and we also compared the efficacy of the three most commonly used symptomatic drugs (Valproic Acid, Haloperidol and Pimozide).
The superiority of immunemodulant treatment, especially of corticosteroids, appears clear in our study which demonstrares a faster clinical improvement and remission if compared with standard therapy.


Authors state that mild SC might not need treatment, while for severe disease, symptomatic treatment such as valproate, haloperidol, pimozide, tiapride, and carbamazepine, and immunosuppressing treatment such as corticosteroids, intravenous immunoglobulin and plasma exchange, could be used.