Panel 2.

Alternative ischaemic cerebrovascular causes with specific treatments that are not to be missed in patients with suspected lacunar stroke, and standard investigations; note that practice varies between countries and hospitals and this is general guidance.

Alternative cause	Clues that the cause is NOT intrinsic small vessel disease	Investigations
		*Brain imaging, neck artery imaging, BP, routine haematology, blood glucose, lipids, coagulation, liver, kidney function tests, proteinuria
Cardioembolic:	• Clinical history, symptoms, and findings suggesting cardiac disease • Contemporaneous cortical and small subcortical infarcts • Multiple contemporaneous infarcts in different arterial territories which may include a small subcortical infarct • Large subcortical infarct on imaging (as a guide, >2 cm axial diameter in the acute stage, although cardioembolic infarcts can be smaller and perceived size may depend on the type of imaging)	*ECG *Cardiac echocardiography including PFO detection** Prolonged ECG monitoring
Large artery atherothromboembolism	• Contemporaneous cortical and small subcortical infarcts • Large subcortical infarct on imaging (>2 cm axial diameter in the acute stage) • Manifestations of atherosclerosis in other organs e.g. coronary arteries, aorta, extremities	*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA
Arterial dissection	• Clinical symptoms and findings suggesting dissection • Odd-shaped subcortical infarct • Presence of cortical infarct	*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA
Intracranial atheromatous stenosis	• Large subcortical infarct (>2 cm axial diameter) • Long tubular infarct (>2 cm long) extending from the inferior perforating substance superiorly into the basal ganglia	Intracranial CT or MR angiography. Vessel wall MRI
Rare monogenic causes	• Worse WMH, more lacunes, perivascular spaces, and microbleeds than usual for age, and vascular risk factors • Concomitant other manifestations from other organs, for example, eye, skin, heart, ear, kidney • Cerebral lesion distribution • Young onset • Family history	Genetic testing

^*Should be routine in all ischaemic strokes including lacunar.

^**PFO detection usually clinically relevant only for patients under 60–65 years of age.