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  1. 1. Guillain Barré Syndrome and the influenza vaccine<br />Ted M. Burns, MD<br />Associate Professor, Neurology<br />University of Virginia<br />OrlyAvitzur, MD<br />Associate Professor, Neurology<br />New York Medical College<br />
  2. 2. Learning Objectives<br />Upon completion of participation, participants will be able to:<br />Discuss the clinical features of GBS, its pathogenesis and treatment options <br />Be aware of prior associations between GBS and influenza vaccines <br />Know when and how to report to VAERS <br />Understand the risks of underreporting<br />
  3. 3. Disclosures<br />Dr. Avitzur has received personal compensation for activities as a speaker from state neurology societies, and various neurology residency training programs, as a medical adviser to Consumers Union, and Associate Medical Editor for Consumer Reports. Dr. Avitzur writes the "In Practice" column for Neurology Today. Dr. Avitzur serves as Editor-in-Chief of AAN.com, and receives compensation for this position.<br />Dr. Burns has received personal compensation in an editorial capacity for the Neurology podcast.<br />Dr. Sejvar has nothing to disclose.<br />
  4. 4. Disclosures<br />Patient Safety Subcommittee<br />Dr. Diamond has nothing to disclose.<br />Dr. Kaminski has nothing to disclose.<br />Dr. Flippen has received personal compensation for activities with GlaxoSmithKline, Inc., Merck &Co., Inc., Ortho-McNeil Pharmaceutical, Inc., and Pfizer Inc as a member of a speaker bureau. Dr. Flippen has received personal compensation in an editorial capacity for Journal Watch Neurology.<br />Dr. Frank has nothing to disclose.<br />Dr. Hohler has nothing to disclose.<br />Dr. Kropp has received personal compensation for activities with Aenta Inc.<br />Dr. Lee has received personal compensation for activities with BoehringerIngelheim Pharmaceuticals, Inc., as a speaker. Dr. Lee has received compensation and/or their research work has been funded, entirely or in part, by a grant to their university. The grant agreement requires that the name of the funding entity and the purpose of the grant may not be disclosed. The funding entity is a governmental organization.<br />Dr. Schafer has nothing to disclose.<br />Dr. Stern has received personal compensation in an editorial capacity for The Neurologist. Dr. Stern has received compensation and/or their research work has been funded, entirely or in part, by a grant to their university. The grant agreement requires that the name of the funding entity and the purpose of the grant may not be disclosed. The funding entity is a governmental organization.<br />
  5. 5. Accreditation Statement<br />The AAN is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.<br />AMA PRA Category 1 Credit<br />The AAN designates this educational activity for a maximum of 1 (one) AMA PRA Category1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.<br />
  6. 6. Outline<br />Overview of Guillain-Barre Syndrome (GBS)<br />Influenza vaccine and GBS<br />VAERS <br />
  7. 7. Outline<br />Overview of Guillain-Barre Syndrome (GBS)<br />Influenza vaccine and GBS<br />VAERS <br />
  8. 8. Clinical features – classic GBS<br />Motor > sensory polyradiculoneuropathy<br />Weakness <br />Positive neuropathic sensory symptoms<br /><ul><li>tingling, pain</li></ul>Areflexia (or hyporeflexia)<br />Diaphragmatic and cranial nerve weakness ~ 50%<br />Autonomic involvement > 50%<br />Acute-to-subacute onset<br />Nadir within 4 weeks<br />Monophasic illness<br />Seminars Neurol 2008;28:152-167<br />
  9. 9. Clinical features – classic GBS<br />Motor > sensory polyradiculoneuropathy<br />Weakness <br />Positive neuropathic sensory symptoms<br /><ul><li>tingling, pain</li></ul>Areflexia (or hyporeflexia)<br />Diaphragmatic and cranial nerve weakness ~ 50%<br />Autonomic involvement > 50%<br />Acute-to-subacute onset<br />Nadir within 4 weeks<br />Monophasic illness<br />Seminars Neurol 2008;28:152-167<br />
  10. 10. Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135<br />Classic GBS: clinical features<br />
  11. 11. Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135<br />Classic GBS: clinical features<br />
  12. 12. Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135<br />Classic GBS: clinical features<br />
  13. 13. Variants<br />AMAN<br />AMSAN<br />Seminars Neurol 2008;28:152-167<br />MFS<br />
  14. 14. Antecedent infection in ~ two-thirdsRespiratory infection >> diarrhea<br />Jacobs BC, Rothbarth PH, van der Meche FG, et al. Neurology 1998;51:1110-1115.<br />
  15. 15. Infectious agent: C. jejuni > CMV, EBV<br />Jacobs BC, Rothbarth PH, van der Meche FG, et al. Neurology 1998;51:1110-1115.<br />
  16. 16. Diagnosis: consider mimics of GBS<br />Acute myelopathy: corticospinal tract findings, back pain<br />Vasculitic neuropathy: Systemic symptoms, pain, asymmetry<br />Thiamine deficiency: Alcohol abuse, s/p bariatric surgery<br />West Nile poliomyelitis: lower motor neuron, fever, meningitis, pleocytosis<br />Lyme neuroborreliosis: polyradiculitis, rash, systemic symptoms<br />Tick paralysis: children, pure motor (low CMAPs)<br />Botulism: oculobulbar, motor, nausea/vomiting/constipation<br />Acute intermittent porphyria: GI symptoms, autonomic crisis<br />Heavy metals, acute: systemic, GI symptoms, skin<br />Organophosphates: insecticide exposure, cramps, axonopathy<br />n-Hexane: glue- and gasoline-sniffers<br />Poliomyelitis: lower motor neuron, fever, meningitis, pleocytosis<br />Buckthorn toxin: berries of buckthorn shrub, 1-3 weeks later; SW US<br />CMV polyradiculopathy: advanced AIDS, pleocytosis<br />Diphtheria: 2-3 months after pharyngitis<br />Marine toxins: pufferfish, shellfish<br />Seminars Neurol 2008;28:152-167. Neurologist. 2004;10:61-74<br />
  17. 17. Diagnosis: CSF in GBS<br />CSF protein – abnormal initially in ~ 60%<br />Don’t let normal CSF during first week dissuade you from treating early<br />After first week, protein is almost always elevated<br />> 90% “in fully developed illness”<br />Few WBC’s (<10)<br />Ropper AH, NEJM 1992;326:1130-1136; Al-Shekhlee et al, Muscle Nerve 2005;32:66-72.<br />
  18. 18. Diagnosis: EDX in early GBS <br />Frequently abnormal:<br />H – reflex, F – waves, low distal CMAP amplitude, dispersion of CMAP, prolonged distal latencies<br />“Sural sparing” pattern on sensory NCS<br />Often normal in early GBS:<br />Conduction block and temporal dispersion on motor NCS<br />Non-uniform slowing on motor NCS<br />Gordon PH, Wilbourn AJ. Arch Neurol 2001;58:913-917; Albers et al, Muscle Nerve 1985;8:528-539; Al-Shekhlee et al. Muscle Nerve 2005;32:66-72<br />
  19. 19. Pathogenic events of early GBS<br />Otherwise trivial infection<br />
  20. 20. 1. Otherwise trivial infection<br />Jacobs BC, Rothbarth PH, van derMeche FG, et al. Neurology 1998;51:1110-1115. <br />
  21. 21. Pathogenic events of early GBS<br />Otherwise trivial infection<br />Molecular mimicry with humoral response<br />
  22. 22. Pathogenic events of early GBS<br />Otherwise trivial infection<br />Molecular mimicry with humoral response<br />Complement activation<br /><ul><li>MAC damages Schwann cell myelin
  23. 23. MAC damages terminal axons</li></ul>Macrophage-mediated myelin stripping<br />
  24. 24. Neurology 2003;61;736-740. Neurology 1985;35:1096-1104. Annals Neurol 1987;22:753-761. Lancet 1997; 349:225-230<br />Plasma exchange<br /><ul><li>Exchanging one plasma volume, 50 mL/kg, on 5 separate occasions over 1 – 2 weeks</li></ul>Intravenous immunoglobulin<br /><ul><li>2 gm/kg divided over 2 – 5 days</li></li></ul><li>Immunotherapy: additional considerations<br />Duration of disease<br /><ul><li>~ efficacy demonstrated in RCTs in first ~ 4 weeks of illness</li></ul>Severity of disease<br /><ul><li>Most trials show efficacy for non-ambulating patients</li></ul>Temporal evolution<br /><ul><li>i.e. how active is it? i.e. what will tomorrow bring?</li></ul>Vital capacity, walking status<br />Seminars Neurol 2008;28:152-167<br />
  25. 25. Remember supportive care<br />Mechanical ventilation<br />Dysautonomia<br />DVT prophylaxis<br />Pain management<br />Issues following acute care hospitalization<br />Rehabilitation<br />Persistent disability and fatigue<br />Seminars Neurol 2008;28:152-167<br />
  26. 26. Outline<br />Overview of Guillain-Barre Syndrome (GBS)<br />Influenza vaccine and GBS<br />VAERS <br />
  27. 27. Epidemiology of GBS<br /><ul><li>Background incidence:
  28. 28. Annual incidence of GBS is 1 – 1.5 per 100,000
  29. 29. Higher incidence in elderly (e.g. 4 per 100,000 in those 75 years and older)
  30. 30. Lower incidence in children
  31. 31. Thus, background monthly incidence of ~ 1 per million
  32. 32. GBS in the US:
  33. 33. US population: 308 million
  34. 34. In the US, ~ a dozen new cases of GBS each day</li></li></ul><li>GBS following influenza vaccination?<br />1976 Swine flu vaccination: number of GBS cases appeared to be in excess of background incidence<br />1976 vaccination: Relative Risk of GBS among vaccinees – 8<br />1 excess case of GBS / 100,000 vaccine recipients<br />Within 6 weeks of vaccine; peak at 2-3 weeks<br />Arch Intern Med 2006;166:2217-2221. JAMA 2004;292:2478-2481. Arch Intern Med 2006;166:1301-1304. NEJM 1998;339:1797-1802. Am J Epid 2009;169:382-388. JID 2009;200:321-328<br />
  35. 35. After 1976…<br />1992-1993 and 1993-1994 seasonal influenza: perhaps one excess case per million adult vaccines<br />Other studies have failed to demonstrate an increase of GBS following influenza vaccination<br />US Army, 5.6 million, 1980-1988<br />UK General Practice Research Database, 1990-2005<br />Some studies suggest a decrease in risk of GBS<br />Decrease in GBS cases reported: VAERS - 1.7/million in 1993-94 to 0.4/million in 2002-03<br />Arch Intern Med 2006;166:2217-2221. JAMA 2004;292:2478-2481. Arch Intern Med 2006;166:1301-1304. NEJM 1998;339:1797-1802. Am J Epid 2009;169:382-388. JID 2009;200:321-328<br />
  36. 36. Vaccination in patients with GBS history?<br />In UK, GBS Support Group sent questionnaire to its 3000 members:<br />1114 patients completed (927 GBS, 179 CIDP)<br />GBS: 311/927 pts reported receiving vaccines after GBS<br />11/311 (3.5%) reported symptoms after vaccine<br />Mild: fatigue, numbness, paresthesias (no hospitalizations)<br />One pt unable to walk for 6 weeks<br />Risk of relapse that modified Rankin score = 0.3%<br />Influenza vaccine - 4% “relapse”<br />29/311 had a vaccine before the first GBS <br />2/29 had recurrence after a different vaccine<br />CIDP: 65/179 reported receiving vaccine after diagnosis of CIDP<br />5/65 had symptom recurrence; one leading to re-treatment<br />Influenza (4%), tetanus, pneumococcus<br />J Neurol, Neurosurg, Psych 2002;73:348-349<br />
  37. 37. Vaccination in patients with GBS history?<br />In the Netherlands, none of 106 previous GBS patients who received influenza vaccine (1 – 37 times, total 775 vaccinations) reported another episode of GBS<br />J Periph Nerv System 2009;14(suppl)81-82<br />
  38. 38. Consensus-based recommendations<br />“Immunization is not recommended during the acute phase of GBS and probably not during a period, possibly a year, after the onset of disease.”<br />“After that, immunization need not be withheld, but the need for the immunization should be reviewed on an individual basis.”<br />“If GBS occurs within 6 weeks after a particular immunization, consideration should be given to avoiding that immunization in the future.”<br />Supportive care for patients with Guillain-Barre Syndrome. Arch Neurol 2005;62:1194-1198.<br />
  39. 39. For more information, listen to the AANEM podcast with Richard Hughes (AANEM podcast # 048). <br />
  40. 40. ...So Why The Concern??<br />Partial “swine” origin of 2009 A/H1N1 virus—first since 1976<br />Could vaccine against 2009 H1N1 virus lead to similar increased GBS risk?<br />Improvements in influenza vaccine manufacturing<br />2009 H1N1 vaccine manufactured the same as seasonal flu vaccine<br />Surveillance being conducted out of “abundance of caution”<br />
  41. 41. Outline<br />Overview of Guillain-Barre Syndrome (GBS)<br />Influenza vaccine and GBS<br />VAERS <br />
  42. 42. VAERS: Background<br />US postlicensure vaccine safety surveillance <br />Receivesvoluntary reports of adverse events following immunization<br />Co-managed by CDC and FDA<br />Receives ~23,000 reports per year (2005-2008 average)<br />Data publicly available <br />Healthcare providers are encouraged to report clinically significant adverse events after vaccination<br />Anyone can submit a report to VAERS<br />
  43. 43. VAERS Strengths<br />Can detect very rare adverse events<br />Generates hypotheses<br />Helps identify new and/or rare adverse events following immunization<br />Helps determine if further investigations are needed<br />Monitors trends of previously reported adverse events <br />Monitors vaccine lot safety <br />
  44. 44. VAERS Limitations<br />Passive surveillance; therefore, risk of underreporting<br />Stimulated reporting due to media attention<br />Possibly incomplete and inaccurate data on report form<br />Lack of availability of denominator data <br />No information on number of persons vaccinated<br />VAERS generally cannot determine if an adverse event was coincidental or caused by a vaccine<br />
  45. 45. VAERS “Non-Serious” Reports*<br />92% of VAERS reports are “non-serious”<br />Most frequent adverse events** <br />Local reactions<br />Fever<br />Rashes or itching <br />Headache<br />Dizziness <br />* Data from 91,669 VAERS reports received during 2005 through 2008<br />** A vaccinee may have had more than one adverse event listed in the report <br />
  46. 46. VAERS definition of “Serious” Reports<br /><ul><li>Death
  47. 47. Life-threatening illness
  48. 48. Hospitalization
  49. 49. Prolonged existing hospitalization
  50. 50. Persistent or significant disability
  51. 51. Certain other medically important conditions</li></ul>*Code of Federal Regulations<br />Title 21 (21CFR 314.80)<br />From VAERS form<br />
  52. 52. What to Report<br />Report any clinically significant adverse event following immunization (www.vaers.hhs.gov)<br />Adverse event of concern to the healthcare provider or vaccinee/caregiver or other VAERS reporter<br />The National Childhood Vaccine Injury Act of 1986 mandates that healthcare providers report specific adverse events that occur after immunization for some vaccines.*<br />*The National Childhood Vaccine Injury Act does not apply to 2009 H1N1 vaccines<br />
  53. 53. How to find it<br />
  54. 54.
  55. 55. Form, if faxing<br />
  56. 56. Remember, report all cases regardless of whether cause-and-effect is suspected<br />
  57. 57. VAERS Follow-up<br />Follow-up conducted for reports of serious adverse events or for vaccines/adverse events designated for enhanced surveillance<br />Letter sent to reporters to check recovery status for all reports with “no” or “unknown” recovery listed on initial VAERS form (60 days and 1 year)<br />
  58. 58. Analysis of 2009 H1N1 VAERS reports<br />CDC and FDA have primary responsibility for analysis <br />Assess for signals for new or unexpected adverse events of concern<br />Review individual reports for serious adverse events <br />Additional information available from follow-up medical records and autopsy reports<br />
  59. 59. Emerging Infections Program<br />CDC is engaging in active surveillance for GBS in 10 Emerging Infections Program (EIP) states<br />Collecting ALL new GBS cases, regardless of previous vaccination<br />Surveillance Officers for each of the 10 EIP areas of surveillance will be in contact with neurologists in those areas<br />Physicians are strongly encouraged to take these calls/read these emails <br />Some states may have additional mandated reporting requirements<br />Your EIP Surveillance Officer will advise you on your local reporting requirements<br />* Metro areas only<br />^ all state except NYC<br />California<br />Colorado*<br />Connecticut<br />Georgia*<br />Maryland<br />Minnesota<br />New Mexico<br />New York^<br />Oregon*<br />Tennessee<br />
  60. 60. Neurologists in EIP Sites<br />Few, time-limited tasks that are being requested from neurologists participating in the EIP reporting system<br />Each practice should identify a point of contact (POC) within their practice (either themselves, a practice manager or nurse manager) <br />If they have not already heard from your POC, EIP sites will be contacting that POC weekly to confirm that no new GBS cases have been diagnosed<br />You might be asked to answer a few brief follow-up or clarification questions on cases reported<br />
  61. 61. Thank you. Questions? Comments?<br />

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