Cerebral vascular disease: Pathology review

At the emergency department, 30-year-old Lydia presents with severe headache and confusion. Clinical examination reveals low grade fever and nuchal rigidity. Past medical history reveals she has polycystic kidney disease. Non-contrast CT reveals blood between the arachnoid and the pia mater. Lydia is treated supportively and sent home. Three days later she suddenly develops a severe headache, vomiting, and confusion. Later that day, 70-year-old Amanda presents with left-sided weakness and numbness, with her foot and leg more affected than her arm. She can speak fluently and understands everything being said to her. Past medical history includes hypertension, hyperlipidemia, and a myocardial infarction last year.

Based on their presentation, the diagnosis is that both Lydia and Amanda had a cerebral vascular accident, most often referred to as a stroke. A stroke is when there’s a sudden focal neurological deficit due to a part of the brain losing its blood supply.

Now, to safeguard the brain from hypoxia, the brain has a dual circulation called the circle of Willis, divided into an anterior and posterior circulation. The anterior circulation starts in the neck, where the common carotid artery splits into the external and internal branches. The internal carotid passes through the carotid canal of the temporal bone of the skull and into the cranial cavity. Once inside, the internal carotid artery gives off branches. First are the middle cerebral arteries that supply the lateral portions of the frontal, parietal, and temporal lobes. It’s also important to remember that the middle cerebral arteries supply the two language areas, Broca’s and Wernicke’s. From the initial segment of the middle cerebral arteries, small perforating arteries called lenticulostriate arteries arise to supply a part of the basal ganglia called the striatum, which includes the caudate and putamen, as well as the internal capsule. And that’s something you absolutely must remember for the exams! The internal carotid artery also gives rise to the anterior cerebral artery, which supplies the medial portion of the frontal and parietal lobes. The two anterior arteries connect with one another via a short blood vessel called the anterior communicating artery, forming the anterior portion of the circle of Willis.

An important area supplied by the anterior circulation is the cortical homunculus, which is kind of a neurological map of the areas and proportions of the brain that are in charge of the motor and sensory functions for different parts of the body. The motor homunculus belongs to the frontal lobe, while the sensory homunculus is right behind it in the parietal lobe. Knowing the distribution of the cortical homunculus is important because the stroke will manifest as symptoms involving the body area that is controlled by the affected brain area, and this gives us a clue to where the stroke occurred. The cortical homunculus can be represented as a body lying on top of the brain like this, where each body part lies on top of its corresponding brain area. The toes are represented first, and then as one moves down, progressively higher parts of the body are represented, until the last part is the face. These representations on each side of the brain control the corresponding opposite side of the body. Now, the medial area of the homunculus, representing the lower body, is supplied by the anterior cerebral artery, while the lateral area representing the upper body and face is supplied by the middle cerebral artery.

Moving on, the posterior circulation starts with the vertebral arteries, which head up through the transverse foramina of the cervical vertebrae and then through the foramen magnum into the cranial cavity. The vertebral arteries send branches that form the anterior spinal artery, which supplies the medial medulla and the anterior portion of the spinal cord above the level of T8. Below that level, the spinal cord is supplied by the artery of Adamkiewicz, which is a branch of the aorta. In addition, the vertebral arteries give off the posterior inferior cerebellar artery, or PICA, which supplies the lateral medulla and part of the cerebellum. Then, at the base of the medulla, both vertebral arteries join into a single artery called the basilar artery. As the basilar artery ascends, it first gives off the anterior inferior cerebellar artery, or AICA, which supplies the lateral pons and part of the cerebellum. Then, the basilar artery sends small branches called pontine arteries to supply the mid-pons. Now, going up towards the midbrain, the basilar artery also gives off a few pontine branches, which supply much of the pons medially; as well as the right and left superior cerebellar arteries, which supply a part of the pons laterally and the superior part of the cerebellum. The basilar artery also gives off the right and left posterior cerebral arteries, which supply the occipital lobe. Both of these arteries give the left and right posterior communicating arteries, which merge with the internal carotid arteries, thereby closing the posterior portion of the Circle of Willis.

In general, the brain can get by on diminished blood flow when it happens gradually, because that allows enough time for collateral circulation to develop. But when blood supply is reduced suddenly, it causes tissue damage, which we call a stroke. After 5 minutes of hypoxia, neurons start to die and the damage becomes irreversible. The cells that are most vulnerable to hypoxia and get damaged first are the pyramidal cells of the hippocampus; the cells of the neocortex; and the Purkinje cells of the cerebellum. And that’s something you have to know for the exams!

All right, now let’s dive deeper into strokes. There are two main types of stroke, ischemic and hemorrhagic. Most strokes are ischemic, where a blocked artery reduces blood flow to the brain. Ischemic strokes can be classified into thrombotic, embolic, and hypoxic. Thrombotic strokes usually occur when a clot forms over an atherosclerotic plaque, but they can also develop in non-inflammatory diseases like fibromuscular dysplasia. They’re more common in large vessels like the middle cerebral artery. But there’s a type of stroke that affects small vessels, called lacunar strokes and these are very high yield! Lacunar refers to “lake.” It receives its name because, after a lacunar stroke, the damaged brain tissue develops fluid-filled cysts, which look like little lakes under a microscope. Lacunar strokes typically involve the lenticulostriate arteries that supply the striatum and internal capsule. Now, lacunar strokes can be associated with conditions like hypertension and diabetes that can lead to a type of arteriosclerosis called hyaline arteriolosclerosis where the arteriole walls get filled with protein. This can make the arteriole wall thicker, reducing the size of the lumen and leading to lacunar strokes.

Next, embolic strokes occur when a blood vessel is blocked by an embolus. If it arises from the heart, it’s called cardioembolic, and that usually occurs in the setting of atrial fibrillation, where blood pools in the atria and can become clotted. That clot can then travel up to the blood vessels supplying the brain. Now, another cause of embolic stroke that gets frequently tested is infective endocarditis! Vegetations can detach from the infected valve to float through the bloodstream, and these are called septic emboli. Mind that septic emboli from the left side of the heart can lodge in the arterial circulation of the brain, causing a stroke, while right-sided ones usually lodge in the pulmonary circulation. More rarely, there might be a paradoxical embolus that dislodges from the right side, and then slips through an atrial septal defect or patent foramen ovale. It enters the left atrium, and from there it can head off to the brain, causing a stroke. Now, an embolus can also dislodge from a thrombus or atherosclerotic plaque in the carotid arteries, and that results in a thrombo embolic or atheroembolic stroke. Rarely, there might be a paradoxical embolus, which dislodges from a thrombus in the veins, like a deep vein thrombosis, and then slips through an atrial septal defect or patent foramen ovale, enters the left atrium, and from there, to the brain.

Finally, there’s hypoxic stroke, aka hypoxic ischemic encephalopathy, or global cerebral ischemia, which develops when there’s systemic hypoperfusion or hypoxemia. This can occur in cardiovascular surgeries, during cardiac arrest, due to ischemia during birth, and things like septic shock, or drowning. In these cases, the pattern of injury is called a watershed infarct or watershed stroke, where healthy tissue continues to extract what it needs from the blood flowing by, leaving little or no oxygen and nutrients for the tissue furthest away and as a result, the tissues that are the furthest downstream are affected the most. The “furthest downstream” tissues are the watershed areas, which are at the border of blood supply from two separate groups of cerebral arteries, making them more vulnerable to ischemia. There are three main watershed areas where watershed infarcts typically occur; between the anterior cerebral and the middle cerebral arteries, as well as between the posterior cerebral and the middle cerebral arteries, and between the external and internal branches of the middle cerebral arteries.

All right, now let’s switch gears and talk about hemorrhagic strokes, in which a blood vessel bursts and bleeds out, creating a pool of blood that increases pressure in the skull and on nearby tissue and blood vessels. In addition, less oxygen-rich blood is flowing downstream to the cells that need it. Healthy tissue can die from both the direct pressure and the lack of oxygen within a few hours. Increased pressure within the skull can lead to brain herniation, which is when the brain moves across structures in the skull. These structures include the falx cerebri, which divides the two halves of the brain; the tentorium cerebelli, which divides the occipital lobes from the cerebellum; and the foramen magnum, which is the hole in the base of the skull where the spinal cord connects with the brain.

A hemorrhagic stroke can be caused by either an intracerebral hemorrhage or a subarachnoid hemorrhage. Intracerebral hemorrhage is when bleeding occurs within the brain, and is usually caused by hypertension, which can cause microaneurysms, or Charcot–Bouchard aneurysms. These are so small that they are not visible with an angiography. Charcot-Bouchard aneurysms are most likely found on small arteries that supply deep gray matter structures. So, intracerebral hemorrhage due to hypertension usually occurs in the basal ganglia, which is supplied by the lenticulostriate arteries, especially in the putamen; but it can also occur in other deep gray matter structures like the thalamus, pons, or cerebellum. Another cause of intracerebral hemorrhage is degenerative disease like cerebral amyloid angiopathy, in which abnormal amyloid proteins deposit in the walls of small to medium sized blood vessels in the brain. This weakens the structure of the vessel walls and makes them prone to recurrent hemorrhage. Cerebral amyloid angiopathy usually manifests in the elderly with multiple asymptomatic microbleeds restricted to the cerebral cortex or superficial cerebellar regions. Cerebral amyloid angiopathy can also be associated with larger spontaneous lobar hemorrhage, but in this case, unlike hypertension, it spares the white matter, deep gray matter, and the brainstem. Some additional causes of intracerebral hemorrhage include arteriovenous malformations, which are abnormal vessels that can easily rupture; as well as conditions like vasculitis and vascular tumors, like hemangiomas. Intracerebral hemorrhage can also arise after an ischemic stroke. Arteries within the ischemic tissue are themselves made up of endothelial cells that die off. If there’s reperfusion or a return to blood flow, there’s an increased chance that the damaged blood vessel might rupture and cause a hemorrhage. This is called a hemorrhagic conversion.

Next, there’s subarachnoid hemorrhage, which is extremely high yield! Here, bleeding occurs between the middle and inner layers of the meninges, so between the arachnoid and pia mater respectively. The most common cause of subarachnoid hemorrhage in general is head trauma, while the most common cause of a spontaneous or primary subarachnoid hemorrhage is the rupture of an aneurysm. Now, sometimes, subarachnoid hemorrhage can be caused by both, since even minimal trauma could lead to rupture of an occult aneurysm. Most cerebral aneurysms arise in the anterior half of the circle of Willis, typically at bifurcations, most often between the anterior communicating artery and the anterior cerebral artery. For the test, you have to know that the most common aneurysms in the brain are saccular cerebral aneurysms, aka berry aneurysms, which have a characteristic rounded shape on one side of the artery. Some genetic disorders can predispose individuals to having saccular aneurysms, such as autosomal dominant polycystic kidney disease or ADPKD, Marfan syndrome, and Ehlers-Danlos syndrome, and that’s a fact that gets frequently tested on the exams! Other risk factors include advanced age, smoking, and being of African descent. For the test also remember that a less frequent cause of spontaneous subarachnoid hemorrhage is an arteriovenous malformation. Normally, arteries and veins are connected by small leaky blood vessels called capillaries. But in arteriovenous malformations, they are replaced with abnormally formed tangled blood vessels characterized by at least one direct connection between the artery and vein. Over time these abnormal vessels can dilate and since veins aren’t used to dealing with high arterial pressures, they can rupture causing a subarachnoid hemorrhage. Subarachnoid hemorrhage has specific symptoms that you must absolutely know for the exams! Most cases present an excruciating headache of acute onset known as thunderclap headaches that are described as "the worst headache of my life". There can also be nuchal rigidity caused by blood irritating the meninges. Occasionally people can develop seizures, fever and symptoms of increased intracranial pressure like vomiting, vision changes, and confusion.

Now regardless of the type of stroke, the region of the brain that’s affected typically corresponds to a specific focal neurological deficit. For the exams, it’s important to know some very high yield presentations. Let’s start with strokes of the anterior circulation. An anterior cerebral artery stroke affects the cortical homunculus for the feet and legs, causing contralateral paralysis and sensory loss. Urinary incontinence is also common. Whereas, the middle cerebral artery stroke affects the cortical homunculus for the hands, arms, face, causing contralateral paralysis and sensory loss of the hands, arms and face. In addition, if it involves the dominant hemisphere, which is usually the left, it can affect the language centers, so Broca’s and Wernicke's area. If the Broca area is affected, there’s expressive aphasia, meaning that speaking is impaired while comprehension remains intact. On the other hand, if Wernicke’s area is defective, there’s receptive aphasia, which means that you can speak fluently but comprehension is impaired. Now, if the stroke affects the non-dominant hemisphere, which is usually the right, it can lead to hemineglect, where you become unaware of one side of your body.

All right, now strokes of the posterior circulation are a bit more tricky because there are a lot of different structures that can be affected. A posterior cerebral artery stroke leads to homonymous hemianopia, which is a loss of vision in either the left or right halves of the visual fields of both eyes. The vision is lost in halves that are contralateral to the posterior cerebral artery that is affected. Although there is a partial loss of vision, macular function is spared, meaning that central vision is still sharp and detailed. This is because the part of the occipital lobe in charge of the macula gets blood from both the posterior cerebral artery as well as the middle cerebral artery. Now, if the dominant hemisphere is affected, a syndrome called alexia without agraphia can develop. So, in alexia without agraphia, the individual cannot read, but they can write.

Okay, now, if the basilar artery is affected, there’s bilateral damage of the pons leading to locked-in syndrome, where the individual is quadriplegic and mute. However, consciousness is preserved since the reticular activating system, or RAS, is preserved. RAS is a network of neurons in the pons and midbrain that sends out neuronal connections to both cerebral cortices, which are responsible for producing awareness. Also, there’s loss of horizontal eye movements since the paramedian pontine reticular formation is affected, while vertical eye movements are preserved.

Next, the occlusion of the paramedian branches of the anterior spinal artery or the vertebral arteries can lead to infarction of the medial part of the medulla and medial medullary syndrome. The medial part of the medulla contains several important structures, including lateral corticospinal tract, medial lemniscus, and hypoglossal nerve.

The involvement of the lateral corticospinal tract results in contralateral paralysis of both upper and lower extremities; while the lesion of medial lemniscus leads to impaired contralateral proprioception. Sometimes, the involvement of medial lemniscus can also result in contralateral decrease of vibration and fine touch. But, keep in mind that pain and temperature sensation is spared since these impulses are sent over the spinothalamic tract which is located laterally. Finally, the involvement of hypoglossal nerve causes the tongue to deviate meaning towards the side of the stroke.Now, individuals with a stroke of the PICA, develop lateral medullary syndrome, also known as Wallenberg syndrome, in wiich there’s infarction of the lateral part of the medulla. The lateral part of the medulla contains several important structures, including nucleus ambiguus and fibers of cranial nerves IX, X, and XI; vestibular nucleus; spinal trigeminal nucleus; as well as sympathetic fibers and lateral spinothalamic tract.