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REVIEW , memory loss, and “”. Neurological features of the antiphospholipid (Hughes’) syndrome G R V Hughes ......

Postgrad Med J 2003;79:81–83 The antiphospholipid syndrome (APS, Hughes’ away the commonest symptom reported was syndrome), first described in 1983, is a prothrombotic : not evidence based medicine perhaps, but a pointer to the importance of this disease in which neurological events feature symptom.5 prominently. , transient ischaemic attacks, and The history is remarkably similar in many (including migraine) are important patients with teenage headaches that are fre- quently migrainous—often premenstrual—often complications. However, it is clear that other disappearing for 10–20 years only to return in the neurological symptoms, including diplopia, memory 30s or 40s. There is, significantly, a strong family loss, ataxia, and “multiple sclerosis-like” features are history of headaches or of migraine in many of our patients, pointing to genetic influences. In common. A notable feature of Hughes’ syndrome is the some patients the headaches are accompanied by clinical response to anticoagulants; features such as visual or speech disturbance, or by transient headache and memory loss often improving ischaemic attacks. It is my view that antiphospholipid antibody dramatically with appropriate warfarin dosage. APS testing should be among the armamentarium of may well become recognised as an important (and those investigating migraine or recurrent potentially treatable) cause of neurological disease. headache.6 ...... Memory loss All those dealing with large numbers of patients t is now recognised that antiphospholipid with the syndrome recognise memory loss as syndrome (APS) is a major neurological possibly the most important feature. Unfortu- disease.1 The syndrome, first described in 1983, I nately, as yet, there have been few formal psycho- is characterised by recurrent thrombosis (both metric studies of these patients—for example, venous and arterial), recurrent miscarriage, before and after anticoagulation treatment is neurological disease, including , and the started. presence of circulating antibodies against In some patients, the disease, if untreated, phospholipids.2 progresses to widespread infarction, grossly Our early studies focused on lupus, but we rec- abnormal magnetic resonance images and, ulti- ognised that the syndrome was just as prevalent mately, multi-infarct . outside lupus and called this syndrome the In the majority of patients, the memory loss is antiphospholipid syndrome. The title is not strictly correct—the antibodies are in fact di- less extreme—though sufficiently frightening for the patient to worry about the possibility of rected against phospholipids and proteins. 7 The syndrome is now recognised as a common Alzheimer’s disease. It is this aspect of the and important prothrombotic condition with syndrome which—like headaches—often im- ramifications into almost all spheres of medicine, proves when anticoagulation is started. surgery, and obstetrics. While our earliest descriptions highlighted the neurological aspects of the syndrome (strokes, are a feature of APS: indeed in a patient , , headaches, memory loss, and with lupus presenting with seizures, APS is the dementia),34 the full impact of the syndrome on most likely underlying pathology—an observa- is now becoming more widely recog- tion with therapeutic implications. nised. All ages are affected, and all forms of epilepsy ...... are seen, as are subclinical (abnormal electroen- CLINICAL FEATURES cephalogram) forms. The association of anti- Correspondence to: This short review addresses these phospholipid antibody with epilepsy, first re- Dr Graham Hughes, Lupus features, their pathogenesis, and their manage- ported in 1985,8 may be of significant importance Unit, St Thomas’ Hospital, 9 London SE1 7EH; ment. in the investigation of seizures in general. [email protected] Headache and migraine Submitted 29 July 2002 Recently, we set up a patients’ website on APS Accepted ...... 30 October 2002 (www.hughes-syndrome.org). In the first week of Abbreviations: APS, antiphospholipid syndrome; INR, ...... operation we received over 20 000 hits. Far and international normalised ratio

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most significantly of all, in the majority of the patients A typical scenario ultimately correctly diagnosed and appropriately anticoagu- lated, there were no further neurological events. A 39 year old woman complained of headaches, , Clearly, there will be many similar studies to come. and memory loss. She was concerned about a possible However, it seems probable that a small percent of patients diagnosis of Alzheimer’s disease. diagnosed with multiple sclerosis do in fact have Hughes’ syn- Two years earlier, she had suffered from similar drome, a condition with totally different treatment and prog- headaches, associated with gait disturbance and ataxia. nosis. She had been investigated for multiple sclerosis but brain magnetic resonance imaging had been normal. Chorea Her past history included a strong teenage tendency to Our original studies in 1983 included chorea. Although rare, headaches, often migrainous. this feature has been strongly associated with the presence of In her 20s she had been investigated for infertility, but antiphospholipid antibodies—indeed, the combination in on two occasions had conceived only to suffer a some APS patients of joint , heart murmurs and chorea miscarriage at three months. At the age of 35 she had a has led, not unexpectedly, to a label of “rheumatic ”. successful . Although the precise pathophysiology of the chorea is unclear, In view of the possible diagnosis of APS (Hughes’ syn- an interesting clinical observation has been made that in a drome), blood tests for antiphospholipid antibodies were small number of patients, the chorea has ceased with the ordered and found to be strongly positive. institution of anticoagulants. She was treated initially with 75 mg daily, with moderate though incomplete resolution of the headaches. Neuropathy Ultimately, in view of the known prothrombotic nature of Possibly one of the more surprising findings has been the APS, and especially its neurological and obstetric sequlae, association in some patients between antiphospholipid the patient was anticoagulated with warfarin. antibodies and neuropathy, both peripheral and cranial. In Not only did this treatment result in disappearance of the classical lupus, peripheral neuropathy is relatively uncommon, headaches, but the patient noted a marked improvement in and larger numbers will be required before this possible memory. Interestingly, these two major symptoms returned association can be confirmed. whenever the international normalised ratio (INR) fell below 2.5. Behavioural disorders A number of cases of frontal lobe ischaemia, with its attendant behavioural disorder, have been seen (this author was referred Stroke one 3 year old boy with an aggressive behavioural disorder The commonest serious complication of APS is stroke. Indeed, found to be associated with multiple cerebral infarcts). To date the syndrome is becoming recognised as a major, and there have been surprisingly few studies detailing the potentially preventable, cause of stroke. It has been estimated neuropsychiatric manifestations of APS. that up to one in five of all young (under 45) strokes are asso- ciated with Hughes’ syndrome, although all ages can be Treatment affected. The clinical spectrum ranges from transient ischae- Anticoagulation is required. Current experience shows that mic attacks and focal lesions—such as —to antiphospholipid antibodies constitute a significant risk for widespread cerebral infarction, ataxia, bladder, and gait thrombosis, including stroke. For example, in our clinic, in a disturbance and—in extreme cases—multi-infarct dementia. 10 year retrospective analysis, no fewer than 50% of those More than anything else, it is this propensity to (arterial) individuals (mainly lupus patients or women with recurrent stroke which marks out Hughes’ syndrome from the other less miscarriage) with positive antibodies in 1985 had developed serious coagulopathies such as factor V Leiden deficiency. thrombosis by 1995.12 A more difficult decision is whether to use aspirin alone or Myelopathy to anticoagulate with warfarin. Most data currently available Transverse myelopathy is a rare but well recognised feature of point to the superiority of warfarin if there has been clear cut APS. It is sometimes associated with optic ischaemia cerebral ischaemia. (Devic’s disease). The pathology of the myelopathy is poorly Khamashta et al analysed APS patients over a 10 year understood. However, some interesting observations have period.13 Of those treated with aspirin alone, over half come from the mouse model of APS. Some of these animals developed further thrombosis. Likewise, in those treated with which develop an APS-like disease became paraplegic. Histol- warfarin to an INR of less than 3, one half developed further ogy of the in these animals showed vessel thrombosis. Only in those maintained at an INR of 3 or over thrombosis.10 These observations might be taken to support was there a significant 10 year benefit. the suggestion that anticoagulation may have to be considered Our study had two possible weaknesses. Firstly, it was in addition to the more conventional steroid and immunosup- retrospective. Secondly, it was directed mainly to patients with pressive regimens generally given to some lupus patients with arterial rather than —it could be argued myelopathy, for example. that subsets of patients with venous thrombosis alone might require less aggressive anticoagulation. Multiple sclerosis One point, however, is clear. The danger of thrombosis and Not surprisingly, a number of patients with APS have carried stroke in these patients far outweighs the risks of anticoagu- a working diagnosis of “multiple sclerosis”. In a recent study lant induced bleeding. The traditional fear of cerebral from our unit, 28 APS patients were reviewed in whom an haemorrhage has, almost certainly, resulted in the under- original diagnosis of multiple sclerosis had been made.11 treatment of many patients with APS. Some interesting lessons were learnt. Firstly, differential Finally, what of the “non-thrombotic” neurological fea- diagnosis was difficult—in this particular study the magnetic tures? What of the patient with severe, recurrent headaches resonance imaging did not clearly distinguish the two condi- who has antiphospholipid antibodies but who has not had a tions. Secondly, with hindsight, there had been clues to the previous thrombosis. It is a common observation that warfarin underlying diagnosis, notably recurrent headaches, previous treatment when finally given (for example, for a deep vein thrombosis, or recurrent miscarriage. Thirdly, and perhaps thrombosis) results in dramatic improvement in headache.

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Recently, we have introduced a “” of heparin in between APS and multiple sclerosis are recognised but require this situation. A two week trial of self administered heparin further validation. In any event the diagnosis of this (for example, Fragmin 5000 units daily) is both safe, and, in prothrombotic condition, and its response to anticoagulation, our preliminary studies, has provided a clear indication (for has major therapeutic and economic implications. example, immediate disappearance of the headaches) as to Up to one in five of all strokes in the under 45 year olds are whether anticoagulation might be suitable.514We are involved associated with APS and are potentially preventable. The eco- in a prospective controlled trial of this treatment in APS asso- nomic cost of strokes per annum in the UK has been estimated ciated headache and migraine. at £2.3 billion and in the USA at £23 billion. More frequent and earlier diagnosis of APS and precise anticoagulant RESEARCH AND SPECULATION could have an impact on these costs, both economic and Epidemiology human. APS (Hughes’ syndrome) may well prove to be a much more common neurological diagnosis than hitherto realised. Multi- ACKNOWLEDGEMENT centre studies are now in progress in migraine, multiple scle- This review is based on a lecture given at the 6th European rosis, memory loss, epilepsy, and stroke clinics. The observa- Lupus Congress, May 2002. tion that some patients have strong family histories of APS features (especially migraine) suggests that genetic studies REFERENCES should broaden the clinical spectrum beyond “classical” cases. 1 Narvarreta MG, Boey RL, Levine SR. Cerebral disease in the antiphospholipid syndrome. In: Khamashta MA, ed. Hughes syndrome: Why the brain? antiphospholipid syndrome. London: Springer-Verlag, 2000: 43–58. The 20 year experience of the syndrome has shown that the 2 Hughes GRV. Thrombosis, abortion, cerebral disease and the lupus anticoagulant.BMJ1983;287:1088–9. appears to be particularly at risk. The 3 Khamasha MA. Hughes syndrome: history. In: Khamashta MA, ed. reasons (if this observation proves correct) are uncertain. Hughes syndrome: antiphospholipid syndrome. London: Springer-Verlag, However, interactions between brain and clotting processes 2000: 3–7. 4 Harris EN, Gharavi AE, Asherson RA, et al. Cerebral infarction in have a long history. systeic lupus. Association with anticardiolipin antibodies. Clin Exp The coagulation mechanism within the central nervous Rheumatol 1984;2:47–51. system has clear differences from that found in other organs. 5 Cuadrado MJ, Khamashta MA, Hughes GRV. Sticky blood and headache. Lupus 2001;10:392–3. For example, the brain endothelium expresses little thrombo- 6 Cuadrado MJ, Khamashta MA, Hughes GRV. Migraine and stroke in modulin, unlike other endothelial surfaces. While some young women. QJMed2002;93:317–19. experimental work has suggested that antiphospholipid anti- 7 Hughes GRV. Off the beaten track: a clinician’s view. In: Khamashta MA, ed. Hughes syndrome: the antiphospholipid syndrome. London: bodies may have direct antineuronal ties, at the present time, Springer-Verlag, 2000:105–10. the available evidence suggests that the major underlying 8 Mackworth-Young CG, Hughes GRV. Epilepsy: an early symptom of mechanism in the cerebral features of Hughes’ syndrome is SLE. J Neurol Neurosurg Psychiatry 1985;48:185. either vascular thrombosis or sludging. 9 Peltola JT, Haapala A, Isojarvi JI, et al. Antiphospholipid and antinuclear antibodies in patients with epilepsy or new-onset disorders. AmJMed2000;109:712–17. Future trends 10 Blank M, Krause I, Shoenfeld Y.The contribution of experimental models As imaging techniques improve, so presumably will the diag- to our understanding of etiology, pathogenesis and novel in the nostic yield. Conventional magnetic resonance imaging may antiphospholipid syndrome. In: Khamashta MA, ed. Hughes syndrome: antiphospholipid syndrome. London: Springer-Verlag, 2000:379–90. be normal in some cases of classical APS (as in the case 11 Cuadrado MJ, Khamashta MA, Ballesteros A, et al. Can Hughes presented at the beginning of this review). (antiphospholipid) syndrome be distinguished from multiple sclerosis? The standard blood tests—anticardiolipin and lupus Analysis of 27 patients and review of the literature. Medicine (Baltimore) 2002;79:57–68. anticoagulant—are reasonably standardised internationally, 12 Shah MN, Khamashta MA, Atsumi T, et al. Outcome of patients with but do have limitations. To date, the addition of other tests anticardiolipin antibodies: a ten year follow-up of 52 patients. Lupus such as IgA anticardiolipin, anti-β2 GP1, antiprothrombin, 1998;7:3–6. 13 Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of and antiphosphatidyl serine, for example, have not added thrombosis in the antiphospholipid antibody syndrome. N Engl J Med much in the way of further clinical definition.15 1995;332:993–7. 14 Cuadrado MJ, Khamashta MA, D’Cruz D, et al. Migraine in Hughes Health economics syndrome—heparin as a therapeutic trial. Q J Med 2001;94:114–15. 15 Bertolaccini ML, Atsumi T, Escudero A, et al. The value of IgA The links between APS and stroke, migraine, and epilepsy are antiphospholipid testing for the diagnosis of antiphospholipid (Hughes) well established. The links between APS and memory loss and syndrome in SLE. J Rheumatol 2001;28:2637–43.

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