Guillain-Barre Syndrome

William Woodfin MD

K.F. 40 y.o. r/h woman

3/17 Nausea, diarrhea & severe myalgias

Son dxed c rotavirus 1 wk. Previously

4/21 “Creepy-crawlies” legs>arms

4/25 Weakness legs progressing

4/26 Handwriting looks like “hen scratch”

K.F. 40 y.o. woman

4/28 Admitted to outside hospital.

L.P. wnl

EMG positive waves in some leg

muscles

NCVs absent H-reflexes

F responses & motor latencies wnl

K.F. 40 y.o. woman

4/29 Transferred to PHD

Hx.: diabetic x 10 yrs.

hypothyroid- treatedx yrs.

no sphincter disrubance

aching pain low back & buttocks

mild postural light headedness

no SOB or palpatations

Exam

BP 150/90 P 80 Wt. 250 lbs.

Mild weakness neck flexors

4/5 biceps, grip & interossei- symmetric

2/5 iliopsoas & quadriceps

3/5 hamstrings & adductors

4/5 abductors

4/5 ankles & toes- extensors & flexors

Exam

Sensory- intact

DTRs- biceps, BR, knees are trace c

reinforcement. Triceps & ankles

unobtainable

Plantars- flexor

F to N- intact

Gait- not testable

Lab

H/H 10.3/33.5 c microcytic indices

A1c Hgb 10.1

TSH 0.97

LDL 182

Serum immunofixation- wnl. No IgA def.

FVCs- consistently 4+ liters

MRI

LS spine s & c contrast- no nerve root enhancement

Course in hospital

Treated c IVIG 0.4 gms/kgm daily x 5

Strength fluctuated only mildly

Blood sugars ok in AM, high in afternoons

Repeated NCVs show mild dispersion of F waves

Transferred back to referring hospital 5/6

Telephone FU

Ambulating fairly well c walker. Strength

clearly improving.

Still bothered by “creepy-crawlies”

What is the GBS?

• Due to the breadth of clinical presentation it is of limited help to try to define rigid diagnostic criteria.

• Thomas Munsat 1965: “…The GBS is easy to diagnose but difficult to define

The typical illness evolves over weeks usually following an infectious disease and involves:• 1. Paresthesiaes

usually hearld the disease

• 2. Fairly symmetric weakness in the legs, later the arms and, often, respiratory and facial muscles

• 3. Dimunition and loss of the DTRs

• 4. Albuminocytologic dissociation

• 5. Recovery over weeks to months

History

Waldrop 1834

Olliver 1837

Landry 1859

Graves 1884

Ross & Bury 1893

Brussel’s Conf. 1937

Haymaker & Kernohan 1949

Waksman & Adams 1955

Miller Fisher 1956

Asbury, Aranson & Adams 1969Guillain, Barre & Strohl

1916-1920

Note sur la paralysie ascendante aigue 1859

• March 16- a febrile illness• May 11- mild sensory symptoms in the fingers

and toes• June 13- knees buckle• June 16- unable to walk• Subsequent respiratory failure and death.• Autopsy unrevealing. Peripheral nerves probably

not examined

Late 19th century

• Westphal 1876- “Landry’s Ascending Paralysis”• Graves 1884- localized neurologic disease to the

peripheral nerves, “the nervous cords”• Ross & Bury 1893- 90 cases. A disease of the

peripheral nerves• Numerous reports emphasizing various aspects of

the disease with most authors crediting Landry

Georges Guillain

Revue Neurologique 1916

Guillain, Barre & Strohl 1916Revue Neurologique

• Two soldiers in Amiens developing paralysis and loss of DTRs.

• A new diagnostic feature: albuminocytologic dissociation in the CSF

• No mention of Landry

Foundations

• Quincke- CSF observations 25 years earlier

• Siccard & Foix- “albuminocytologic dissociation” in Pott’s disease

Late 19th century: examination of the reflexes had become a part of the neurologic exam with appreciated as a sign of neuropathy based on observations in tabes dorsalis areflexia

Haymaker & Kernohan 1949

• Landmark in pathological description c 50 fatal cases & detailed review of clinical findings

• Emphasized prominent damage to proximal nerves often at junction of ventral & dorsal roots. Little study of more distal nerves

• Unified findings of Landry & Guillain, Barre & Strohl

Waksman & Adams 1955

• Experimental Allergic Neuritis

• First animal model of a noninfectious inflammatory neuritis

• Rabbit nerve and Freund’s adjuvant injected intradermally

• Target of activated T cells uncertain

Asbury, Aranson & Adams 1969

• 19 pts. All with well developed mononuclear infiltrates in spinal roots and nerves within days of clinical onset

• Pathological hallmark: perivascular mononuclear inflammatory infiltrates to adjacent to the areas of demyelination

Overview of Adaptive Immunity

• Lymphocytes: “command & control,” identify antigen components, respond specifically, mobilize other elements and direct the attack c memory for each antigenic assault

• Antibodies: specialized immunoglobulin molecules directly neutralize and remove antigen

T lymphocytes

• CD8- recognize epitopes paired c MHC-I• CD4- activate and control the immune response• Scavenger cells break down antigen into small

peptide fragments (T cell epitopes), MHC-II epitope complexes are expressed on the surface & the scavenger become an APC which docks on a CD4 c a compatible TCR. CD4 proliferates releasing cytokines.

Antibodies

• Cytokines activate other lymphocytes including B cells that differentiate into plasma cells and serve as immunoglobulin factories.

• Abs are Ig molecules that recognize, bind, neutralize and opsonize Ag for phagocytosis. They activate complement(membrane attack complex) & induce target cells to activate the inflammatory response

Cellular & Humoral Immune Mechanisms

Self-tolerance

• The process of self recognition

• T & B cells learn self tolerance during maturation

• Autoimmunity occurs when the mechanisms of self protection are defective

Mechanisms of Autoimmunity

• Molecular mimicry- microbe cell surface Ag resembles self protein. Damage results from “friendly fire” The inciting Ag is usually unidentified & may not exist as a single stimulus.

• Excessive cytokine release due to profound immune stimulus may awaken self tolerant T cells or may cause expression of MHC complexes.

• Self Ags bound to drugs may lose tolerated status

Antecedent Events: Infectious

• Viral: Influenza, Coxsackie, EBV, Herpes,

HIV, Hepatitis, CMV, WNV

Bacterial: Campylobacter jejuni,

Mycoplasma, E. coli

Parasitic: Malaria, Toxoplasmosis

Antecedent Events: Systemic disease

• Hodgkins

• CLL

• Hyperthyroidism

• Sarcoidosis

• Collagen Vascular d.

• Renal d.

Other antecedent events

• Surgery

• Immunization

• Pregnancy

• Envenomization

• Bone marrow transplantation

• Drug ingestion

Features of AIDP

• 2/3s have identifiable preceding event• 50% begin with paresthesias followed by

weakness in legs; 10% begin with arm weakness; rarely begins in face

• Ophthalmoplegia: partial 15%, total 5%• Autonomic dysfunction in 65%,

arrhythmias, hypotension,urinary retention in 10-15%, pupillary inequality

AIDP

• Progresses for days to 4 weeks• 15% with severe disability• Mortality 3-5%• CSF: protein may be normal early, elevated

in 90% by clinical nadir, cells< 10 in 95%, >50 suggests HIV

• EDX: prolonged F & distal motor latencies, conduction block 30-40% in routine studies

AIDP

• Pathology: immune attack directed at schwann cell plasmalemma esp. at nerve roots with IgG & complement deposits preceding demyelination

CIDP

• Evolves over months• Fluctuates• Respiratory failure, dysautonomia, facial

weakness, ophthalmoplegia- all are rare• CSF protein often highly elevated• Marked slowing of motor nerve conduction• Steroid responsive

Features of AMSAN

• Commonly preceded by diarrhea esp. c. jejuni

• Abrupt onset of weakness c rapid progression to quadriplegia & respiratory insufficiency

• Other features as c AIDP• Longer recovery, more residual & mortality

10-15%

AMSAN

• CSF as in AIDP

• EDX: no response in some motor nerves, decreased amplitude of the CMAPs, fibrillations on needle study, absent SNAPs

• Immune attack directed at axon plasmalemma at nodes of Ranvier. Wallerian degeneration

Features of AMAN

• Often preceded by diarrhea affecting younger population in China. Sporadic in USA

• Prognosis similair to AIDP• Mortality <5%• EDX: reduced CMAPs c normal F & distal

motor latencies and sensory studies. Fibrillations in 2-3 weeks

AMAN

• Pathology: again axonal plasmalemma at nodes of Ranvier sometimes limited to physiologic dysfunction c nodal lengthening. May go on to extension through axonal basal lamina. Most axons recover s Wallerian degeneration

Miller Fisher Syndrome

• Ophthalmoplegia, Ataxia, Areflexia• May be heterogonous: 1. Related to other patterns

of GBS

2. Related to brainstem encephalitis, Bickerstaff

1952

3. CNS demyelination in association with GBS

Miller Fisher Syndrome

• 95% have serum IgG Ab to ganglioside GQ1b• Studies show preferential location of anti-GQ1b to

cerebellar molecular layer & Cranial Nerves 3,4 & 6

• May act at N-M junction depleting acetylcholine from nerve terminals

Acute Panautonomic Neuropathy

• Manifests over 1-2 weeks but may be of subacute onset

• Frequent preceding infection

• DTRs lost in 1/3, distal sensory changes 1/4

• Albuminocytologic dissociation

• EDX: NCVs usually normal

• Recovery is gradual and incomplete

Differential Diagnosis

• Consider the possibility of an upper motor neuron lesion

• Other considerations are rare. Diphtheritic neuritis & poliomyelitis belong more to the history section of this presentation. A new possibility is West Nile Virus.

Differential

• N-M: MG, LES, Antibiotics• Toxic: Cigutera (ciguatoxin), Pufferfish

(tetrodotoxin), Shellfish (saxitioxin), Botulism, Tick paralysis (Lone Star tick, Gulf Coast tick), Glue sniffing, Buckthorn

• Mononeuritis multiplex assoc. c Wegner’s. PAN, SLE, RA, Sjogren’s, Cryoglobulinemia etc.

Differential

• Metabolic: Periodic paralyses, Hypokalemia, Hypermagnesemia, Hypophoshatemia c parenteral hyperailimentation, Thyrotoxicosis, ICU myoneuropathy (CIP)

• Heavy metal: Lead, Arsenic, Thallium, Barium c hypokalemia

Differential: Miller Fisher Syn.• Multiple sclerosis

• Encephalitis

• Posterior circulation ischemia or infarct

• Other: Botulism, MG, Tick

Treatment

Respiratory failure

Autonomic dysfunction

DVT & PE

Pain

Positioning & Skin care

Physical therapy

Nutrition

Respiratory Failure

• Oropharyngeal weakness in ~25% with impaired swallowing of secretions & aspiration

• Mechanical respiratory failure- mainly due to diaphragmatic weakness (Phrenic nerves.) Inspiratory c MIF (Max. Inspir. Force) a good supplement measure to FVC

Respiratory Failure

• ~33% require intubation

• Avg. time to intubation is 1 week & these pts. have substantially longer recovery time

• Need is unlikely if patient does well for 2 wks. post onset of paresthesiaes

• Guidelines: FVC <15 mL/kgm

MIF < 25 cm water

Psychological

• Fear

• Helplessness

• Communication

• Pain

• Sleep deprivation & hallucinosis

• Depression

• Visits from other GBS patients

Personal Experience

• Bowes, Denise; The doctor as patient: an encounter with Guillain-Barre syndrome. Can Med Assoc J 131:1343-1348

Corticosteroids

• Lancet 1993 242 pts.

IV Methylprednisilone 500 mgm/day x 5.

Ineffective

May cause relapse

Plasma Exchange

• Removal of the blood’s liquid soluble components including complement, immunoglobulin, immune complexes, cytokines and interleukins

• A typical session removes about 60% of the body mass of plasma proteins which is replaced c saline, albumin & FFP

• Done qod for 3-5 sessions

Plasma Exchange

• Various studies since 1985

• Time on ventilator reduced by ½

• Full strength regained at 1 year: Exchange 71%, Untreated 52%

• Limitations: Limited availability

Avoid with autonomic instability

Intravenous Immune Globulin

• Originally used for immune insufficiency

• Use as an immunosuppresant “seems to defy reason”

• 1981 Rx for ITP

• 5,000-10,000 donors/batch. Diversity of Abs from large donor pool maximizes effect

IVIG

• Mechanism of action- unknown ? Antiidiotypic antibody action ? Inhibition of cytokines ? “Sponging” of complement ? Binding to Fc receptors so macrophages can’t bind

IVIG

• Dosage: 0.4 gms/kgm/day x 5 c each dose given over 3-4 hours preceded by IV diphenhydramine &/or po ibuprofen

• Caution c renal insufficiency or IgA deficiency

• 38 Center trial in 1997

• Equal to plasma exchange

J.H.C. 48 yo welder

• June ’02 H.A. followed in 2 wks by Lt. Facial weakness

• June ’03 Rhinorrhea & cough• August 6 Pain lt. Hip spreading over a few

days to back 7 legs• August 15 Legs buckle c lt.facial weakness

1 wk later. LP c protein of 70. NCVs c prolonged F waves

• 1 Week post discharge, elevated titers to West Nile Virus

• Follow up at 1 month- continued improvement