Clinical: Hughes' syndrome

Hughes' syndrome is very common but significantly under-recognised, says Professer Graham Hughes.

Do you have patients with migraine, recurrent miscarriages, DVT, early strokes or MI?

These are all features of Hughes syndrome, a potentially treatable autoimmune disorder, more commonly known as antiphospholipid syndrome (APS), or 'sticky blood'.

Despite being a 'new' disease (first described in detail 25 years ago), Hughes' syndrome is common; there are doubtless numerous cases of this preventable condition in every general practice. There are, at present, few prevalence data available.

In obstetrics, Hughes' syndrome is now recognised as the most common treatable cause of recurrent pregnancy loss, and has been described as one of the major advances in obstetrics in the late 20th century.

The circulatory problems seem to have a particular impact on the brain, resulting in migraine, memory loss and stroke. However, clotting and 'sludging' of the blood can affect any organ, some clinical features being listed below.

A large literature on Hughes' syndrome is now available.

Clinical features
There is a tendency to thrombosis. Critically, and clinically almost uniquely, the thromboses can involve arteries (including stroke and MI), as well as veins.

MRI scan of a leg vein by a thrombus (Photograph: James King-Holmes/ SPL)

In pregnancy, 'sticky blood' can impair the circulation to the fetus, resulting in a tendency to miscarriage.

For some conditions, Hughes' syndrome is thought to be implicated in around one in five cases (see below).

Hughes' syndrome

In the following conditions one in five cases are thought to be associated with Hughes' syndrome:

  • DVT
  • Recurrent miscarriage
  • Young (under 45) stroke
  • MI in young females

Testing for Hughes' syndrome is based on simple blood tests to detect the causative antiphospholipid antibodies (aPL) (see below).

Symptoms
Patients with Hughes' syndrome are at greater risk of:
  •  Migraine
  • Memory loss
  • Balance problems
  • Recurrent leg ulcers
  • Idiopathic teenage epilepsy
  • DVT
  • Arterial thrombosis, leading to MI and stroke, headache and neurological problems
  • Heart valve disease
  • Livedo reticularis
  • Recurrent pregnancy loss

Aetiology
Despite the extraordinarily strong link between aPL and thrombosis, the causes of the clotting tendency are unclear. Actions on the blood vessel endothelium, on clotting proteins and on platelet membranes are all described. Counter-intuitively, low platelet counts are an occasional feature of Hughes' syndrome.

Epidemiologically, trigger factors for increased thrombosis risk in Hughes' syndrome include the oral contraceptive pill, smoking, and possibly even diet and lifestyle habits.

Obstetrics
Although the mechanisms behind recurrent miscarriage are still being researched, progressive clotting of the placenta is the most likely process - as evidenced by the striking improvement in pregnancy success rates since the introduction of screening for Hughes' syndrome and the subsequent use of aspirin or heparin.

Critically, the pregnancy loss can be late, and any woman with late fetal death should be screened for aPL.

Neurology
One of the most common manifestations of Hughes' syndrome is headache - often migrainous. I have suggested that the syndrome may prove to be the suspected link between migraine and stroke, although the mechanism behind migraine in these patients is not known.

As well as stroke and TIA, other symptoms include memory loss, chorea (and other movement disorders) and epilepsy. Some cases are misdiagnosed as multiple sclerosis.

Cardiovascular system
Coronary artery thrombosis is well recognised - and it has been reported that up to one in five of all coronaries in females under 35 are due to Hughes' syndrome.1 Other cardiac and pulmonary complications include cardiac syndrome X, heart valve disease and pulmonary hypertension.

A number of vascular stenotic lesions are described, and there are suggestions that aPL are implicated in accelerated atheroma, possibly through their cross-reactivity with oxidised low density lipoproteins.

Both venous and arterial thrombosis can affect any organ, including the kidney (including renal artery stenosis and hypertension), liver (including Budd-Chiari syndrome), adrenals, skin (including chronic skin ulceration and livedo reticularis) and bone (leading to idiopathic bone fracture).

Livedo reticularis (Photograph: Dr Marazzi/SP:)

Diagnosis
The key test is for the presence of circulating aPL.

In clinical practice, tick two boxes: anticardiolipin antibodies (aCL) and lupus anticoagulant (LA). This is unfortunately necessary because some patients with Hughes' syndrome are positive for one test only. The blood tests are inexpensive and relatively simple, and are carried out by most laboratories.

Predictions

1. That the syndrome will become a major chapter in neurology.

2. That Hughes' syndrome patients on warfarin will be more commonly advised to 'self-test' their INR, in addition to attending anticoagulant clinics. Fluctuations in INR appear to be more prominent in Hughes' syndrome patients.

3. That Hughes' syndrome will be found to be an important link between migraine and stroke.

4. That aPL testing will be routine in pregnancy - in all pregnancies (certainly in any woman with miscarriage), not just in those women with more than two miscarriages.

5. That aPL testing will become routine in younger patients with stroke or heart attack, with DVT, and in the routine work-up of complex neurology patients.

6. That future treatments may include selective (targeted) immunosuppression and new oral anticoagulants.

7. That Hughes' syndrome will become recognised by all physicians as a common, important and potentially preventable illness.

Treatment
Treatment is largely limited to preventing thrombosis - with low dosage aspirin, heparin or warfarin.

Not surprisingly, the best data come from the pregnancy clinic, where, since the routine testing for aPL and treatment with aspirin and/or heparin, the pregnancy success has improved from a dreadful 15 per cent to over 90 per cent.

As well as prophylaxis, anticoagulation has provided other interesting observations in Hughes' syndrome. These include the sometimes instant cessation of migraine attacks, and the marked improvement in cognitive function seen on starting anticoagulation.

To date, attempts at suppressing the antibody production have been largely unsuccessful though anecdotal reports of success with the anti-B cell drug rituximab are appearing.

  • Professor Hughes is head of the London Lupus Centre at London Bridge Hospital

References

1. Khamashta M A. Hughes Syndrome - The antiphospholipid syndrome (2nd edition). Guildford: Springer, 2007.

Further reading

  • Hughes G R V. Understanding Hughes' syndrome. Case studies for patients. Guildford: Springer, 2009.
  • Hughes G R. Migraine, memory loss, and "multiple sclerosis". Neurological features of the antiphospholipid (Hughes') syndrome. Postgrad Med J 2003; 79(928): 81-3.
  • Hughes G. Hughes' syndrome. The antiphospholipid syndrome - A clinical overview. Clin Rev Allergy Immunol 2007; 32(1): 3-12.

Have you registered with us yet?

Register now to enjoy more articles and free email bulletins

Register

Already registered?

Sign in

Follow Us: