Heparin, antiphospholipid antibodies and the brain

Abstract

One of the most striking observations in the clinical world of antiphospholipid syndrome (APS) is the dramatic and almost immediate improvement seen in many patients with neurological features such as headache, balance problems and memory loss, following the institution of low molecular weight (LMW) heparin treatment. From the earliest clinical descriptions of the syndrome, neurological involvement has been recognized as a common – indeed a central – feature. It was also noted that with anticoagulation treatment, many of those symptoms and signs, some of which had been present for months (for example chorea) or even years (epilepsy), rapidly improved. One of the problems facing clinicians dealing with APS patients is the limitation of treatment choices. Aspirin yes – but then what? Warfarin (Coumadin) poses a grave medical (and social) decision in a patient with worsening headache and concerns about stroke, yet with no previous thrombosis. Some lessons have been learnt from the management of APS in pregnancy. Those women on warfarin, usually changed to LMW heparin at the onset of pregnancy, are often free of cerebral symptoms for the whole eight to nine months of their pregnancy (and some assert that they are even better on LMW heparin than warfarin). Some years ago, in the absence of any more scientific guidance, we introduced a ‘heparin therapeutic trial’ for patients with increasing clinical APS problems despite anti-platelet therapy. This involved a two to three week course of LMW heparin (dalteparin/enoxaparin) with a clinical outcome defined by the patient. Placebo effects, certainly. But very often a decisive response. Such observations again focus on the pathogenesis and management of APS. Antibody mediated, undoubtedly, but is the brain pathology thrombotic, direct anti-neuronal attack, or predominantly vascular ‘sludging’? The rapid improvement in cognitive function, or in migraine severity when heparin is introduced, or on warfarin when the INR is carefully maintained at a higher level (e.g. 3.5–4) suggests that improvement in blood flow is important, though radiological and isotopic supporting evidence of this is scanty. At the present time, stroke and transverse myelitis are the two most feared neurological sequelae of antiphospholipid antibody (aPL) positivity – so much so that it remains an unfortunate fact that aPL testing is not yet routine in stroke screening. However, other non-stroke neurological features of APS are now widely recognized – balance problems, multiple sclerosis-like syndrome, deafness, anosmia, sleep disturbance. And, most prominent of all, memory loss There is little doubt that APS will become an important chapter in the broader field of neurology. Are there lessons for lupus? In lupus patients, many attempts have, over the years, been made to link particular antibodies to brain involvement – lymphocytotoxic antibodies, anti-NR2 and anti-ribosomal-P, for example. Most have proved disappointing as major diagnostic candidates. The link between brain pathology and aPL, however, appears to be more substantial, both in APS as well as in lupus. In a recent Italian multi-centre study of 959 lupus patients, the two items in the survey with the strongest link to neuropsychiatric involvement were anticardiolipin antibodies (p> 0.001) and lupus anticoagulant (p> 0.001). Thirty years ago, the pathogenesis of many nonfocal neuropsychiatric disorders in lupus was considered to involve both vascular and immune mechanisms. Much the same today. Correspondence to: GRV Hughes, London Lupus Centre, London Bridge Hospital, London SE1 2PR, UK Email: graham.hughes@hcaconsultant.co.uk Received 18 May 2012; accepted 21 May 2012