Chapter 14: Injury and Illness

In this chapter…

  • Brain Tumors
  • Multiple Sclerosis
  • Neurological AIDS
  • Neurological Trauma
  • Pain
  • Seizures and Epilepsy
  • Stroke

Brain Tumors

  • Primary brain tumors: tumors that begin in brain tissue but don’t spread to other tissues
    • These tumors can spread through the brain but be benign
  • Malignant brain tumors: harmful tumors that can originate from brain or spread to the brain
    • They have a greater likelihood to grow faster and invade
    • These tumors are coupled with the identity of specific cells in tumor
    • Some of these criteria are used to classify a tumor’s grade
      • grade: severity of a tumor
  • No matter what grade the tumor is it’s harmful because it can interfere with normal brain activity
  • Symptoms of brain tumors vary with the location and size
    • Seizures and headaches are the most common symptoms
  • Gliomas: brain and spinal cord tumors originating in and comprised of cancerous glial cells
    • These cancerous glia release glutamate at toxic concentrations
    • Glutamate kills off neurons near the tumor, making room for expansion
    • The glutamate is also responsible for seizures
  • The expanding tumor can increase the pressure in the skull
    • This causes headaches, vomiting, visual disturbances, and impaired mental functioning
  • Tumors are diagnosed with MRI & CT scans
    • Early imaging is beneficial because tumors can be identified at a lower grade
    • This improves the course of disease & outcome
  • Treatment options for primary brain tumors are limited
    • Surgery is generally the first step
    • This can only be done if the tumor is accessible and won’t damage vital structures
    • Radiation can be used to stop a tumor’s growth or cause it to shrink
    • Chemotherapy destroys tumor cells that remain after surgery and radiation
    • Unfortunately it is not very effective for gliomas
      • The blood-brain barrier makes it hard for drugs to reach the brain
  • Trials for targeted therapies are aimed at the biologic characteristics of tumors
    • Possibilities include:
    • Vaccines made from the tumor with things that boost the immune system or kill tumor cells
    • Monoclonal antibodies that hone in on receptors on the surface of tumor cells
      • Monoclonal antibodies: antibodies produced by clones of a single cell
    • Anti-angiogenic therapy: restricting the tumor’s blood supply
    • Immunotherapy: using the body’s own immune system against the tumor
    • Gene therapy: delivering bioengineered genes to tumor cells to kill them
    • There are several approaches for targeted delivery of antibodies, toxins, or growth-inhibiting molecules that attach to tumor cells and interfere with growth
      • Chlorotoxin: a scorpion-derived toxin that can interfere with the spread of tumor
      • Shows promise in studies
        • Extended individuals’ life expectancy significantly
  • Stem cells might have a role in the origin of brain tumors
  • Cells in tumors that may be most harmful may be able to be tracked
  • Epidemiologists are looking into tumor genetics and patients’ lifestyles, environments, occupations, medical histories
    • Epidemiologists: scientists who study disease in human populations

Multiple Sclerosis

  • Multiple Sclerosis (MS): Autoimmune disease where the immune system attacks the myelin sheath covering the axons of neurons in the Central Nervous System
    • Diagnosed between 20-40
    • Affects essentially every aspect of a patient’s life
  • The lossoss of myelin results in damage to nerve fibers
    • Damage may be so severe that the nerve fiber deteriorates
    • Comparable to loss of insulating material around electrical or cutting of wire
    • This interferes with the transmission of signals
  • After the loss of myelin, the axon sheath is repaired and replaced by scars (scleroses) of hardened patches of tissue
    • Usually associated with further degeneration of nerve fibers
    • Lesions/plaques: areas of disease activity appearing in multiple places in the CNS
  • Both genetic and environmental factors probably play a role in determining who contracts MS
    • Siblings of MS patients have a 2-3% risk while identical twin has a risk of approximately 30%
    • MS is 5x more prevalent in temperate zones than in the tropics
    • Caucasians are more susceptible than other races
  • Studies show that people who got MS before 15 were affected by environmental factors
    • But now, studies suggest that there is no exact age cutoff
  • The spinal cord, cerebellum, and the optic nerve are commonly affected areas
    • Numbness, clumsiness, blurred vision often occur because of this
    • MS can affect many other brain areas, including white matter and grey matter
    • white matter: areas comprised of myelinated nerve fibers
    • grey matter: areas rich in neuron cell bodies and dendrites
  • Symptoms of MS may include
    • slurred speech
    • weakness
    • loss of coordination
    • pain
    • uncontrollable tremors
    • loss of bladder control
    • memory loss
    • depression
    • fatigue
    • other cognitive problems
    • Cognitive symptoms of MS depend on the site of damage
  • Relapsing/remitting MS- there are flares of the disease and then periods where it improves
  • Progressive MS: ongoing nerve fiber degeneration causes the symptoms become permanent and gradually worsen
    • This usually leads to progressive accumulation of disability that affects mobility, strength, balance, and coordination
    • At this point, the MS can’t be cured
  • Many medications control relapsing forms of MS by limiting the immune attack & reducing associated inflammation
    • Steroids may be effective in shortening attacks
    • They help to speed recovery from MS-related acute attacks
    • There are medications and therapies for symptoms but none for the nerve degeneration that causes the progression of MS

Neurological AIDS

  • AIDS (acquired immunodeficiency syndrome): advanced HIV infection
    • Life-prolonging drugs make HIV a chronic illness instead of a death sentence in the US
  • In developing countries, only 36% of those who need therapy are getting such treatments
    • Women now represent half of all HIV cases worldwide
  • The main target of HIV is the immune system, but the nervous system can be affected as well
  • HAND: HIV associated neurocognitive disorder
    • Affects 50+ % of HIV patients
    • HAND tends to affect people not receiving CART (combination antiretroviral treatment)
    • CART (combination antiretroviral treatment): a cocktail of 3+ drugs that are meant to work against HIV
    • Side effects of HAND include
    • mild difficulty with concentration
    • memory
    • complex decision-making
    • coordination to progressive
    • fatal dementia
    • HAND may be related to secreted viral products or cytokines
    • cytokines: cell-coded immune signaling molecules
  • Some viral proteins are neurotoxic
    • They may play role in ongoing damage that occurs during infection
    • Viral Tat- a protein released by HIV-infected cells that is suspected of neurotoxicity
  • HIV is the prime mover in HAND
    • Antiretroviral treatment may prevent or reverse the condition in many patients
  • Patients can develop increasing difficulty with concentration and memory as well as experience general slowing of mental processes in late stages of HAND
    • At the same time, the patient may develop leg weakness and a loss of balance
  • Brains of these patients have undergone some shrinkage
  • Neurological effects of AIDS in patients
    • loss of neurons
    • abnormalities in white matter
    • injury to cellular structures involving in interneuron signaling
    • may be related to inflammation and abnormalities with blood vessels
  • Highly active CART is effective in reducing the incidence of severe HAND
    • Such treatment can reverse cognitive abnormalities attributed to brain HIV infection
  • Peripheral neuropathy: nerve injury in the extremities that results in the disease or dysfunction of one or more peripheral nerves
    • Causes discomfort ranging from tingling to burning to severe pain
    • Virus triggers sensory neuropathy by releasing neurotoxins
    • This reaction has been unmasked by antiretroviral drugs that produce mitochondrial toxins
    • Makes neuropathies more frequent and serious
  • Rare opportunistic infections and malignancies are seen more frequently in HIV patients due to immunodeficiency
    • CART greatly reduced the incidence of most of these kinds of infections

Neurological Trauma

  • Traumatic brain & spinal cord injuries can lead to significant disabilities and death
  • Methods to hold off severe neurological damage caused by trauma exist
    • Accomplished by working to prevent secondary pathogenesis
    • secondary pathogenesis: damage that occurs after the initial injury
    • Support regeneration & repair
    • Refine & optimize rehabilitation techniques

Traumatic Brain Injury

  • The main concern is brain pressure
    • It is monitored to prevent bleeding or swelling
  • Treatments for increased intracranial pressure include:
    • the removal of cerebrospinal fluid
    • moderate hyperventilation to decrease blood volume
    • drugs to reduce cellular metabolism
    • removal of water from injured tissue
  • Lesions can consist of surface bleeding or in-brain bleeding
    • This causes the formation of bruises called contusions
    • Contusions can increase brain pressure and contribute to the development of post-traumatic epilepsy
  • Blood leaking from vessels and touching the brain tissue causes localized pressure and reduced cerebral blood flow
    • Blood itself can be also toxic to brain cells
  • Decompressive craniectomy: removal of part of the skull to allow the brain space to swell
    • This is used as a last resort
  • Administering rogesterone cut the number of deaths in severely injured patients by 50%
    • Functional recovery improved by 30 days in moderately injured individuals
  • Treatments of injury-induced reduction of cerebral blood flow are drugs that increase arterial blood pressure
    • These treatments result in an increase in blood flow with the reduction of intracranial pressure
    • Allows more blood to reach vital areas

Spinal Cord Injury

  • Methylprednisolone: the only FDA-approved treatment for spinal cord injury
    • Studies showed some recovery when those with spinal cord injuries got a high IV dose of methylprednisolone within 8 hours of injury
  • After a spinal cord injury, animals can regain the ability to bear their weight and walk at various speeds on a treadmill belt
    • The level of recovery depends a lot on whether the tasks are practiced after injury
  • New nerve cells can be born in the adult brain
    • But these are not sufficient to help the injured brain regenerate

Pain

Treating Pain

  • Local anesthesia: loss of sensation in a limited area
    • These temporarily interrupt the action of all nerve fibers by interfering with sodium channels
    • Examples of local anesthesia include novocaine and lidocaine
    • Topical lidocaine is effective where a light touch to the skin can produce severe pain in neuropathy
  • Analgesia: loss of pain sensation
  • There are 5 main types of analgesics (painkillers)
    • Nonopioids: aspirin and NSAIDs (nonsteroidal anti-inflammatory drugs)
    • Examples include ibuprofen and naproxen
    • NSAIDs are useful for treating mild to moderate pain, arthritis, and post-operative pain
      • NSAIDs work by inhibiting the cyclooxygenase enzymes that make prostaglandin
      • Moderate pain can be treated by combining a mild opioid with aspirin or an NSAID
    • Opioids- analgesics that work by binding to opioid receptors
    • Examples include morphine and codeine
    • They are the most potent painkillers and are used for severe pain
      • Adverse side effects include respiratory depression and constipation
      • Opioids have a high potential for abuse
    • Antiepileptic agents: used for treating epilepsy but are also used to treat neuropathic pain and fibromyalgia
    • Examples include gabapentin and topiramate
    • Antiepileptic and antidepressants are useful for treating neuropathic pain coming from injury to the nervous system
      • Includes neuropathy caused by diabetic neuropathy, damage from high blood sugar, nerve pain or numbness from viruses, phantom limb pain, and post-stroke pain
    • Antidepressants: used for treating depression, chronic, and neuropathic pain
    • Examples include amitriptyline, duloxetine
    • Best results come with using antidepressants that regulate serotonin and norepinephrine
      • SSRIs don’t help relieve neuropathic pain
    • Acetaminophen: has analgesic properties but does not reduce inflammation
    • This is the active ingredient in tylenol

The Body’s Pain Control System

  • Opioid receptors are concentrated in the spinal cord
    • This finding led to use of injections of opioids into cerebrospinal fluid without causing paralysis, numbness, or other side effects
    • Injecting morphine into the spinal cord produced large pain control in animal tests
  • Nociceptors: peripheral nerve fibers that initially respond to an injury stimulus
    • Many ion channels and receptors are predominantly or exclusively expressed by nociceptors
  • Adverse side effects of drugs arise from the widespread location of molecules targeted by analgesics
    • Constipation results from morphine’s action on opioid receptors in the gut
  • New painkillers that only target nociceptors will have fewer side effects
    • One specialized receptor channel is activated by capsaicin
    • Capsaicin is the pungent chemical responsible for spice in hot peppers
    • Another receptor channel is activated by mustard oil
    • Blocking the activity of many receptors like these has proven effective
    • This suggests that the creation of drugs targeting these molecules in humans has great value for the treatment of acute and persistent pain
  • The topical application of capsaicin has recently been approved for some neuropathic pain conditions
    • Capsaicin kills the sensing portion of pain fibers
    • But these sensory areas will regenerate, so the process needs to be repeated
  • Pain is in the brain, not in nociceptors that respond to injury
    • Pain involves emotional factors
    • Placebos and hypnosis can significantly reduce pain
    • This shows the importance of psychological factors

Seizures and Epilepsy

  • Seizures: occur due to sudden, disorderly changes in interconnected brain neurons
    • They can alter one or morebrain functions
    • Seizures are associated with epilepsy
  • Epilepsy: a chronic neurological disorder characterized by the occurrence of unprovoked seizures
    • Epilepsy can start at any age
    • Idiopathic epilepsies: epilepsies arising from uncertain or unknown cause
    • Idiopathic epilepsies are probably due to the inheritance of 1+ mutant genes
      • These genes are often mutant ion channel genes
    • Symptomatic epilepsies: epilepsies with a known or presumed cause
    • Symptomatic epilepsies can result from a wide variety of brain diseases or injuries including:
      • Birth trauma
      • Head injury
      • Neurodegenerative disease
      • Brain infection
      • Brain tumor
      • Stroke
  • There are two main types of epilepsies
    • Generalized epilepsy: characterized by the loss of consciousness and range of behavioral changes including convulsions and sudden changes in muscle tone
    • Generalized epilepsy occurs when there is simultaneous excessive electrical activity over a wide area of the brain
      • This often involves thalamus and cerebral cortex
    • Generalized epilepsy is easier to treat
      • Up to 80% of patients become seizure-free with antiepileptic drugs
    • Partial epilepsy: the individual maintains consciousness or has altered awareness and behavioral changes
    • Partial epilepsy can produce
      • localized visual, auditory, skin sensory disturbances
      • repetitive uncontrolled movements
      • confused, automatic behaviors
    • Arises from excessive electrical activity in one area of the brain
      • This is restricted to the cortical or hippocampal area
    • Partial epilepsies are harder to treat
      • Sometimes a combination of drugs is necessary
  • The principal targets of antiepileptic drugs are ion channels or neurotransmitter receptors
  • Surgery is an option for patients with specific partial seizures who don’t respond to antiepileptic drugs
    • Electrical recordings of brain activity from patients allow for the precise localization of the brain area where seizures originate from
    • Improvement or complete remission of seizures occurs for at least several years after the surgery
  • Electrical stimulation therapy: an implanted device delivers small bursts of electrical energy to the brain via the vagus nerve on the side of the neck
    • Vagal nerve stimulation has been shown to reduce the frequency of partial seizures in many patients

Stroke

  • Stroke: occurs when a blood vessel bringing oxygen and nutrients bursts or is clogged by a blood clot or some other particle
    • This causes the brain to be deprived of blood
    • Neurons downstream of the blockage can die within minutes
  • The effects of stroke are location-dependent
    • It can cause permanent disorders like paralysis on one side of the body or the loss of speech
  • Until recently, if someone had a stroke, there were few treatment options outside of physical or speech therapy
    • Patients would live out their remaining months or years with a severe neurological impairment
  • tPA (tissue plasminogen activator): opens blocked vessels rapidly to restore circulation before oxygen loss causes permanent damage
  • Strokes can be prevented by controlling the risk factors
    • These risk factors include diet, exercise, and the use of certain drugs
  • Treatments for stroke include
    • Surgery to place arterial stents
    • keeps arteries open
    • clears clogs in neck arteries
    • Targeting treatment of heart disease to prevent the cutoff of blood supply
    • Anticoagulant drugs to reduce the likelihood of clots forming
    • Targeting mechanisms inside the neuron to slow down mass biochemically-induced neuron death
    • The use of the weakened limb by temporarily restricting the use of the other limb may help functional recovery following a stroke affecting the movement of one limb
    • Neural stem cells can help recovery even if administered several days after the injury
    • Administering growth factors may further enhance the benefits of stem cell transplantation

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