Mainpage

Stroke and Collagen Vascular Disease

There are several collagen vascular disorders which have been implicated in the aetiology of stroke. The incidence of stroke arising as a consequence of these conditions is comparatively small when compared to atherosclerosis and cardioembolism, however, this is no reason to neglect gaining an understanding of these conditions. Through describing some of the relevant pathology and clinical medicine involved, this piece aims to improve the understanding of collagen vascular diseases and highlight the roles played by several conditions within stroke.

Giant cell arteritis ( also known as temporal arteritis ), is an inflammatory disease affecting medium to large sized arteries. With respect to stroke, this means that the common carotid, internal carotid and vertebral arteries may be implicated, whilst importantly for understanding signs and symptoms, the post.ciliary and superficial temporal arteries may be affected.

The disease itself is not rare, and, incidence increases dramatically with age. The incidence rates are 133 per 100,000 for over 50’s according to a large study carried out in Olmsted County, Minnesota, and approximately 2% of death in these patients resulted from stroke. In various studies, cerebrovascular disease has been implicated as the cause of death, in between 1-25% of GCA patients. Women also appear four times more likely to develop the condition, whilst caucasions are seven times more likely to develop the condition than African Americans. The basis of this difference is thought to lie in the HLA DR4 antigen.

Giant Cell Arteritis develops due to a CD4+ T-helper cell response to macrophage presented antigens. Inflammation begins in the adventitia and extends to involve the internal elastic lamina and media. Intimal proliferation and fibrosis results in focal narrowings of the vessel, without thrombosis or aneurysm formation. This change results in an increased risk of ischaemia due to vascular insufficiency. Granulomas may be found within the lesion, but are not invariably present, whilst the antigenic trigger for the inflammation is still not known today, although elastin has been implicated.

The most common presentation of the disease is headache. The headache is described as constant, predominately temporal with radiation to the jaw, face and scalp, and of greater intensity during the night. Systemic manifestations such as weight loss, night sweats, fever and malaise have also been described by most patients. Other symptoms with possible associations to GCA include temporal pulselessness, jaw claudication, facial pain and earache, however, the extent to which they are present is highly variable. Neurological manifestations may be observed, such as peripheral neuropathies and seizures, however, a more common manifestation is visual disturbance. Partial or complete visual loss is reported in between 10-60% of patients and is mostly due to anterior ischaemic optic neuropathy (AION), a condition which results in GCA due to ischaemia of the optic nerve head, which is supplied by the afore mentioned posterior ciliary arteries.

As with any condition, it is important to know what to look for in investigations. There are many general associations described, including; elevated ESR, elevated CRP, mild anaemia, mild lymphocytosis and mild thrombocytosis. There are also specific investigations, which can yield far more conclusive results, such as superficial temporal artery biopsy (TAB) and aortic arch angiography. TAB is generally accepted as the best method for definitive diagnosis, but it is worth remembering that a negative result, does not disclude the diagnosis as ‘skip’ lesions are present in GCA, and in a symptomatic patient the same investigation should be carried out on the opposite side. Obviously, a CT scan is appropriate in patients with a CVA, and we would expect to see multiple infarcts if the stroke was due to GCA.

With respect to treatment, high dose steroids ( prednisolone ) are the mainstay of therapy, until the symptoms of the disease are controlled. However, steroids also bring about a further risk of stroke, through their effects on blood pressure, cholesterol, weight and their propensity to cause diabetes. There may be roles for other immunosuppressants such as Azathioprine within the condition in order to decrease the steroid dose required, and therefore decrease the risk of developing some of the cardiovascular risk factors described above.

It is clear that GCA does not affect the cerebral circulation directly, as these arteries lack an internal elastic lamina, which plays a crucial role in the pathology of the disease. Another condition, which is restricted entirely to the cerebral circulation is ‘isolated granulomatous angiitis of the CNS’. This is a disease which may afflict patients of any age, producing neurological disease to a far greater extent than systemic illness, usually resulting in death due to poor treatment response.

Any of the small blood vessels in the brain or the spinal cord may be involved, especially the leptomeningeal vessels. The inflammatory infiltrate consists of lymphocytes, plasma cells and granulomas with giant cells. Occasionally, the larger cerebral arteries will also be affected by this process. The inflammatory process, can lead to the development of small aneurysms, which may burst to produce multiple small areas of infarction and haemorrhage, known as ‘brain purpura’.

The aetiology of this inflammatory response is also unknown, however, a viral cause has long been suspected. Prognosis is poor because there are few clues to diagnosis, prior to stroke or autopsy. Vague clinical symptoms may be reported, such as headache, nausea, vomiting and confusion, however, this rare condition is often never discovered. Any diagnosis made is usually by leptomeningeal biopsy, however, it may take a stroke and its devastating consequences to bring this disease to the fore.

Takayasu’s Arteritis is a further condition which must be considered. The condition is almost identical to GCA, yet it tends to affect young women. The disease predominately affects the aorta and its branches, but there are few diagnostic features until late on in the disease process. Systemic symptoms, as previously described tend to predominate early on, and some patients may complain of arm claudication and syncope. As the disease develops, patients tend to develop, retinopathy, hypertension secondary to renal artery stenosis, aortic re-gurgitation due to inflammation of the aorta and aortic aneurysms.

It is at this advanced stage when stroke tends to occur, and it may arise due to multiple abnormalities. Cerebral infarction may occur due to stenosis of a cerebral or vertebral artery, whilst intracerebral haemorrhage may also occur due to the afore described hypertension. Heart valve disease also predisposes to cardioembolism, and thus the disease may cause stroke through direct and in-direct effects on the cardiovascular system. Treatment again involves a regimen of corticosteroids, whilst cyclophosphamide has also been shown to be of value. Surgery is also indicated for heart valve defects in this condition.

A more common condition than some of those previously described is SLE, a chronic systemic autoimmune disorder, often described as the disease of 1,000 faces. A recent Canadian study, published in ‘Arthritis and Rheumatism’, found that the incidence of MI and stroke in patients with SLE was up to seventeen times more common than in SLE negative patients with the same cardiovascular risk factors.

There are many different pathophysiological processes occurring within SLE, however, one of the most important of these when considering stroke, is the development of antiphospholipid antibodies, which create a prothrombotic state. The significance of these antibodies was underlined by the fact that in study results: 43% of SLE patients with a stroke were shown to be positive for these antibodies. Aswell as this, hypertension has been shown to be more frequent within patients with SLE, and this may be associated with the incidence of intracerebral haemorrhage within these patients. Thirdly, immune complex deposition in small cerebral arterioles has been associated with episodes of microinfarction and haemorrhage.

There is no standard therapy used, although steroids, antiplatelet agents and anticoagulants all have roles in certain instances.

A further condition, which is significantly rarer is Sneddon’s syndrome. This is a syndrome describing a cerebrovascular event in association with livedo reticularis ( a condition caused by impaired venous drainage of the skin ). Most of these patients exhibit the afore mentioned antiphospholipid antibodies, but also develop a non-inflammatory intimal hyperplasia due to fibroelastic proliferation, which may occlude medium sized arteries. These events are often recurrent, and lead to multiple ischaemic strokes or TIA’s. Treatment for this rare condition involves antiplatelet agents and warfarin to try and compensate for the narrowed vessels.

Many inflammatory diseases have an unknown aetiology, and their diagnosis depends on noticing certain specific clinical signs. One of these is Behcet’s disease. Behcet’s is classified clinically by the triad of oral apthous ulcers, genital ulcers and uveitis. However, with established disease, on very rare occasions it can lead to a stroke. The condition is associated with a lymphocyte pleocytosis, and perivascular infiltration may occur, causing inflammation and occlusion. Anticardiolipin antibodies should be measured by serological investigation and a treatment regimen of corticosteroids, cyclophosphamide, azathioprine and chlorambucil should be given.

There are many collagen vascular diseases which have the capacity to cause stroke. Some conditions are very rare, but others, although they do not affect the cerebrovascular system to the same extent as atherosclerosis, have significant morbidity associated with them. The diseases are often overlooked by busy medical professionals and students, however, this cannot be an excuse for failing to diagnose and treat conditions; for failing to prevent strokes and other secondary complications. There is a great deal to learn about collagen vascular disease and its significance with regards to stroke, however, hopefully this piece conveys some of the basics to be considered in our practice.

Stroke and Collagen Vascular Disease: Chapter 16, Stroke Explained

Machado EBV et al. Epidemiology of GCA: Arthritis and Rheumatology 31:745, 1988

Park et al. Immune system in GCA: Ann. Rheumatology Disorders 40:360, 1981

Hamilton CR. Clinical Symptoms of GCA: Baltimore Journal of Medicine 50:1, 1971

Howard GF et al. Clinical Investigations and GCA: Ann. Neurology 1984

Hall S et al. TAB in GCA: Lancet 2:1217, 1983

Giant Cell Arteritis: Dr. Manolette Rangel Rogue, Dept. of Immunology, Harvard Medical School

Temporal/Giant Cell Arteritis: Dr Richard J Caselli, MD, E – Medicine

Koo EH et al. Isolated Granulomatous Angiitis of the CNS: Journal of Neurology, Neurosurgery and Neuropsychiatry 51:1126, 1988

Cupps TR et al. Treatment of IGA of the CNS: American Journal of Medicine 74:97, 1983

Ishickawa K et al. Takayasu’s Arteritis and Stroke: Stroke 18:677, 1987

Anderson RA et al. Sneddon’s Syndrome: British Journal of Dermatology 120:215, 1989

Rubello M. Pathology and Sneddon’s Syndrome: Brain 106:965, 1983

Rubenstein LJ. Pathology of Behcet’s Disease: Brain 86:151, 1963

Feinglass et al. Epidemiology of SLE: Medicine ( Baltimore ) 55:323

Kitagawa Y et al. Epidemiology of SLE: Stroke 21:1533, 1990

John Hopkins University, Resource Centres