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