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

BELL'S PALSY

BELL’S PALSY

 

 The facial nerve courses through a portion of the temporal bone commonly referred to as the facial canal. A popular theory proposes that edema and ischemia results in compression of the facial nerve within this bony canal. 

Given the tight confines of facial canal, it seems logical that inflammatory, demyelinating, ischemic, or compressive processes may impair neural conduction at this site.

  

The location of injury of the facial nerve in Bell palsy is peripheral to the nerve’s nucleus. The injury is thought to occur near, or at, the geniculate ganglion. If the lesion is proximal to the geniculate ganglion, the motor paralysis is accompanied by gustatory and autonomic abnormalities. Lesions between the geniculate ganglion and the origin of the chorda tympani produce the same effect, except that they spare lacrimation. If the lesion is at the stylomastoid foramen, it may result in facial paralysis.

ETIOLOGY

situations that produced cold exposure (eg, chilly wind, cold air conditioning, or driving with the car window down) were considered the only triggers to Bell palsy. believe that the herpes simplex virus autoimmune reactions causing the facial nerve to demyelinate, resulting in unilateral facial paralysis , autosomal dominant.

Symptom

·    Change in facial expression (for example, grimacing)

·         Difficulty with eating and drinking

·         Drooling due to lack of control over muscles of the face

·         Droopy eyelid or corner of mouth

 ·         Dry eye or mouth

·         Face feels stiff or pulled to one side

·         Facial paralysis of one side of the face, makes it hard to close one eye

·         Headache

·         Loss of sense of taste

·         Pain behind or in front of the ear

·         Sensitivity to sound (hyperacusis) on the affected side of the face

·         Twitching in face

·         Weakness in face

Complications:

·         Abnormal movements, such as tears when laughing or salivation at the wrong times (synkinesis)

·         Change in appearance of the face (disfigurement) from loss of movement

·         Chronic problems with taste

·         Chronic spasm of face muscles or eyelids

·         Damage to the eye (corneal ulcers and infections

PARKINSONS DISEASE

Is slowly progressing neurologic movement disorder that eventually leads to disability.

 

Destruction of dopaminergic neuronal cells in the substantial nigra in the basal ganglia.

Depletion of dopamine stores.

 

Degeneration of the dopaminergic nigrostriatal

Imbalance of excitatory ( acetyl-choline) and inhibiting (dopamine) neurotransmitters in the corpus stria-tum.

ALZHEIMERS DISEASE

A progressive, irreversible degenerative neurologic disease that begins insidiously and characterized by gradual losses of cognitive function and disturbances in behavior and affect.

The neurofibrilarry tangles (tangle masses of nonfunctioning neurons) and senile or neuritic plaques (deposits of amyloids protein, part of a large protein the brain.)

The neuronal damage occurs in the cerebral cortex result in decreased brain size. Cells that use in the neurotransmitter acetylcholine are principally affected and the biochemical level, the enzyme active in producing acetylcholine, which is specifically involved in memory processing, is decreased.

The complex ways in which aging and genetic and monogenetic factors affect brain cells over time, leading to Alzheimer’s

Huntington's Disease

is 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 neuro degenerative 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.) 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. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea.

• Some studies demonstrate 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). (For more on apoptosis, see "Mutant huntingtin protein and intracellular abnormalities.")

• Evidence suggests that the formation of toxic compounds known as oxygen-free radicals may contribute to striatal cell injury. An imbalance between free radical production and elimination results in an increasing accumulation of these toxins in certain tissues.

MENINGITIS

 

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia.

Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space.

There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure.

Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, Meningitis is a clinical syndrome characterized by inflammation of the meninges, 

EPILEPSY

tends to stay within the brain, not affecting the rest of the body. Complications from epilepsy tend to happen when people injure themselves during seizures. It is especially dangerous if a seizure occurs while driving or swimming, but even in a less demanding situation, a person could fall and hurt themselves during an episode.

Epilepsy can cause abnormalities in the electrical signals in the brain, so often doctors use an electroencephalogram (EEG) to diagnose it

Recently, gene defects underlying four monogenic epilepsies (generalized epilepsy with febrile seizures, autosomal dominant nocturnal frontal lobe epilepsy, benign familial neonatal convulsions and episodic ataxia type 1 with partial seizures) have been identified,

Although epileptic syndromes differ pathophysiologically, common ictogenesis-related characteristics as increased neuronal excitability and synchronicity are shared as well as mechanisms involved in interictal-ictal transition.

Emerging insights point to alterations of synaptic functions and intrinsic properties of neurons as common mechanisms underlying hyperexcitability. This work also reviews the neurochemical mechanisms of epilepsy.

An imbalance between glutamate and gamma-aminobutyric acid neurotransmitter systems can lead to hyperexcitability but catecholaminergic neurotransmitter systems and opioid peptides were shown to play a role in epileptogenesis as well.

An overview of currently available anti-epileptic drugs and their presumed mechanisms of action is given as an illustration of the neurochemistry of epileptogenesis. Most anti-epileptic drugs exert their anti-epileptic properties through only a few neurochemical mechanisms that are meanwhile basic pathophysiological mechanisms thought to cause seizures.