2. Case
• CC: Lower extremities numbness and paralysis
• HPI: MW is 34 yo female who is admitted to the hospital on 8/5 due
to numbness and paralysis in her right leg, weakness in her left leg,
and inability to walk. She also complains of daily, non-bloody
diarrhea for the last 2 months and some urinary incontinence.
Patient lost 40 lbs in the last month. The burning she feels in both
legs started 2 days ago. MW has thoracic, lumbar and sacroiliac pain
as well. She denies any trauma, MVA or recent labor. She has not
had any recent URI.
• PMH: HTN, anxiety, s/p cholecystectomy, T2DM, RA, fibromyalgia,
asthma, hypothyroidism, hx of DVT.
• FH: Significant for CAD and MI
• SH: Chronic smoker (1 pack/day for 18 years); denies alcohol or
illicit drug use
3. Case (cont.)
• Home Medications: Synthroid 25 mcg PO QD; Metformin 1000 mg PO QD;
Prilosec PRN; Arava 20 mg PO QD; Hydroxychloroquine 200 mg PO BID;
Endocet 10/325 PO Q 6H PRN pain; Valium 0.5 mg PO BID; Benicar 20 mg
QD
• Allergies: codeine; penicillin
• PE:
– Vital signs: T 97.6F; P 57bpm; BP 127/79 mmHg; RR 16 bpm; O2 sat 95%;
– HEENT: PERRL; EOMI; no JVD; no lymphadenopathy; no meningism;
– Cardiovascular: RRR; no murmurs, gallops, rubs; no LE edema; no calf
tenderness
– Respiratory: CTA
– GI: soft, nontender, nondistended
– Psychiatric: Cooperative, but tearful
– Integumentary: lower extremity cyst consistent with RA
– Neurologic: Cranial nerves 2-12 intact; intact upper motor; lacking tendon
reflexes in LE
4. Problems
1. Bilateral LE paraplegia with paresthesias (neurology consult):
Suspect AIDP; spine imaging and lumbar puncture is needed
to rule out other causes; discuss IVIg tx with patient and if
OK start Privigen 10% 35 g/350 ml IVPB every 24 H for 5 days
(0.4 g/Kg max 2g/kg for 5 days); rule out infections or
structural causes; cardiac telemetry to evaluate for
arrhythmia; pain and anxiety rx.
2. Diarrhea:
3. Hypothyroidism, RA, HTN- continue home medications,
T2DM
4. DVT prophylaxis
5. Guillain-Barre Syndrome (GBS)
Introduction
• Definition: heterogeneous group of immune-mediated
peripheral neuropathies
– Common to all variants: rapidly evolving polyradiculoneuropathy
preceded by a triggering event
– Cytomegalovirus or Campylobacter jejuni infection
• Prevalence:
– GBS affects between 1 and 4 per 100,000 of the world’s population
annually.
• Prognosis:
– 67% - persistent fatigue
– 25% - respiratory failure requiring ventilation
– 20% - persistent disability
– 4% to 15% - death
Hughes RAC, Wijdicks EFM, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome—report
of the quality standards subcommittee of the American Academy of Neurology. Neurology 2003; 61: 736–40.
7. Subtypes of GBS
Harrison's Principles of Internal Medicine, 18ed. Chapter 385. Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies. Access
Pharmacy. Accessed 8/24/2014
8. GBS Pathophysiology AIDP
Ang CW, Jacobs BC, Laman JD. The Guillain-Barre Syndrome: a true case of molecular mimicry. Trends in Immunology. 2004. 25(2):61-66.
9. Signs and Symptoms
• Weakness
• Tingling dysesthesias in the extremities
– legs more often affected than arms
• Paresthesias
– seldom extends past the wrists and ankles
• Loss of deep tendon reflexes
– within the first few days of symptom onset
• Progressive phase lasts few days to 4 weeks
• Plateau phase: persistent, unchanging symptoms
• Improvement begins within days of the plateau
– The time to resolution of symptoms varies
Newswanger DL, Warren CR. Guillain-Barre Syndrome. Am Fam Physician. 2004 May 15;69(10):2405-10.
10. Diagnosis
Newswanger DL, Warren CR. Guillain-Barre Syndrome. Am Fam Physician. 2004 May 15;69(10):2405-10
• Required Factors:
– Progressive weakness in both arms and legs
– Areflexia (e.g. loss of knee jerk reflex)
• Strongly Supporting Diagnosis:
– Progression of symptoms over days, up to 4 weeks
– Relative symmetry of symptoms
– Mild sensory symptoms or signs
– Cranial nerve involvement ( bilateral weakness of facial muscles)
– Recovery beginning 2-4 weeks after progression ceases
– Absence of fever at onset
– High concentration of protein in CSF
11. 2003 American Academy of Neurology
(AAN) Treatment Guidelines
Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of
the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003 Sep 23;61(6):736-40.
12. AAN Guidelines
• Treatment with PE or IVIg hastens recovery from GBS.
• PE and IVIg are equally effective in patients with advance GBS symptoms.
• PE may carry a greater risk of side effects and is more difficult to
administer.
• Combining the two treatments is not recommended.
• Steroid treatment is not beneficial.
• High-dose IVIg (400 mg per kg daily for 5 days) or plasmapheresis (5
exchanges over 5-8 days) can be initiated.
• Supportive care and monitoring for autonomic dysfunction
• Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003 Sep 23;61(6):736-40
• Newswanger DL, Warren CR. Guillain-Barre Syndrome. Am Fam Physician. 2004 May 15;69(10):2405-10
13. IVIg, PE or Combination RCT
• International, multicenter, randomized trial of 383 adult patients with
Guillain-Barré syndrome.
• Objectives:
– Whether IVIg is equivalent/ superior to PE
– PE followed by IVIg is superior to single treatment
• Methods:
– Random assignment to:
• PE (five 50 mL/kg exchanges over 8–13 days)
• IVIg (Sandoglobulin, 0·4 g/kg daily for 5 days)
• PE course immediately followed by the IVIg course.
• Retreatment with original treatment was permitted if relapse
Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomized trial of plasma
exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 1997 Jan
25;349(9047):225-30.
14. Outcomes Measurements: Disability
Assessment Grades
Grades Disability Assessment Arm Assessment
0 Healthy; no signs or symptoms of
GBS
Normal
1 Minor symptoms; able to run Minor symptoms; able to put hand
on top of head and able to oppose
thumb to each finger
2 Able to walk 5 m without
assistance
Able to do one or the other @ 1 not
both
3 Able to walk 5 m with assistance Some movement ; unable to perform
either tasks above
4 Chair - bound; unable to walk No movement
5 Require assisted ventilation ( part
of the day)
Dead
6 Dead N/A
Plasma Exchange Group. Lancet 1997.
15. IVIg, PE or Combination RCT (cont.)
• Inclusion criteria:
– GBS diagnosis by a qualified neurologist
• Clinical and
• Cerebrospinal-fluid diagnostic criteria
– Severe disease (requiring aid to walk or worse)
– Older than 16 years
– Onset of neuropathic symptoms within the previous 14 days
• Statistics
– Equivalence definition: If the true mean difference in the improvement of
the disability grade among the two groups <0.5
– Power: 122 patients were expected to give 90% power to detect a true
difference of ≥0.5 in the IVIg versus PE comparison and to exceed 0
Plasma Exchange Group. Lancet 1997.
17. Primary Outcome and Results
Mean disability-grade improvement after 4 weeks: No significant difference
between the groups
– Difference of improvement between PE vs IVIg : 0.09 grade (95% CI
0.23 to 0.42)
– Proved equivalence between groups
– Difference between the PE+IVIg and IVIg alone groups: 0.29 grade
(95% CI 0.04 to 0.63)
– The difference between the PE+IVIg and PE alone groups: 0.20 grade
(0.14 to 0.54).
– The combined treatment was not superior to either treatment
alone
Plasma Exchange Group. Lancet 1997.
18. Adverse Events
• 8 cases in PE group : hypotension in five, septicemia, pneumonia, malaise,
abnormal clotting, and hypocalcaemia
• 6 cases in IVIg group: nausea or vomiting, meningism, exacerbation of
chronic renal failure, possible myocardial infarction, and painful erythema
at the infusion site
• Conclusion
– IVIg may be preferable to PE (in severe GBS that requires aid to walk
and the disorder was diagnosed < 2 weeks of onset) based on :
• equal therapeutic benefit
• greater convenience
Plasma Exchange Group. Lancet 1997.
19. Treatment of the patient
• Bilateral LE paraplegia with paresthesias (neurology consult): Suspect AIDP; spine
imaging and lumbar puncture is needed to rule out other causes; discuss IVIg tx
with patient and if OK start Privigen 10% 35 g/350 ml IVPB every 24 H for 5 days
(0.4 g/Kg max 2g/kg for 5 days); rule out infections or structural causes; cardiac
telemetry to evaluate for arrhythmia; pain and anxiety rx.
• Workup
– MRI of cervical and thoracic spine: soft tissue density in the epidural space
causing effacement of the right lateral thoracic cord at C7, T1 and T2
– LP: 2WBC, 11RBC, protein 48
• Patient was treated with 5-day course of IVIg;
– Weakness in leg improved, discharged home after 6 days of hospitalization
• MW came back to hospital less than 24 hours later for almost the same complaint:
– Progressive weakness in her LE and UE
– Was able to walk but with difficulty
• Patient treated successfully with PE @5
20. Assessment of the Treatment
• Patient received Provigen 10% 35 g/350 ml IVPB every 24 hours
for 5 days
• MW weighs 119Kg ( IBM 75.4Kg, AdjBW 92.6 Kg)
– If dosed at 0.4g/Kg* 119Kg= 47.6 g/day
– Patient received 35 g/day (dosed based on ~ Adj BW : 37
g/day)
• Patient came back less than 24 hours later
– MRI was ordered to asses for possible worsening of abnormal tissue
density at level C7-T12
• PE was ordered, @ 5 exchanges patient improved
Assessment:
Starting with a higher dose of IVIg could have been more
effective (use ABW instead of Adj BW)
21. Future Possible Treatment
• Chinese herbal medicine Tripterygium polyglycoside ( Thunder
God Vine)
– Significantly better outcome after 8 weeks compared with
high-dose corticosteroids*
• Very low quality of evidence RCT, found after
• Meta analysis of 1271 references to possible RCT
• Other trials not large enough to find clinical significant
benefits
– Interferon beta-1a (IFNb-1a) vs placebo
– Brain-derived neurotrophic factor (BDNF) vs placebo
– CSF filtration vs regular PE
*Hughes RA, Pritchard J, Hadden RD. Pharmacological treatment other than corticosteroids, intravenous immunoglobulin
and plasma exchange for GBS. Cochrane Database of Systematic Reviews, Feb 01, 2013, No. 2.
There are 3 types of neuronal cells (glia) in the nervous system:
Oligodendrocytes provide myelin and support to neurons in CNS.
Schwann cells provide myelin to the nerves in peripheral nervous system.
Astrocytes, which are the most common glia in the CNS, contact both capillaries and neurons and are thought to help neurons get nutrition and also are involved in forming the blood–brain barrier.
The main purpose of a myelin layer (or an electrical insulating sheet) is to increase the speed at which impulses propagate along the nerve fiber.
Unmyelinated fibers, don’t have the Rannier nodes, so the impulses move continuously as waves and thus the speed of propagation is slow
In myelinated fibers, the impulses hop from node to node , thus a faster the signal transmission
Damage to the myelin sheath and nerve fiber results in increased functional insufficiency.
But, a damaged myelinated nerve fiber can regenerate (due to the myelin sheet), a damaged unmyelinated nerve fiber does not regenerate.
A sensory nerve fiber caries sensory information from the periphery to the CNS (afferent )
A motor nerve fiber caries information from the CNS to the periphery (efferent)
Guillain-Barre Syndrome (GBS) is a rare, post-infectious, inflammatory autoimmune disease that is characterized by an ascending limb weakness and numbness in the extremities that can progress, in some cases, to paralysis (Yuki, 2005)
The most common underlying subtype of GBS is the acute inflammatory demyelinating polyradiculoneuropathy (AIDP)- which affects the myelin sheets by attacking the Schwan cells
The acute motor axonal neuropathy (AMAN)- the neurologic deficit is purely motor
Acute motor and sensory axonal neuropathy (AMSAN) -sensory and motor fibers are also affected.
GBS can occur at all ages and its development is usually associated with infections by bacteria and viruses.
The mechanism proposed thus far for the development of GBS is molecular mimicry: the body mounts an antibody response against a pathogen protein that resembles neural glycolipids (gangliosides), resulting in an attack on the peripheral nervous system.
Most patients recover eventually with varying degrees of nerve damage.
However there is an 8-10% mortality rate associated with GBS attributable to respiratory failure in advanced cases.
Treatments consist of immunoglobulin therapy or plasma exchange (along with intravenous corticosteroids in some cases) (Harel and Shoenfeld, 2005; Shahar, 2006).
Pathogens and Autoimmunity in GBS Subtypes
Figure 6. Mechanism of molecular mimicry involved in GBS autoimmune response after C. jejuni infection. (Image from Ang et al., 2004. Reproduced with permission of the author.)
Two-thirds of GBS cases are associated with prior acute infection of several bacterial species and virusus. Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, Haemophilus influenzae, and Varicella-zoster virus have been found in patient serum after the onset of GBS (Kuwabara, 2004). The most commonly proposed mechanism for the development of autoimmune disease is molecular mimicry (Yuki, 2005). Molecular mimicry refers to the situation where the pathogen and host share nearly identical antigens, which induces an antibody and T cell immune response that is cross reactive. There is more than one way that an immmune response can become cross-reactive. The pathogen and host can have homologous or identical amino acid sequences or the host B cell receptors and T cell receptors can recognize non-homologous peptides (Ang et al., 2004). The strongest evidence for the molecular mimicry hypothesis has come from discoveries in research with C. jejuni strains, the most common pathogen associated with GBS (specifically AMAN) (Neisser et al., 2000; Yuki, 2005). Since definite mechanisms and evidence of correlation between autoimmune responses and infection are limited in the cases of many pathogens listed above, only those with evidence-based correlations with GBS subtypes will be further described.
GBS is a postinfectious, immune-mediated disease. Cellular and humoral immune mechanisms probably play a role in its development. Most patients report an infectious illness in the weeks prior to the onset of GBS. Many of the identified infectious agents are thought to induce production of antibodies that cross-react with specific gangliosides and glycolipids, such as GM1 and GD1b, that are distributed throughout the myelin in the peripheral nervous system.[9]
The pathophysiologic mechanism of an antecedent illness and of GBS can be typified by Campylobacter jejuni infections.[10, 11] The virulence of C jejuni is thought to be based on the presence of specific antigens in its capsule that are shared with nerves.
Immune responses directed against lipopolysaccharide antigens in the capsule ofC jejuni result in antibodies that cross-react with ganglioside GM1 in myelin, resulting in immunologic damage to the peripheral nervous system. This process has been termed molecular mimicry.[12, 13]
Pathologic findings in GBS include lymphocytic infiltration of spinal roots and peripheral nerves (cranial nerves may be involved as well), followed by macrophage-mediated, multifocal stripping of myelin. This phenomenon results in defects in the propagation of electrical nerve impulses, with eventual absence or profound delay in conduction, causing flaccid paralysis. Recovery is typically associated with remyelination.
In some patients with severe disease, a secondary consequence of the severe inflammation is axonal disruption and loss. A subgroup of patients may have a primary immune attack directly against nerve axons, with sparing of myelin. The clinical presentation in these patients is similar to that of the principal type
AIDP
The classic pathological picture of Guillain-Barré
syndrome is of multifocal mononuclear cell infiltration
throughout the peripheral nervous system in which the
distribution of inflammation corresponds to the clinical
deficit.3 Macrophages invade the myelin sheaths and
denude the axons. For the most part, macrophages seem
to invade intact myelin sheaths (figure 1), as occurs in
experimental autoimmune neuritis. According to
one hypothesis, the activated macrophages are targeted
to antigens on the surface of Schwann cells or the myelin
sheath by activated T lymphocytes, which are major
actors in experimental autoimmune neuritis. The initial
invasion of the Schwann cell basement membrane is a
consequence of matrix metalloproteinases, toxic nitric
oxide radicals, and other mediators released by activated
macrophages.65,66 According to an alternative, but not
mutually exclusive hypothesis, the initial event is the
binding of antibodies to the surface of the Schwann cell,
fixation of complement, probable damage to the
Schwann cell, and vesicular dissolution of myelin in
advance of cell invasion. Evidence for this theory comes
from autopsy material early in the course of the disease.67
In severe lesions, the axons are also damaged probably as
a secondary or “bystander” consequence of the toxic
enzymes and radicals released by the immune mediated
inflammatory response directed against the myelin.
In North America and Europe, typical patients with
Guillain-Barré syndrome usually have AIDP as the
underlying subtype, and only about 5% of patients have
axonal subtypes of the disease
Dysesthesias- spontaneous unpleasant but not painful sensation in the absence of stimuli ( wetness, electric shock, burning, pins and needles)
Paresthesia- dystorted sensation (prickling, itching)
Progressive weakness of more than two limbs, < 4 weeks
Areflexia
Other causes of an acute neuropathy such as lead poisoning, vasculitis, botulism, and porphyria require exclusion. Supportive criteria include relatively mild sensory signs, raised protein in the cerebrospinal fluid (CSF), with a relatively normal cell count, and neurophysiological evidence of conduction block. Weakness is frequently proximal and distal, unlike dying back axonopathies, and respiratory involvement occurs in about a quarter of cases. The CSF protein may be normal in the first week of the illness8 but may then rise to several g/dl. The CSF cell count usually remains below 500 cells/litre. Oligoclonal bands are sometimes found in the CSF. Routine blood tests sometimes reveal a raised sedimentation rate with hyponatraemia from inappropriate antidiuretic hormone release, and mild impairment of liver function tests is not uncommon.
.
AIDP, with only the sensory nerves or roots being
affected; but this condition needs to be distinguished from
acute sensory neuronopathy. The differential diagnosis of
Fisher’s syndrome includes an acute brainstem lesion,
especially brainstem encephalitis.
In Guillain-Barré syndrome, the onset phase has been
arbitrarily defined as lasting for up to 4 weeks.37
Differentiation between subacute and chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP),
in which the onset phase lasts 4–8 weeks39,40 or more
than 8 weeks,41 respectively, may only be able to be done
retrospectively. Difficulties in classification arise when
patients have recurrent attacks of Guillain-Barré
syndrome: such cases overlap with CIDP.42,43 Between
8% and 16% of patients presenting with a Guillain-
Barré-like illness have one or more episodes of
worsening after initial improvement. In one study,44
patients who deteriorated more than 9 weeks after the
onset of their neuropathy or who had more than two
treatment-related fluctuations were more likely to
develop CIDP.
Plasma exchange (washing harmful substances out of the blood) and intravenous immunoglobulin
(infusion into the blood stream of human antibodies harvested from blood donations) are beneficial but corticosteroids are not
Plasma exchange is a process of replacing the plasma in
a person’s blood. Plasma is the liquid part of blood. The
solid parts are white and red blood cells. In plasma
exchange, blood is drawn from the person. The plasma
is separated from the solid parts of the blood. It is then
replaced with a protein fluid such as human albumin.
Albumin is an important protein in plasma. In rare cases,
plasma donated by a blood donor is used instead of
albumin. The replacement fluid is mixed with the solid
parts of the blood. A machine pumps this mixture through
a tube into the body.
The
mechanism of action of IVIg is probably multifactorial,
possibly involving blockade of Fc receptors, provision of
anti-idiotypic antibodies, interference with complement
activation, and T-cell regulation
Autonomic dysfunctions: fluctuations in blood pressure, cardiac dysrhythmias, gastrointestinal pseudo-obstruction, and urinary retention.
Sandoglobulin preparation: screened serum batches pooled from more than 8000 unpaid donors, was fractionated and treated with pepsin
Relapse, defined as an increase of 1 or more disability grades for at least 1 week after the disability grade had been stable or had improved by 1 or more
grades for at least a week.
My patient: Disability grade 4 ( unable to walk without assitance), arm : 2
Enteritis: patient had diarrhea daily for 1 month prior
15 cases in the PE+IVIg group including: (pulmonary edema, retroperitoneal hemorrhage, and endocarditis with cerebral embolism,
Guillain-Barré syndrome (off-label) - ( Click here for full Off-Label monograph ) Efficacy, safety risks, and optimal dosing are clearly identified in appropriate population as evidenced by consistent favorable data from at least one well-designed, controlled trial and/or dramatic results from uncontrolled experiments supported by guidelines published by expert panels. A total dose of 2 g/kg given over 2 to 5 days