NEUROPATHOPHYSIOLOGY III Finish Sensory

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NEUROPATHOPHYSIOLOGY IIIFinish Sensory Motor
Disease and thenTrauma, Stroke and Toxins

• Nancy Long Sieber, Ph.D.
• October 1, 2012

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Multiple Sclerosis

• An autoimmune disease that leads to
  demyelinization of neurons in the CNS
• Patients usually present with blurred or double
  vision. They go on to experience abnormal
  sensations, and muscle weakness.
• 50 of patients need help with walking within 15
  years of diagnosis.

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MS is characterized by demyelinization of neurons
in the CNS
http//www.riversideonline.com/source/images/image
_popup/ww5r308_big.jpg
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Pathogenesis of MS

• In patients with MS, T lymphocytes, which are
  normally excluded from the brain by the
  blood-brain barrier (BBB) are able to enter.
• These cells are thought to trigger the damage to
  myelinated neurons in the CNS.
• The cause of this opening of the BBB is unknown
  it the cause of the problem, or is it just a
  consequence of inflammation caused by something
  else?

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Many factors are thought to contribute to MS

• Intrinsic problems with immune system - probably
  common to all autoimmune diseases, probably
  genetic.
• Problems with the blood-brain barrier, allowing T
  cells to enter the CNS and promote production of
  antibodies against myelin
• Viral infection, eg Epstein-Barr, or Human
  Herpes Virus 6 (HHV-6) - MS is more common in
  people who have had mononucleosis, which is
  caused by Epstein-Barr. Some propose that a
  virus primes the immune system, setting the stage
  for an autoimmune response.
• Vitamin D deficiency the geographic
  distribution supports this. Vit D is involved in
  regulating the immune system, as well as neural
  function. Low Vit D levels correlate with higher
  MS risk.
• Multiple factors are likely to be involved.

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http//sofija.files.wordpress.com/2007/01/ms_world
map.jpg
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Proposed scheme for virus-mediated autoimmunity
in multiple sclerosis.
                                                                                                                                                 Grigoriadis and Hadjigeorgiou Journal of Autoimmune Diseases 2006 31   doi10.1186/1740-2557-3-1
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MRI Images help diagnose and monitor MS
http//content.revolutionhealth.com/contentimages/
h9991221.jpg
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Treatments for MS

• Anti-inflammatory agents corticosteroids,
  chemotherapeutic agents, etc.
• Drawbacks These drugs have many side effects.
  In addition, they generally increase the risk of
  infection, and viral and bacterial infections
  have been shown to speed the progression of MS.
• Newer drugs Aubagio , BG-12, reduce remittance
  by 30-50
• Supplemental vitamin D has been shown to slow
  progression
• Tysabri A monoclonal antibody against T cells,
  which blocks their entry into the CNS.
• Drawback cripples brain defenses against
  infection. Patients are at risk of deadly brain
  infections, especially progressive multifocal
  leukoencephalopathy (PML).
• Doctors are developing criteria to determine who
  is at high risk of developing PML. At highest
  risk are people with JC Virus. This virus is
  found in about 50 of the population, but only
  causes disease in people who are
  immunuosuppressed. The immunosuppressive effects
  of tysabri allow the virus to enter the brain,
  causing PML.

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Guillain-Barre Syndrome is caused by
demyelinization of peripheral nerves

• Thought to be caused by the autoimmune attack on
  myelin in peripheral nerves.
• Often occurs after a viral infection, or (rarely)
  after vaccination.
• Onset of the disease is sudden, and many patients
  are immediately admitted to the intensive care
  unit of the hospital.
• While many cases are mild, some patients
  experience significant weakness of the
  respiratory muscles, and must rely on mechanic
  ventilation.
• About half of the people who get Guillain-Barre
  recover fully within 1 year. Some have lingering
  weakness and numbness or tingling sensations
  (paresthesia).

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Guillain-Barre Syndrome
http//www.monografias.com/trabajos37/sindrome-gui
llain-barre/Image8645.jpg
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Amyotrophic Lateral Sclerosis (ALS) affects both
upper (within the CNS) and lower (those that
directly innervate muscle) motor neurons.
http//len.epfl.ch/webdav/site/len/shared/import/m
igration/ALS1.jpg
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Genetics and ALS

• 5-10 of cases are strictly genetic (Familial
  ALS).
• Of these about 20 are due to a defect in an
  enzyme called superoxide dismutase 1 (SOD1),
  which scavenges free radicals.
• This finding has led some to speculate that free
  radical damage may be involved in other forms of
  the disease.
• The defective protein may also interfere with
  movement of ADP into mitochondria, interfering
  with ATP production.
• More recent studies have identified a defect in
  the gene for Ubiquilin?2, a housekeeping
  protein, as a cause of certain hereditary forms
  of the condition. Without this protein, damaged
  and misfolded proteins remain in the neuron,
  eventually causing neuronal death.

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Possible environmental risk factors

• Exposure to a dietary toxin called BMAA, found in
  the fruit of a palm-like plant, as well as in the
  meat of animals that eat the plant, may account
  for high incidence in Guam and other places in
  the western Pacific.
• US military veterans from both the Pacific and
  the Gulf War.
• Exposure to herbicides has long been suspected,
  as clusters have been seen in athletes and
  farmers.

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Possible Mechanisms of ALS Pathogenesis

• Oxidant injury, perhaps due to some abnormality
  in antioxidant systems
• Glutamate toxicity, perhaps due to a defect in
  astroglial cells which normally remove this
  neurotransmitter from the synapse. The resulting
  excitotoxicity leads to neuronal death, causing
  further release of glutamate.

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Treatments for ALS

• Riluzole, a drug that decreases glutamate release
  is the only FDA-approved drug for ALS. It is
  only moderately effective suggesting that other
  mechanisms are involved in the pathogenesis of
  ALS.
• Other drugs are used to treat symptoms of the
  disease, including muscle cramps, spasms,
  fatigue, etc.
• Physical therapy

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Disease and Trauma of the Peripheral Nerves
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Dermatomes are the regions on the body that
correspond with specific cranial or spinal
nerves.
Damage to a given peripheral nerve will cause
loss of sensation and motor function in that
region of the body.
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Injury and Trauma to the CNS
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http//dailyme.com/gallery/medical-condition/head-
injury.html
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Injury to the spinal cord causes loss of function
below the lesion site. Causes 45 motor
vehicle 18 falls 17 violence 13 sports, esp.
diving Who 82 male Avg age at injury 40.2
yrs. Most common age at injury 19 (lots of
young people older people)
from http//www.cureparalysis.org/faq/spine.gif
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Sequence of events following spinal cord injury

• Spinal shock transient (hours to days) loss of
  reflexes in area below lesion. Muscles become
  flaccid, motor function lost due to injury
  inflammation. May lose sympathetic tone.
• Reflexes gradually return over the next few days
  to weeks.
• Axons of surviving cells begin to recover
• Patient may experience hyperreflexia, as normal
  inhibitory signals that descend down the spinal
  cord are blocked by the injury. Gradually
  stabilizes.

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Sensory pathways cross to the opposite side of
the spinal cord or medulla before ascending to
the cortex.
http//thalamus.wustl.edu/ course/bsen1.gif
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Injury to one side of the spinal cord can cause
loss of function on both sides of the body.
From McPhee, Lingappa, Ganong Lange
Pathophysiology of Disease 1995
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Concerns with spinal cord injury

• Loss of function below site of lesion may be
  complete or partial, depending on the injury.
• Loss of thermoregulation
• Pressure wounds
• Autonomic dysreflexia strong activation of the
  sympathetic nervous system due to irritation of
  lower part of the body. Cause sharp increase in
  blood pressure, can lead to seizures, stroke,
  death

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StrokeHemorrhagic and Ischemic
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Adaptations to Maintain Brain Blood Flow

• Anastomoses interconnections between blood
  vessels, compensate for blocked vessels.
• Autoregulation
• Myogenic autoregulion brain blood vessels dilate
  in response to a fall in blood pressure, and
  constrict in response to an elevation in blood
  pressure
• Metabolic autoregulation matches brain
  bloodflow to metabolic activity
• Helps maintain blood flow if vessel is partially
  occluded.

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http//ww2.heartandstroke.ca/images/english/stroke
_isc_web.jpg
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http//ww2.heartandstroke.ca/images/english/stroke
_hem_web.jpg
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Neurotoxins

• Organophosphates pesticides nerve gas
• Strychnine poisoning
• Tetanus toxin
• A bit more about botulism
• Heavy Metals
• Lead
• Mercury

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Organophosphate pesticidesinhibit
acetylcholinesterase.
http//www.environmentalhealthnews.org/ehs/newscie
nce/depressed-about-pesticides/
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Strychnine
Strychnine blocks the activity of glycine, an
inhibitory neurotransmitter.
http//www.drugstoremuseum.com/sections/level_info
2.php?level1level_id74
http//animalpetdoctor.homestead.com/PoisonRat.htm
l
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Tetanus inhibits release of inhibitory
neurotransmitter GABA
A soldier dying from tetanus. Painting by
Charles Bell in the Royal College of Surgeons,
Edinburgh.
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More about Botulism

• Less than 1 kg of toxin would kill off the
  population of the US.
• Treatment includes botulism anti-toxin. This
  binds to and inactivates the toxin, so that it
  cannot interact with nerve cells.
• Antibiotics are not useful the bacteria grows
  on food in non-acidic, anaerobic conditions (eg
  canned peas). The bacteria doesnt grow in the
  gut, but the toxin produced by the bacteria gets
  into the bloodstream via the gut.

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Medical Cosmetic Uses of Botox

• Dystonia
• involuntary skeletal muscle contraction that
  results in twisting, postural problems,
  involuntary movements, pain and general
  discomfort..
• Sometimes genetic, sometimes due to injury,
  illness or drugs.
• Botox (botulism toxin) is commonly used to treat
  focal dystonia (i.e. dystonia in a specific set
  of muscle, such as in the hand, larynx or neck.
• The goal is to weaken the contraction without
  completely paralyzing the muscle. Effect begins
  to wear off after 3 months, returns to
  pre-treatment state by 6 months.
• Early studies showed promise in treating
  migraines, but follow-up studies have shown
  little benefit.
• Wrinkle relaxer

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Heavy Metals

• Lead
• Mercury
• Elemental mercury (quicksilver)
• Methylmercury

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Intelligence quotient as a function of lifetime
average blood lead concentration.
Koller, et al. Recent Developments in Low-Level
Lead Exposure and Intellectual Impairment in
Children. Envtl. Health Persp. VOLUME 112
NUMBER 9 June 2004
http//www.ncbi.nlm.nih.gov/pmc/articles/PMC124719
1/pdf/ehp0112-000987.pdf
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Elemental mercury is used in artisanal gold
mining
http//www.ghana-mining.org/ghweb/en/pmu-mssp/mer-
abate.html
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http//www.worstpolluted.org/projects_reports/disp
lay/56
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http//www.nimd.go.jp/archives/english/tenji/a_cor
ner/a03.html
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Adverse effects to nervous system caused by
methylmercury.
1. Gait disturbance, loss of balance (ataxia),
speech disturbance (dysarthria) 2. Constriction
of the visual fields 3. Stereo anesthesia 4.
Muscle weakness, muscle cramp 5. Loss of hearing
6. Disturbance of sense of pain, touch or
temperature.
http//www.nimd.go.jp/archives/english/tenji/a_cor
ner/a03.html
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Lupus and the nervous system

• About 10-15 of people with lupus have CNS
  effects, typically fatigue, headaches,
  disorientation.
• More common peripheral neuropathy, typically as
  a result of vasulitis. Pain, loss of function of
  extremities, esp. feet. Sometimes autonomic
  systems is affected as well.

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