Answers

Short answers

1 Magnetic resonance imaging shows bilateral thalamic infarcts with a larger lesion on the left thalamic nucleus than on the right (fig 3). A few small foci of hypodensity are indicative of small haemorrhages. The overall findings suggest basilar artery embolisation.

View larger version (131K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3 Magnetic resonance imaging of the brain showing bilateral thalamic infarcts with a larger lesion on the left thalamic nucleus than on the right. A few small foci of hypodensity are indicative of small haemorrhages

 

2 Transoesophageal echocardiography with contrast shows bubbles of contrast in the right atrium being shunted into the left atrium through the interatrial septum (fig 4). This confirms the diagnosis of a patent foramen ovale (PFO).

View larger version (66K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4 Transoesophageal view of the patent foramen ovale (PFO) with contrast crossing through. The interatrial septum (IAS), the right atrium (RA), and the left atrium (LA) are highlighted

 

3 The initial management of the patient involves recognition of acute brainstem stroke and consideration of thrombolysis.

4 It is important to investigate stroke in young patients thoroughly because many causes are treatable and preventable. Tests should include assessment for risk factors, magnetic resonance imaging of the head and neck, and a transthoracic echocardiography (with contrast).

5 This patient had the confirmed presence of both a PFO and a cerebrovascular accident, so the most appropriate treatment was percutaneous closure of the PFO.

Long answers
1 MRI result and diagnosis
MRI shows bilateral thalamic infarcts with a larger lesion on the left thalamic nucleus than on the right. A few small foci of hypodensity are indicative of small haemorrhages. The overall findings suggest basilar artery embolisation, and a review of the computed tomography scan showed bilateral thalamic infarcts (fig 5). The presence of multiple lesions in more than one vascular territory of the brain, especially if bilateral, suggests a proximal source of emboli, and a cardiac source should be investigated.¹ Bilateral thalamic infarction often has an embolic origin because paradoxical venous emboli selectively enter the vertebrobasilar circulation.² Conversely, single or multiple lesions found unilaterally in the carotid circulation are usually associated with atherosclerotic disease of the ipsilateral carotid artery or middle cerebral artery.

View larger version (87K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5 Computed tomography scan of the brain showed bilateral thalamic infarcts

 
The clinical syndrome of acute midbrain dysfunction with sudden loss of consciousness and unequal pupils is highly suggestive of distal basilar artery embolisation, and this was backed up by the bilateral haemorrhagic thalamic infarction seen on the magnetic resonance imaging. This clinical syndrome is also called distal basilar artery syndrome or "top of the basilar artery" syndrome; it can also affect the occipital lobes or temporal lobes in addition to the midbrain and thalami.

The basilar artery is the main blood supply to the posterior part of the brain; it begins at the medullopontine junction and ends at the junction of the pons and midbrain. Occlusive lesions can occur anywhere along the basilar artery and will lead to disruption of vital functions in the brain stem; among the acute stroke syndromes, basilar artery embolisation carries the worst prognosis.³

The most important sign of basilar artery thrombosis is an altered level of consciousness—patients may present with coma when the bilateral medial pontine tegmentum is ischaemic.⁴ The pontine tegmentum is supplied mostly by arteries that arise from the distal basilar artery, so if the artery remains patent the tegmentum is relatively spared.

Our patient presented with features of top of the basilar syndrome, a result of occlusion of the rostral portion of the basilar artery.⁵ In most cases this is caused by embolism from a proximal source such as the heart, the aorta, or the vertebral arteries in the neck. Less commonly, the syndrome is caused by intrinsic occlusive disease of the rostral portion of the basilar artery. In many patients infarction is limited to the rostral brainstem. Clinically it produces signs of midbrain and thalamic ischaemia, signs of occipital and temporal ischaemia, or both. The clinical features are⁶:

• Abnormalities of ocular movements such as disruption of voluntary and reflex vertical gaze or problems with gazing upwards or downwards
  
• Changes in pupillary function
  
• Altered consciousness and hypersomnia
  
• Visual hallucinations
  
• Memory dysfunction or abulia, or both, as a result of thalamic involvement.
  

Occlusive basilar artery disease in proximal vessels and mid-vessels has a worse prognosis and more serious consequences. Most patients with symptomatic basilar artery occlusive disease and pontine ischaemia have some transient or persistent degree of paresis and corticospinal tract abnormalities. The initial motor weakness is often lateralised and has been referred to as the "herald hemiparesis" of basilar artery occlusion. It is rarely confined to one side of the body and is almost always associated with motor or reflex abnormalities on the non-hemiparetic side. Bulbar dysfunction—including facial weakness or jaw weakness (or both), dysphonia, dysphagia, and aspiration pneumonia—occurs, and some patients totally lose the ability to speak, open their mouth, protrude their tongue, swallow, or move their face at will or on command. "Locked in" syndrome is an extreme motor manifestation of pontine ischaemia characterised by complete loss of all voluntary limb and facial movement, with retained consciousness and preserved vertical gaze. Other symptoms include:

• Oculomotor abnormalities, especially disordered horizontal eye movement
  
• Effects on the pupils—pinpoint reactive pupils may be seen in comatose patients with large pontine lesions
  
• Cerebellar or somatosensory deficits, or both.
  

It is vital to recognise patients who present with signs of basilar artery disease so that serious adverse sequelae such as locked in syndrome can be prevented. Fortunately our patient had top of basilar syndrome and recovered independently. Thrombolysis is indicated in basilar artery occlusion, and all emergency and acute doctors should be aware of this.

2 Transoesophageal echocardiography
Transoesophageal echocardiography (fig 4) highlighted the passage of contrast bubbles through the interatrial septum from the right atrium to the left atrium and confirmed the diagnosis of PFO. This is the most common cause of cardioembolism in young adults with cryptogenic stroke—it is present in more than 50% of such patients being evaluated.⁷

PFO has been increasingly implicated in the aetiology of stroke, particularly in young patients with presumed cryptogenic stroke.

PFO is a haemodynamically insignificant interatrial communication present in more than 25% of the adult population. It is a remnant of the fetal circulation and results from failure of postnatal fusion of the primum and secundum septa. Persistence of the one way "flap valve" overlying the fossa ovalis allows right to left shunting of blood when right atrial pressure exceeds left atrial pressure. Venous thromboemboli can therefore enter the arterial circulation through a PFO. Case reports have shown images of thromboli straddling PFOs in patients with deep vein thrombosis and systemic embolism.⁸ Such "thromboli in transit" confirm the diagnosis of paradoxical embolism but are a rare "catch," and diagnosis tends to depend on the concurrence of arterial embolism, venous thrombosis, interatrial communication, and a gradient favouring right to left shunting.⁹

Echocardiography is the best method of identifying PFO. Unfortunately, guidelines from professional societies do not advise on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (<45 years old) with cerebrovascular accidents or older patients (>45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official guidance on whether to use transthoracic echocardiography or transoesophageal echocardiography,¹⁰ and the decision is often left to the individual doctor. A reasonable, evidence based diagnostic approach in young stroke patients is to proceed to transoesophageal echocardiography when routine transthoracic echocardiography with valsalva manoeuvre and electrocardiography are uninformative.

In a case series, transoesophageal echocardiography identified a potential cardiac source of embolism in 45 of 79 patients with cryptogenic stroke, compared with only 12 with transthoracic echocardiography.¹¹ Evolving technologies mean that newer treatments are emerging. Contrast transthoracic echo has improved to the extent that it should be used in conjunction with transoesophageal echocardiography—a study comparing the two techniques found that PFO can be diagnosed by both bubble contrast transthoracic echocardiography and transoesophageal echocardiography on modern echo machines with a sensitivity of about 80%.¹² Both techniques have pitfalls—transthoracic echocardiography has problems with the quality of the echo window, whereas the problems with transoesophageal echocardiography relate to the ability to perform a valsalva manoeuvre (this is difficult with a transoesophageal echocardiography probe in place). Most centres in the United Kingdom initially perform transthoracic echocardiography and follow this with transoesophageal echocardiography if the transthoracic echocardiogram is normal.¹³

Transcranial contrast enhanced Doppler ultrasound is an alternative imaging technique that has similar accuracy to that of transoesophageal echocardiography. Right to left shunting of microbubbles is detected by imaging of the middle cerebral arteries,⁸ but it cannot detect the shunt within the heart.

A history of migraine, as in our patient, should raise the suspicion of a PFO because patients with stroke and a PFO have a high prevalence of migraine (27-52%).⁸ A plausible explanation for the association between migraine and PFO is that paradoxical microemboli from the venous system are shunted from right to left across the PFO into the arterial circulation, thus bypassing the normal pulmonary "filter."⁹ These microemboli then enter the cerebral arterial circulation and trigger migraine attacks.

Several studies of PFO closure devices have reported a significant reduction in the frequency of migraine, particularly in patients with aura. However, the results of a more recent double blinded prospective placebo controlled study were less convincing, with no significant difference in the primary end point of being headache free at six months between the groups. Patients undergoing device closure did have a 50% decrease in the number of headache days however,¹⁴ but it should be remembered that although a history of migraine is relevant, device closure has a 1% serious complication rate. Definitive proof of a cerebral ischaemic event documented by MRI or computed tomography is therefore needed before closure of a PFO is considered.¹⁵

3 Management in the acute setting
Usually these patients have altered levels of consciousness and cardiorespiratory compromise. Patients are initially managed by resuscitation, and respiration and haemodynamics may need to be supported. Adequate nursing care is also important.

The diagnosis should be confirmed by urgent cerebral imaging (usually a computed tomography scan) and suitability for thrombolysis—which is indicated in basiliar artery thrombosis—should be assessed. Thrombolysis was not given to our patient because the service was not available in our hospital. She was treated symptomatically and supportively with intravenous fluids, aspirin, and close observation.

4 Investigating the aetiology
Stroke is a common clinical presentation, and up to 12% of cases occur in young patients (<45 years old), who often present with no apparent risk factors.⁷The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification can be used to define the aetiology of stroke. The causes are large artery atherosclerosis, cardioembolism, small vessel disease, stroke of other determined aetiology, and stroke of undetermined aetiology.¹⁶ In up to 43% of affected young adults, strokes are cryptogenic (no definite cause despite extensive evaluation).¹⁷ The main causes of acute stroke in young people are haemorrhage, cardioembolic ischaemia, large vessel disease, haematological disorders, and migraine (box).

Causes of stroke in young people    Ischaemic causes (70%) Cardioembolic (19-30%) Congenital Rheumatic valve disease Mitral valve prolapse Patent foramen ovale Endocarditis Atrial myxoma Arrythmias Cardiac surgery Large vessel disease (3-20%) Premature atherosclerosis Dissection (spontaneous or traumatic) Inherited metabolic diseases (Fabry’s disease, homocystinuria, mitochondrial stroke-like episodes) Fibromuscular dysplasia Vasculitis Toxins (up to 9%) Haematological disease (10-19%) Sickle cell disease Leukaemia Hypercoagulable states (up to 5% are inherited or acquired conditions associated with a predisposition to venous thrombosis) Polycythaemia vera Thrombotic thrombocytopenic purpura Venous occlusion Small vessel disease (2-10%) Vasculopathy Infection Microangiopathy Migraine (1.9%)    Haemorrhagic causes(30%) Subarachnoid haemorrhage Intraparenchymal haemorrhage Arteriovenous malformation Neoplasms Haematological disease Drugs Iatrogenic causes

Once the patient has been stabilised the aetiological factors need to be investigated. This is particularly important in young patients because many will have a treatable underlying cause. After an initial computed tomography scan, basic investigations should include the measurement of fasting glucose and a lipid screen (a low concentration of high density lipoprotein cholesterol is associated with an increased risk of stroke in younger people, regardless of the presence of atherosclerosis).¹⁸ Erythrocyte sedimentation rate and autoimmune screens should be carried out to rule out a vasculitic process, and a haematological profile should also be assessed.¹⁹ Antiphospholipid antibodies and serum homocysteine concentrations should be checked in all young patients with stroke but no obvious cause. In selected patients, urine or serum toxicology (or both) should be checked if clinically suspected because several case-control studies have found that the risk of stroke is 4.5-6.5 times higher in people who misuse drugs than in controls.²⁰ All patients should undergo a transthoracic echocardiography with contrast to look for an embolic source and MRI of the head to look for alternative pathology. Other investigations such as MRI of the neck depend on the clinical presentation.

Rare causes to be considered include CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), which is inherited as an autosomal dominant disease. It appears after the third decade of life with multiple episodes of migraine (usually associated with aura) and recurrent cerebral infarcts in patients without important risk factors for cerebrovascular disease. Dementia becomes evident 20 years after the onset of symptoms. MRI shows characteristic features,²¹ but the findings are not diagnostic. It is usually diagnosed by genetic studies to look for the Notch3 gene or a by skin biopsy, which should be examined by electron microscopy for electron dense granular osmiophilic material in the media of the arterioles.²²

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke mitochondrial stroke-like episodes) is characterised by stroke-like episodes before 40 years of age and encephalopathy. Patients may have seizures, dementia, and either ragged red fibres (on muscle biopsy) or lactic acidosis. The diagnosis is established if patients have at least two of the following additional criteria—normal early development, recurrent headache, and recurrent vomiting.²³

Fabry’s disease is an inherited X linked disorder caused by a deficiency of galactosidase, which results in the progressive deposition of uncleaved neutral lipids in the small blood vessels of the skin and viscera. It is characterised by angiokeratomas along body creases—especially in the abdomen and groin, neuropathic pain, myocardial infarction, renal failure, and transient ischaemic attacks.²⁴

The thalamus is affected in 25% of all vertebrobasilar strokes, usually in combination with other structures.²⁵ The most common cause of thalamic infarcts in patients in younger age groups is arterial occlusion secondary to dissection, then cardioembolism in 27%, either through a PFO or as a result of rheumatic heart disease.²⁶

5 Long term management
Three treatment options are available for patients with a presumed paradoxical embolism and PFO:

• Antiplatelet treatment with aspirin
  
• Oral anticoagulation with warfarin
  
• Surgical or percutaneous device closure.
  

Despite the growing evidence for PFO and atrial septal aneurysm being associated with paradoxical embolism that has neurological effects, there is no consensus on how to treat a cryptogenic stroke and none of the above treatments has been evaluated in randomised controlled trials.^{15 27} We treated our patient with percutaneous device closure because she was young, she did not have deep vein thrombosis, and she was not taking anticoagulants. Our patient was followed up after device closure and had not experienced further episodes of transient ischaemic attack or any recurrence of stroke.

Learning points Ischaemic stroke in the young has diverse causes, with cardioembolism being the most common It is important to investigate such an incident thoroughly because many causes are treatable and preventable Loss of consciousness indicates brainstem involvement, and basilar artery thrombosis should be considered Basilar artery thrombosis is under-recognised and has an unfavourable prognosis It is important to recognise basilar artery thrombosis early because it can be treated with thrombolysis Transthoracic echocardiography should be performed in all young patients with stroke even if the stroke is haemorrhagic Transoesophageal echocardiography with contrast should be performed if the transthoracic echocardiogram is normal

Cite this as: BMJ 2009;338:b813