Mycophenolate mofetil therapy for two cases of antiphospholipid antibody-associated chorea.

Chorea is associated with involuntary movement and may occur via an autoimmune mechanism. Until now, we treated immune-mediated chorea with glucocorticoids and cyclophosphamide as the efficacy of mycophenolate mofetil (MMF) therapy for this condition was unknown. Here, we report two cases of antiphospholipid antibody (aPL)-associated chorea that were cured by MMF. Measurement of aPL could help for future management of chorea patients. This report provides new insight into the beneficial effects of MMF on aPL-associated chorea.

Autoimmune choreas.

Chorea, a movement disorder characterised by a continuous flow of unpredictable muscle contractions, has a myriad of genetic and non-genetic causes. Although autoimmune processes are rare aetiology of chorea, they are relevant both for researchers and clinicians. The aim of this article is to provide a review of the epidemiology, clinical and laboratory features, pathogenesis and management of the most common autoimmune causes of chorea. Emphasis is given particularly to Sydenham's chorea, systemic lupus erythematosus, primary antiphospolipid antibody syndrome, paraneoplastic chorea and anti-N-methyl-d-aspartate receptor encephalitis.

Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease.

How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1-mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1(a) autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called "pediatric autoimmune neuropsychiatric disorder associated with streptococci" (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor.

BACKGROUND: Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). METHODS: We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. RESULTS: The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. CONCLUSIONS: These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

N-methyl-D-aspartate receptor antibody-associated movement disorder without encephalopathy.

N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a well-recognized clinico-immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody-mediated movement disorder: a 5-year-old female with acute onset hemichorea, a 10-year-old female with generalized chorea, and a 12-year-old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.

Hemichorea in a thymoma patient without anti-CRMP-5 antibody.

We reported a 72-year-old man with thymoma who presented with hemichorea. Although his brain CT and MRI revealed no abnormality, regional cerebral blood flow changes, identified by single photon emission computed tomography, suggested that the mechanism underlying the chorea seemed to be a dysfunction of the subthalamic nucleus and pallidum. His hemichorea was completely resolved after thymectomy. Absence of serum anti-neural autoantibodies, including small-cell lung carcinoma-related chorea anti-CRMP-5 antibody, suggests that mechanisms different from cross-talk neural-targeted tumor immune response can be responsible for the thymoma-associated paraneoplastic chorea.

Streptococcus and rheumatic fever.

PURPOSE OF REVIEW: To give an overview of the current hypotheses of the pathogenesis of rheumatic fever and group A streptococcal autoimmune sequelae of the heart valve and brain. RECENT FINDINGS: Human monoclonal antibodies (mAbs) derived from rheumatic heart disease have provided evidence for crossreactive autoantibodies that target the dominant group A streptococcal epitope of the group A carbohydrate, N-acetyl-beta-D-glucosamine (GlcNAc), and heart valve endothelium, laminin and laminar basement membrane. T cells in peripheral blood and in rheumatic heart valves revealed the presence of T cells crossreactive with streptococcal M protein and cardiac myosin. For initiation of disease, evidence suggests a two-hit hypothesis for antibody attack on the valve endothelium with subsequent extravasation of T cells through activated endothelium into the valve to form granulomatous lesions and Aschoff bodies. Autoantibodies against the group A streptococcal carbohydrate epitope GlcNAc and cardiac myosin and its peptides appear during progression of rheumatic heart disease. However, autoantibodies against collagen that are not crossreactive may form because of the release of collagen from damaged valve or to responses to collagen bound in vitro by certain serotypes of streptococci. In Sydenham chorea, human mAbs derived from disease target the group A carbohydrate epitope GlcNAc and gangliosides and dopamine receptors found on the surface of neuronal cells in the brain. Human mAbs and autoantibodies in Sydenham chorea were found to signal neuronal cells and activate calcium calmodulin-dependent protein kinase II (CaMKII) in neuronal cells and recognize the intracellular protein biomarker tubulin. SUMMARY: To summarize, pathogenic mechanisms of crossreactive autoantibodies which target the valve in rheumatic heart disease and the neuronal cell in Sydenham chorea share a common streptococcal epitope GlcNAc and target intracellular biomarkers of disease including cardiac myosin in the myocardium and tubulin, a protein abundant in the brain. However, intracellular antigens are not believed to be the basis for disease. The theme of molecular mimicry in streptococcal autoimmune sequelae is the recognition of targeted intracellular biomarker antigens such as cardiac myosin and brain tubulin, while targeting extracellular membrane antigens such as laminin on the valve surface endothelium or lysoganglioside and dopamine receptors in the brain. Antibody binding to these cell surface antigens may lead to valve damage in rheumatic heart disease or neuropsychiatric behaviors and involuntary movements in Sydenham chorea.

Long-term outcome of 32 patients with chorea and systemic lupus erythematosus or antiphospholipid antibodies.

OBJECTIVE: The aim of this work was to describe chorea during systemic lupus erythematosus or antiphospholipid antibodies and its long-term outcome. METHODS: We retrospectively analyzed clinical features, laboratory findings, imaging characteristics, and outcome in a series of 32 patients. RESULTS: Most patients were women (28 of 32), and mean age at onset of chorea was 20.6 (9-62) years. Chorea was inaugural for 28 patients. Improvement was observed with various treatments. During follow-up (12.2 ± 11.3 years), severe manifestations of systemic lupus erythematosus were rare. Antiphospholipid antibodies were repeatedly positive for 90% of the patients. Twelve patients developed arterial thrombosis. Prophylactic treatment with antithrombotic therapy might reduce the risk of further thrombosis (8% versus 57%; P = 0.01). Cardiac valvulopathy occurred in 22 patients during follow-up. Chorea relapsed in 8 cases. CONCLUSIONS: Chorea had a good outcome in itself. This long-term follow-up shows, for the first time, that these patients have substantial risk for further arterial thrombosis.

Antiphospholipid syndrome and rheumatic fever: a case spanning three decades of changing concepts and common immunological mechanisms.

We present a case of primary antiphospholipid syndrome (APS), initially diagnosed as acute rheumatic fever, resulting in severe mitral valve incompetence. This case raises questions of the specificity of the Jones diagnostic criteria for rheumatic fever in a population where it is infrequently encountered. There are similarities in clinical, pathological and echocardiographic presentations between rheumatic fever and APS, in addition to common immunological mechanisms. Our case highlights the possibility that rather than rheumatic fever being primarily responsible for her recurrent attacks of chorea and arthritis, the streptococcal infections in our patient occurred either in the setting of underlying antiphospholipid antibodies ('second hit' phenomenon), or may have triggered the development of pathogenic antibodies (molecular mimicry), subsequently leading to the clinical evolution of APS. During the three decades of our patient and her recurrent problems, there has been an evolving knowledge of the mechanisms of APS and rheumatic fever, allowing us to extend our understanding beyond symptoms and syndromes, to a better realization of the underlying immunological relationship between the two.

Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea.

Streptococcus pyogenes-induced acute rheumatic fever (ARF) is one of the best examples of postinfectious autoimmunity due to molecular mimicry between host and pathogen. Sydenham chorea is the major neurological manifestation of ARF but its pathogenesis has remained elusive, with no candidate autoantigen or mechanism of pathogenesis described. Chorea monoclonal antibodies showed specificity for mammalian lysoganglioside and N-acetyl-beta-D-glucosamine (GlcNAc), the dominant epitope of the group A streptococcal (GAS) carbohydrate. Chorea antibodies targeted the surface of human neuronal cells, with specific induction of calcium/calmodulin-dependent protein (CaM) kinase II activity by monoclonal antibody 24.3.1 and sera from active chorea. Convalescent sera and sera from other streptococcal diseases in the absence of chorea did not activate the kinase. The new evidence implicates antibody-mediated neuronal cell signaling in the immunopathogenesis of Sydenham chorea and will lead to a better understanding of other antibody-mediated neurological disorders.

Chorea in systemic lupus erythematosus.

BACKGROUND: Chorea is recognized as one of the neurologic manifestations of systemic lupus erythematosus (SLE). Most reports show an association between chorea and antiphospholipid (aPL) antibodies in SLE patients. OBJECTIVES: The objective of this study was to describe the association of aPL antibodies with lupus chorea and its possible role in the pathogenesis of chorea. METHODS: We made a retrospective review of all cases of lupus chorea between 1989 and 2007 in a tertiary care center in Mexico City. RESULTS: We found 7 episodes of chorea in 5 patients with SLE. In 2 patients (3 episodes), chorea was associated with cerebral ischemia; one of these cases had positive anticardiolipin (aCL) immunoglobulin G (IgG) antibodies, whereas the other was diagnosed as having vascular lipohyalinosis as the probable cause of cerebral ischemia. In 3 patients (4 episodes), an immune-mediated mechanism was suspected; these cases had negative aPL at the onset of chorea, but IgM aCL antibodies became positive later. CONCLUSIONS: In most episodes, chorea seems to be immunologically mediated and was associated with a later appearance of IgM aCL antibodies. Chorea in patients with lupus may also be caused by cerebral ischemia, and in some cases, it may be associated with IgG aCL antibodies.

Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever.

46% of sera from 30 children with rheumatic chorea showed IgG antibody reacting with neuronal cytoplasm of human caudate and subthalamic nuclei. The antibody was also detected in 14% of 50 children with active rheumatic carditis. 55 normal control sera, as well as 148 sera from a broad variety of other disease states showed a low prevalence (1.8-4.0%) of positive reactions. In rheumatic chorea the presence of anti-neuronal antibody appeared to correlate with severity and duration of clinical attacks. Antibody reacting with neuronal cytoplasm was completely removed by absorption with Group A streptococcal membranes or with isolated human neurons from caudate nucleus. Partial absorption of antibody was also recorded using Group A cell wall preparations but not with Group A carbohydrate. No absorption of positive reactions was seen with streptococcal Group D membranes or cell walls. In rheumatic chorea, anti-neuronal antibody appeared to represent cross-reaction with antigens shared by Group A streptococcal membranes.

Persistence of streptococcal group A antibody in patients with rheumatic valvular disease.

Antibody levels to streptococcal Group A and A-variant carbohydrates were determined using a radioactive immune precipitation technique on patients with rheumatic fever, with and without valvular disease, on patients with post-streptococcal acute glomerulonephritis, and on age-matched controls. During the acute phase of the above illness, the means of the antibody levels to both carbohydrate antigens were equally elevated and were significantly higher than the normal controls. When Group A antibody levels were determined on sera obtained at intervals of 5-12 months and 1-5 yr after the acute illness) it was found that the antibody levels declined within the normal range at the 5-12 month interval in patients with glomerulonephritis as well as in patients with rheumatic fever in whom no valvular involvement had complicated the disease, i.e., patients with pure Sydenham's chorea. However, in patients with rheumatic valvulitis, who had been on penicillin prophylaxis after the last acute episode, the A antibody level showed little decline from the level obtained during the acute illness. The elevated antibody level in patients with rheumatic valvulitis, including patients with Sydenham's chorea with valvulitis, persisted for periods of at least 1 yr and up to 20 yr after the last acute attack. The pattern of the decline of the antibody levels to the A-variant carbohydrate as well as of the antibody titers to the other streptococcal antigens tested, ASO and anti-DNase B, was similar in all patients studied regardless of the presence of valvular disease. These findings suggest that prolonged persistence of the Group A antibody is a phenomenon peculiar to patients with rheumatic valvular disease. Whether this persistence is involved in the pathogenesis or is an outcome of the valvular disease remains to be determined.

Beneficial use of immunoglobulins in the treatment of Sydenham chorea.

This double case report indicates that treatment with intravenous immunoglobulins (IVIG) is effective in patients with Sydenham chorea (SC). SC is a rare but impressive clinical manifestation following streptococcal infection. This movement disorder characterised by chorea, emotional lability and muscle weakness, is one of the major criteria of acute rheumatic fever. Treatment of SC is typically limited to supportive care and palliative medications. Curative treatment is still in the experimental stage. Recent research on patients with SC proved that antibodies against the group A streptococcus cross-react with epitopes of neurons in the basal ganglia, namely, intracellular tubulin and extracellular lysoganglioside. Therefore, immune modulating therapy by means of prednisone, plasma exchange and IVIG are mentioned in the literature as possible effective treatment. Beneficial effect of IVIG has been shown in several diseases with molecular mimicry as the underlying pathophysiology. In this paper, we describe two girls aged 11 and 13 years, respectively, who presented with SC having severe disabilities in their daily live. We treated both patients with IVIG 400 mg/kg/day for 5 days. Treatment was tolerated well and had a pronounced positive effect. Shortly after the drug was administered, all signs and symptoms disappeared in both patients. Based upon these patients, we highlight IVIG as a serious treatment option for SC.

Anti-Thyroid Peroxidase/Anti-Thyroglobulin Antibody-Related Neurologic Disorder Responsive to Steroids Presenting with Pure Acute Onset Chorea.

Background: Pure acute onset chorea without encephalopathy has rarely been reported in anti-thyroid peroxidase (anti-TPO)/anti-thyroglobulin (anti-TG) antibody-related neurologic disorders responsive to steroids (ATANDS). Case report: We report a 16-year-old female who presented with acute chorea without encephalopathy. Anti-TPO antibodies were found to be strongly positive (>1200 IU/ml) along with anti-thyroglobulin and anti-thyroid stimulating hormone receptor antibodies. After pulse intravenous methylprednisolone therapy (1 g/day for five consecutive days), all the movements seized, and she was discharged with oral prednisolone 30 mg/day with gradual tapering over next three months. After one year of follow-up, she is stable, drug-free, and never had any other problems. Discussion: Anti-thyroid antibodies testing should be included in routine/conventional panel that is done for elucidating causes of chorea as ATANDS can be easily missed and is treatable with widely available, relatively low-cost drugs like steroids with a promising outcome.

[A case of anti-SRY-Related HMG-Box Gene 1 (SOX1) antibody-positive chorea].

A 77-year-old man with a history of lung cancer at the age of 71 developed involuntary right leg movement for a month. Neurological examination revealed a right-sided hemi-chorea. Autoimmune disease was suspected owing to the presence of oligoclonal bands and the elevated IgG-index in the cerebrospinal fluid. We detected anti-SRY-Related HMG-Box Gene 1 (SOX1) antibodies, known to be serological markers of Lambert-Eaton syndrome with small cell lung cancer, but not tumors. The results of tests for antiphospholipid, anti-LGI1, and anti-CASPR2 antibodies associated with non-paraneoplastic autoimmune chorea were all negative. This is the first suggestive case of autoimmune chorea in which anti-SOX1 antibodies were detected.

Obsessive-compulsive disorder and immunology: a review.

Interest in the possibility of an immune-mediated pathophysiology of obsessive-compulsive disorder and related disorders has increased. In the late 1980s, the National Institute of Mental Health reported an increase in obsessive-compulsive symptoms (OCS) in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCS but no chorea led to the coining of PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). This association has furthered interest in biological measures for immune and genetic susceptibility in non-PANDAS obsessive-compulsive disorder patients (OCD). Furthermore, some studies are trying to demonstrate alterations of immune parameters in OCD patients, with few positive results. In this narrative review, our objective was to describe the immunologic findings in OCD, PANDAS, and their association with SC.