NEUROPATHOPHYSIOLOGY III Finish Sensory & Motor Disease and then Trauma, Stroke and Toxins

1. NEUROPATHOPHYSIOLOGY IIIFinish Sensory & Motor Disease and thenTrauma, Stroke and Toxins Nancy Long Sieber, Ph.D. October 1, 2012

2. 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.

3. MS is characterized by demyelinization of neurons in the CNS http://www.riversideonline.com/source/images/image_popup/ww5r308_big.jpg

4. 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?

5. 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.

6. http://sofija.files.wordpress.com/2007/01/ms_worldmap.jpg

7. Proposed scheme for virus-mediated autoimmunity in multiple sclerosis.

8. MRI Images help diagnose and monitor MS http://content.revolutionhealth.com/contentimages/h9991221.jpg

9. 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.

10. 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).

11. Guillain-Barre Syndrome http://www.monografias.com/trabajos37/sindrome-guillain-barre/Image8645.jpg

12. 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/migration/ALS1.jpg

13. 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.

14. 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. Possible environmental risk factors

15. 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.

16. 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

17. Disease and Trauma of the Peripheral Nerves

18. 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.

19. Injury and Trauma to the CNS

20. http://dailyme.com/gallery/medical-condition/head-injury.htmlhttp://dailyme.com/gallery/medical-condition/head-injury.html

21. 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

22. 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.

23. 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

24. 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

25. 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

26. Stroke:Hemorrhagic and Ischemic

27. 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.

29. http://ww2.heartandstroke.ca/images/english/stroke_isc_web.jpghttp://ww2.heartandstroke.ca/images/english/stroke_isc_web.jpg

30. http://ww2.heartandstroke.ca/images/english/stroke_hem_web.jpghttp://ww2.heartandstroke.ca/images/english/stroke_hem_web.jpg

31. Neurotoxins • Organophosphates – pesticides & nerve gas • Strychnine poisoning • Tetanus toxin • A bit more about botulism • Heavy Metals • Lead • Mercury

32. Organophosphate pesticidesinhibit acetylcholinesterase. http://www.environmentalhealthnews.org/ehs/newscience/depressed-about-pesticides/

34. Strychnine Strychnine blocks the activity of glycine, an inhibitory neurotransmitter. http://www.drugstoremuseum.com/sections/level_info2.php?level=1&level_id=74 http://animalpetdoctor.homestead.com/PoisonRat.html

35. Tetanus inhibits release of inhibitory neurotransmitter GABA A soldier dying from tetanus. Painting by Charles Bell in the Royal College of Surgeons, Edinburgh.

36. 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 doesn’t grow in the gut, but the toxin produced by the bacteria gets into the bloodstream via the gut.

37. 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

38. Heavy Metals • Lead • Mercury • Elemental mercury (quicksilver) • Methylmercury

39. 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/PMC1247191/pdf/ehp0112-000987.pdf

40. Elemental mercury is used in artisanal gold mining http://www.ghana-mining.org/ghweb/en/pmu-mssp/mer-abate.html

41. http://www.worstpolluted.org/projects_reports/display/56

42. http://www.nimd.go.jp/archives/english/tenji/a_corner/a03.htmlhttp://www.nimd.go.jp/archives/english/tenji/a_corner/a03.html

43. 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_corner/a03.html

44. 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.