guillain-barre syndrome. k.f. 40 y.o. r/h woman 3/17 nausea, diarrhea & severe myalgias son dxed...
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Guillain-Barre Syndrome
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
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