Examining the Spectrum of Neurologic Manifestations in Antiphospholipid Syndrome

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  • Ischemic stroke is the most common severe neurologic complication of APS. Among 1000 people with APS participating in the Euro-Phospholipid Project, 20% presented with stroke and 11% presented with transient ischemic stroke.2,5 About 13% of patients with stroke are aPL-positive,2 and they are more likely to be younger or female compared with aPL-negative patients.3 More than 20% of strokes in patients <45 years may be related to APS.3 In APS, stroke occurs when a clot forms in an arterial vessel of the brain or when clot or plaque debris travels from another site (usually the heart) to a blood vessel in the brain.2,3 Less common cerebrovascular diseases seen in patients with APS that may increase stroke risk are cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome, acute ischemic encephalopathy (a rare feature of SLE), and Sneddon syndrome.3 To reduce stroke risk, clinicians may want to discuss modifiable risk factors for vascular disease, such as smoking and obesity, with those who are positive for aPL.3 Image Credit: Zephyr/Science Source

    Cerebrovascular Disease

    Ischemic stroke is the most common severe neurologic complication of APS. Among 1000 people with APS participating in the Euro-Phospholipid Project, 20% presented with stroke and 11% presented with transient ischemic stroke.2,5 About 13% of patients with stroke are aPL-positive,2 and they are more likely to be younger or female compared with aPL-negative patients.3 More than 20% of strokes in patients <45 years may be related to APS.3

    In APS, stroke occurs when a clot forms in an arterial vessel of the brain or when clot or plaque debris travels from another site (usually the heart) to a blood vessel in the brain.2,3 Less common cerebrovascular diseases seen in patients with APS that may increase stroke risk are cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome, acute ischemic encephalopathy (a rare feature of SLE), and Sneddon syndrome.3 To reduce stroke risk, clinicians may want to discuss modifiable risk factors for vascular disease, such as smoking and obesity, with those who are positive for aPL.3

    Image Credit: Zephyr/Science Source

  • Evidence suggests 19% to 40% of those who are aPL-positive and 42% to 80% of those with primary APS have CD.3 In addition, 2.5% of patients with APS have multi-infarct dementia resulting from recurrent ischemic events.6 Because cognitive deficits are also observed in patients with APS who have no evidence of neurologic involvement, the mechanism of CD in APS is likely multifactorial.3,7 Animal studies have also observed CD in APS models with no evidence of ischemic lesions, and findings suggest that aPL antibodies may affect brain tissue directly.3,7 The spectrum of CD varies from mild to severe, but deficits in attention, concentration, processing speed, executive function, and memory loss are common.3 Patients with APS-related dementia may have impaired judgment, language impairment, and memory loss that can be severe enough to arouse suspicion of Alzheimer disease.6,8 Empirical observation has shown that anticoagulation therapy improves memory loss in some patients.8 Image Credit: ISM/SOVEREIGN

    Cognitive Dysfunction

    Evidence suggests 19% to 40% of those who are aPL-positive and 42% to 80% of those with primary APS have CD.3 In addition, 2.5% of patients with APS have multi-infarct dementia resulting from recurrent ischemic events.6 Because cognitive deficits are also observed in patients with APS who have no evidence of neurologic involvement, the mechanism of CD in APS is likely multifactorial.3,7 Animal studies have also observed CD in APS models with no evidence of ischemic lesions, and findings suggest that aPL antibodies may affect brain tissue directly.3,7

    The spectrum of CD varies from mild to severe, but deficits in attention, concentration, processing speed, executive function, and memory loss are common.3 Patients with APS-related dementia may have impaired judgment, language impairment, and memory loss that can be severe enough to arouse suspicion of Alzheimer disease.6,8 Empirical observation has shown that anticoagulation therapy improves memory loss in some patients.8

    Image Credit: ISM/SOVEREIGN

  • Although chronic headache and migraine are not diagnostic for APS, headache is the most common symptom of APS and migraine is the most frequent neurologic manifestation, with a prevalence of 20% at initial patient presentation.2,9 APS-related migraine may occur with or without aura and may transiently impair vision or speech. 8,9 Migraine in APS typically does not respond to analgesic therapies,3,6 but like memory loss, frequently improves when patients start anticoagulation therapy.8 A correlation may exist between aPL positivity and migraine.9 Studies show that 18% to 40% of people who are aPL-positive have migraine,10 and one study found 12% of individuals with migraine were aPL-positive compared with 3% of controls who did not have headache or migraines.9 Migraine onset is often years before an APS diagnosis.6,9 Lupus anticoagulation and prior stroke increase migraine risk in APS, but migraine also occurs when ischemic lesions are absent.10 Genetic risk factors for migraine may be involved. 8

    Chronic Headache and Migraine

    Although chronic headache and migraine are not diagnostic for APS, headache is the most common symptom of APS and migraine is the most frequent neurologic manifestation, with a prevalence of 20% at initial patient presentation.2,9 APS-related migraine may occur with or without aura and may transiently impair vision or speech. 8,9 Migraine in APS typically does not respond to analgesic therapies,3,6 but like memory loss, frequently improves when patients start anticoagulation therapy.8

    A correlation may exist between aPL positivity and migraine.9 Studies show that 18% to 40% of people who are aPL-positive have migraine,10 and one study found 12% of individuals with migraine were aPL-positive compared with 3% of controls who did not have headache or migraines.9 Migraine onset is often years before an APS diagnosis.6,9 Lupus anticoagulation and prior stroke increase migraine risk in APS, but migraine also occurs when ischemic lesions are absent.10 Genetic risk factors for migraine may be involved. 8

  • Seizures and epilepsy (≥2 unprovoked seizures) are more common in patients with APS compared with the general population.6,10 Between 3% and 10% of patients with APS have seizures/epilepsy, a prevalence that is 10 times greater than that of the general population.10 In half of these patients, epilepsy onset is after diagnosis.3 Epilepsy is more common in APS secondary to SLE vs primary APS (13.7% vs 6%; P <.05).11 Evidence of a correlation between aPL positivity and seizure is inconclusive.10 Seizures and epilepsy in patients with APS are primarily attributable to vascular disease.6 In a cohort study of 538 patients with APS, the odds ratio for epilepsy was 4.05 (95% CI, 2.05-8.00) in those with a prior central nervous system thromboembolic event.11 Epilepsy was also associated with higher rates of thrombocytopenia, livedo reticularis, and autoimmune hemolytic anemia.11 Some patients with APS with epilepsy have normal brain MRI results,3 and in vitro studies have implicated interactions between autoantibodies and neural structures.6

    Seizures and Epilepsy

    Seizures and epilepsy (≥2 unprovoked seizures) are more common in patients with APS compared with the general population.6,10 Between 3% and 10% of patients with APS have seizures/epilepsy, a prevalence that is 10 times greater than that of the general population.10 In half of these patients, epilepsy onset is after diagnosis.3 Epilepsy is more common in APS secondary to SLE vs primary APS (13.7% vs 6%; P <.05).11 Evidence of a correlation between aPL positivity and seizure is inconclusive.10

    Seizures and epilepsy in patients with APS are primarily attributable to vascular disease.6 In a cohort study of 538 patients with APS, the odds ratio for epilepsy was 4.05 (95% CI, 2.05-8.00) in those with a prior central nervous system thromboembolic event.11 Epilepsy was also associated with higher rates of thrombocytopenia, livedo reticularis, and autoimmune hemolytic anemia.11 Some patients with APS with epilepsy have normal brain MRI results,3 and in vitro studies have implicated interactions between autoantibodies and neural structures.6

  • Movement disorders are rare in APS.10 The most common is chorea, which causes jerky involuntary movements and affects 1% to 5% of patients with APS.10 Movement disorders less frequently observed in patients with APS include dystonia, ballismus, dyskinesia, parkinsonism, cerebellar ataxia, tics, and tremor.3,10 Chorea is more prevalent in women with APS and is usually of mild to moderate severity.3 Chorea is more common in patients with SLE and is strongly correlated with aPL positivity.6,10 However, chorea has also been observed in patients with primary APS, especially children.6 Limited evidence is available regarding the mechanism of chorea in APS/aPL,10 although brain imaging has revealed white matter lesions and cerebral infarctions.3 In addition, aPLs may have neurotoxic effects on the basal ganglia, which are primarily responsible for motor control.6 Image Credit: ISM/SOVEREIGN

    Movement Disorders

    Movement disorders are rare in APS.10 The most common is chorea, which causes jerky involuntary movements and affects 1% to 5% of patients with APS.10 Movement disorders less frequently observed in patients with APS include dystonia, ballismus, dyskinesia, parkinsonism, cerebellar ataxia, tics, and tremor.3,10 Chorea is more prevalent in women with APS and is usually of mild to moderate severity.3 Chorea is more common in patients with SLE and is strongly correlated with aPL positivity.6,10 However, chorea has also been observed in patients with primary APS, especially children.6

    Limited evidence is available regarding the mechanism of chorea in APS/aPL,10 although brain imaging has revealed white matter lesions and cerebral infarctions.3 In addition, aPLs may have neurotoxic effects on the basal ganglia, which are primarily responsible for motor control.6

    Image Credit: ISM/SOVEREIGN

  • Multiple sclerosis (MS)-like symptoms will occur in a small number of patients with APS, including balance or motor issues, visual disturbances, and neurologic deficits.3,10 Symptoms relapse and remit, as in MS.3 The lack of definitive diagnostic tests for MS or for APS6 results in some patients with APS being misdiagnosed with MS.8 Both MS and APS are more prevalent in women of childbearing age, which complicates efforts to differentiate the disease states.12 In addition, 6% to 28% of patients with MS have aPLs, and aPLs alone are not definitive for APS.10,12 T2 hyperintense brain lesions also occur in both populations.3 Differences in MRI and clinical findings between MS and APS, however, can point to the right diagnosis. For example, brain lesions on MRI change over time in MS but not in APS, and white matter disease is more widespread in MS.12 Thrombosis, headache, epilepsy, pregnancy morbidity, livedo reticularis, thrombocytopenia, or hypocomplementemia implicate APS.3,12 In APS, MS-like syndrome may respond to anticoagulation therapy.12 Image Credit: Scott Camazine

    Multiple Sclerosis-Like Syndrome

    Multiple sclerosis (MS)-like symptoms will occur in a small number of patients with APS, including balance or motor issues, visual disturbances, and neurologic deficits.3,10 Symptoms relapse and remit, as in MS.3 The lack of definitive diagnostic tests for MS or for APS6 results in some patients with APS being misdiagnosed with MS.8 Both MS and APS are more prevalent in women of childbearing age, which complicates efforts to differentiate the disease states.12 In addition, 6% to 28% of patients with MS have aPLs, and aPLs alone are not definitive for APS.10,12 T2 hyperintense brain lesions also occur in both populations.3

    Differences in MRI and clinical findings between MS and APS, however, can point to the right diagnosis. For example, brain lesions on MRI change over time in MS but not in APS, and white matter disease is more widespread in MS.12 Thrombosis, headache, epilepsy, pregnancy morbidity, livedo reticularis, thrombocytopenia, or hypocomplementemia implicate APS.3,12 In APS, MS-like syndrome may respond to anticoagulation therapy.12

    Image Credit: Scott Camazine

  • The estimated prevalence of transverse myelitis (TM) in the APS population is 0.4% to 4%.3 TM is more common in secondary APS (especially in patients with SLE) compared with primary APS.6 The higher prevalence of TM in SLE likely correlates with aPL positivity instead of SLE activity.10 TM is characterized by acute inflammation of the spinal cord. Patients have sudden onset of sensory loss, motor deficits, weakness, and autonomic dysfunction that affects control of the bowel or bladder.3,6 The pathogenesis of TM in APS is unclear, but some researchers believe direct neuronal injury to the spinal cord from an aPL-initiated process is a more likely culprit than central nervous system vasculitis or thrombotic infarction of the spinal cord.6 Neuromyelitis optica spectrum disorder (NMOSD) also causes TM, and screening for aquaporin-4 immunoglobin G can help differentiate between NMOSD and APS.3 Intravenous methylprednisolone may be used to treat TM in patients with APS.6 Image Credit: M.I. Walker/Science Source

    Transverse Myelitis

    The estimated prevalence of transverse myelitis (TM) in the APS population is 0.4% to 4%.3 TM is more common in secondary APS (especially in patients with SLE) compared with primary APS.6 The higher prevalence of TM in SLE likely correlates with aPL positivity instead of SLE activity.10 TM is characterized by acute inflammation of the spinal cord. Patients have sudden onset of sensory loss, motor deficits, weakness, and autonomic dysfunction that affects control of the bowel or bladder.3,6

    The pathogenesis of TM in APS is unclear, but some researchers believe direct neuronal injury to the spinal cord from an aPL-initiated process is a more likely culprit than central nervous system vasculitis or thrombotic infarction of the spinal cord.6 Neuromyelitis optica spectrum disorder (NMOSD) also causes TM, and screening for aquaporin-4 immunoglobin G can help differentiate between NMOSD and APS.3 Intravenous methylprednisolone may be used to treat TM in patients with APS.6

    Image Credit: M.I. Walker/Science Source

  • The reported prevalence of ophthalmologic involvement in APS varies widely from 15% to 88%.13 Several ocular syndromes have been documented in patients with APS, of which amaurosis fugax is among the most common.3,6 Amaurosis fugax, a painless condition that causes temporary vision loss in one or both eyes, affects approximately 5% of patients with APS and is associated with cerebral ischemia.3 Optic neuropathy (ON) is less common, affecting 1% of patients with APS.3 It can be anterior or posterior (retrobulbar) and nonarteritic or arteritic. Anterior nonarteritic ischemic ON (NAION) is a thrombotic condition, whereas retrobulbar ON has thrombotic and inflammatory mechanisms.3 Both NAION and retrobulbar ON produce acute visual decline and unilateral color vision deficiency, but NAION typically causes papillary edema with linear hemorrhage.3 Mild ocular disorders, including conjunctivitis, telangiectasia, keratitis, dry eye, uveitis, and scleritis are also observed in patients with APS.6 Image Credit: Hercules Robinson

    Ocular Syndromes

    The reported prevalence of ophthalmologic involvement in APS varies widely from 15% to 88%.13 Several ocular syndromes have been documented in patients with APS, of which amaurosis fugax is among the most common.3,6 Amaurosis fugax, a painless condition that causes temporary vision loss in one or both eyes, affects approximately 5% of patients with APS and is associated with cerebral ischemia.3

    Optic neuropathy (ON) is less common, affecting 1% of patients with APS.3 It can be anterior or posterior (retrobulbar) and nonarteritic or arteritic. Anterior nonarteritic ischemic ON (NAION) is a thrombotic condition, whereas retrobulbar ON has thrombotic and inflammatory mechanisms.3 Both NAION and retrobulbar ON produce acute visual decline and unilateral color vision deficiency, but NAION typically causes papillary edema with linear hemorrhage.3 Mild ocular disorders, including conjunctivitis, telangiectasia, keratitis, dry eye, uveitis, and scleritis are also observed in patients with APS.6

    Image Credit: Hercules Robinson

  • Neuroimaging detects abnormalities in 35% to 90% of patients with APS and may be useful for assessing a patient’s risk for neurologic disease.3 Most neurologic characteristics observed in the brain of patients with APS are ischemic changes, including multifocal cerebral infarctions, white matter lesions, and cerebral atrophy.14 An estimated 22% to 46% of patients with APS have infarcts, 17% to 45% (with primary APS) have white-matter lesions, and 12% to 36% have cerebral atrophy on MRI.3 In a retrospective analysis of 16 Chinese people with APS and neurologic manifestations, infarcts were detected primarily in the basal ganglia and cerebral cortex.14 Neuroimaging also showed occlusions or stenosis affecting the anterior, middle, and posterior cerebral arteries and their respective branches. More advanced imaging techniques like diffusion tensor imaging may be able to detect brain abnormalities like white matter lesions earlier than MRI in patients with APS.3 Image Credit: ISM/SOVEREIGN

    Neuroimaging Abnormalities

    Neuroimaging detects abnormalities in 35% to 90% of patients with APS and may be useful for assessing a patient’s risk for neurologic disease.3 Most neurologic characteristics observed in the brain of patients with APS are ischemic changes, including multifocal cerebral infarctions, white matter lesions, and cerebral atrophy.14 An estimated 22% to 46% of patients with APS have infarcts, 17% to 45% (with primary APS) have white-matter lesions, and 12% to 36% have cerebral atrophy on MRI.3

    In a retrospective analysis of 16 Chinese people with APS and neurologic manifestations, infarcts were detected primarily in the basal ganglia and cerebral cortex.14 Neuroimaging also showed occlusions or stenosis affecting the anterior, middle, and posterior cerebral arteries and their respective branches. More advanced imaging techniques like diffusion tensor imaging may be able to detect brain abnormalities like white matter lesions earlier than MRI in patients with APS.3

    Image Credit: ISM/SOVEREIGN

  • Most neurologic manifestations of APS are managed with long-term anticoagulation therapy, which is standard treatment to reduce the risk for thrombotic events.3 There is a lack of consensus regarding the ideal thromboprophylaxis for patients with APS.3 Limited evidence is available for managing nonthrombotic neurologic manifestations of APS. Treatment varies according to the patient’s neurologic presentation, although anticoagulation and immunomodulation therapies appear to improve some neurologic manifestations.3 Developing an evidence-based strategy for managing the neurologic manifestations of APS will depend on well-conducted studies to determine the role of aPLs in their pathogenesis and on adequately populated trials of novel APS treatments, such as immunosuppressant or anticytokine therapies.6

    Management

    Most neurologic manifestations of APS are managed with long-term anticoagulation therapy, which is standard treatment to reduce the risk for thrombotic events.3 There is a lack of consensus regarding the ideal thromboprophylaxis for patients with APS.3

    Limited evidence is available for managing nonthrombotic neurologic manifestations of APS. Treatment varies according to the patient’s neurologic presentation, although anticoagulation and immunomodulation therapies appear to improve some neurologic manifestations.3 Developing an evidence-based strategy for managing the neurologic manifestations of APS will depend on well-conducted studies to determine the role of aPLs in their pathogenesis and on adequately populated trials of novel APS treatments, such as immunosuppressant or anticytokine therapies.6

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by vascular thrombosis or specific obstetric complications in individuals with persistent laboratory evidence of antiphospholipid antibodies (aPLs).1 The exact prevalence of APS is unknown but is estimated at 40 to 50 cases per 100,000 persons, whereas the estimated prevalence of aPL positivity in the general population is 1% to 5%.2 It is more common in women and in older adults.1 Approximately half of APS cases are primary, whereas most of the remaining cases occur secondary to another autoimmune rheumatic disease such as systemic lupus erythematosus (SLE).1

The aPLs implicated in APS are lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein-I, all of which promote a hypercoagulable state.1 APS can cause venous or arterial occlusions, often in multiple vessels at once.2 The predominant vascular event in patients with APS is deep vein thrombosis (usually in a lower extremity), followed by stroke, pulmonary embolism, and transient ischemic attack.1 The most frequent pregnancy morbidity is recurrent early miscarriage, followed by late fetal loss, premature birth, preeclampsia, and eclampsia.1,2 Pregnancy morbidity in APS appears to have thrombotic and nonthrombotic mechanisms.1

In addition to experiencing cerebrovascular accidents resulting from thrombotic mechanisms, many patients with APS develop neurologic disorders that appear to have a nonthrombotic pathogenesis.3,4 Common nonthrombotic neurologic manifestations of APS are chronic headache or migraine, seizures, movement disorders, a multiple sclerosis (MS)-like syndrome, transverse myelitis (TM), visual disturbances, and cognitive dysfunction (CD).3 Despite the association of these disorders with APS, they are not part of the condition’s clinical diagnostic criteria. However, some neurologic manifestations of APS are manageable, and it is important that clinicians and patients be aware of them.

Slideshow compiled by Christin Melton, ELS

References

    1. Clark KEN, Giles I. Antiphospholipid syndrome. Medicine. 2018;46(2):118-125.

    2. Cervera D. Antiphospholipid syndrome. Thromb Res. 2017;151(Suppl 1):S43-S47.

    3. Ricarte IF, Dutra LA, Abrantes FF, et al. Neurologic manifestations of antiphospholipid syndrome. Lupus. 2018;27(9):1404-1414.

    4. Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med. 2017;17:257-267.

    5. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicenter prospective study of 1000 patients. Ann Rheum Dis. 2015;74(6):1011-1018.

    6. Rodrigues CEM, Carvalho JF, Shoenfeld Y. Neurological manifestations of antiphospholipid syndrome. Eur J Clin Invest. 2010;40(4):350-359.

    7. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med. 2006;166(20):2278-2284.

    8. Hughes GRV. Migraine, memory loss, and “multiple sclerosis.” Neurological features of the antiphospolipid (Hughes’) syndrome. Postgrad Med J. 2003;78(928):81-83.

    9. Cavestro C, Micca G, Molinari F, et al. Migraineurs show a high prevalence of antiphospholipid antibodies. J Thromb Haemost. 2011;9(7)1350-1354.

    10. Yelnik CM, Appenzeller S, Sanna G, Kozora E, Bertolaccini ML. Neuropsychiatric manifestations of antiphospholipid syndrome. In: Erkan D, Locksin MD, eds. Antiphospholipid Syndrome: Current Research Highlights and Clinical Insights. Cham, Switzerland: Springer International Publishing; 2017:201-222.

    11. Shoenfeld Y, Lev S, Blatt I, et al. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol. 2004;31(7):1344-1348.

    12. Uthman I, Noureldine MHA, Berjawi A, et al. Hughes syndrome and multiple sclerosis. Lupus. 2015;24(2):115-121.

    13. Sanna G, D’Cruz D, Cuadrado MJ. Cerebral manifestations in the antiphospholipid (Hughes) syndrome. Rheum Dis Clin North Am. 2006;32(3):465-490.

    14. Zhu DS, Fu J, Zhang Y, et al. Neurological antiphospholipid syndrome: clinical, neuroimaging, and pathological characteristics. J Neurol Sci. 2014;346(1-2):138-144.

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