1. Guillain-Barré Syndrome (gee-YAH-buh-RAY)
Christine Lovato, Miranda Garcia, Emma Pindra, Tracy Yellowhair

2. Why Guillain-Barré Syndrome??
Guillain-Barré Syndrome is a neurodegenerative disorder that can target any individual
It induces muscle weakness and possibly paralysis, lasting weeks or months
Many patients recover, but not all (comparable to “temporary” paralysis)
Its etiology and mechanism of action have yet to be fully determined
Guillain-Barré Syndrome is rare & rapidly progressive
There is no definite cure, only treatment
Pathogen induced autoimmunity is especially interesting because other pathogens may be capable of such molecular mimicry
Being a rare syndrome makes it particularly interesting as it is novel and its consequent study may bring some new insight to academia and medicine

3. Table of Contents Background of Guillain-Barré Syndrome History
Etiology
Pathophysiology
Signs/Symptoms
Treatments/Prevention
Prognosis
Case Study
Current Investigative Research

4. What is Guillain-Barré Syndrome?
Guillain-Barré Syndrome(GBS) is rare autoimmune disorder, that attacks the peripheral nervous system (PNS).
An autoimmune disorder results in the body’s immune system attacking its own healthy tissue.
The Peripheral Nervous System includes sensory and motor nerve cells and ganglia which are not part of the brain or spinal cord.
GBS results in the degeneration of the myelin sheath of neurons communicating with the muscles
Results are rapidly progressive, symmetrical weakness of the extremities and acute paralysis
Muscle weakness usually plateaus two to four weeks after the first symptoms occur, recovery will last another two to four weeks after this plateau
25% develop respiratory insufficiencies and autonomic dysfunction
If patients do not recover within a few weeks, permanent nerve damage may occur as it has been noted in some GBS cases

5. Neurons & Myelin
A neuron, also called a nerve cell, is a cell of the nervous system. Neurons consist of a cell body, called a soma, and an axon. The cell body contains the nucleus and is responsible for receiving incoming nerve impulses. The axon is responsible for carrying the impulse away from the soma.
The axon of a neuron is covered in a myelin sheath with gaps called Nodes of Ranvier. These nodes contain voltage-gated channels. When a signal propagates down the insulated axon, these voltage-gated channels are triggered resulting in an action potential. Myelinated neurons are thus key to rapid action potential propagation.

6. Neurons & Myelin (cont’d)
The myelin sheath acts as an insulator to prevent energy loss while the Nodes of Ranvier boost or “amplify” the signal. These combined mechanisms are dubbed saltatory conduction (rapid means of signal
transmission).
Thus, if the body creates antibodies which attack the myelin, the axon becomes demylinated (as seen in GBS). Demyelination results in slower transmission of action potentials, which results in weaker muscles and the loss of deep tendon reflexes.

7. Syndrome vs Disease
Why is Guillain-Barré classified as a syndrome and not a disease?
Diseases have known causative agents.
Syndromes are medical conditions that are characterized by a set of symptoms outlined by the patient and signs observed by the physician.
Guillain-Barré is thus a syndrome, not a disease-- a causative agent is unknown and thus, diagnosis is dependent upon observed signs and symptoms.

8. The Discovery of Guillain-Barré Syndrome
1859: Guillain-Barré was first reported by Jean Baptiste Octave Landry de Thezillat. When he published a report where he described 10 patients with “ascending paralysis”. At the time “ascending paralysis” was the only term used to describe the syndrome.
1916: Jean-Alexander Barre, Georges Charles Guillain and Andre Strohl published a report in which they recorded and interpreted the muscle reflexes of their patients during World War I. They were able to identify that the syndrome was associated with the peripheral nerves.
1927: The syndrome was officially given the name of Guillain-Barré Syndrome.

9. Susceptibility
Anyone can contract GBS, no matter the age, gender, or geographical locality.
However individuals 50 and over, are at a greater susceptibility
Certain conditions can also increase susceptibility
Pathogenic (bacterial or viral) infection of respiratory or gastrointestinal tract
Surgery
Vaccination (very rare; 1 in 100,000 cases reported after Influenza A vaccine in 1976 and 2009)
GBS is NOT contagious

10. Common Risk Factors
As mentioned previously, GBS can target all ages, genders, and ethnicities, but generally there is an increased risk for older aged adult males.
In addition, GBS may be triggered by:
Infection with Campylobacter jejuni, a bacteria often found in undercooked poultry
Influenza virus
Epstein-Barr virus
HIV, the virus that causes AIDS
Mycoplasma pneumonia
Surgery
Hodgkin's lymphoma
Rarely, influenza vaccinations or childhood vaccinations

11. Epidemiology and Societal Impact
Annual incidence increases with age and pregnancy:
~1/100,000 - age 30 and below
~4/100,000 - older than 75 years
~1.7/100,000 while pregnant
Congentital and neonatal GBS has also been reported
Men are 1.5 times more likely to be affected than women.
Occasional outbreaks occur, for example during the U.S. swine influenza vaccination program in 1976.
Medical costs associated with Campylobacter jejuni induced GBS is estimated by the USDA to be between $57-$425 million per year in the U.S.

12. Pathophysiology: Overview
GBS is generally a post-infectious disease (⅔ report infection of respiratory and gastrointestinal tract)
C. jejuni most common pathogen (⅓ of total cases)
Also, Epstein Barr Virus (EBV), Influenza A, Mycoplasma pneumonia
Neurodegeneration ultimately due to production of antibody (against pathogen borne antigen) which in turn not only attacks the invasive pathogen, but also has an affinity for host gangliosides (neural cells)
Severity and progression of disease are greatly dependent on gene polymorphism of the patient and the pathogen

13. Pathophysiology: Mechanism
Complement activation
Demyelination and neurodegenration of PNS neurons
Disappearance of voltage-gated sodium channels resulting in
detachment of paranodal myelin
nerve conduction failure
De-stabilization of schwann cell microvilli and nodal cytoskeletal strucutres
Macrophages recruited to scavenge remaining axon
After C. jejuni infection, immune response is activated
Antibodies produced against C. jejuni antigen cross react with host gangliosides (involved in neuronal cell to cell communication)
C. jejuni have polymorphic enzymes which mimic host cell gangliosides
Severity of response dependent on the proper set of polymorphic enzymes in C. jejuni
See Figure 1 and Figure 2 (next slide)

14. Figure 1| Generation of humoral and autoimmune response
Figure 2| Degeneration of PNS neuron by antibody, complement, and macrophage
Figure 1| C. jejuni exhibits ganglioside mimicry, thus immune response generates cross reactive Ab against pathogen and against host gangliosides
Figure 2| Cross reactive antibodies activates complement system, together they attack PNS nerve cells (nodes of ranvier and schwann cell) with assistance by macrophages

15. Pathophysiology: Other contributing factors
Patient polymorphic related factors may also be contributing to severity of GBS:
TNF (tumor necrosis factor produced during initial immune response ) gene polymorphism
Suspected MBL2 gene polymorphism
Vaccination poses predisposition
1 in 100,000 cases observed in 1976 and 2009 of post Influenza A vaccination GBS
GBS is 4-7 times more likely to occur after influenza infection than after vaccination

16. Pathophysiology: disease progression
Antibody production (green) begins directly after infection (red)
Direct correlation between symptom manifestation (blue) and antibody production
Recovery phase initiated as antibody levels decrease
Figure 1: Demonstrates autoimmune property of GBS by showing that muscle weakness is associated with antibody production.

17. 4 Guillain-Barre Syndrome Subtypes
1) AIDP (acute inflammatory demyelinating polyneuropathy)
Myelin removed
Cranial damage
Sensory damage
Autonomic dysfunction
Most common form (90%) in North America and Europe
2) AMAN (acute motor axonal neuropathy)
Damage to axon
No sensory or cranial nerve damage
<10% affected in North America, >40% in China and Japan
3) ASMAN (acute sensory motor axonal neuropathy)
Both motor and sensory damage
Rare, <10% of AMAN cases develop into ASMAN
4) Miller fisher syndrome
Opthomaloplegia (eye weakness)
Ataxia (inability to coordinate voluntary muscle movement)
Areflexia
Facial and bulbar damage (rare, but lethal as it impairs involuntary processes such as breathing)
Most rare, <5% cases worldwide
Subtype and severity determined by preliminary infection, patient factors, and gene polymorphism of pathogen.

18. Signs & Symptoms: Early
The patient will complain of sensory symptoms
“Rubbery legs”
Distal to proximal progression of paraesthesia
(numbness and tingling of the muscles)
Stinging pain in the muscles
Weakness of the muscles
Areflexia (decreased tendon reflex)
Ataxia (lack of voluntary control)
These signs and symptoms usually begin in the feet and travel up toward the mid-body and arms, signifying symmetrical deposition of symptoms. Only about 10% of GBS cases start in the arms or face.

19. Signs & Symptoms: Late Patient may experience Bladder control problems
Digestive system problems
Facial weakness: patient may drool or have difficulty swallowing
Temporary paralysis of legs, arms, and face
Decreased heart rate and blood pressure
Pain in the weakened muscles as well as severe pain in the lower back
Respiratory problems (usually a result of the paralysis )
Sensory loss (in some cases)
NO fever
If these signs and symptoms progress they can lead to paralysis, which can become life threatening, as paralysis can interfere with breathing, blood pressure, and heart rate.

20. Diagnosis
The first test to lead to a diagnosis is the knee jerk reflex which tests for areflexia
Signs and Symptoms of GBS can vary between individuals and overlap with symptoms of other nervous system disorders, which can make GBS difficult to diagnose early in the prognosis.
There are different tests that can be ordered to assist in diagnosis such as:
Nerve Conduction Velocity Test
Electromyography
Lumbar Puncture
Blood test

21. Nerve Conduction Velocity Test
A Nerve Conduction Velocity Test is helpful in determining diagnosis. If a patient is affected by GBS the signals traveling along the nerves will be slow.
To Conduct a Nerve Conduction Test:
A physician places patches called surface electrodes on the patient’s skin
These patches give off mild electrical pulses that stimulate underlying nerves
The speed of the nerve signal is determined by the distance between electrodes and the time it takes for the electrical impulse to travel between these electrodes
If the speed of the signal is delayed, it is due to demyelination of the axon
GBS is the diagnosis

22. Electromyography (EMG)
This test assists in diagnosis because it is used to determine the health of the muscle and nerves controlling muscles.
To Conduct an EMG:
An EMG is similar to a Nerve Conduction Velocity Test
A health care provider will insert an electrode through the skin and into the selected muscle
A surface electrode will be placed on the skin over the selected nerve
The nerve is stimulated and the response time of the muscle is recorded.

23. Lumbar Puncture
Cerebrospinal fluid is located around the spinal cord and the brain. If a patient has GBS, the cerebrospinal fluid contains more proteins than usual.
This test is performed by inserting a needle into the patient’s lower back and extracting a small amount of cerebrospinal fluid to test protein concentration. :)

24. Blood Test
This test is only ordered to rule out other causes of the symptoms.
Also remember a sign of GBS is an absence of fever. If a fever is present the diagnosis is not GBS.

25. Other Complications
40% of GBS patients will develop some compromise in
their breathing ability, and approximately 25% will require artificial
ventilation over a given period of time.
Other complications include:
Diaphragmatic paralysis
Cranial nerve disorder
Bulbar palsy
Tonic pupil
Systemic pulmonary hypertension
Immobility
Type 2-Respiratory failure
Bladder infections
Pneumonia
Bedsores
Chronic neuropathic pain
Thromboembolism

26. Treatment
Currently, there is no known cure for GBS, so treatment consists of supportive therapies and treatment/monitoring of underlying causes to reduce the duration of the illness.
Supportive therapies:
Plasmapheresis: blood is removed from the body. The red and white blood cells are separated from the plasma and only the blood cells are returned to the patient.
Intravenous immunoglobulins (I.V.I.G): immunoglobulins are given intravenously, which shows a positive impact on the speed of recovery.
Research has shown that both therapies are almost equally effective at reducing symptoms and increasing recovery.

27. Treatment (cont’d)
Once the patient becomes stabilized and regains some strength a multidisciplinary method of treatment is provided:
Rehabilitation
Physiotherapy:
Maintains structure/function of joints
Prevents bedsores, contractures, cardiopulmonary difficulties
Improves Activities of Daily Living (ADLs) (i.e eating and walking)
Occupational therapy:
Helps the patient achieve ADL independence
Speech/language therapy:
Helps the patient regain speaking and swallowing ability
Psychiatric therapy:
Helps the patient deal with depression and re-enter society
-Other alternative therapies the patient may engage in can include acupuncture, Hatha yoga, massage therapy, magnetic therapy, etc.

28. Prevention
Physicians and scientists currently do not know the exact cause of GBS; therefore, making it very difficult to prevent and find a cure.
The best line of defense is early recognition of the signs/symptoms and to immediately visit a physician.

29. Prognosis
The prognosis of GBS is generally good, with 70% of patients regaining their full strength
Recovery may range from a few weeks to a few years
20% of severely affected patients remain unable to walk after 6 months
30% have residual weakness even after 3 years
3% may suffer a relapse of muscle weakness and tingling sensations many years after the initial attack
In general, most patients recover from the most severe cases of GBS, but the level of recovery depends on the age of the patient and the timing in which treatment is received.

30. Case Study
Did our 32nd president, Franklin D. Roosevelt actually have Guillain-Barré Syndrome instead of Polio??

31. Franklin D. Roosevelt
1912: Franklin D. Roosevelt became sick and later developed paralysis.
The paralysis began in his legs and moved up toward his neck
Polio usually paralyzes the body unevenly, unlike GBS which has the characteristic of symmetrical deposition of symptoms
The paralysis struck Franklin D. Roosevelt in his adulthood
Atypical of polio which generally targets children; GBS can strike at any age
Franklin D. Roosevelt experienced intense pain upon stimulus to leg
A common symptom of GBS, but not seen in Polio

32. Current Research and Clinical Trial Studies
Current studies are looking at:
The presynaptic motor nerve terminal at the neuromuscular junction. This junction may be a prominent target as it is highly enriched in gangliosides and lies outside the blood–nerve barrier. Damage in this area might contribute to the muscle weakness in GBS patients.
Complement inhibitors and regulators as therapeutic targets. For example, Eculizumab, a monoclonal antibody, which functions as a complement inhibitor could be effective in preventing progression of weakness in patients with GBS.
Mannose-binding lectin and its role in the activation of the complement system. This complement system aids in the induction of postinfectious immune-mediated peripheral nerve damage associated with GBS.
Corticosteroids and their function in reducing nerve damage associated with GBS.
Drug response relationships for plasmapheresis and I.V.I.G therapies.
Scientific Research on GBS is advancing significantly, as a result a cure could be near.
Additional studies in a GBS mouse model provided evidence that blockade of complement activation prevents emergence of the clinical signs of antiganglioside-mediated neuropathy.6

33. References
Doorn, Pieter A Van, Liselotte Ruts, and Bart C. Jacobs. "Clinical Features, Pathogenesis, and Treatment of Guillain-Barré Syndrome." The Lancet Neurology 7.10 (2008): Web.
Parry, Gareth J., and Joel S. Steinberg. Guillain-Barré Syndrome: From Diagnosis to Recovery. New York, NY: American Academy of Neurology, Print.
Van, . B. B., Walgaard, C., Drenthen, J., Fokke, C., Jacobs, B. C., & van, D. P. A. (January 01, 2014). Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nature Reviews. Neurology, 10, 8,