final pathophysilogy

HUNTINGTON’S DISEASE

associated with progressive degeneration of neurons in certain regions of the brain and the presence of astrocytes that accumulate due to destruction of nearby neurons (gliosis).

These neurodegenerative changes primarily occur within the caudate nuclei and the putamen, substructures of the basal ganglia that are collectively known as the striatum. (The basal ganglia consist of specialized nerve cell clusters deep within the brain that organize motor behavior.

Major substructures of the basal ganglia include the caudate nuclei, the putamen, and the globus pallidus as well as other cell groups.) HD is also characterized by associated neuronal degeneration within the temporal and frontal lobes of the cerebral cortex.

This part of the brain is responsible for integrating higher mental functioning, movements, and sensations.

The degenerative changes in HD primarily affect certain nerve cells of the striatum known as medium-sized "spiny" neurons, which are named for their size and appearance and project into the globus pallidus and substantia nigra.

These highly specialized "spiny" neurons secrete gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits the release of neurotransmitters from other nerve cells. One theory suggests that selective loss of these specialized cells results in decreased inhibition (i.e., increased activity) of the thalamus.

Therefore the thalamus increases its output to certain regions of the brain's cerebral cortex. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea.

reduced uptake of the neurotransmitter dopamine within the striatum, potentially playing a role in causing the choreic movements associated with HD.

Several investigations indicate that impaired energy metabolism (mitochondrial dysfunction) may result in excessive or prolonged activation (excitotoxicity) by neurotransmitters, such as glutamate or N-methyl-D-aspartate (NMDA). This may cause damage to and loss of nerve cells (apoptosis)

GUILLANE BARRE

SYNDROME

is a postinfectious, immune-mediated disease. Cellular and humoral immune mechanisms probably play a role in its development.

Most patients report an infectious illness in the weeks prior to the onset of GBS. Many of the identified infectious agents are thought to induce production of antibodies that cross-react with specific gangliosides and glycolipids, such as GM1 and GD1b, that are distributed throughout the myelin in the peripheral nervous system.^[3]

Immune responses directed against lipopolysaccharide antigens in the capsule of C jejuni result in antibodies that cross-react with ganglioside GM1 in myelin, resulting in the immunologic damage to the peripheral nervous system. This process has been termed molecular mimicry.

include lymphocytic infiltration of spinal roots and peripheral nerves (cranial nerves may be involved as well), followed by macrophage-mediated, multifocal stripping of myelin. This phenomenon results in defects in the propagation of electrical nerve impulses, with eventual absence or profound delay in conduction, causing flaccid paralysis. Recovery is typically associated with remyelination.

severe inflammation is axonal disruption and loss. A subgroup of patients may have a primary immune attack directly against nerve axons, with sparing of myelin. The clinical presentation in these patients is similar to that of the principal type.

is the pressure in the skull that results from the volume of three essential components: cerebrospinal fluid (CSF), intracranial blood volume and central nervous system tissue. The normal intracranial pressure is between 5-15 mmHg. This is slightly lower than the mean systemic arterial pressure but considerably higher than venous pressure.

The intact cranium is essentially inexpandable containing about 1400 grams of central nervous system (CNS) or brain tissue, 75 ml of blood and about 75 ml of cerebrospinal fluid (CSF). These three components of the cranial vault maintain a state of equilibrium. Their pressure and volume determine the condition of balance.

According to Monro-Kellie hypothesis, any increase in one of these elements must be balanced or compensated by a proportional constriction either or both of the other two components such as decreasing the volume of cerebral blood flow, shifting CSF flow (into the spinal canal) or increasing CSF absorption. Absence of these compensatory changes results to increased intracranial pressure. Once ICP reaches around 25 mmHg marked elevation in intracranial pressure will be noted.

CSF is formed from the blood by the choroid plexuses, which are hanging at the roof of the brain’s ventricles. From the point where it is produced, it flows through the aqueduct of Sylvius to the fourth ventricles. Three apertures (opening) are found in the fourth ventricle which serves as passageway going to the subarachnoid spaces in the brain and spinal cord. These openings are Foramina of Magendie (median aperture) and two Foramina of Luschka (lateral apertures). A presence of tumor in choroid plexus may cause an overproduction of CSF. If the passageway of CSF is obstructed or brain tissue damage during surgery occurs, elevated ICP is inevitable.

Normally, a change in CSF and blood volume occurs. For instance, during exhalation a temporary rise in intrathoracic pressure occurs. This impairs cerebral venous drainage and thereby reabsorption of CSF. An increase in ICP might likely occur, unless the blood will be expelled or the brain tissue will shrink (compensatory mechanism). If no compensation will occur, based on Monro-Kellie hypothesis, a slight increase in intracranial pressure will take place. The same process occurs during Valsalva maneuver (forcible exhalation against a closed glottis), sneezing, coughing and straining at stool. This is the main reason why people with increase ICP and at risk for cerebral hemorrhage are instructed to avoid these instances.

Presence of carbon dioxide can also increase ICP. Carbon dioxide is a potent vasodilator that dilates aretrioles (including those in the chorionic plexus)

CEREBROVASCULAR DISEASE   

Neurons and glia die when they no longer receive oxygen and nutrients from the blood or when they are damaged by sudden bleeding into or around the brain.

These damaged cells can linger in a compromised state for several hours. With timely treatment, these cells can be saved.

Intriguingly, when the brain cells suffer the ischemia, they begin to fill up with free zinc ions which are released from some of their proteins, especially metallothionein, which can release 7 zinc ions per molecule.

This released zinc is a major player in the ensuing death of the brain cells. Drugs that buffer the zinc and reduce the level of free zinc are already being tested to reduce brain cell death after stroke.

ANGINA PECTORIS

develops when coronary blood flow becomes inadequate to meet myocardial oxygen demand. This causes myocardial cells to switch from aerobic to anaerobic metabolism, with a progressive impairment of metabolic, mechanical, and electrical functions. Angina pectoris is the most common clinical manifestation of myocardial ischemia.

It is caused by chemical and mechanical stimulation of sensory afferent nerve endings in the coronary vessels and myocardium. adenosine may be the main chemical mediator of anginal pain. During ischemia, ATP is degraded to adenosine, which, after diffusion to the extracellular space, causes arteriolar dilation and anginal pain.

Heart rate, myocardial inotropic state, and myocardial wall tension are the major determinants of myocardial metabolic activity and myocardial oxygen demand. Increases in the heart rate and myocardial contractile state result in increased myocardial oxygen demand. Increases in both afterload (ie, aortic pressure) and preload (ie, ventricular end-diastolic volume) result in a proportional elevation of myocardial wall tension and, therefore, increased myocardial oxygen demand.

The ability of the coronary arteries to increase blood flow in response to increased cardiac metabolic demand is referred to as coronary flow reserve (CFR).

ICP