Neurologic Manifestations of Hughes Syndrome
Features of Hughes Syndrome
<p>Hughes syndrome is a primary immune disorder, or a disorder that is secondary to connective tissue disease such as systemic lupus erythematosus (SLE), in which circulating levels of antiphospholipid (APL) antibodies accumulate. The reported incidence is 5/100,000 persons yearly, with an estimated prevalence of 40-50/100,000 persons.<sup>2,3</sup></p> <p>The main symptoms include thrombosis (venous or arterial), multiple pregnancy losses, and moderate thrombocytopenia.<sup>1-3</sup> In its most severe form (catastrophic APS), thrombosis becomes resistant to anticoagulant therapy, leading to multiorgan failure.<sup>1-3</sup> Mortality and morbidity in APS are significant.<sup>2</sup></p>
Neurologic Features Associated With APS
<p>Common symptoms of APS include cardiovascular disease, epilepsy, headache, cognitive dysfunction and dementia, movement disorders, multiple sclerosis, and neuropsychiatric disorders. Uncommon symptoms include transverse myelitis, idiopathic intracranial hypertension, sensorineural hearing loss, Guillain-Barré syndrome, transient global amnesia, and ocular syndromes.<sup>4,5 </sup></p>
<p>Multiple types of cerebrovascular events are associated with both primary and secondary APS.<sup>5</sup></p> <p>After arterial thrombosis, strokes (cerebrovascular accidents) and transient ischemic attacks (TIAs) are the second most frequent neurological events in APS. Recurrent strokes and/or TIAs can lead to other neurological manifestations, including dementia, and may be directly related to headache. Other rare cerebrovascular manifestations include acute ischemic encephalopathy and cerebral venous thrombosis.</p>
<p>A stroke is the most frequent neurologic complication of APS, and produces the most serious consequences.<sup>4</sup> They can occur in any vascular region of the brain, and women are more likely to be affected than men. Patients who are APL-positive also tend to be younger compared with other patients with stroke who are APL-negative, with at least 20% of these strokes occurring in people <45 years. People who have APS secondary to SLE may be at higher risk for stroke.<sup>6</sup> The risk for recurrence in primary APS may be higher, but this is not well established.<sup>4,5</sup></p>
<p>The prevalence of epilepsy, estimated at 7.0% to 8.6%, appears to be increased in patients with SLE who are APL-positive compared with those who are not.<sup>4</sup> In particular, the presence of the immunoglobulin G (IgG) anticardiolipin antibodies isotope is most associated with seizures (compared with the IgM isotope), and moderate to high titers are more predictive of epilepsy than lower titres.<sup>5,7</sup></p> <p>The use of antiepileptic drugs may increase the presence of antibodies associated with APL, although the mechanisms have not been clarified, as IgM antibodies are more often found.<sup>4,5</sup> Thromboembolic events were shown in a study of 538patients to increase the risk for seizures by a rate of 4 to 1.<sup>8</sup></p>
<p>Although the origins are not yet clear, headache is a common event in APS, with multiple presentations from migraine to chronic daily headache. The true prevalence of migraine in APS is hard to capture, as research suggests overlaps with the general population, where migraine is also common. The types of headaches are also not clearly defined across studies. Headaches reported as migraines may actually be associated with TIAs or cerebrovascular accidents.<sup>5</sup> Migraine in APS may be particularly refractory to treatment, with headaches persisting for months or years, especially where APS has remained undetected.<sup>4</sup></p>
Cognitive Impairment and Dementia
<p>Cognitive dysfunction is widespread in patients with APS, with estimated prevalence rates of 42% or higher.<sup>4</sup> The most common symptoms include memory impairment and a lack of concentration and focus, which may signify further neurological involvement. Changes to cognitive function often increase over time as part of a preclinical pattern of APS, with high frequency of infarcts in the cortical, subcortical, and basal ganglia regions of the brain, although this is controversial.<sup>4</sup></p> <p>Signs of dementia are more difficult to assess, as some studies report a low frequency (0%-6%), whereas others report a much greater prevalence (56%) as a result of much broader definitions. Dementia in APS is believed to occur in a similar manner to the general population, resulting directly from multiple small vessel infarctions.<sup>4</sup></p>
<p>Although relatively rare in occurrence, movement disorders are strongly associated with APS. Chorea is the most frequently observed, with a prevalence ranging from 1.3% to 4.5%.<sup>4</sup> Other movement disorders can also occur, including ballismus, dyskinesia, cerebellar ataxia, and parkinsonism.</p> <p>The majority of patients who develop APL-related chorea are young and female, and have primary APS or APS secondary to SLE. The use of oral contraception or pregnancy may trigger chorea in some patients,<sup>4,5</sup> the symptoms of which may evolve slowly over weeks or longer, usually isolated to 1 side of the body. Often there is only 1 attack, which may precede other neurologic symptoms.<sup>5</sup> Chorea associated with APS is generally treated symptomatically with dopamine receptor agonists and immunosuppressive therapies such as corticosteroids and cyclophosphamide.<sup>4</sup></p>
<p>It is difficult to distinguish between idiopathic multiple sclerosis and that which is directly associated with APS, as testing is not specific to either.<sup>4</sup> APS may be associated with the presence of MS-type lesions on MRI, including those indicating ischemic optic neuritis (commonly seen in up to 30% of APL-positive patients) and transverse myelitis (a rare event, reported in <1% of patients with SLE). Treatment with corticosteroids or cyclophosphamides is often effective, and may be combined with anticoagulant therapies.<sup>4</sup></p>
<p>Psychotic disorders including chronic schizophrenia, hallucinations, delusions, and bipolar disorder, as well as obsessive-compulsive disorder, have been tied to the presence of APL. It is believed that psychosis in APS may be the result of chronic antipsychotic treatments that have been linked to increased production of IgG anticardiolipin antibodies. The highest risks to psychosis in APS are in those patients who are older, and who have a previous history of cerebral ischemic attacks or being triple-antibody-positive to APL, anti-beta-2-glycoprotein, and lupus anticoagulant factor.<sup>4</sup></p>
Central nervous system and neurologic involvement are common features of antiphospholipid (APS) syndrome, also known as Hughes syndrome, with a range of presentations that carry high morbidity and mortality.1,2
Compiled by Linda Peckel
- Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013:675-680.
- Gómez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun. 2014;48-49:20-25.
- Cervera R. Antiphospholipid syndrome. Thromb Res. 2017;151:S43-S47.
- Graf J. Central nervous system manifestations of antiphospholipid syndrome. Rheum Dis Clin North Am. 2017;43:547-560.
- Sanna G, Bertolaccini ML, Cuadrado MJ, Khamashta MA, Hughes GR. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford). 2003;42:200-213.
- de Amorim LCD, Maia FM, Rodrigues CEM. Stroke in systemic lupus erythematosus and antiphospholipid syndrome: risk factors, clinical manifestations, neuroimaging, and treatment. Lupus. 2017;26:529-536.
- Herranz MT, Rivier G, Khamashta MA, Blaser KU, Hughes GRV. Association between antiphospholipidantibodies and epilepsy in patients with systemic lupus erythematosus. Arthritis Rheum. 1994;37:568-571.
- Shoenfeld Y, Lev S, Blatt I, et al. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol. 2004;31:1344-1348.
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