Hereditary amyloidosis

Definition

Cerebral amyloid angiopathy (CAA) is also known as congophilic angiopathy or cerebrovascular amyloidosis. It is a disease of small blood vessels in the brain in which deposits of amyloid protein in the vessel walls may lead to stroke, brain hemorrhage, or dementia. Amyloid protein resembles a starch and is deposited in tissues during the course of certain chronic diseases.

Description

CAA may affect patients over age 45, but is most common in patients over age 65, and becomes more common with increasing age. Men and women are equally affected. In some cases, CAA is sporadic but it may also be inherited as an autosomal dominant condition (a form of inheritance in which only one copy of a gene coding for a disease need be present for that disease to be expressed; if either parent has the disease, a child has a 50% chance of inheriting the disease). CAA is responsible for 5-20% of brain hemorrhage and up to 30% of lobar hemorrhages localized to one lobe of the brain. CAA may be found during an autopsy in over one-third of persons over age 60, even though they may not have had brain hemorrhage, stroke, or other manifestations of the disease during life. In Alzheimer's disease, CAA is more common than in the general population, and may occur in more than 80% of patients over age 60.

Causes & symptoms

The cause of amyloid deposits in blood vessels in the brain in sporadic CAA is not known. In hereditary CAA, genetic defects, typically on chromosome 21, allow accumulation of amyloid, a protein made up of units called beta-pleated sheet fibrils. The fibrils tend to clump together, so that the amyloid cannot be dissolved and builds up in the brain blood vessel walls. One form of amyloid fibril subunit proteins is the amyloid beta protein.

Different theories have been suggested for the source of amyloid beta protein in the brain. The systemic theory suggests that amyloid beta protein in the blood stream is deposited in blood vessels in the brain, causing weakness in the blood vessel wall and breakdown in the blood-brain barrier. Normally, the blood-brain barrier keeps proteins and other large molecules from escaping from the blood vessel to the brain tissue. When there is breakdown of the blood-brain barrier, amyloid beta protein leaks through the blood vessel wall, and is deposited in the brain substance, where it forms an abnormal structure called a neuritic plaque.

A second, more likely, theory is that amyloid fibrils that form amyloid beta protein are produced by perivascular microglia, or support cells in contact with the brain blood vessel wall. The third theory is that the brain tissue gives rise to amyloid beta protein. Both the nerve cells and the glia are known to produce amyloid precursor protein, which increases with aging and with cell stress.

Bleeding into the brain may occur as tiny blood vessels carrying amyloid deposits become heavier and more brittle, and are therefore more likely to burst with minor trauma or with fluctuating blood pressure. Aneurysms, or ballooning of the blood vessel wall, may develop, and are may also rupture as the stretched wall becomes thinner and is under more pressure. Amyloid deposits may destroy smooth muscle cells or cause inflammation in the blood vessel wall. This may also cause the blood vessel to break more easily.

The most common form of CAA is the sporadic form associated with aging. This type of CAA usually causes lobar hemorrhage, which may recur in different lobes of the brain. The frontal lobe (behind the forehead) and parietal lobe (behind the frontal lobe) are most often affected; the temporal lobe (near the temple) and occipital lobe (at the back of the brain) are affected less often; and the cerebellum (under the occipital lobe) is rarely affected. Approximately 10-50% of hemorrhages in sporadic CAA involve more than one lobe.

Symptoms of lobar hemorrhage in CAA include sudden onset of headache, neurologic symptoms such as weakness, sensory loss, visual changes, or speech problems, depending on which lobe is involved; and decreased level of consciousness (a patient who is difficult to arouse), nausea, and vomiting. Sporadic CAA may be associated with symptoms unrelated to lobar hemorrhage. Petechial hemorrhages (tiny hemorrhages involving many small vessels) may produce recurrent, brief neurologic symptoms secondary to seizures or decreased blood flow, or may produce rapidly progressive dementia (loss of memory and other brain functions) that worsens in distinct steps rather than gradually. Over 40% of patients with hemorrhage secondary to CAA also have dementia.

Genetic factors play a role in certain types of CAA and in diseases associated with CAA:

• Dutch type of hereditary cerebral hemorrhage with amyloidosis (build up of amyloid protein in blood vessels): autosomal dominant, with a genetic mutation involving the amyloid precursor protein. Onset is at age 40-60 with headaches, brain hemorrhage often in the parietal lobe, strokes, and dementia. More than half of patients die from their first hemorrhage. Patients with the Dutch type of CAA may produce an abnormal anticoagulant, or blood thinner, which makes hemorrhage more likely.
• Flemish type of hereditary cerebral hemorrhage with amyloidosis: autosomal dominant, with a mutation involving the amyloid precursor protein. Symptoms include brain hemorrhage or dementia.
• Familial Alzheimer's disease: autosomal dominant, comprising 5-10% of all Alzheimer's disease cases (a brain disease in which death of nerve cells leads to progressive dementia).
• Down Syndrome: caused by trisomy 21, (three rather than two copies of chromosome 21), causing excess amyloid precursor protein gene. Children with Down syndrome are mentally handicapped and may have heart problems.
• Icelandic type of hereditary cerebral hemorrhage with amyloidosis: autosomal dominant, with mutation in the gene coding for cystatin C. Symptoms often begin at age 30-40 with multiple brain hemorrhages, dementia, paralysis (weakness), and death in 10-20 years. Headache occurs in more than half of patients, and seizures occur in one-quarter. Unlike most other forms of CAA, most hemorrhages involve the basal ganglia deep within the brain (Basal ganglia are islands of tissues in the cerebellum part of the brain.).
• Familial oculo-leptomeningeal amyloidosis: autosomal dominant with unknown gene defect(s), described in Japanese, Italian, and North American families. Symptoms can include dementia, ataxia (problems with coordination), spasticity (limb stiffness), strokes, seizures, peripheral neuropathy (disease affecting the nerves supplying the limbs), migraine, spinal cord problems, blindness, and deafness. Brain hemorrhage is rare as the amyloid protein is deposited in blood vessels in the eye and meninges (brain coverings), but not in the brain itself. In Italian families with the disease, patients may be affected as early as 20-30 years of age.
• British type of familial amyloidosis: autosomal dominant with unknown gene defect(s), associated with progressive dementia, spasticity, and ataxia. Brain stem, spinal cord, and cerebellum all exhibit amyloid deposits, but hemorrhage typically does not occur.

Diagnosis

As in most neurologic diseases, diagnosis is made most often from the patient's history, with careful inquiry into family history and the patient's onset and pattern of symptoms, as well as neurologic examination. Brain computed tomography (CT) or magnetic resonance imaging (MRI) may identify lobar hemorrhage, stroke, or petechial hemorrhages, and are important in excluding arteriovenous malformation, brain tumor, or other causes of hemorrhage. Angiography (x-ray study of the interior of blood vessels and the heart) is not helpful in diagnosis of CAA, but may be needed to exclude aneurysm. Brain biopsy (surgical removal of a small piece of brain tissue) may show characteristic amyloid deposits, but is rarely performed, as the risk may not be justifiable in the absence of effective treatment for CAA. If diagnosis is uncertain, biopsy may be needed to rule out conditions which are potentially treatable. Definite diagnosis requires microscopic examination of brain tissue, either at biopsy, at autopsy, or at surgery when brain hemorrhage is drained. Lumbar puncture to examine cerebrospinal fluid proteins may show characteristic abnormalities, but is not part of the routine exam. In familial forms, genetic analysis may be helpful.

CAA with hemorrhage must be distinguished from other types of brain hemorrhage. In CAA, hemorrhage typically occurs in the lobar region, often ruptures into the subarachnoid space between the brain and its coverings, and occurs at night. In hemorrhage related to high blood pressure, hemorrhage is usually deeper within the brain, ruptures into the ventricles or cavities deep inside the brain, and occurs during daytime activities. Other causes of brain hemorrhage, are arteriovenous malformations, trauma, aneurysms, bleeding into a brain tumor, vasculitis (inflammation of blood vessels), or bleeding disorders.

Treatment

Although there is no effective treatment for the underlying disease process of CAA, measures can be taken to prevent brain hemorrhage in patients diagnosed with CAA. High blood pressure should be treated aggressively, and even normal blood pressure can be lowered as much as tolerated without side effects from medications. Blood thinners such as Coumadin, antiplatelet agents such as aspirin, or medications designed to dissolve blood clots may cause hemorrhage in patients with CAA, and should be avoided if possible. If these medications are required for other conditions, such as heart disease, the potential benefits must be carefully weighed against the increased risks.

Seizures, or recurrent neurologic symptoms thought to be seizures, should be treated with anti-epileptic drugs, although Depakote (sodium valproate) should be avoided because of its antiplatelet effect. Anti-epileptic drugs are sometimes given to patients with large lobar hemorrhage in an attempt to prevent seizures, although the benefit of this is unclear.

Once brain hemorrhage has occurred, the patient should be admitted to a hospital (ICU) for neurologic monitoring and control of increased pressure within the brain, blood pressure control, and supportive medical care. Antiplatelet agents and blood thinners should be discontinued and their effects reversed, if possible. Surgery may be needed to remove brain hemorrhage, although bleeding during surgery may be difficult to control.

CAA may be rarely associated with cerebral vasculitis, or inflammation of the blood vessel walls. In these cases treatment with steroids or immune system suppressants may be helpful. Without tissue examination, vasculitis cannot be diagnosed reliably, and probably coexists with CAA too rarely to justify steroid treatment in most cases.

Prognosis

Since CAA is associated with progressive blood vessel degeneration, and since there is no effective treatment, most patients have a poor prognosis. Aggressive neurosurgical management allows increased survival following lobar hemorrhage, but as of 1998, between 20-90% of patients die from the first hemorrhage or its complications, which include progression of hemorrhage, brain edema (swelling) with herniation (downward pressure on vital brain structures), seizures, and infections such as pneumonia. Many survivors have persistent neurologic deficits related to the brain lobe affected by hemorrhage, and are at risk for additional hemorrhages, seizures, and dementia. Prognosis is worse in patients who are older, or who have larger hemorrhages or recurrent hemorrhages within a short time.

Key Terms

Amyloid

Amyloid protein resembles a starch and is deposited in tissues during the course of certain chronic diseases.

Ataxia

Problems with coordination and walking.

Autosomal dominant

A form of inheritance in which only one copy of a gene coding for a disease need be present for that disease to be expressed. If either parent has the disease, a child has a 50% chance of inheriting the disease.

Chromosome

A cellular structure containing genetic information in the form of DNA.

Dementia

Loss of memory and other higher functions, such as thinking or speech, lasting six months or more.

Hemorrhage

Bleeding, or escape of blood through ruptured or unruptured blood vessel walls.

Lobar hemorrhage

Bleeding into one of the lobes of the brain.

Seizure

Epileptic convulsion, fit, or attack.

Sporadic

A form of disease found in persons without a family history of the disease.

Spasticity

Limb stiffness related to disease of the brain or spinal cord.

Stroke

Sudden neurological deficit related to impaired blood supply to the brain.

Further Reading

For Your Information

Periodicals

• Bornebroek, M., et.al. "White Matter Lesions and Cognitive Deterioration in Presymptomatic Carriers of the Amyloid Precursor Protein Gene Codon 693 Mutation." In Archives of Neurology, 53 (1) (1996): 43-48.
• Itoh, Y., et.al. "Cerebral Amyloid Angiopathy: a Significant Cause of Cerebellar as well as Lobar Cerebral Hemorrhage in the Elderly." In Journal of Neurological Sciences, 116 (2) (1993):135-41.
• Neau, J.P., et.al. "Recurrent Intracerebral Hemorrhage." In Neurology, 49 (1) (1997):106-113.
• Olichney, J.M., et.al. "Cerebral Infarction in Alzheimer's Disease Is Associated with Severe Amyloid Angiopathy and Hypertension." In Archives of Neurology, 52 (7) (1995): 702-8.

Gale Encyclopedia of Medicine. Gale Research, 1999.