Endgames Picture Quiz

A young woman presenting with severe headache

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2448 (Published 23 May 2013) Cite this as: BMJ 2013;346:f2448
  1. Maria Stavrou, foundation year 2 trainee, general medicine 1,
  2. Solomis Solomou, medical student2,
  3. Oliver Spooner, core trainee, year 23,
  4. Richard Perry, consultant neurologist 4
  1. 1North Central Thames Foundation School, London WC1E6BT, UK
  2. 2Barts and the London School of Medicine and Dentistry, London, UK
  3. 3Department of Geriatric Medicine, Lister Hospital, Stevenage, UK
  4. 4National Hospital for Neurology and Neurosurgery, London, UK
  1. Correspondence to: M Stavrou zchabz6{at}ucl.ac.uk

A 20 year old woman with a history of migraine with visual aura in the form of both positive (fortification spectrum) and negative features was admitted to hospital because of unilateral pulsatile right sided headache of one day’s duration. The headache was associated with photophobia, intense nausea and vomiting, right sided facial and upper arm numbness, and a right sided temporal visual field defect. She described the headache as similar to her habitual migraines in character but “the worst ever.” On examination she was normotensive and her Glasgow coma scale was 15. On neurological examination the visual field defect was confirmed and she reported reduction in light touch over the right side of her face and right upper limb.

With the exception of recurrent migraines at intervals of two to three months her medical history was unremarkable. She was not using any drugs on a regular basis apart from a progesterone contraceptive implant. She had no history of drug or alcohol misuse and did not smoke.

Diffusion weighted magnetic resonance imaging (MRI) of the head was performed (fig 1).


  • 1 What abnormality is seen on diffusion weighted MRI?

  • 2 What was the differential diagnosis at presentation?

  • 3 How would you investigate this patient?

  • 3 What is the appropriate strategy for secondary prevention?


1 What is the abnormality seen on diffusion weighted MRI?

Short answer

The image shows an area of restricted diffusion—that is, an acute infarct in the left thalamus (fig 2).


Fig 2 Diffusion weighted magnetic resonance image of the head showing an area of increased signal (arrow) indicative of restricted diffusion that is in keeping with an acute infarct

Long answer

The area of increased signal in the left thalamus seen on the image is indicative of restricted diffusion and is in keeping with an acute infarct. The remainder of the brain parenchyma appears normal.

T1 weighted scans are useful to differentiate fat from water because water appears darker and fat brighter. In T2 weighted scans fat is also differentiated from water, but fat appears darker and water brighter. T1 images are often used to visualise soft tissue damage, whereas T2 images are often used to detect damage to structures that contain fluid.

2 What is the differential diagnosis?

Short answer

Ischaemic stroke (coexisting with migraine); migrainous infarction; embolic stroke secondary to patent foramen ovale that enables right to left intracardiac shunting; arterial dissection; vasculitis and collagen vascular diseases; cerebral vasoconstriction syndrome (including drug induced vasoconstriction); and homocysteinuria.

Long answer

The patient presented with a migraine, which was perceived as unusually severe, being characterised by intense nausea and vomiting, visual field defect, and right sided facial and upper arm numbness. Computed tomography and diffusion MRI imaging of the brain showed an acute infarct. The case demonstrates a common diagnostic conundrum. Was this a particularly severe migraine caused by cerebral ischaemia or was it an infarct caused by particularly severe migraine? The safest pragmatic approach is to assume the first scenario. The cause of stroke should be searched for just as vigorously as in patients without a history of migraine, even if there is a migraine at stroke onset. In this way a potentially remediable risk of future stroke is unlikely to be missed.

The terms stroke, transient ischaemic attack, and migraine must be distinguished. A transient ischaemic attack is defined as “a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia, without acute infarction.”1 These attacks involve acute neurological dysfunction due to focal cerebral ischaemia, which is not associated with permanent cerebral infarction. The associated features mimic those of stroke in the same arterial territories.

The International Headache Society defines migraine with aura as “a recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually develop gradually over five to 20 minutes and last for less than 60 minutes.”2 Migraine with aura can be divided into five stages: premonitory, aura, headache, resolution, and recovery.

Premonitory symptoms occur hours to a day or two before a migraine attack. These may include difficulty in concentrating, neck stiffness, sensitivity to light or sound, nausea, blurred vision, yawning, and pallor.2 Aura follows the premonitory symptoms and may include fully reversible visual symptoms, including positive features (such as flickering lights, spots, or lines) and negative features (loss of vision). Aura may last less than one hour. Fully reversible sensory symptoms, such as positive features (pins and needles) or negative features (numbness), may occur. Moreover, fully reversible speech disturbance, homonymous visual symptoms, and unilateral sensory symptoms are sometimes seen.2 Headache follows aura, and symptoms include vomiting, anorexia, nausea, malaise, lethargy, phonophobia, photophobia, osmophobia, difficulty focusing, and poor concentration.3 Headache may last for four to 72 hours. This is followed by resolution (deep sleep, vomiting, lasting two to 12 hours) and eventually recovery (limited food tolerance, feeling high or low, diuresis, lasting two to 24 hours).3

The International Headache Society defines migrainous infarction as “one or more migrainous aura symptoms associated with an ischaemic brain lesion in appropriate territory demonstrated by neuroimaging.”2 The diagnostic criteria are as follows:

  • The present attack is typical of previous migraines with aura, except that one or more aura symptoms persists for more than 60 minutes

  • Ischaemic infarction in a relevant area is detected by neuroimaging

  • Not attributed to another disorder such as cervical arterial dissection, cardiac arrhythmia, coagulation abnormalities, and paradoxical embolism in the presence of a patent foramen ovale. Furthermore, if a patient with a history of migraine develops ischaemic stroke after a migraine attack, the disease is not classified as “migrainous infarction” but “ischaemic stroke coexisting with migraine.”

Epidemiological studies have shown that 0.5-1.5% of all ischaemic strokes are migrainous infarctions and that migraine with aura is an independent risk factor for ischaemic stroke. A registry study reported that migrainous infarction accounted for 13% of first ischaemic strokes in younger patients.4 A case-control study reported an increased risk of migrainous stroke in women under the age of 45 with a background of migraine with aura, especially in the presence of recognised risk factors, such as smoking and use of oral contraceptives.5

Migraines present typically before the age of 45 years and affect 12% of the population, with a 3:1 female predominance. In contrast, stroke is an acute event that occurs in two per 1000 people per year at a mean age of 70 years, with a 2:1 male preponderance. A complex bidirectional association has been suggested between migraine and stroke, including migraine as a cause of stroke and migraine as a risk factor for, or as a consequence of, cerebral ischaemia. In a large prospective cohort of women, active migraine with aura was associated with increased risk of major cardiovascular disease, myocardial infarction, ischaemic stroke, and death due to ischaemic cardiovascular disease, as well as with coronary revascularisation and angina.6

Headache is common in the setting of acute stroke and can start before, at the same time, or after focal signs.7 Prevalence varies widely (18-64.5%). In one study, patients admitted to a stroke unit were interviewed using a validated headache questionnaire.7 Of the 668 patients interviewed, 124 reported headache, and in half of these patients headache was a reactivation of previous primary headache. In some patients, headache associated with stroke is triggered by vascular insult, ischaemia, blood products, or an acute stressful situation (severe acute illness and hospital admission); in others it is caused by de novo activation of the trigeminovascular system. Transient neurological symptoms are typical of migraine with aura, but it can be difficult or even impossible to differentiate between migrainous aura, transient ischaemic attacks, and migrainous infarction on clinical grounds alone, emphasising the importance of MRI, including diffusion weighted imaging, in these patients.

Computed tomography and MRI based studies have investigated ischaemic lesion patterns in patients with migraine. Silent infarctions were detected mainly in the posterior circulation territory, especially in migraine with aura. It is currently unclear why the posterior circulation territory is mainly affected by acute and chronic ischaemic lesions. Cortical spreading depression with transient hypoperfusion and hyperperfusion, part of the pathophysiology of migraine, also occurs mainly in the posterior part of the brain. Cortical spreading depression with excessive vasoconstriction may be linked to cerebral ischaemia. Visual aura is the most common type of aura, probably because of perfusion changes in the occipital cortex8

The link between migraine and ischaemic stroke is unclear, although recent studies have suggested that generalised peripheral vasoconstriction may be responsible. A case-control study found that migraine is independently associated with increased aortic stiffness and enhanced pressure wave reflection.9 A spectroscopy study found that the time delay between the R wave of an electrocardiogram and the arterial pulse wave of cerebral microcirculation was longer in patients with migraine, indicating that migraine is independently associated with a mild vasoconstriction of cerebral arterioles.10 Interestingly, an MRI study suggested that migraine without aura is associated with dilation of extracerebral and intracerebral arteries and that the headache occurs on the same side as the vasodilation.11 In addition, migraine with aura and cardiovascular disease may share risk factors and mechanisms,12 including:

  • Traditional cardiovascular risk factors, such as higher cholesterol, lower high density lipoprotein cholesterol, higher total cholesterol to high density lipoprotein cholesterol ratio, and higher blood pressure

  • The proinflammatory or vasoactive peptide that is released during migraine attacks could damage the vascular endothelium, leading to stroke

  • Migraineurs have low numbers of endothelial progenitor cells, suggesting a reduced endothelial repair capacity

  • Genetic risk factors could play a role.12

The differential diagnosis can include arterial dissection, such as dissection of carotid and vertebral arteries, which can result in stenosis or dilation of the vessel.13 Stroke can be caused by pooling of blood, which eventually impedes flow; clotting of blood inside vessels; or small pieces of clot breaking off, flowing, and becoming trapped in smaller vessels of the brain. Spontaneous dissections can occur in Marfan’s syndrome or collagen disorders (Ehlers-Danlos syndrome), but most patients have no previous identifiable risk factors14 The vertebral arteries are particularly susceptible to trauma, because of their position in relation to the cervical spine at the intervertebral foramina, the atlanto-axial joint, and the occipito-atlantal joint. Carotid dissection may present as painful isolated Horner’s syndrome or lower cranial nerve palsies.14

Vasculitis and collagen vascular diseases should also be included in the differential diagnosis. Inflammation of blood vessels can damage the vessels, disrupting blood flow and resulting in stroke. These disorders probably have an immune basis. Antibody-antigen complexes lodge in gaps between vessel endothelial cells, resulting in the activation of complement cascade and the production of lysoenzymes; this leads to destruction of the vessel wall, with haemorrhage and fibrinoid necrosis.14 Vasculitis includes conditions associated with connective tissue disease, polyarteritis nodosa, allergic angiitis, and giant cell arteritis. Granulomatous vasculitis includes Wegener’s granulomatosis. Collagen vascular diseases include systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders.14

Another possible cause is cerebral vasoconstriction syndrome, where vasospasm of the arteries in the brain occurs. The possibility of drug induced vasoconstriction should also be considered.

Homocysteinuria, an inherited disorder that affects the metabolism of the amino acid methionine, is associated with blood clots so is also a risk factor for stroke. In a study that examined the association between homocysteinuria and stroke, Framingham study participants who had stroke were split into quarters—the first comprised those with the lowest total homocysteine concentrations and the fourth contained those with the highest concentrations.15 Compared with participants in the first quarter, those in the fourth quarter had an 82% increased risk of total stroke, a 79% increased risk of non-haemorrhagic stroke, and a 90% increased risk of atherothrombotic brain infarction.

3 How would you investigate this patient?

Short answer

Clinical assessment, together with blood tests and imaging of the brain and heart to look for other causes of stroke. Thrombolysis, antiplatelet drugs, and acute supportive management should be considered.

Long answer

A change in the pattern of headaches should always prompt investigations, particularly if one of the new features is a focal neurological disturbance. Clinical information and investigations should be collected and recorded in accordance with national guidelines.16 A comprehensive history, with cardiovascular and neurological examination should be undertaken. Systematic assessment tools such as the National Institutes of Health stroke scale can be used on and during admission.

Clinical presentation is important: the character of onset, duration, and severity of headache; history of migraine (with or without aura), frequency of attacks, use of prophylactic drugs (such as propranolol, topiramate, or amitriptyline), and family history of migraines. Explore risk factors such as arterial hypertension, oral contraceptives, smoking and alcohol consumption, diabetes, hyperlipidaemia, coagulation abnormalities, and known diagnosis of patent foramen ovale. A detailed history of illicit drug use, especially cocaine or amfetamine, as well as routine urine toxicology screening should be conducted in young patients presenting with stroke.17 In a study of 17 patients with migraine associated stroke among 8137 patients with stroke over 11 years, arterial hypertension was the most common risk factor (eight patients), followed by use of oral contraceptives in seven patients, smoking (six patients), and hyperlipidaemia (six patients).18 Coagulation abnormalities were found in two patients.

Electrocardiography (including Holter electrocardiograph monitoring for detection of paroxysmal arrhythmias), blood pressure monitoring, and pulse oximetry should all be carried out. Laboratory tests should include measurement of homocysteine plus platelet and vasculitis screens.19

Diffusion weighted imaging is valuable in the hyperacute phase for diagnosing stroke and excluding mimics, such as migrainous aura, because of its high sensitivity in detecting acute ischaemic lesions, including small lacunar or punctate cortical infarcts.20 However, a small proportion of patients with acute stroke will have false negative scans, especially if the scan is done early; moreover, in a posterior stroke these scans cannot exclude ischaemia. Other imaging modalities should include magnetic resonance angiography to exclude abnormalities in the intracranial vascular network and Duplex ultrasound examination of the extracranial circulation. Contrast enhanced magnetic resonance angiography has been reported to be a fast and effective investigation for intacranial artery dissection in young people.21 In the United Kingdom, however, MRI is rarely available on this timescale. Combined computed tomography and computed tomography angiography are more accessible and therefore more suitable as immediate first line imaging modalities, although they involve radiation exposure and calcification artefact is a possibility.

Echocardiography with bubble study (usually transthoracic, which provides a better view of the left ventricle) is needed to detect patent foramen ovale, which is associated with migraine with aura and is an independent risk factor for migrainous stroke. One study detected a relevant right to left shunt suggestive of this defect in 64.7% of patients with migrainous stroke.18 Presence of a patent foramen ovale was equally distributed among patients with cerebral ischaemia in the anterior (66.6%) and posterior circulation (63.3%). Six of seven cases with multiple lesions on diffusion weighted imaging had a patent foramen ovale, suggesting a possible cardiogenic mechanism of brain ischaemia in these patients. The mechanism of migraine attacks in patients with this defect is unclear, but paradoxical embolism might provoke transient focal neurological symptoms through vasoconstriction or transient cerebral ischaemia, or secondary to vasospasm (as a result of vascular changes postulated by some authors). The association between patent foramen ovale and migraine may result from a common embryonic development, with the most likely cause being genetically determined common endothelial-endocardial dysfunction.20

Although some studies have associated patent foramen ovale with an increased risk of stroke, others have failed to do so. For example, in one cohort study of 1100 people, 164 of whom had patent foramen ovale, followed up for an average of 79.8 months an ischaemic stroke occurred in 68 subjects (6.2%).22 After adjusting for demographics and risk factors, patent foramen ovale was not found to be significantly associated with stroke. More studies are needed to fully elucidate the association between patent foramen ovale and stroke. Similarly, it is not currently clear whether there is a causal or comorbid association between migraine with aura and patent foramen ovale.

Transoesophageal echocardiography has a 99% sensitivity and specificity for detecting cardiac anomalies implicated in stroke.23 This technique is indispensible in patients with stroke in whom a definite cause has not been identified. Other cardiogenic sources of cerebral stroke include: atrial and ventricular thrombosis, infective endocarditis, valve strands, atrial septal aneurysm, atheromatous plaque of the aorta, and dystrophy and calcification of the mitral annulus.23 Identification of a cardiac anomaly in ischaemic stroke does not, however, justify a diagnosis of cardioembolic stroke. It has been estimated that about a third of such patients also have disease of the cerebral vessels. In such cases it is often difficult to establish the cause of the ischaemic process.23

The indications for thrombolysis in patients with suspected migraine associated stroke are the same as those for patients with suspected ischaemic stroke without migrainous symptoms. If thrombolysis is not indicated or not applicable as per exclusion criteria, antiplatelet drugs should be given.

The box provides a summary of the most important investigations to undertake in young patients with stroke.24

Investigating young patients with stroke

Blood tests

Full blood count, blood glucose, cholesterol, clotting screen, erythrocyte sedimentation rate

Cerebrospinal fluid

Perform lumbar puncture if subarachnoid haemorrhage is suspected


Computed tomography or magnetic resonance imaging; computed tomography is usually used initially because it is readily available and is sensitive for acute haemorrhage

Electrocardiography and echocardiography

To investigate cardiac causes

Duplex ultrasonography of carotids, magnetic resonance angiography, computed tomography angiography

To investigate vascular disease of the carotids or arteriovenous malformations


If there are specific indications, the following investigations can be performed24:

  • Antinuclear antibodies: to detect systemic lupus erythematosus

  • Anticardiolipin antibodies/lupus anticoagulant: to detect antiphospholipid antibody syndrome

  • Protein C, protein S, antithrombin III: to investigate possible thrombophilia

  • Prothrombin time, activated partial thromboplastin time, platelet count: to detect coagulopathy

  • Urinary amino acids, methionine loading test: to detect homocystinuria

  • Magnetic resonance imaging of the brain, genetic analysis, skin biopsy: to look for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy

  • Serum lactate, muscle biopsy: to detect mitochondrial cytopathy

  • Syphilis serology: to detect neurovascular syphilis

4 What is the appropriate strategy for secondary prevention?

Short answer

Antiplatelet drugs and anticoagulants are established in secondary prevention of stroke. Closure of patent foramen ovale may be appropriate in selected cases.

Long answer

Secondary prevention with antiplatelet agents, antihypertensives, statins, and anticoagulation (in atrial fibrillation), as well as carotid endarterectomy if appropriate, should be initiated urgently after transient ischaemic attack or minor stroke because of the high risks of early stroke recurrence. Some studies have reported a reduction in the occurrence of migraine attacks during the use of oral anticoagulants.25 Increased platelet aggregation has been documented in patients with migraine.25 For long term secondary prevention most guidelines recommend aspirin and dipyridamole or clopidogrel as the first line approach for cerebral ischaemia of arterial origin. Currently, use of clopidogrel alone is cheaper.

Atrial septal abnormalities (such as patent foramen ovale) are common in young patients with cryptogenic stroke, although a causal association has not been established.26 Whether mural thrombus is formed locally within the atrial septum or deep venous thrombosis serves as a donor source of transcardiac cerebral emboli is still unclear. Another possibility could be thrombus formation due to atrial arrhythmias, such as paroxysmal atrial fibrillation or atrial flutter. Current treatment consists of life long anticoagulation (for arrhythmias).

In the context of migrainous stroke, closure of patent foramen ovale may be appropriate in selected cases. One study reported decreased intensity and frequency of migraine attacks in two patients with migrainous stroke who underwent closure.17 The role of patent foramen ovale closure in prevention of stroke remains unclear however—a recent American study (CLOSURE-1) failed to show benefit over medical treatment.27

Patient outcome

The patient’s headache resolved within four hours of adequate analgesia. The sensory disturbance resolved over the next few days. Diffusion weighted MRI identified a left thalamic infarct. Transthoracic echocardiography results were consistent with a small sized ostium secundum atrial septal defect. Doppler ultrasound of the leg veins showed sluggish flow but no evidence of deep vein thrombosis.

Three days later her sensory and visual deficits were negligible and she was discharged from the stroke unit to follow-up, pending a thrombophilia screen and further stroke and cardiovascular work-up.


Cite this as: BMJ 2013;346:f2448


  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.