Case 1: The girl who couldn’t sit still

A seven-year-old Caucasian girl was referred to the hospital from the community with concerns about abnormal movements of her upper and lower extremities and slurring of speech. Before this, she had a two-week history of low grade fever, difficulty with feeding herself, deterioration in handwriting and trouble concentrating in school. She was seen by her family doctor at the onset and was believed to have had a viral infection. There was no history of a preceding sore throat or any concurrent symptoms such as headache, vomiting or fluctuating level of consciousness. Her past medical history was unremarkable. She was not taking any medications and there was nothing to suggest any intentional or accidental drug or poison ingestion.

On examination, she was afebrile with stable vital signs. She was alert and cooperative but would not speak to hospital staff. She displayed facial grimacing, thrusting of the tongue and bilateral writhing nonpurposeful movements of her arms and legs, as well as the ‘milk maid’ sign when asked to squeeze the examiner’s fingers. She had a mild fleeting erythematous macular rash over her forearms. Cardiac auscultation revealed normal heart sounds, with no audible murmur or rub. The remainder of her examination was normal.

Laboratory investigations showed a white blood cell count of 11.1×10⁹/L (polymorphs 4.8×10⁹/L, bands 1.1×10⁹/L, lymphocytes 4.0×10⁹/L), hemoglobin of 128 g/L, and platelets of 536×10⁹/L. Her erythrocyte sedimentation rate was elevated at 30 mm/h (normal <10 mm/h). Throat swab, cerebrospinal fluid culture, blood and urine toxicology screens and a head CT scan were normal. Antinuclear antibody, anti-double stranded DNA antibody, and 24 h urine copper level and serum ceruloplasmin were normal. Anticardiolipin antibody and the lupus anticoagulant screen were both negative. A further laboratory test confirmed the diagnosis.

CASE 1 DIAGNOSIS: ACUTE RHEUMATIC FEVER

Although a throat swab culture was negative at the time of referral, the antistreptolysin O titre was 1600 (normal <300), confirming a previous infection with Group A beta-hemolytic Streptococcus. Her electrocardiogram showed a normal sinus rhythm with no PR prolongation. The diagnosis of acute rheumatic fever (ARF) was made based on her chorea, elevated erythrocyte sedimentation rate and history of fever, in addition to evidence of a preceding streptococcus infection (revised Jones Criteria, 1992). After admission, an echocardiogram revealed slightly thickened mitral and aortic valves with mild mitral regurgitation and aortic insufficiency consistent with ARF. She was treated with amoxicillin 250 mg three times daily for 10 days as well as diazepam 1.25 mg orally every 6 h as necessary for her chorea.

Chorea is characterized by facial grimacing, tics or contortions and abrupt, purposeless, nonrhythmic involuntary movements of the extremities, usually worse on one side. It can be differentiated from athetosis, which consists of slow, writhing, twisting movements, and from ballismus, which is a more forceful, high-amplitude, coarse chorea. When a young child presents with chorea or any sort of involuntary movement disorder, the clinician must consider a wide variety of causes. Hyperthyroidism and toxic ingestions should be considered in the initial work-up. The neurological deterioration seen in Wilson’s Disease, an autosomal recessive disorder characterized by abnormal accumulation of copper in the liver, eyes, kidneys and brain may result in intention tremors, clumsiness and poor handwriting. Other diagnoses to consider include tics, Tourette’s syndrome, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), systemic lupus erythematosus and antiphospholipid antibody syndrome.

Acute rheumatic fever is still the leading cause of heart disease in children in the developing world. The peak age is five to 15 years and it is more prevalent in low socioeconomic conditions that favour spread of group A streptococci through overcrowding. Although the exact mechanism of disease has not been fully elucidated, it is thought that certain strains of group A streptococci have more ‘rheumatogenicity’ than others. Two implicated cell wall surface antigens, the M-protein surface epitope and the group A carbohydrate, are known to induce an antibody response that cross-reacts with human host tissue in an autoimmune process known as molecular mimicry. Antibodies from patients with carditis and Sydenham’s chorea have been shown to react to heart myocytes and neuronal cells in the caudate and subthalamic nuclei, respectively, as well as cross-react with group A streptococcal membranes.

The Jones’ criteria for the diagnosis of acute rheumatic fever were revised in 1992 to be applied only to those cases with evidence of a preceding infection with group A streptococci. This requires a positive throat culture or positive rapid streptococcal antigen test. When these are negative, elevated or rising antistreptolysin O titre, antideoxyribonuclease B or antihyaluronidase titres may also be used. To make the diagnosis, the patient must fulfil two major criteria, or one major and two minor Jones’ criteria. These criteria apply only to the first presenting episode of rheumatic fever and not to recurrences.

Of the five major criteria, polyarthritis is the most common presenting complaint, found in up to 75% of patients. Typically, the arthritis is exquisitely painful and migratory, affecting large joints such as knees, ankles, elbows and wrists. Over 40% of patients will have evidence of carditis, presenting almost always within the first three weeks, with one or more of: a new cardiac murmur reflecting valvular insufficiency, pericarditis, congestive heart failure or cardiomegaly on chest radiograph. Sydenham’s chorea is more common in female patients and usually occurs in a ‘pure’ form, presenting as the sole major criteria, and can manifest up to eight months after the preceding streptococcal infection. For this reason, late presenting chorea is the only instance in which Jones criteria do not have to be fulfilled, because a significant proportion of patients will fail to produce any evidence of prior streptococcal infection, making the diagnosis of ARF one of exclusion. Erythema marginatum, a pink, evanescent, nonitchy rash on the trunk and limbs is rare, but usually found only in patients with carditis. Also rare are subcutaneous nodules that appear almost always in the presence of carditis, and are firm, nontender nodules found on extensor bony surfaces or prominences and over tendons. Minor criteria are much less specific and include fever, electrocardiogram abnormality (prolonged PR interval), arthralgias, and elevated acute phase reactants (erythrocyte sedimentation rate or C-reactive protein).

Acute management includes treatment of group A streptococcal infection with penicillin for 10 days, even if the culture is negative. High dose aspirin is effective for treating fever and joint inflammation. In severe cases of carditis or congestive heart failure, corticosteroids may be used. Continuous long term antibiotic prophylaxis is important because recurrent attacks are more likely and may present with carditis even though the initial presentation did not. Patients should continue to have standard bacterial endocarditis prophylaxis (eg, for dental procedures) over and above their continuous streptococcal prophylaxis.

Sydenham’s chorea is generally self-resolving but may wax and wane for weeks to months. Symptomatic relief can be provided by antiepileptic medications (eg, carbamazepine or valproate) or benzodiazepines (eg, diazepam or clonazepam).

CLINICAL PEARLS

• Syndenham’s chorea may present as the only manifestation of acute rheumatic fever and can occur up to eight months after a group A streptococcal infection.

• The onset of chorea can be subtle with parental reports of increased clumsiness, deterioration in handwriting and emotional lability.

• The diagnosis of a first presenting episode of ARF requires objective evidence of a preceding streptococcal infection PLUS either two major criteria OR one major AND two minor criteria. A useful memory aid is two PECCS (polyarthritis, erythema marginatum, carditis, chorea, subcutaneous nodules) or one PECCS and two FEALs (fever, electrocardiogram changes, arthralgia, lab abnormality).

• Patients require both long term continuous secondary prophylaxis against recurrence of rheumatic fever and standard bacterial endocarditis prophylaxis.