Clinical manifestations of intraparenchymal hemorrhage are determined by the size and location of hemorrhage, but may include the following:

- Hypertension, fever, or cardiac arrhythmias

- Nuchal rigidity

- Subhyaloid retinal hemorrhages

- Altered level of consciousness

- Anisocoria, Nystagmus

- Focal neurological deficits

- Putamen - Contralateral hemiparesis, contralateral sensory loss, contralateral conjugate gaze paresis, homonymous hemianopsia, aphasia, neglect, or apraxia

- Thalamus - Contralateral sensory loss, contralateral hemiparesis, gaze paresis, homonymous hemianopia, miosis, aphasia, or confusion

- Lobar - Contralateral hemiparesis or sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, abulia, aphasia, neglect, or apraxia

- Caudate nucleus - Contralateral hemiparesis, contralateral conjugate gaze paresis, or confusion

- Brain stem - Tetraparesis, facial weakness, decreased level of consciousness, gaze paresis, ocular bobbing, miosis, or autonomic instability

- Cerebellum - Ataxia, usually beginning in the trunk, ipsilateral facial weakness, ipsilateral sensory loss, gaze paresis, skew deviation, miosis, or decreased level of consciousness

In younger patients, vascular malformations, specifically AVMs and cavernous angiomas are more common causes for hemorrhage. In addition, venous malformations are associated with hemorrhage.

In the elderly population, amyloid angiopathy is associated with cerebral infarcts as well as hemorrhage in superficial locations, rather than deep white matter or basal ganglia. These are usually described as "lobar". These bleedings are not associated with systemic amyloidosis.

Hemorrhagic neoplasms are more complex, heterogeneous bleeds often with associated edema. These hemorrhages are related to tumor necrosis, vascular invasion and neovascularity. Glioblastomas are the most common primary malignancies to hemorrhage while thyroid, renal cell carcinoma, melanoma, and lung cancer are the most common causes of hemorrhage from metastatic disease.

Other causes of intraparenchymal hemorrhage include hemorrhagic transformation of infarction which is usually in a classic vascular distribution and is seen in approximately 24 to 48 hours following the ischemic event. This hemorrhage rarely extends into the ventricular system.

The most common presentation of cerebrovascular diseases is an acute stroke, which occurs when blood supply to the brain is compromised. Symptoms of stroke are usually rapid in onset, and may include weakness of one side of the face or body, numbness on one side of the face or body, inability to produce or understand speech, vision changes, and balance difficulties. Hemorrhagic strokes can present with a very severe, sudden headache associated with vomiting, neck stiffness, and decreased consciousness. Symptoms vary depending on the location and the size of the area of involvement of the stroke. Edema, or swelling, of the brain may occur which increases intracranial pressure and may result in brain herniation. A stroke may result in coma or death if it involves key areas of the brain.

Other symptoms of cerebrovascular disease include migraines, seizures, epilepsy, or cognitive decline. However, cerebrovascular disease may go undetected for years until an acute stroke occurs. In addition, patients with some rare congenital cerebrovascular diseases may begin to have these symptoms in childhood.

Patients with intraparenchymal bleeds have symptoms that correspond to the functions controlled by the area of the brain that is damaged by the bleed. Other symptoms include those that indicate a rise in intracranial pressure caused by a large mass putting pressure on the brain.

Intracerebral hemorrhages are often misdiagnosed as subarachnoid hemorrhages due to the similarity in symptoms and signs. A severe headache followed by vomiting is one of the more common symptoms of intracerebral hemorrhage. Another common symptom is a patient can collapse. Some people may experience continuous bleeding from the ear. Some patients may also go into a coma before the bleed is noticed.

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension (high blood pressure) is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

A stroke usually presents with an abrupt onset of a neurologic deficit - such as hemiplegia (one-sided weakness), numbness, aphasia (language impairment), or ataxia (loss of coordination) - attributable to a focal vascular lesion. The neurologic symptoms manifest within seconds because neurons need a continual supply of nutrients, including glucose and oxygen, that are provided by the blood. Therefore if blood supply to the brain is impeded, injury and energy failure is rapid.

Besides hypertension, there are also many less common causes of cerebrovascular disease, including those that are congenital or idiopathic and include CADASIL, aneurysms, amyloid angiopathy, arteriovenous malformations, fistulas, and arterial dissections. Many of these diseases can be asymptomatic until an acute event, such as a stroke, occurs. Cerebrovascular diseases can also present less commonly with headache or seizures. Any of these diseases can result in vascular dementia due to ischemic damage to the brain.

It is also possible to classify angiopathy by the associated condition:

- Diabetic angiopathy

- Congophilic angiopathy

There are two types of angiopathy: macroangiopathy and microangiopathy.

In macroangiopathy, atherosclerosis and a resultant blood clot forms on the large blood vessels, sticks to the vessel walls, and blocks the flow of blood. Macroangiopathy may cause other complications, such as ischemic heart disease, stroke and peripheral vascular disease which contributes to the diabetic foot ulcers and the risk of amputation.

In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. The decrease of blood flow through stenosis or clot formation impairs the flow of oxygen to cells and biological tissues (called ischemia) and leads to cellular death (necrosis and gangrene, which in turn may require amputation). Thus, tissues which are very sensitive to oxygen levels, such as the retina, develop microangiopathy and may cause blindness (so-called proliferative diabetic retinopathy). Damage to nerve cells may cause peripheral neuropathy, and to kidney cells, diabetic nephropathy (Kimmelstiel-Wilson syndrome).

Certain changes in morphology are associated with cerebral edema: the brain becomes soft and smooth and overfills the cranial vault, gyri (ridges) become flattened, sulci (grooves) become narrowed, and ventricular cavities become compressed.

Symptoms include nausea, vomiting, blurred vision, faintness, and in severe cases, seizures and coma. If brain herniation occurs, respiratory symptoms or respiratory arrest can also occur due to compression of the respiratory centers in the pons and medulla oblongata.

Cerebral atherosclerosis is a type of atherosclerosis where build-up of plaque in the blood vessels of the brain occurs. Some of the main components of the plaques are connective tissue, extracellular matrix, including collagen, proteoglycans, fibronectin, and elastic fibers; crystalline cholesterol, cholesteryl esters, and phospholipids; cells such as monocyte derived macrophages, T-lymphocytes, and smooth muscle cells. The plaque that builds up can lead to further complications such as stroke, as the plaque disrupts blood flow within the intracranial arterioles. This causes the downstream sections of the brain that would normally be supplied by the blocked artery to suffer from ischemia. Diagnosis of the disease is normally done through imaging technology such as angiograms or magnetic resonance imaging. The risk of cerebral atherosclerosis and its associated diseases appears to increase with increasing age; however there are numerous factors that can be controlled in attempt to lessen risk.

The signs and symptoms of carotid artery dissection may be divided into ischemic and non-ischemic categories:

"Non-ischemic signs and symptoms"

- Localised headache, particularly around one of the eyes.

- Neck pain

- Decreased pupil size with drooping of the upper eyelid (Horner syndrome)

- Pulsatile tinnitus

"Ischemic signs and symptoms"

- Temporary vision loss

- Ischemic stroke

The causes of internal carotid artery dissection can be broadly categorised into two classes: spontaneous or traumatic.

Intracerebral hemorrhage (ICH), also known as cerebral bleed, is a type of intracranial bleed that occurs within the brain tissue or ventricles. Symptoms can include headache, one-sided weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. Often symptoms get worse over time. Fever is also common. In many cases bleeding is present in both the brain tissue and the ventricles.

Causes include brain trauma, aneurysms, arteriovenous malformations, and brain tumors. The largest risk factors for spontaneous bleeding are high blood pressure and amyloidosis. Other risk factors include alcoholism, low cholesterol, blood thinners, and cocaine use. Diagnosis is typically by CT scan. Other conditions that may present similarly include ischemic stroke.

Treatment should typically be carried out in an intensive care unit. Guidelines recommended decreasing the blood pressure to a systolic of less than 140 mmHg. Blood thinners should be reversed if possible and blood sugar kept in the normal range. Surgery to place a ventricular drain may be used to treat hydrocephalus but corticosteroids should not be used. Surgery to remove the blood is useful in certain cases.

Cerebral bleeding affects about 2.5 per 10,000 people each year. It occurs more often in males and older people. About 44% of those affected die within a month. A good outcome occurs in about 20% of those affected. Strokes were first divided into their two major types, bleeding and insufficient blood flow, in 1823.

Symptoms of AVM vary according to the location of the malformation. Roughly 88% of people with an AVM are asymptomatic; often the malformation is discovered as part of an autopsy or during treatment of an unrelated disorder (called in medicine an "incidental finding"); in rare cases, its expansion or a micro-bleed from an AVM in the brain can cause epilepsy, neurological deficit, or pain.

The most general symptoms of a cerebral AVM include headaches and epileptic seizures, with more specific symptoms occurring that normally depend on the location of the malformation and the individual. Such possible symptoms include:

- Difficulties with movement coordination, including muscle weakness and even paralysis;

- Vertigo (dizziness);

- Difficulties of speech (dysarthria) and communication, such as aphasia;

- Difficulties with everyday activities, such as apraxia;

- Abnormal sensations (numbness, tingling, or spontaneous pain);

- Memory and thought-related problems, such as confusion, dementia or hallucinations.

Cerebral AVMs may present themselves in a number of different ways:

- Bleeding (45% of cases)

- Acute onset of severe headache. May be described as the worst headache of the patient's life. Depending on the location of bleeding, may be associated with new fixed neurologic deficit. In unruptured brain AVMs, the risk of spontaneous bleeding may be as low as 1% per year. After a first rupture, the annual bleeding risk may increase to more than 5%.

- Seizure or brain seizure (46%) Depending on the place of the AVM, it can cause loss of vision in one place.

- Headache (34%)

- Progressive neurologic deficit (21%)

- May be caused by mass effect or venous dilatations. Presence and nature of the deficit depend on location of lesion and the draining veins.

- Pediatric patients

- Heart failure

- Macrocephaly

- Prominent scalp veins

Cerebral edema is excess accumulation of fluid in the intracellular or extracellular spaces of the brain.

It is usually associated with amyloid beta.

However, there are other types:

- the "Icelandic type" is associated with Cystatin C

- the "British type" is associated with ITM2B

Research is currently being conducted to determine if there is a link between cerebral amyloid angiopathy and ingestion of excessive quantities of aluminum.

Arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. This vascular anomaly is widely known because of its occurrence in the central nervous system (usually cerebral AVM), but can appear in any location. Although many AVMs are asymptomatic, they can cause intense pain or bleeding or lead to other serious medical problems.

AVMs are usually congenital and belong to the RASopathies.

The genetic transmission patterns of AVM, if any, are unknown. AVM is not generally thought to be an inherited disorder, unless in the context of a specific hereditary syndrome.

Diseases associated with cerebral atherosclerosis include:

- Hypertensive arteriopathy

This pathological process involves the thickening and damage of arteriole walls. It mainly affects the ends of the arterioles which are located in the deep gray nuclei and deep white matter of the brain. It is thought that this is what causes cerebral microbleeds in deep brain regions. This small vessel damage can also reduce the clearance of amyloid-β, thereby increasing the likelihood of CAA.

Diseases cerebral atherosclerosis and associated diseases can cause are:

- Alzheimer's disease

Alzheimer's disease is a form of dementia that entails brain atrophy. Cerebral amyloid angiopathy is found in 90% of the cases at autopsy, with 25% being severe CAA.

- Cerebral microbleeds (CMB)

Cerebral microbleeds have been observed during recent studies on dementia sufferers using MRI.

- Stroke

Strokes occur from the sudden loss of blood flow to an area of the brain. The loss of flow is generally either from a blockage or hemorrhage. Studies of postmortem stroke cases have shown that intracranial athreosclerotic plaque build up occurred in over half of the individuals and over one third of the overall cases had stenotic build up.

Microangiopathy (or microvascular disease, or small vessel disease) is an angiopathy (i.e. disease of blood vessels) affecting small blood vessels in the body. It can be contrasted to macroangiopathy, or large vessel disease.

Cerebral small vessel disease refers to a group of diseases that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms.

Coronary small vessel disease is a type of coronary heart disease (CHD) that affects the arterioles and capillaries of the heart. Coronary small vessel disease is also known as cardiac syndrome X, microvascular dysfunction, non-obstructive coronary disease, or microvascular angina.

All symptoms normally resolve within three weeks, and may only last days. Permanent deficits are seen in a minority of patients, ranging from under 10% to 20% in various studies. Less than 5% of patients experience progressive vasoconstriction, which can lead to stroke, progressive cerebral edema, or even death. Severe complications appear to be more common in postpartum mothers.

One cause of microangiopathy is long-term diabetes mellitus. In this case, high blood glucose levels cause the endothelial cells lining the blood vessels to take in more glucose than normal (these cells do not depend on insulin). They then form more glycoproteins on their surface than normal, and also cause the basement membrane in the vessel wall to grow abnormally thicker and weaker. Therefore they bleed, leak protein, and slow the flow of blood through the body. As a result, some organs and tissues do not get enough blood (carrying oxygen & nutrients) and are damaged, for example, the retina (diabetic retinopathy) or kidney (diabetic nephropathy). Nerves and neurons, if not sufficiently supplied with blood, are also damaged, which leads to loss of function (diabetic neuropathy, especially peripheral neuropathy).

Massive microangiopathy may cause microangiopathic hemolytic anemia (MAHA).

The key symptom of RCVS is recurrent thunderclap headaches, which over 95% of patients experience. In two-thirds of cases, it is the only symptom. These headaches are typically bilateral, very severe and peak in intensity within a minute. They may last from minutes to days, and may be accompanied by nausea, photophobia, phonophobia or vomiting. Some patients experience only one headache, but on average there are four attacks over a period of one to four weeks. A milder, residual headache persists between severe attacks for half of patients.

1–17% of patients experience seizures. 8–43% of patients show neurologic problems, especially visual disturbances, but also hemiplegia, ataxia, dysarthria, aphasia, and numbness. These neurologic issues typically disappear within minutes or a few hours; more persistent symptoms may indicate a stroke. Posterior reversible encephalopathy syndrome is present in a small minority of patients.

This condition features the unique property that the patient's cerebral arteries can spontaneously constrict and relax back and forth over a period of time without intervention and without clinical findings. Vasospasm is common post subarachnoid hemorrhage and cerebral aneurysm, but in RCVS only 25% of patients have symptoms post subarachnoid hemorrhage.

Clinical symptoms of CNS origin include recurrent headaches, focal neurological deficits, hemorrhagic stroke, and seizures, but CCM can also be asymptomatic. The nature and severity of the symptoms depend on the lesion's location.

Since this can be caused by the same amyloid protein that is associated with Alzheimer's dementia, brain bleeds are more common in people who have a diagnosis of Alzheimer's Disease, however they can also occur in those who have no history of dementia. The bleeding within the brain is usually confined to a particular lobe and this is slightly different compared to brain bleeds which occur as a consequence of high blood pressure (hypertension) - a more common cause of a hemorrhagic stroke (or bleeding in the brain).

Autosomal Dominant Retinal Vasculopathy with Cerebral Leukodystrophy (AD-RVCL) (previously known also as Cerebroretinal Vasculopathy, CRV, or Hereditary Vascular Retinopathy, HVR or Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke, HERNS) is an inherited condition resulting from a frameshift mutation to the TREX1 gene. This genetically inherited condition affects the retina and the white matter of the central nervous system, resulting in vision loss, lacunar strokes and ultimately dementia. Symptoms commonly begin in the early to mid-forties, and treatments currently aim to manage or alleviate the symptoms rather than treating the underlying cause. The overall prognosis is poor, and death can sometimes occur within 10 years of the first symptoms appearing.

AD-RVCL (CRV) Acronym

Autosomal Dominance (genetics) means only one copy of the gene is necessary for the symptoms to manifest themselves.

Retinal Vasculopathy means a disorder that is associated with a disease of the blood vessels in the retina.

Cerebral means having to do with the brain.

Leukodystrophy means a degeneration of the white matter of the brain.

Pathogenesis

The main pathologic process centers on small blood vessels that prematurely “drop out” and disappear. The retina of the eye and white matter of the brain are the most sensitive to this pathologic process. Over a five to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death.

Most recently, AD-RVCL (CRV) has been renamed. The new name is CHARIOT which stands for Cerebral Hereditary Angiopathy with vascular Retinopathy and Impaired Organ function caused by TREX1 mutations.

Treatment

Currently, there is no therapy to prevent the blood vessel deterioration.

About TREX1

The official name of the TREX1 gene is “three prime repair exonuclease 1.” The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes.

Changes (mutations) to the TREX1 gene can result in a range of conditions one of which is AD-RVCL. The mutations to the TREX1 gene are believed to prevent the production of the 3-prime repair exonuclease 1 enzyme. Researchers suggest that the absence of this enzyme may result in an accumulation of unneeded DNA and RNA in cells. These DNA and RNA molecules may be mistaken by cells for those of viral invaders, triggering immune system reactions that result in the symptoms of AD-RVCL.

Mutations in the TREX1 gene have also been identified in people with other disorders involving the immune system. These disorders include a chronic inflammatory disease called systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin.

The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644

The immune system.

- The immune system is composed of white blood cells or leukocytes.

- There are 5 different types of leukocytes.

- Combined, the 5 different leukocytes represent the 2 types of immune systems (The general or innate immune system and the adaptive or acquired immune system).

- The adaptive immune system is composed of two types of cells (B-cells which release antibodies and T-cells which destroy abnormal and cancerous cells).

How the immune system becomes part of the condition.

During mitosis, tiny fragments of “scrap” single strand DNA naturally occur inside the cell. Enzymes find and destroy the “scrap” DNA. The TREX1 gene provides the information necessary to create the enzyme that destroys this single strand “scrap” DNA. A mutation in the TREX1 gene causes the enzyme that would destroy the single strand DNA to be less than completely effective. The less than completely effective nature of the enzyme allows “scrap” single strand DNA to build up in the cell. The buildup of “scrap” single strand DNA alerts the immune system that the cell is abnormal.

The abnormality of the cells with the high concentration of “scrap” DNA triggers a T-cell response and the abnormal cells are destroyed. Because the TREX1 gene is identical in all of the cells in the body the ineffective enzyme allows the accumulation of “scrap” single strand DNA in all of the cells in the body. Eventually, the immune system has destroyed enough of the cells in the walls of the blood vessels that the capillaries burst open. The capillary bursting happens throughout the body but is most recognizable when it happens in the eyes and brain because these are the two places where capillary bursting has the most pronounced effect.

Characteristics of AD-RVCL

- No recognizable symptoms until after age 40.

- No environmental toxins have been found to be attributable to the condition.

- The condition is primarily localized to the brain and eyes.

- Optically correctable, but continuous, deterioration of visual acuity due to extensive multifocal microvascular abnormalities and retinal neovascularization leading, ultimately, to a loss of vision.

- Elevated levels of alkaline phosphatase.

- Subtle vascular changes in the retina resembling telangiectasia (spider veins) in the parafovea circulation.

- Bilateral capillary occlusions involving the perifovea vessels as well as other isolated foci of occlusion in the posterior pole of the retina.

- Headaches due to papilledema.

- Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to “firm masses” and white, granular, firm lesions in the brain.

- Jacksonian seizures and grand mal seizure disorder.

- Progressive neurologic deterioration unresponsive to systemic corticosteroid therapy.

- Discrete, often confluent, foci of coagulation necrosis in the cerebral white matter with intermittent findings of fine calcium deposition within the necrotic foci.

- Vasculopathic changes involving both arteries and veins of medium and small caliber present in the cerebral white matter.

- Fibroid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue.

- Obliterative fibrosis in all the layers of many vessel walls.

- Parivascular, adventitial fibrosis with limited intimal thickening.

Conditions with similar symptoms that AD-RVCL can be misdiagnosed as:

- Brain tumors

- Diabetes

- Macular degeneration

- Telangiectasia (Spider veins)

- Hemiparesis (Stroke)

- Glaucoma

- Hypertension (high blood pressure)

- Systemic Lupus Erythematosus (SLE (same original pathogenic gene, but definitely a different disease because of a different mutation in TREX1))

- Polyarteritis nodosa

- Granulomatosis with polyangiitis

- Behçet's disease

- Lymphomatoid granulomatosis

- Vasculitis

Clinical Associations

- Raynaud's phenomenon

- Anemia

- Hypertension

- Normocytic anemia

- Normochromic anemia

- Gastrointestinal bleeding or telangiectasias

- Elevated alkaline phosphatase

Definitions

- Coagulation necrosis

- Endothelium

- Fibrinoid

- Fibrinoid necrosis

- Frameshift mutation

- Hemiparesis

- Jacksonian seizure

- Necrotic

- Necrosis

- Papilledema

- Perivascular

- Retinopathy

- Telangiectasia

- Vasculopathy

- Vascular

What AD-RVCL is not:

- Infection

- Cancer

- Diabetes

- Glaucoma

- Hypertension

- A neurological disorder

- Muscular dystrophy

- Systemic Lupus Erythematosis (SLE)

- Vasculitis

Things that have been tried but turned out to be ineffective or even make things worse:

- Antibiotics

- Steroids

- X-Ray therapy

- Immunosuppression

History of AD-RVCL (CRV)

- 1985 – 1988: CRV (Cerebral Retinal Vasculopathy) was discovered by John P. Atkinson, MD at Washington University School of Medicine in St. Louis, MO

- 1988: 10 families worldwide were identified as having CRV

- 1991: Related disease reported, HERNS (Hereditary Endiotheliopathy with Retinopathy, Nephropathy and Stroke – UCLA

- 1998: Related disease reported, HRV (Hereditary Retinal Vasculopathy) – Leiden University, Netherlands

- 2001: Localized to Chromosome 3.

- 2007: The specific genetic defect in all of these families was discovered in a single gene called TREX1

- 2008: Name changed to AD-RVCL Autosomal Dominant-Retinal Vasculopathy with Cerebral Leukodystrophy

- 2009: Testing for the disease available to persons 21 and older

- 2011: 20 families worldwide were identified as having CRV

- 2012: Obtained mouse models for further research and to test therapeutic agents

Sneddon's syndrome generally manifests with stroke or severe, transient neurological symptoms, and a skin rash (livedo reticularis). Livedo reticularis appears as a bluish-purple, netlike mottling of the skin. Sneddon's syndrome may instead present with livedo racemosa, which involves larger, less organized patches of bluish-purple mottling of the skin. Both are generally found first in the extremities, both worsen in cold and either may occur without Sneddon's Syndrome or any other systemic disease.

Sneddon's Syndrome can be characterized by: transient amnesia, transient aphasia, palsy, headaches, hypertension, transient ischemic attacks (TIA), stroke, coronary disease and dementia. The skin manifestations may precede the neurologic symptoms by years.