Neurological Disorders PDF

Neurological Disorders Tumors and Seizures 680,000 individuals are living with brain tumors. These two conditions can occur separately. Tumors Mass of cells whose growth is uncontrolled and that serves no useful function. Some are malignant (cancerous tumor) or benign (“harmless”)....

Neurological Disorders Tumors and Seizures 680,000 individuals are living with brain tumors. These two conditions can occur separately. Tumors Mass of cells whose growth is uncontrolled and that serves no useful function. Some are malignant (cancerous tumor) or benign (“harmless”). The major distinction between malignant and benign tumors is whether the tumor is encapsulated. Encapsulated tumor has a distinct border between the mass of tumor cells and surrounding tissue. Can be surgically removed, will not regrow. Malignant tumors grow by infiltrating the surrounding tissue. No clear border between the tumor and healthy tissue. Surgeon removes the tumor, some cells may be missed and will produce a new tumor. Tumors can produce metastases — cells break off of a tumor, travel through the vascular system (bloodstream), and grow elsewhere in the body. Damage brain tissue in two ways: Compression: a benign tumor that occupies space and pushes against the brain. Directly destroy brain tissue, or indirectly blow the flow of cerebrospinal fluid and cause hydrocephalus. Infiltration: process that occurs after a traumatic brain injury when immune cells are recruited to the site of the injury. Causes They come from other cells found in the brain or from metastases originating elsewhere in the body. Most serious types of tumors: Metastases. Gliomas: cancerous brain tumor composed by various types of glial cells. Usually very malignant and grow quickly. Malignancy of brain tumors is caused by rare subpopulations of cells. Malignant gliomas contain tumor initiating cells — originate from transformations of neural stem cells. Rapidly proliferate and give rise to glioma. Meningioma is an encapsulated, benign tumor consisting of cells that typically make up the dura mater or arachnoid membrane. Treatments Some tumors are sensitive to radiation and can be destroyed by a beam of radiation. Radiation targeted to the tumor site, stereotactic radiosurgery.  Some tumors respond to chemotherapy, with or without radiation or surgical interventions. Chemotherapy involves administering a drug thta causes rapidly dividing cells (such as cancer cells) to die, by interfering with their DNA replication. Side effects: hairloss and the reduce blood flow. Seizures Period of sudden, excessive activity of neurons in the brain. A seizure can cause convulsions, uncontrollable activity of the muscles. Not all seizures cause convulsions; in fact, most do not. Seizure disorder to refers to a condition that has many causes. Partial seizures begins at a focus and remains localized, not generalizing to the rest of the brain. Generalized seizures are widespread, involving most of the brain. Two categories of partial seizures: Simple partial seizures: cause changes in consciousness but do not cause loss of consciousness. Complex partial seizures: lead to loss of consciousness. Most severe form of seizure, grand mal seizure (tonic-clonic seizure) – Generalized seizure. Includes the motor systems of the brain, it is accompanied by convulsions. Warning symptoms: changes in mood, jerks of muscular activity upon awakening. Aura: a sensation that precedes a seizure; its exact nature depends on the location of the seizure focus. Likely caused by excitation of neurons surrounding a seizure focus. Beginning of a grand mal seizure is called the tonic phase. Muscles contract forcefully. Arms are rigidly outstretched. Clonic phase Muscle trembles, then starts jerking convulsively. Autonomic nervous system manifests itself in sweating and salivation. Unresponsive sleep. Partial seizures involve small portions of the brain. Sensory changes, motor activity, or both. Seizures can cause brain damage. Damage in the hippocampus. Absence seizures; period of inattention, often seen in children. Generalized seizure. Status epilepticus: series of seizures without regaining consciousness. Excessive release of glutamate during the seizure. Causes Most common cause is scarring. Injury, a stroke, developmental abnormality, or irritating effect of a growing tumor. Genetic factors contribute to incidence of seizure disorders. Genes that control the production of ion channels.  Various drugs and infections that cause a high fever can also produce seizures. Seizures are commonly associated with chronic drugs or alcohol withdrawal. Many cases are idiopathic (of unknown causes). Treatments Treated with anticonvulsant drugs. Work by increasing the effectiveness of inhibitory synapses, via GABAergic synapses. Brain surgery. Usually seizures are eliminated or greatly reduces in frequency. Cerebrovascular Accidents: Causes Types of strokes: Hemorrhagic strokes: Caused by bleeding within the brain. Malformed blood vessel or high blood pressure. Ischemic strokes: Block blood vessel and obstruct the flow of blood. Can be caused by thrombi or emboli. Thrombus: Blood clot that forms in blood vessels. Places that walls are already damaged. Sometime become so large that blood cannot flow through the vessel, causing a stroke. Advised to take drugs such as aspirin. Helps to prevent clot formation. Embolus: Piece of material that forms in one part of the vascular system. Breaks off and carried through the bloodstream until it reaches an artery too small to pass through. Damming the flow of blood through the rest of the vascular tree. Immediate cause of neuron death is excessive amounts of glutamate. Treatments Hemorrhagic stroke caused by high blood pressure = medication given to reduce the person’s blood pressure. Hemorrhagic stroke caused by weak or malformed blood vessels = brain surgery may be used. Thrombus was responsible = dissolve or physically remove the blood clot. Anticoagulant drugs. Antibiotics if embolus broke away from a bacterial infection.  Administer drugs that dissolve blood clots to reestablish circulation to an ischemic brain region. The drug is called tPA (tissue plasminogen activator). An enzyme that helps dissolve fibrin (protein involved in clot formation).. Desmoteplase another anticoagulant enzyme. Cerebral occlusions. Devices are inserted into a cerebral blood vessel and extended until they reach the obstruction. Ways to minimize the amount of brain damage by strokes. Clot-dissolving drugs as soon as the onset of a stroke. Cerebral occlusions can be removed with variousz medical devices. Inserted into a cerebral blood vessel and extended until they reach the obstruction. One device works like a corkscrew, grabbing the obstruction so that the surgeon can pull it out. Second device works by suction vacuum is applied when the device touches the obstruction, and the surgeon pulls out the clot. Other devices like stent, put into place around the occlusion and deployed to trap the occlusion against the vessel wall. Blood flow restore. How to prevent strokes?: Reduce: risk factors such as high blood pressure, cigarette smoking, diabetes, and high blood levels of cholesterol. Atherosclerosis: linings of arteries develop a layer of plaque; Deposits of cholesterol. Fats. Calcium. Cellular waste products Precursor to heart attacks (myocardial infarction) and ischemic stroke, caused by clots that form around atherosclerotic plaques in cerebral and cardiac blood vessels. Often formed in the internal carotid artery Atherosclerotic plaques can cause severe narrowing of the interior of the artery, increasing the risk of a massive stroke. Visualized in an angiogram, produced by injecting a radiopaque dye into the blood. Placement of a stent in a narrowed carotid artery. Implantable device made of mesh that is used to expands and hold open a partiallyy occluded artery. Associated with an increased number of future strokes and the death rate following implantation is higher. What can be done after a stroke has occurred? Drugs that reduce swelling and inflammation may be administered. Depending on the location of the brain damage, people will receive physical, speech, and/or occupational therapy to help them recover that fucntion. In some cases of brain or spinal cord damage, investigators have attempted to devise brain-computer interfaces that permit the patient to control electronic an mechanical devices in order to perform useful actions. Traumatic Brain Injury (TBI) Causes Projectile or fall against a sharp object that fractures the skull (open-head injuries or penetrating brain injuries). Closed-head injuries also occur from impacts but do not involve penetration of the brain. Can damage more than the cerebral cortex at the point of the coup and contrecoup. Chronic traumatic encephalopathy (CTE) a form of TBI: Produces neurodegeneration due to repeated head trauma. Frequent and repeated head trauma. Similar to the brains of individuals with Alsheime’s disease. Abnormal tau protein accumulates in the cortex of CTE. Display reduced brain volume and enlarged ventricles. The corpus callosim, regions of the cortex, and the limbic system appear to be damaged, resulting in characteristic deficits in executive control and mood regulation that are associated with CTE. Treatments Primary treatments. Reducing swelling and intracranial pressure as well as ensuring adequate blood flow to the injured regions. Secondary treatments. Address symptoms that develop after injury. TBI results in increased levels of adenosine and glutamate in the injured brain tissue. Glutamate converts adenosine as an anti-inflammatory agent. Causes further damage. Drug that inhibits the release of glutamate (role of extracellular adenosine). Treatments to the effects of TBI are similar to those caused by cerebrovascular accidents. Disorders of Development Toxic Chemicals Common cause of intellectual disabilities is the presence of toxins during pregnancy. Teratogen is any chemical or toxin that results in abnormal development of an embryo. Intellectual disability can be caused by consuming alcohol during pregnancy (third or fourth week). Children exposed to alcohol prenatally can develop fetal alcohol spectrum disorder> Fetal alcohol syndrome characterized by abnormal facial development. Facial abnormalities associated with this disorder are unimportant. However, more serious are the abnormalities in the development of the brain. Inherited Metabolic Disorders Also called inherited mutations; in the synthesis of some enzymes. Can cause brain damage or impair brain development. Cell functioning requires intricate interactions among many biochemical systems. Depend on enzymes, responsible for constructing or breaking down particular chemical compounds. Inherited mutations in the recipe for a particular enzyme cannot be synthesized correctly. Most common inherited metabolic disorder is phenylketonuria (PKU). Caused by an inherited lack of an enzyme that converts phenylalanine (amino acid) into tyrosine (another amino acid). Excessive amounts of phenylalanine in the blood interfere with the myelinization of neurons in the CNS. Can be treated with a low-phenylalanine diet. Keeps the blood level of phenylalanine low, and myelinization of the CNS takes place normally. Tay-Sachs cannot be treated successfully. Children of Eastern European Jewish descent. Causes brain damage itself against the inside of the skull and against the folds of the dura mater that encase it. Startle response to sounds, listlessness, irritability spasticity, seizures, dementia, and finally death. Cells contain sacs of material encased in membrane, called lysosomes. Metabolic storage disorders are genetic eros of metabolism in which one or more vital enzymes are missing. Particular kinds of waste products cannot be destroyed, so they accumulate in the lysosomes. The brain begins to swell and becomes damaged. Cured someday by the techniques of genetic engineering such as CRISPR-cas 9. Down Syndrome Congenital disorder. Results in abnormal development of the brain. Intellectual disability in varying degrees. Disorder present at birth. Caused by the presence of an extra twenty-first chromosome (includes approximately 300 genes). Associated with the mother’s age. Short stature and changes in physical facial development. They may learn to speak later (by five years of age). Brain is smaller than that of a typically developing peer. Convulsions (gyri and sulci) are smaller and less folded. Frontal lobe is smaller, and the superior temporal gyrus is thinner. Drug treatments may have beneficial effects on learning and memory impairment associated with Down syndrome.  Overactivity of the GABA system may impair hippocampal synaptic plasticity and associated learning and memory. Drugs that reduce GABA activity can result in seizures, and individuals with Down syndrome are already at increased risk for seizures compared to the general population. Selective serotonin reuptake inhibitor fluoxetine (another potential treatment). Causes Symptoms Exposure to Teratogens Exposure to teratogens (such as Intellectual disability alcohol) impairs brain development Inherited Metabolic Genetic abnormalities in the codes Intellectual disability; brain Disorders (PKU, for specific enzymes. If untreated, swelling in Tay-Sachs pyridoxine leads to impaired brain dependency, development. galactosemia, Tay-Sachs disease) Down syndrome Three copies of the twenty-first Intellectual disability; brain chromosome contribute to impaired degeneration in adulthood. brain development. Degenerative Disorders Transmissible Spongiform Encephalopathies An outbreak of bovine spongiform encephalopathy (BSE, “mad cow disease”, or TSE). Fatal contagious brain disease whose degenerative process gives the brain a spongelike appearance. These diseases include: Creutzfeldt-Jakob disease, fata familial insomnia, and kuru. Affect humans and scrapie, which primarily affects sheep. TSEs are caused by proteins called prions, or “protein infectious agents”. Found in the membrane of neurons, where they are believed to play a role in synaptic function and in the preservation of the myelin sheath Resistant to proteolytic enzymes — enzymes that are able to destroy proteins by breaking the peptide bonds that hold protein’s amino acids together. Resistant to levels of heat that denature normal proteins. Sequence of amino acids; normal prion protein (PrPc) and infectious prion protein (PrPSc) are identical, but differents effects.  Aggregations of misfolded proteins (Parkinson’s disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington’s disease). Accumulation of misfolded, abnormal proteins may signal apoptosis Means cells may commit suicide. Can be triggered either externally, by a chemical signal telling the cell that it is no longer needed, or internally, by evidence of biochemical processes. Involves the production of “killer enzymes” called caspases. Responsible for the death of neurons infected with PrPSc TSE are sporadic and occurs in people without a family history of prion protein disease. They can be genetic and sporadic and can be transmitted to others. Parkinson’s Disease Caused by degeneration of the nigrostriatal system. Occurs in approximately 1 percent of people over 65 years of age. Symptoms are muscular rigidity, slowness of movement, a resting tremor, and postural instability. Vibratory movements of the arms and hands diminish somewhat when the individual makes purposeful movements. Shows near-disappearance of nigrostriatal dopaminergic neurons. Surviving dopaminergic neurons show Lewy bodies, abnormal circular structures found within the cytoplasm. Causes No genetic origins.  Mutation of a particular gene located on chromosome 4 will produce this disorder. Produces a protein known as α-synuclein normally found in the presynaptic terminals. Involved in synaptic transmission in dopaminergic neurons. The mutation produces a toxic gain of function; produces a protein resulting in effects that are toxic to the cell. Lewy bodies consists of aggregations, along with neurofilaments and synaptic vesicle proteins. Mutation of a gene on chromosome 6 produces a gene named parkin. The mutation causes a loss of function, which makes it a recessive disorder. Plays a role in transferring defective or misfolded proteins to the proteasomes - organelles responsible for destroying these proteins. Mutation permits high levels of defective protein to accumulate in dopaminergic neurons. Assists in tagging abnormal or misfolded proteins with numerous molecules of ubiquitin (small, compact globular protein). Ubiquitination targets the abnormal proteins for destruction by the proteasomes; breaks them down into their constituent amino acids. Defective parkin fails to ubiquitinate abnormal proteins. They accumulate in the cell, eventually killing it. Majority of the Parkinson’s disease are sporadic. Occur in people without a family history of Parkinson’s disease. May be caused by toxins present in the environment. Faulty metabolism. Unrecognized infectious disorders (insecticides rotenone and paraquat). These chemicals inhibit mitochondrial function. Leads to the aggregation of misfolded α-synuclein, especially in dopaminergic neurons. These accumulated proteins eventually kill the cells. Brain contains two major systems of dopaminergic (DA) neurons: Nigrostriatal system: damage causes Parkinson’s disease. Mesolimbic/mesocortical: consists of dopaminergic neurons in the ventral tegmental area. Innervate the nucleus accumbens and the prefrontal cortex. Calcium channels are involved in regulating the spontaneous activity of DA cells in the nigrostriatal system. Sodium channels are involved in regulating the activity of those in the mesolimbic system. Treatments No cure for Parkinson’s disease. Clinicals have developed options to treat the symptoms of the disease. L-DOPA: increased level of L-DOPA for a time alleviates the symptoms of the disease.  Number of nigrostriatal dopaminergic neurons declines and symptoms can become worse. L-DOPA also activates DA neurons in the mesolimbic/mesocortical system and produces side effects such as hallucinations and delusions. Deprenyl may be given. Toxic effects of MPTP (neurotoxic chemical) could be prevented by administering deprenyl. The drug inhibits the activity of the enzyme MAO-B. Might prevent unknown toxins from producing further damage to dopaminergic neurons. Benefits of deprenyl and other inhibitors of MAO-B appear to be reduction in symptoms. Surgical Procedures Three stereotaxic, surgical procedures to alleviate the symptoms that no longer respond to treatments with L-DOPA. Transplantation of fetal tissue: reestablish the secretion of dopamine in the neostriatum. Implanted into the caudate nucleus and putamen using a tereotaxic procedure. Those who responded L-DOPA likely benefit from the surgery. Transplanted cell remain functional for more than a decade. Some later develop severe, persistent dyskinesias – troublesome and often painful involuntary movements. Lesioning parts of the brain to improve symptoms of Parkinson’s disease. Principal output fo the basal ganglia; internal division of the globus pallidus (GPi). This output, is inhibitory (directed through the subthalamic nucleus – STN, to the motor cortex). Damage to the GPi might be expected to relieve the symptoms of Parkinson’s disease. STN in patients with advanced Parkinson’s disease. Excitatory effect on the GPi. Damage to the subthalamic nucleus, decreases the activity of this region and removes some of the inhibition on motor output. Reinstates motor activity back to normal levels. Implanting electrodes in the STN or the GPi to electrically stimulate the brain through the electrodes. Deep brain stimulation (DBS) of the subthalamic nucleus is as effective as brain lesions in suppressing tremors and has fewer adverse side effects. DBS may also have effects such as depression and dementia, but studies are less clear. Huntington’s Disease Also affects the basal ganglia. Caused by degeneration of the caudate nucleus and putamen.  Causes uncontrollable movements, especially jerky limb movements. Cognitive and emotional changes, and eventually death. 10-15 after the symptoms begin. Age of 30s or 40s. GABAergic medium spiny neurons. Damage to these neurons removes some inhibitory control exerted on the premotor and supplementary motor areas of the frontal cortex. Causes Dominant gene on chromosome 4. Repeated sequence of bases (called CAG repeats) code for the amino acid glutamine. Repeated sequence causes the protein huntingtin (Htt) to contain an elongated stretch of glutamine. Becomes misfolded and forms aggregations that accumulate in the nucleus. The mutation causes the disease through a toxic gain of function — that abnormal Htt causes harm. Abnormal Htt may trigger apoptosis. Impairing the function of the ubiquitin-protease system. Activates caspase, one of the enzymes involved in apoptosis. Treatments No present treatment for the disease. Antibody that acts intracellularly (an intrabody) called Happ1. Targets a portion of the huntingtin protein. Suppress production of mutant Htt and improved animal’s disease symptoms. Injection of small interfering RNAs (siRNA) into the striatum that blocked the transcription of the Htt genes. Decreased the size of inclusion bodies in striatal neurons. Amyotrophic Lateral Sclerosis Degenerative disorder that attacks spinal cord and cranial nerve motor neurons. 5 in 100,000. Spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, and finally paralysis. Executive function, working-memory, language, and social cognition may also be affected. Death occurs 5-10 years after the onset of the disease. Causes 10% are hereditary, the other 90% are sporadic. Hereditary are caused by a mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found in chromosome 21. Toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport, and mitochondrial dysfunction.  Increases extracellular levels of glutamate and causes excitotoxicity in motor neurons. Transmitted from cell to cell. Cannot be transmitted between individuals. The primary cause of spordic ALS is an abnormality in RNA editing. Produces increased amounts of calcium ions. Treatments Riluzole, a drug that reduces glutamate-induced excitotoxicity. Small, temporary help. Multiple Sclerosis MS. Autoimmune demyelinating disease. Immune system attacks myelin sheaths, leaving behind hard patches of debris called sclerotic plaques. Increase in intensity and then decreases, followed by another increase in symptoms after varying periods of time (remitting-relapsing MS). Followed by progressive MS, slow continuous increase in the symptoms. Causes Women are diagnosed more frequently with MS. Usually occurs during the 20s or 30s Risk factors include growing up in places far from the equator and being born late winter or early spring. May come from a virus. Weakened the blood-brain barrier. Attaches itself to myelin. Treatments Interferon β. A protein that modulates the responsiveness of the immune system. Reduces the frequency and severity of attacks and to slow the progression of neurological disabilities in some patients with multiple sclerosis. Partially effective. Glatiramer acetate (copaxone or copolymer-1). Mixture of synthetic peptides composed from random sequences of amino acids tyrosine, glutamate, alanine, and lysine. Suppresses the activity of immune cells that would otherwise attack myelin. Both are only partially effective treatments for remitting-relapsing forms of MS. Transplantation of autologous hemopoietic stem cells. Dementia Alzheimer’s Disease  Occurs in approximately 10 percent of people above age 65 and almost 50 percent of people older than 85. Characterized by progressive loss of memory and other cognitive functions. Memory deficit most critically involves recents events. Abnormal structures develop: amyloid plaques (extracellular deposits, dense core of proteins known as β-amyloid) and neurofibrillary tangles (dying neurons that contain intracellular accumulations of twisted filaments of hyperphosphorylated tau protein). Abnormal accumulation of long-form Aβ but little tau protein. Induces the release of chemicals that destroy cells. Causes Some forms appears to be hereditary. Mutation of gene that produces APP (Amyloid precursor protein) located on chromosome 21. Mutations of two presenilin genes located on chromosomes 1 and 14. Mutation of the gene for apolipoprotein E (ApoE). Traumatic brain injuries. Obesity, hypertension, high cholesterol levels, and diabetes. Lower levels of formal education. Cognitive activity delays the appearance of Alzheimer’s disease. Treatments Acetylcholinesterase inhibitors and NMDA receptor antagonists. ○ No effect on the process of neural degeneration and do not prolong patients’ survival. Noncompetitive NMDA receptor blocker produces slight improvement in symptoms. Vaccine that destroys Aβ by sensitizing the immune system to the protein. ○ Caused inflammation. Korsakoff’s Syndrome Characterized by symptoms of anterograde amnesia Caused by environmental factors, usually related to chronic consumption of alcohol Sometimes occurs in people who have been severely malnourished and then received intravenous infusions of glucose Deficiency of thiamine produces brain damage Disorders Caused by Infectious Diseases Encephalitis Infection that invades the entire brain.  Symptoms include fever, irritability, and nausea; often followed by convulsions, delirium, and signs of brain damage. Causes Herpes simplex virus attacks the frontal and temporal lobes. Acute anterior poliomyelitis, or polio, causes specific damage to motor neurons of the brain and spinal cord. Rabies is passed from saliva by a bite wound. ○ Damages central nervous system and peripheral organs. Human immunodeficiency virus (HIV) causes damage to synapses and death of neurons. Meningitis Inflammation of layers of connective tissue that surround the central nervous system Caused by viruses or bacteria Symptoms include headache, a stiff neck, and sometimes convulsions, confusion or loss of consciousness, and death Bacterial meningitis causes brain damage Often due to use of unclean hypodermic needles