Neurological and Neuroendocrine‐Cytokine Inter‐relationship in the Antiphospholipid Syndrome

Abstract

Although many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in the disease. We presently review clinical data obtained from large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white-matter disease, and behavioral changes in APS, or linked-to-laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with beta(2)-glycoprotein1, a central autoantigen in APS, which induces persistent high levels of aPLs. These mice develop hyperactive behavior after a period of four months, as well as deficits in learning and memory, and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. We have developed another model, in which IgGs from APS patients induce depolarization of brain synaptoneurosomes, and which may serve as a model for the pathogenesis of epilepsy in APS. Hormonal changes are another potential CNS manifestation of APS and this may be potentially linked to the systemic and central effects of cytokines such as interleukin-3. Better understanding of the link between APS and neurological or neuroendocrine manifestations other than stroke will reveal whether they can be used as clinical criteria for the diagnosis of APS and, it is hoped, lead to better treatment.

Neonatal Lupus Erythematosus

“…The known connection between autoantibodies, in the setting of SLE, Sjögren syndrome, and APL syndrome, with adult human CNS diseases like CNS vasculitis, white matter lesions, chorea, seizures, and cognitive dysfunction supports the association between neonatal CNS injury and maternal autoantibodies. Additionally, animal studies show that APL, anti-SSA/Ro, and antidsDNA antibodies mediate neurologic dysfunction, potentiate seizures, and lead to excitotoxic injury to the animal brain [67][68][69][70][71][72][73].…”

A Patient With Bipolar Disorder and Antiphospholipid Syndrome

“…Direct effects of aPLs are another group of mechanisms for a possible causal association between APS-related markers and bipolar disorder. Chapman and Shoenfeld 14 observed that mice immunized with β2-glycoprotein 1, an autoantigen in APS, developed hyperactivity and anxiety behavior after 4 months of having elevated levels of aPL IgG; hyperactivity and anxiety are the clinical features that can be associated with bipolar disorder. Also, Chapman et al 15 demonstrated that aPLs directly depolarized purified rat brain stem synaptoneurosomes.…”

Neonatal effects of maternal antiphospholipid syndrome

“…In animal studies, the intrathecal injection of aPL induces neurologic dysfunction [40][41][42]. The association between aPL and adult human CNS disease, including CNS vasculitis, periventricular and diffuse white matter lesions, and cognitive dysfunction, has been described [43•].…”