Guillain-Barre SyndromeWilliam 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. woman4/28 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 muscles3. Dimunition and loss of the DTRs

4. Albuminocytologic dissociation

5. Recovery over weeks to months

HistoryWaldrop 1834Olliver 1837Landry 1859Graves 1884Ross & Bury 1893 Brussels 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 1859March 16- a febrile illnessMay 11- mild sensory symptoms in the fingers and toesJune 13- knees buckleJune 16- unable to walkSubsequent respiratory failure and death.Autopsy unrevealing. Peripheral nerves probably not examined

Late 19th century Westphal 1876- Landrys Ascending ParalysisGraves 1884- localized neurologic disease to the peripheral nerves, the nervous cordsRoss & Bury 1893- 90 cases. A disease of the peripheral nervesNumerous reports emphasizing various aspects of the disease with most authors crediting Landry

Georges Guillain

Revue Neurologique 1916

Guillain, Barre & Strohl 1916Revue NeurologiqueTwo soldiers in Amiens developing paralysis and loss of DTRs.A new diagnostic feature: albuminocytologic dissociation in the CSFNo mention of Landry

FoundationsQuincke- CSF observations 25 years earlier

Siccard & Foix- albuminocytologic dissociation in Potts 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 1949Landmark in pathological description c 50 fatal cases & detailed review of clinical findingsEmphasized prominent damage to proximal nerves often at junction of ventral & dorsal roots. Little study of more distal nervesUnified findings of Landry & Guillain, Barre & Strohl

Waksman & Adams 1955Experimental Allergic NeuritisFirst animal model of a noninfectious inflammatory neuritisRabbit nerve and Freunds adjuvant injected intradermallyTarget of activated T cells uncertain

Asbury, Aranson & Adams 196919 pts. All with well developed mononuclear infiltrates in spinal roots and nerves within days of clinical onsetPathological 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 assaultAntibodies: specialized immunoglobulin molecules directly neutralize and remove antigen

T lymphocytesCD8- recognize epitopes paired c MHC-ICD4- activate and control the immune responseScavenger 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.

AntibodiesCytokines 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-toleranceThe process of self recognitionT & B cells learn self tolerance during maturationAutoimmunity occurs when the mechanisms of self protection are defective

Mechanisms of AutoimmunityMolecular 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: InfectiousViral: Influenza, Coxsackie, EBV, Herpes, HIV, Hepatitis, CMV, WNV Bacterial: Campylobacter jejuni, Mycoplasma, E. coli Parasitic: Malaria, Toxoplasmosis

Antecedent Events: Systemic diseaseHodgkinsCLLHyperthyroidismSarcoidosisCollagen Vascular d.Renal d.

Other antecedent eventsSurgeryImmunizationPregnancyEnvenomizationBone marrow transplantationDrug ingestion

Features of AIDP2/3s have identifiable preceding event50% begin with paresthesias followed by weakness in legs; 10% begin with arm weakness; rarely begins in faceOphthalmoplegia: partial 15%, total 5%Autonomic dysfunction in 65%, arrhythmias, hypotension,urinary retention in 10-15%, pupillary inequality

AIDPProgresses for days to 4 weeks15% with severe disabilityMortality 3-5%CSF: protein may be normal early, elevated in 90% by clinical nadir, cells< 10 in 95%, >50 suggests HIVEDX: prolonged F & distal motor latencies, conduction block 30-40% in routine studies

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

CIDPEvolves over monthsFluctuatesRespiratory failure, dysautonomia, facial weakness, ophthalmoplegia- all are rareCSF protein often highly elevatedMarked slowing of motor nerve conductionSteroid responsive

Features of AMSANCommonly preceded by diarrhea esp. c. jejuniAbrupt onset of weakness c rapid progression to quadriplegia & respiratory insufficiencyOther features as c AIDPLonger recovery, more residual & mortality 10-15%

AMSANCSF as in AIDPEDX: no response in some motor nerves, decreased amplitude of the CMAPs, fibrillations on needle study, absent SNAPsImmune attack directed at axon plasmalemma at nodes of Ranvier. Wallerian degeneration

Features of AMANOften preceded by diarrhea affecting younger population in China. Sporadic in USAPrognosis similair to AIDPMortality

AMANPathology: 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 SyndromeOphthalmoplegia, Ataxia, AreflexiaMay 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 Syndrome95% have serum IgG Ab to ganglioside GQ1bStudies show preferential location of anti-GQ1b to cerebellar molecular layer & Cranial Nerves 3,4 & 6May act at N-M junction depleting acetylcholine from nerve terminals

Acute Panautonomic NeuropathyManifests over 1-2 weeks but may be of subacute onsetFrequent preceding infectionDTRs lost in 1/3, distal sensory changes 1/4Albuminocytologic dissociationEDX: NCVs usually normalRecovery is gradual and incomplete

Differential DiagnosisConsider the possibility of an upper motor neuron lesionOther considerations are rare. Diphtheritic neuritis & poliomyelitis belong more to the history section of this presentation. A new possibility is West Nile Virus.

DifferentialN-M: MG, LES, AntibioticsToxic: Cigutera (ciguatoxin), Pufferfish (tetrodotoxin), Shellfish (saxitioxin), Botulism, Tick paralysis (Lone Star tick, Gulf Coast tick), Glue sniffing, BuckthornMononeuritis multiplex assoc. c Wegners. PAN, SLE, RA, Sjogrens, Cryoglobulinemia etc.

DifferentialMetabolic: 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 sclerosisEncephalitisPosterior circulation ischemia or infarctOther: Botulism, MG, Tick

Treatment Respiratory failure Autonomic dysfunction DVT & PE Pain Positioning & Skin care Physical therapy Nutrition

Respiratory FailureOropharyngeal weakness in ~25% with impaired swallowing of secretions & aspirationMechanical 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 intubationAvg. 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 paresthesiaesGuidelines: FVC

PsychologicalFearHelplessnessCommunicationPainSleep deprivation & hallucinosisDepressionVisits from other GBS patients

Personal ExperienceBowes, 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 ExchangeRemoval of the bloods liquid soluble components including complement, immunoglobulin, immune complexes, cytokines and interleukinsA typical session removes about 60% of the body mass of plasma proteins which is replaced c saline, albumin & FFPDone qod for 3-5 sessions

Plasma ExchangeVarious studies since 1985Time on ventilator reduced by Full strength regained at 1 year: Exchange 71%, Untreated 52%Limitations: Limited availability Avoid with autonomic instability

Intravenous Immune GlobulinOriginally used for immune insufficiencyUse as an immunosuppresant seems to defy reason1981 Rx for ITP5,000-10,000 donors/batch. Diversity of Abs from large donor pool maximizes effect

IVIGMechanism of action- unknown ? Antiidiotypic antibody action ? Inhibition of cytokines ? Sponging of complement ? Binding to Fc receptors so macrophages cant bind

IVIGDosage: 0.4 gms/kgm/day x 5 c each dose given over 3-4 hours preceded by IV diphenhydramine &/or po ibuprofenCaution c renal insufficiency or IgA deficiency38 Center trial in 1997Equal to plasma exchange

J.H.C. 48 yo welderJune 02 H.A. followed in 2 wks by Lt. Facial weaknessJune 03 Rhinorrhea & coughAugust 6 Pain lt. Hip spreading over a few days to back 7 legsAugust 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

Jean-Baptiste Octave Landry