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Guillain Barré Syndrome and the influenza vaccine

Ted M. Burns, MDAssociate Professor,

NeurologyUniversity of Virginia

Orly Avitzur, MDAssociate Professor,

NeurologyNew York Medical

College

Learning Objectives

Upon completion of participation, participants will be able to:Discuss the clinical features of GBS, its pathogenesis and treatment options Be aware of prior associations between GBS and influenza vaccines Know when and how to report to VAERS Understand the risks of underreporting

Disclosures• 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.

• Dr. Burns has received personal compensation in an editorial capacity for the Neurology podcast.

• Dr. Sejvar has nothing to disclose.

DisclosuresPatient Safety Subcommittee• Dr. Diamond has nothing to disclose.• Dr. Kaminski has nothing to disclose.• 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.

• Dr. Frank has nothing to disclose.• Dr. Hohler has nothing to disclose.• Dr. Kropp has received personal compensation for activities with Aenta Inc.• Dr. Lee has received personal compensation for activities with Boehringer Ingelheim 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.

• Dr. Schafer has nothing to disclose.• 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.

Accreditation StatementThe AAN is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

AMA PRA Category 1 CreditThe AAN designates this educational activity for a maximum of 1 (one) AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Outline

1. Overview of Guillain-Barre Syndrome (GBS)

2. Influenza vaccine and GBS

3. VAERS

Outline

1. Overview of Guillain-Barre Syndrome (GBS)

2. Influenza vaccine and GBS

3. VAERS

Clinical features – classic GBS

Motor > sensory polyradiculoneuropathy1. Weakness 2. Positive neuropathic sensory symptoms

– tingling, pain

3. Areflexia (or hyporeflexia)4. Diaphragmatic and cranial nerve weakness ~

50%5. Autonomic involvement > 50%

• Acute-to-subacute onset Nadir within 4 weeks Monophasic illness

Seminars Neurol 2008;28:152-167

Clinical features – classic GBS

Motor > sensory polyradiculoneuropathy1. Weakness 2. Positive neuropathic sensory symptoms

– tingling, pain

3. Areflexia (or hyporeflexia)4. Diaphragmatic and cranial nerve weakness ~

50%5. Autonomic involvement > 50%

• Acute-to-subacute onset Nadir within 4 weeks Monophasic illness

Seminars Neurol 2008;28:152-167

Classic GBS: clinical features

Initial presentation (%)

Nadir (%)

Paresthesias 70 85

Weak UE 20 90

Weak LE 60 95

Weak face 35 60

Weak swallow 25 50

Sphincter 15 5

Ataxia 10 15

Areflexia 75 90

Sensory loss 40 75

Ventilator 10 30

CSF Pro > 55 50 90

Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135

Classic GBS: clinical features

Initial presentation (%)

Nadir (%)

Paresthesias 70 85

Weak UE 20 90

Weak LE 60 95

Weak face 35 60

Weak swallow 25 50

Sphincter 15 5

Ataxia 10 15

Areflexia 75 90

Sensory loss 40 75

Ventilator 10 30

CSF Pro > 55 50 90

Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135

Classic GBS: clinical features

Initial presentation (%)

Nadir (%)

Paresthesias 70 85

Weak UE 20 90

Weak LE 60 95

Weak face 35 60

Weak swallow 25 50

Sphincter 15 5

Ataxia 10 15

Areflexia 75 90

Sensory loss 40 75

Ventilator 10 30

CSF Pro > 55 50 90

Ropper AH, The Guillain-Barre syndrome, NEJM 1992;326:1130-1135

AMAN

Variants

AMSAN

MFS

Seminars Neurol 2008;28:152-167

Antecedent infection in ~ two-thirdsRespiratory infection >> diarrhea

Jacobs BC, Rothbarth PH, van der Meche FG, et al.

Neurology 1998;51:1110-1115.

Infectious agent: C. jejuni > CMV, EBV

Jacobs BC, Rothbarth PH, van der Meche FG, et al.

Neurology 1998;51:1110-1115.

Diagnosis: consider mimics of GBS

• Acute myelopathy: corticospinal tract findings, back pain• Vasculitic neuropathy: Systemic symptoms, pain, asymmetry• Thiamine deficiency: Alcohol abuse, s/p bariatric surgery• West Nile poliomyelitis: lower motor neuron, fever, meningitis, pleocytosis• Lyme neuroborreliosis: polyradiculitis, rash, systemic symptoms• Tick paralysis: children, pure motor (low CMAPs)• Botulism: oculobulbar, motor, nausea/vomiting/constipation• Acute intermittent porphyria: GI symptoms, autonomic crisis• Heavy metals, acute: systemic, GI symptoms, skin• Organophosphates: insecticide exposure, cramps, axonopathy• n-Hexane: glue- and gasoline-sniffers• Poliomyelitis: lower motor neuron, fever, meningitis, pleocytosis• Buckthorn toxin: berries of buckthorn shrub, 1-3 weeks later; SW US• CMV polyradiculopathy: advanced AIDS, pleocytosis• Diphtheria: 2-3 months after pharyngitis• Marine toxins: pufferfish, shellfish

Seminars Neurol 2008;28:152-167. Neurologist. 2004;10:61-74

Diagnosis: CSF in GBS

•CSF protein – abnormal initially in ~ 60%Don’t let normal CSF during first week dissuade you from treating early

•After first week, protein is almost always elevated> 90% “in fully developed illness”

•Few WBC’s (<10)

Ropper AH, NEJM 1992;326:1130-1136; Al-Shekhlee et al, Muscle Nerve 2005;32:66-72.

Diagnosis: EDX in early GBS

1. Frequently abnormal:– H – reflex, F – waves, low distal CMAP

amplitude, dispersion of CMAP, prolonged distal latencies

– “Sural sparing” pattern on sensory NCS2. Often normal in early GBS:

– Conduction block and temporal dispersion on motor NCS

– Non-uniform slowing on motor NCS

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

Pathogenic events of early GBS

1. Otherwise trivial infection

1. Otherwise trivial infection

Jacobs BC, Rothbarth PH, van der Meche FG, et al. Neurology 1998;51:1110-1115.

Pathogenic events of early GBS

1. Otherwise trivial infection

2. Molecular mimicry with humoral response

Pathogenic events of early GBS

1. Otherwise trivial infection

2. Molecular mimicry with humoral response

3. Complement activation• MAC damages Schwann cell myelin• MAC damages terminal axons

4. Macrophage-mediated myelin stripping

1. Plasma exchange• Exchanging one plasma volume, 50 mL/kg, on 5

separate occasions over 1 – 2 weeks

2. Intravenous immunoglobulin• 2 gm/kg divided over 2 – 5 days

Neurology 2003;61;736-740. Neurology 1985;35:1096-1104. Annals Neurol 1987;22:753-761. Lancet 1997; 349:225-230

Immunotherapy: additional considerations

1. Duration of disease• ~ efficacy demonstrated in RCTs in first ~ 4

weeks of illness

2. Severity of disease• Most trials show efficacy for non-ambulating

patients

3. Temporal evolution• i.e. how active is it? i.e. what will tomorrow bring?

– Vital capacity, walking status

Seminars Neurol 2008;28:152-167

Remember supportive care

1. Mechanical ventilation

2. Dysautonomia

3. DVT prophylaxis

4. Pain management

5. Issues following acute care hospitalization1. Rehabilitation

2. Persistent disability and fatigue

Seminars Neurol 2008;28:152-167

Outline

1. Overview of Guillain-Barre Syndrome (GBS)

2. Influenza vaccine and GBS

3. VAERS

Epidemiology of GBS

• Background incidence: • Annual incidence of GBS is 1 – 1.5 per 100,000

• Higher incidence in elderly (e.g. 4 per 100,000 in those 75 years and older)

• Lower incidence in children• Thus, background monthly incidence of ~ 1 per million

• GBS in the US:• US population: 308 million• In the US, ~ a dozen new cases of GBS each day

GBS following influenza vaccination?

•1976 Swine flu vaccination: number of GBS cases appeared to be in excess of background incidence1976 vaccination: Relative Risk of GBS among vaccinees – 8

– 1 excess case of GBS / 100,000 vaccine recipients– Within 6 weeks of vaccine; peak at 2-3 weeks

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

After 1976…

1. 1992-1993 and 1993-1994 seasonal influenza: perhaps one excess case per million adult vaccines

2. Other studies have failed to demonstrate an increase of GBS following influenza vaccination

US Army, 5.6 million, 1980-1988 UK General Practice Research Database, 1990-

2005

3. Some studies suggest a decrease in risk of GBS– Decrease in GBS cases reported: VAERS - 1.7/million in 1993-94

to 0.4/million in 2002-03

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

Vaccination in patients with GBS history?

In UK, GBS Support Group sent questionnaire to its 3000 members:• 1114 patients completed (927 GBS, 179 CIDP)• GBS: 311/927 pts reported receiving vaccines after GBS• 11/311 (3.5%) reported symptoms after vaccine

Mild: fatigue, numbness, paresthesias (no hospitalizations)– One pt unable to walk for 6 weeks

- Risk of relapse that modified Rankin score = 0.3%

– Influenza vaccine - 4% “relapse” 29/311 had a vaccine before the first GBS

– 2/29 had recurrence after a different vaccine

CIDP: 65/179 reported receiving vaccine after diagnosis of CIDP 5/65 had symptom recurrence; one leading to re-treatment

– Influenza (4%), tetanus, pneumococcus

J Neurol, Neurosurg, Psych 2002;73:348-349

• In the Netherlands, none of 106 previous GBS patients who received influenza vaccine (1 – 37 times, total 775 vaccinations) reported another episode of GBS

J Periph Nerv System 2009;14(suppl)81-82

Vaccination in patients with GBS history?

1. “Immunization is not recommended during the acute phase of GBS and probably not during a period, possibly a year, after the onset of disease.”

2. “After that, immunization need not be withheld, but the need for the immunization should be reviewed on an individual basis.”

3. “If GBS occurs within 6 weeks after a particular immunization, consideration should be given to avoiding that immunization in the future.”

Consensus-based recommendations

Supportive care for patients with Guillain-Barre Syndrome. Arch Neurol 2005;62:1194-1198.

•For more information, listen to the AANEM podcast with Richard Hughes (AANEM podcast # 048).

...So Why The Concern??

• Partial “swine” origin of 2009 A/H1N1 virus—first since 1976

• Could vaccine against 2009 H1N1 virus lead to similar increased GBS risk? Improvements in influenza vaccine manufacturing 2009 H1N1 vaccine manufactured the same as seasonal flu

vaccine

• Surveillance being conducted out of “abundance of caution”

Outline

1. Overview of Guillain-Barre Syndrome (GBS)

2. Influenza vaccine and GBS

3. VAERS

VAERS: Background

• US postlicensure vaccine safety surveillance Receives voluntary reports of adverse events following

immunization Co-managed by CDC and FDA

• Receives ~23,000 reports per year (2005-2008 average)

• Data publicly available • Healthcare providers are encouraged to report clinically significant adverse events after vaccination Anyone can submit a report to VAERS

VAERS Strengths

•Can detect very rare adverse events•Generates hypotheses

Helps identify new and/or rare adverse events following immunization

Helps determine if further investigations are needed•Monitors trends of previously reported adverse events

•Monitors vaccine lot safety

VAERS Limitations

•Passive surveillance; therefore, risk of underreporting

•Stimulated reporting due to media attention•Possibly incomplete and inaccurate data on report form

•Lack of availability of denominator data No information on number of persons vaccinated

•VAERS generally cannot determine if an adverse event was coincidental or caused by a vaccine

VAERS “Non-Serious” Reports*

•92% of VAERS reports are “non-serious”•Most frequent adverse events**

Local reactions Fever Rashes or itching Headache Dizziness

* Data from 91,669 VAERS reports received during 2005 through 2008

** A vaccinee may have had more than one adverse event listed in the report

VAERS definition of “Serious” Reports

DeathLife-threatening illnessHospitalizationProlonged existing

hospitalizationPersistent or significant

disabilityCertain other medically

important conditions

*Code of Federal RegulationsTitle 21 (21CFR 314.80)

From VAERS form

What to Report

•Report any clinically significant adverse event following immunization (www.vaers.hhs.gov)

–Adverse event of concern to the healthcare provider or vaccinee/caregiver or other VAERS reporter

–The National Childhood Vaccine Injury Act of 1986 mandates that healthcare providers report specific adverse events that occur after immunization for some vaccines.*- *The National Childhood Vaccine Injury Act does not apply to

2009 H1N1 vaccines

How to find it

Form, if faxing

Remember, report all cases regardless of whether cause-and-effect is suspected

VAERS Follow-up

•Follow-up conducted for reports of serious adverse events or for vaccines/adverse events designated for enhanced surveillance

•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)

Analysis of 2009 H1N1 VAERS reports

•CDC and FDA have primary responsibility for analysis

•Assess for signals for new or unexpected adverse events of concern

•Review individual reports for serious adverse events Additional information available from follow-up medical

records and autopsy reports

Emerging Infections Program• CDC is engaging in active surveillance for

GBS in 10 Emerging Infections Program (EIP) states Collecting ALL new GBS cases,

regardless of previous vaccination• Surveillance Officers for each of the 10 EIP

areas of surveillance will be in contact with neurologists in those areas Physicians are strongly encouraged to

take these calls/read these emails • Some states may have additional mandated

reporting requirements Your EIP Surveillance Officer will advise

you on your local reporting requirements * Metro areas only

^ all state except NYC

California Colorado* Connecticut Georgia* Maryland Minnesota New Mexico New York^ Oregon* Tennessee

Neurologists in EIP Sites

• Few, time-limited tasks that are being requested from neurologists participating in the EIP reporting system Each practice should identify a point of contact (POC) within

their practice (either themselves, a practice manager or nurse manager)

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

You might be asked to answer a few brief follow-up or clarification questions on cases reported

Thank you. Questions? Comments?