Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous and arterial thromboses and pregnancy morbidity in association with antiphospholipid antibodies (aPL).1 Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease with diverse pathogenesis and various clinical phenotypes.2 Both are associated with a diverse array of neurologic symptoms, including movement disorders.
First described in people who also had SLE, APS can also be present as a primary disorder. It remains unknown, however, if APS and SLE are truly 2 separate diseases with coincidental association in an individual, if the pathophysiology of SLE promotes development of APS, or if the 2 disorders share an underlying disease process.3,4 Approximately 30% to 40% of individuals with SLE will test positive for aPL, although fewer than 50% of people with aPL-positive SLE will develop thrombotic complications.4,5
The revised Sydney classification criteria define APS as being present if at least 1 clinical criterion and 1 laboratory criterion are met (Table 1).3,6 The 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE defines the diagnosis based on entry and additive criteria (Table 2).2
The Euro-Phospholipid Project was initiated in 1999 to classify the prevalence and characteristics of the major clinical and immunologic manifestations of APS in 1,000 individuals.7 The most common clinical manifestation was venous thromboembolic events (31.7%). Thrombocytopenia, stroke, pulmonary embolism, livedo reticularis, heart valve lesions, superficial thrombophlebitis, and obstetric morbidity were also very common (Figure A). Approximately 1% of people with APS develop catastrophic APS, a severe subset of disease characterized by multiple small vessel thromboses with multi-organ involvement over a short period of time.8
Similarly, the Euro-Lupus project followed 1,000 patients with SLE. Throughout the course of the disease, arthritis, malar rash, photosensitivity, nephropathy, fever, Raynaud phenomena, and neurologic involvement were the most common clinical manifestations (Figure B).9
Figure 1. The percentage of cumulative clinical features during the evolution of antiphospholipid syndrome in the Euro-Phospholipid Project (A) and in systemic lupus erythematosus in the Euro-Lupus cohort (B).
Movement Disorders in APS and SLE
The pathophysiology of movement disorders in APS and SLE is not completely understood, and multiple mechanisms may play a role. Specific antigenic targets of aPL include phospholipids, phospholipid-protein complexes, and phospholipid-binding proteins to result in an intricate cascade of reactions that may contribute to clinical manifestations.10 Classically, aPL antibody-antigen binding affects coagulation to result in thrombosis. Many, although not all, people who develop movement disorders in the context of APS and SLE have ischemic-appearing lesions on neuroimaging.11-17 In the majority of those with chorea, which is the most common movement disorder seen in these conditions, however, there are no specific imaging findings.11 An immune-mediated mechanism is suspected, but the precise central nervous system (CNS) antigen has not been found. In 4 children with chorea and APS, the presence of IgG antibodies binding to surface antigens on neurons with dopaminergic features was observed.18 In people with chorea and APS or SLE, positron emission tomography (PET) scans have shown hyperactivity in the basal ganglia, which is seen in other types of autoimmune chorea.17 The response of several movement disorders to immunotherapy has also been suggested as a surrogate marker of immunopathogenesis.17
Finally, APS- and SLE-associated chorea is seen more commonly in women. In addition, the known association of chorea with oral contraceptives (OCPs) use and pregnancy have led to the hypothesis that estrogen may play a role in pathophysiology, although the exact mechanism is not understood. As with most autoimmune diseases, a combination of genetic and environmental factors likely contributes to disease onset.19
Chorea. The most common movement disorder in APS is chorea, with a prevalence estimated at 1% to 4%.4,11,17 Chorea may be the presenting symptom of APS.4,11 In the largest review to date of chorea in APS, clinical manifestations, neurologic characteristics, and immunologic findings in 50 participants with APS and chorea were characterized. Of those included, 96% were female, and the mean age of onset of chorea was 21 years (range 6-77 years). Notably, 70% (n=35) also met criteria for SLE or SLE-like syndrome; 30% (n=15) had primary APS. The majority (66%, n=33) had only 1 episode of chorea; the rest had between 2 and 6 reported episodes. In 55% of those in whom laterality of chorea was reported (n=38), it was bilateral; in 4 others, chorea began unilaterally and reappeared later on the contralateral side. Interestingly, 6 patients developed chorea soon after starting on OCPs, 3 developed chorea during pregnancy, and 1 developed it shortly after delivery. Immunologic testing revealed lupus anticoagulant (LA) in 92% and anticardiolipin antibodies (aCL) in 91% (β-2-glycoprotein [β2GP] antibody levels were not reported). Neuroimaging was normal in the majority23 of cases (65%, n=31). Various treatments were tried, including combinations of steroids, haloperidol, aspirin, anticoagulants, and immunosuppressive agents, based on the combined clinical characteristics. All but 1 person recovered, suggesting that regardless of treatment, the prognosis is generally good.11
Ataxia. Both subacute and chronic ataxia have been described in the context of APS, often associated with other neurologic symptoms including parkinsonism, chorea, dystonia, tremors, cognitive decline, dysarthria, and optic neuropathy.15,20 An underlying malignancy was found in many of these cases, often several years after the initial presentation.20-22 There were no consistently reported imaging abnormalities. Multiple treatments have been tried, including plasmapheresis, prednisone, hydroxychloroquine, warfarin, aspirin, levodopa, and piracetam. In a series of 10 cases, all individuals who presented with subacute onset of ataxia (n=4) recovered, regardless of treatment. All who presented with chronic ataxia (n=6), in contrast, ultimately died of myocardial infarction (n=2), sepsis, or multiorgan failure with sepsis in the context of a cancer diagnosis (n=4).20
Other Hyperkinetic Movement Disorders. Other hyperkinetic movement disorders have been reported in association with APS. A case series reported 3 children with hemidystonia and elevated aCL associated with MRI T2 hyperintensities in the contralateral internal capsule, caudate, and putamen.23 In another case report, a person presented with paroxysmal choreiform movements of the right upper and lower extremities, consistent with paroxysmal nonkinesigenic dyskinesia. This person had T2 hyperintensities in the medial right frontal lobe and basal ganglia on MRI, LA, and elevated aCL. Symptoms resolved within several weeks after she was started on anticoagulants and advised to stop smoking and discontinue OCPs.24 A series of 2 cases of hyperkinetic movement disorders associated with APS includes a person who presented with tics associated with dysarthria and psychiatric symptoms, elevated aCL IgG, and a positive dilute Russell viper venom test (DRVVT)—a test for LA. Brain MRI showed T2 hyperintensities in the centrum semiovale and right occipital lobe. The second person presented with an action tremor, myoclonus, and dyskinetic movements of the tongue. Laboratory findings included elevated aCL, antinuclear antibodies (ANA), and positive DRVVT. Brain MRI showed T2 hyperintense lesions in the bilateral subcortical white matter and small bilateral cerebellar infarcts. This individual had significant improvement after starting treatment with warfarin.12 Finally, there is a case report of a person with an acute onset “complex hyperkinetic syndrome” consisting of chorea, left foot dystonia, oral dyskinesias, and speech impairment associated with multiple subcortical lesions and a large ischemic-appearing lesion in the left posterior temporal lobe. The individual had elevated aCL and β2GP and positive findings for LA. Movement disorder symptoms improved after treatment with warfarin and prednisone.13
Hypokinetic Movement Disorders. There are 8 cases associated with parkinsonism reported to date, 7 of which were associated with ischemic-appearing changes on MRI.12,14-16,25-27 Of these, 5 individuals had associated cognitive dysfunction,12,14,15 and 2 had other movement disorders (dystonia and ataxia).14,15 Only 1 person improved with levodopa treatment, and notably, his parkinsonism occurred in the context of transient basal ganglia hyperintensities after pulmonary endarterectomy under total cardiopulmonary bypass for chronic thromboembolic pulmonary hypertension attributed to his history of APS.16
A list of movement disorders that have been reported in association with APS, excluding chorea, can be found in Table e1, at the bottom of this article.
Systemic Lupus Erythematosus
Chorea. Similar to APS, chorea is the most common movement disorder seen in SLE, with prevalence estimated at 2%.11,17 Typically, chorea occurs early in the course of SLE, and may be the first symptom. Chorea is highly associated with aPL, which are found in 25% to 35% of people with SLE and in up to 92% of people with SLE who also have chorea.11,17 There are no specific MRI findings associated with SLE-related chorea, although some cases show evidence of ischemic damage in the basal ganglia.11,17 Multiple treatments have been tried with some success, including tetrabenazine, haloperidol, valproic acid, clonidine, carbamazepine, aspirin, and anticoagulants.17 In refractory cases, corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis have been used.17
Other Hyperkinetic Movement Disorders. Ataxia, myoclonus, dystonia, and tremors have been described in the context of SLE. Cerebellar findings have been reported in less than 2% of people with SLE overall but in up to 25% of those who have infarcts.17 Cerebellar symptoms have been reported most commonly in young adults and are frequently associated with other brainstem and/or cranial nerve dysfunction. Unlike in chorea, aPL have not been consistently seen in people with other hyperkinetic movement disorders and SLE. Treatment has centered mainly on the use of immunosuppressive agents including corticosteroids, azathioprine, and cyclophosphamide. Anticoagulation has also appeared to be beneficial in the context of ischemia and the presence of aPL. Most individuals have improvement within 6 to 9 months, although recurrences have been described up to 12 years later.17 Myoclonus is also commonly reported, although rarely as the initial manifestation of SLE.28 A case report described a patient with a complex hyperkinetic movement disorder that included myoclonus, choreoathetoid movements, and dystonia in the context of SLE with APS.29 In this case, brain MRI showed bilateral cortical and subcortical T2 hyperintensities and improvement occurred with a combination of corticosteroids, mycophenolate mofetil, and aspirin.29 Other types of focal dystonia and tremors have also been reported in SLE, although a causal relationship is not well established.17
Hypokinetic Movement Disorders. Parkinsonism, stiff-person syndrome, and other hypokinetic movement disorders have also been reported in the context of SLE. Parkinsonism has been described in over 30 cases and is highly associated with other neuropsychiatric symptoms.17 The majority of people with SLE and parkinsonism have had thalamic and/or basal ganglia T2 hyperintensities on MRI. Improvement has been reported with immunosuppressive agents (ie, corticosteroids, azathioprine, and cyclophosphamide) and dopaminergic therapy (ie, levodopa and dopamine agonists). Clinical response to treatment is variable, although improvement has occurred in most cases.17 Stiff-person syndrome has been reported in 2 individuals with SLE; both had positive antiglutamic acid decarboxylase (GAD) antibodies (see Stiff-Person Syndrome in this issue). Neither person described responded to corticosteroids, but both eventually improved with cyclophosphamide or IVIG treatment.17 Table e2 in the online edition provides a summary of movement disorders associated with SLE.
The management of movement disorders associated with APS and SLE is complex. Most therapeutic decisions are made based on the suspected pathophysiologic mechanism causing neurologic damage. A variety of empiric therapeutic options have been tried including immunotherapy, anticoagulation, antiplatelets, and symptomatic treatments based on movement disorder phenomenology.
The first distinction to be made is whether the neurologic manifestation is thrombotic in nature. Long-term anticoagulation is the cornerstone treatment of thrombotic manifestations in APS.30,31 Individuals with definitive APS who are having a first venous thrombosis event should receive oral anticoagulation with heparin bridging.31 There is still lack of consensus regarding optimal antithrombotic management of ischemic stroke or transient ischemic attack (TIA) and APS.30-32 In these cases, data from the XV International Congress on Antiphospholipid Antibodies reinforced that an international normalized ratio (INR) higher than 3.0, or between 2.0 to 3.0 in combination with an antiplatelet agent, should be used for secondary thromboprophylaxis; this recommendation did not reach panel consensus owing to a lack of clinical trials and alternative explanations for stroke.30-32 Recurrent thrombotic events are usually associated with inadequate anticoagulation and should be managed by increasing the target INR to 3.0 to 4.0 or adding aspirin.33,35 If there is inadequate anticoagulation with warfarin, low molecular weight heparin (LMWH) may be beneficial.33 The role of direct oral anticoagulants (DOACs) remains unclear,30 and 2 major trials are investigating rivaroxaban or apixaban vs warfarin in the management of thrombotic APS.35,36 Current guidelines recommend the use of DOACs for individuals with known warfarin allergy, warfarin intolerance, or poor anticoagulation control.37
In thrombotic APS refractory to adequate anticoagulation, rituximab, IVIG, and plasmapheresis have been used.34 Hydroxychloroquine has been used as an adjunctive treatment in refractory APS. Although there is a lack of randomized controlled trials to confirm the efficacy and safety of hydroxychloroquine for thrombosis prevention, it has been reported to decrease the risk of thrombosis in people with SLE with APS.4,38,39 In pregnancy, APS is recognized as the most treatable cause of miscarriage and LMWH and low-dose aspirin are often used.4 Treatment modalities used for catastrophic APS include plasmapheresis, IVIG, and immunosuppressants.4
Data regarding the management of nonthrombotic neurologic APS is limited; most comes from case reports or retrospective nonrandomized studies.30 Although an autoimmune mechanism has been proposed, improvement of neurologic symptoms (including movement disorders) has also been reported with antiplatelets and anticoagulants.30
A variety of movement disorders have been recognized in the context of APS and SLE, although chorea is by far the most commonly reported. Because chorea may be the presenting symptom in APS and SLE, laboratory testing for the presence of ANA, antidouble-stranded DNA, and aPL should be included in the initial work-up of new-onset chorea. Although many cases have been associated with ischemic-appearing lesions of the basal ganglia and surrounding structures, many have occurred in the context of normal or nonspecific brain imaging, suggesting a more complicated pathophysiologic mechanism. Most individuals see improvement in movement symptoms with a combination of symptomatic therapies, antiplatelets, anticoagulants, and immunosuppressants. More research is needed to better understand the underlying pathophysiology of these disorders and guide the development of effective treatments.
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DSS, CD, MRO, and HM report no disclosures
This work was funded in part by a grant from the Parkinson’s Foundation