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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