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
Guillain, Barre & Strohl 1916-1920

Brussels Conf. 1937 Haymaker & Kernohan 1949 Waksman & Adams 1955 Miller Fisher 1956 Asbury, Aranson & Adams 1969

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- Landrys 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 1916 Revue 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 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 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 Freunds 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 Wegners. PAN, SLE, RA, Sjogrens, 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 bloods 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 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 cant 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