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