What is Guillain-Barre Syndrome || Causes,types, pathophysiology, investigations & Management

Guillain-Barre Syndrome

GBS is regarded as a heterogeneous group of immunologically mediated disorders of peripheral nerve function. This is a autoimmune polyneuropathy appears some day after respiratory or gastrointestinal infection. Progression is variable, ranging from nearly total paralysis in 24hrs to progression over several weeks.

Pathophysiology:

• GBS is a postinfectious, immune-mediated disease.
o Cellular and humoral immune mechanisms probably play a role in its development.
o Most patients report an infectious illness in the weeks prior to the onset of GBS.
o 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.
• The pathophysiologic mechanism of an antecedent illness and of GBS can be typified by Campylobacter jejuni infections.
o The virulence of C jejuni is thought to be based on the presence of specific antigens in its capsule that are shared with nerves.
o Immune responses directed against lipopolysaccharide antigens in the capsule of C 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.
• 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.

Antecedent infective agents in GBS:

• Campylobacter jejunii
• Influenza A      
• Parainfluenza
• Epstein-Barr
• Varicella-Zoster
• Mycoplasma
• Measles
• Cytomegalovirus
• HIV
• Mumps
• Chickenpox

Types of Guillain-Barré syndrome:

• Acute inflammatory demyelinating polyneuropathy

o It is generally preceded by a bacterial or viral infection. Nearly 40% of patients with AIDP are seropositive for C jejuni.
o Lymphocytic infiltration and macrophage-mediated peripheral nerve demyelination is present.
o Symptoms generally resolve with remyelination.

• Acute motor axonal neuropathy
o The acute motor axonal neuropathy (AMAN) subtype is a purely motor disorder that is more prevalent in pediatric age groups.
o AMAN is generally characterized by rapidly progressive symmetrical weakness and ensuing respiratory failure.
o Nearly 70-75% of patients with AMAN are seropositive for Campylobacter, with the majority of cases of AMAN being associated with preceding C jejuni diarrhea.
o Patients typically have high titers of antibodies to gangliosides (ie, GM1, GD1a, GD1b). Inflammation of the spinal anterior roots may lead to disruption of the blood-CNS barrier. Biopsies show wallerianlike degeneration without significant lymphocytic inflammation.
o Prognosis is often quite favorable. Although recovery for many is rapid, severely disabled patients with AMAN may show improvement over a period of years. [16]
o One third of patients with AMAN may actually be hyperreflexic. Hyperreflexia is significantly associated with the presence of anti-GM1 antibodies.

• Acute motor-sensory axonal neuropathy
o Acute motor-sensory axonal neuropathy (AMSAN) is a severe acute illness differing from AMAN in that it also affects sensory nerves and roots.  Patients are typically adults.
o AMSAN often presents as rapid and severe motor and sensory dysfunction. Marked muscle wasting is characteristic, and recovery is poorer than it is from electrophysiologically similar cases of AMAN.
o As with AMAN, AMSAN is often associated with preceding C jejuni diarrhea.
o Pathologic findings show severe axonal degeneration of motor and sensory nerve fibers with little demyelination.

• Miller-Fisher syndrome
o Miller-Fisher syndrome (MFS), which is observed in about 5% of all cases of GBS, classically presents as a triad of ataxia, areflexia, and ophthalmoplegia. 
o Acute onset of external ophthalmoplegia is a cardinal feature.
o Ataxia tends to be out of proportion to the degree of sensory loss. Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar palsy. Patients have reduced or absent sensory nerve action potentials and absent tibial H reflex.
o Anti-GQ1b antibodies are prominent in MFS, and have a relatively high specificity and sensitivity for the disease.  Dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia. Patients with acute oropharyngeal palsy carry anti-GQ1b/GT1a IgG antibodies. 
o Recovery generally occurs within 1-3 months.

• Acute panautonomic neuropathy
o Acute panautonomic neuropathy, the rarest GBS variant, involves the sympathetic and parasympathetic nervous systems.
o Patients have severe postural hypotension, bowel and bladder retention, anhidrosis, decreased salivation and lacrimation, and pupillary abnormalities.
o Cardiovascular involvement is common, and dysrhythmias are a significant source of mortality. Significant motor or sensory involvement is lacking.
o Recovery is gradual and often incomplete.

• Pure sensory GBS
o It is typified by a rapid onset of sensory loss, sensory ataxia, and areflexia in a symmetrical and widespread pattern.
o Lumbar puncture studies show albuminocytologic dissociation in the CSF, and results from electromyography (EMG) show characteristic signs of a demyelinating process in the peripheral nerves.
o The prognosis in pure GBS is generally good. Immunotherapies, such as plasma exchange and the administration of IVIGs, can be tried in patients with severe disease or slow recovery.

• Other variants
o The pharyngeal-cervical-brachial variant of GBS is distinguished by isolated facial, oropharyngeal, cervical, and upper limb weakness without lower limb involvement.
o Acute pandysautonomia, symptoms of which include diarrhea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension, urinary retention, pupillary abnormalities, an invariant heart rate, decreased sweating, salivation, and lacrimation. The deep tendon reflexes are absent or diminished and sensory symptoms may be present.
o Pure sensory GBS, with involvement of large sensory fibers leading to significant sensory ataxia. The deep tendon reflexes are absent and there may be minor motor involvement. An association with antibodies to GD1b has been noted.
o Facial diplegia and distal limb paresthesia. This is considered a variant of acute inflammatory demyelinating polyneuropathy.
o Sixth nerve palsy and distal paresthesia.
o Bilateral lumbar radiculopathy.
o Paraparesis, with weakness restricted to the legs at presentation.

Clinical features:

• The weakness usually starts in the legs, but it begins in the arms or facial muscles. Weakness, usually bilateral and symmetrical, typically ascending from legs but may affect any region first
• Muscle weakness or Paraesthesia- following by numbness begins in the toes and is rapidly followed by flaccid paralysis of the lower limbs which may ascend to involve the arms and sometimes facial muscles, muscles of the palate, pharynx (causing dysphasia) and the external occular muscles. Bilateral facial weakness develops in 50% of patients
• Reduction in both power and deep tendon reflexes.
• Cranial nerve deficits are apparent in 45% of cases, with VII, IX and X being the most frequently affected. Facial nerve palsies occur in more than 50 percent, and oropharyngeal weakness eventually occurs in 50 percent. Oculomotor weakness occurs in about 15 percent of patients.
• The Miller-Fisher variant is a well-described form of GBS cranial nerve abnormality, accompanied by ataxia, areflexia and ophthalmoplegia.
• Bulbar involvement may occur
• 90% patients are maximally affected within 3-4 weeks
• Areflexia occurs: Decreased or absent reflexes in affected arms or legs are found in approximately 90 percent of patients
• Respiratory muscle may be affected and tracheal intubation and IPPV are necessary
• Pain due to nerve root inflammation, typically located in the back and extremities
• Hypotension Sensory disturbance: reduced touch sensation and joint position sence may also occur.
• Features of autonomic disturbance include hypotension or hypertension, tachycardia, arrythymia, ileus and urinary retension
• The syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may be due to autonomic involvement, is another complication of GBS.
• Diagnosed by history or clinical features
• CSF protein is raised without an increase in white cell count
• Recovery takes from several weeks to months and upto years if axonal damage has occurred

Investigation:

• Blood for CBC
• Urine for R/E
• S. Electrolytes
• Urea, Creatinine
• Calcium
• AFP, and Protein profile
• LFT and Sugar (R)
• CSF for R/E & C/S: The typical finding with lumbar puncture in patients with GBS is an elevated cerebrospinal fluid (CSF) protein with a normal white blood cell count.
• X-Ray chest P/A view
• ECG
• CT scan of brain.
• MRI: Spinal MRI may reveal thickening and enhancement of the intrathecal spinal nerve roots and cauda equina. The anterior spinal nerve roots only may be involved, or both the anterior and posterior spinal nerve roots can be involved. In exceptional cases of Miller Fisher syndrome, abnormalities of the spinal cord posterior columns have been described. In the brain, enhancement of the oculomotor, abducens, and facial nerves may be seen
• Electrodiagnostic studies:
o Demyelinating forms of GBS are supported by features of demyelination, including decreased motor nerve conduction velocity, prolonged distal motor latency, increased F wave latency, conduction blocks, and temporal dispersion.
o Axonal forms of GBS are supported by decreased distal motor and/or sensory amplitudes. Transient motor nerve conduction block (ie, reversible conduction failure) can be present.
• Antibodies:
o Glycolipid antibodies may be associated with different forms or aspects of GBS.
o The GQ1b antibody associated with the Miller Fisher variant of GBS
o Antibodies to GQ1b may also be present in GBS with ophthalmoparesis, Bickerstaff encephalitis, and the pharyngeal-cervical brachial GBS variant, but not in disorders other than GBS.

Diagnostic criteria:

• Required features include:
o Progressive weakness of the legs and arms (sometimes initially only in the legs), ranging from minimal weakness of the legs to total paralysis of all four limbs, the trunk, bulbar and facial muscles, and external ophthalmoplegia
o Areflexia or decreased reflexes in weak limbs.
• Supportive features include:
o Progression of symptoms over days to four weeks (80 percent reach nadir in two weeks)
o Relative symmetry
o Mild sensory symptoms or signs
o Cranial nerve involvement, especially bilateral facial nerve weakness
o Recovery starting two to four weeks after progression halts
o Autonomic dysfunction
o Pain
o No fever at the onset
o Elevated protein in CSF with a cell count ≤50/mm3 (usually <5 cells/mm3)
o Electrodiagnostic abnormalities consistent with GBS
• The following features make the diagnosis of GBS doubtful:
o Sensory level (decrement or loss of sensation below a spinal cord root level as determined by neurologic examination)
o Marked, persistent asymmetry of weakness
o Bowel and bladder dysfunction at onset
o Severe and persistent bowel and bladder dysfunction
o Severe pulmonary dysfunction with little or no limb weakness at onset
o Severe sensory signs with little or no weakness at onset
o Fever at onset
o CSF pleocytosis with a white cell count >50/mm3

Treatment:

The ICU management of GBS broadly consists of:
A. Specific therapeutic interventions
B. General supportive measures in the interim of disease resolution 
C. The avoidance of complications and iatrogenic insult

A. Specific therapeutic:

a.Plasmapherisis:
• Plasmapheresis is thought to remove circulating antibodies, complement, and soluble biological response modifiers.
• Plasma exchange was most effective when started within seven days of symptom onset. Most beneficial performal with the first 2 weeks and before ventilatory support is required.  However, in the North American study that allowed enrollment up to 30 days after symptom onset, there was still an improvement in outcome in the plasma exchange group compared with controls.
• Four exchanges were superior to two in patients with moderately severe GBS.
• Plasma exchange is usually given for four to six treatments over eight to 10 days.
• The main complications are hypotension, sepsis, and problems with intravenous access.

b.Immunoglobin therapy:
o The precise mechanism of action for IVIG in GBS is unknown but may include providing anti-idiotypic antibodies, modulating expression and function of Fc receptors, interfering with activation of complement and production of cytokines, and interfering with activation and effector functions of T and B cells.
o Intravenous immune globulin is given for five days at 0.4 gram/kg per day over 3-5 days
o Side effects include aseptic meningitis, rash, acute renal failure and (rarely) hyperviscosity leading to stroke.
o IgA deficiency can lead to anaphylaxis

c.CSF filtration has been used in severe , resistance cases

B. General ICU Supportive measure :

i. Respiratory support :
• Vigilance is essential when caring for a patient with GBS, since deterioration due to progression of muscle weakness can occur rapidly.
• Chest physiotherapy and close respiratory monitoring with frequent measurement (eg, every four hours) of vital capacity and negative inspiratory force (NIF) should be instituted initially in all patients.
• Bulbar dysfunction with swallowing problems and inability to clear secretions may add to the need for ventilatory support.

Indication for intubation:
• The following parameters warn of impending respiratory arrest and are an indication for intubation:
o Forced vital capacity <20 mL/kg
o Maximum inspiratory pressure <30 cmH2O
o Maximum expiratory pressure <40 cmH2O

• The following factors were identified as predictors of respiratory failure:
o Time of onset to admission less than seven days
o Inability to cough
o Inability to stand
o Inability to lift the elbows
o Inability to lift the head
o Liver enzyme increases

Clinical markers of failing respiration include:
• The triad of:
o Rapid and substantial weakness, occurring over a few  days, with, for example, inability to lift elbows or head  off the bed,10 (Mehta) especially if accompanied by either
o Facial weakness (e.g. Flattening of naso-labial fold, inability to smile), and/or
o Bulbar palsy (cranial nerve damage), indicated by,  e.g., difficulty swallowing, with choking, coughing or  drooling, absent gag reflex or slurred or weak speech;
• Shallow or rapid breathing with poor breath sounds in the  bases of the lungs;
• Staccato speech, so only a few words are spoken with each  breath;
• Autonomic instability (dysautonomia) as indicated by, e.g.,  fluctuating blood pressure and/or heart rate;
• Tachycardia and/or brow sweating, from stress induced  adrenergic drive; and
• Paradoxical breathing, i.e., inward movement of abdominal  muscles during inspiration, reflecting diaphragm fatigue;  and/or  episodic use of accessory muscles of respiration.

Lab markers of failing respiration include:
• Oxygen saturation less than 92%; pCO2 > 45 mmHg, per ABG,  in patients without chronic lung disease;
• Inspiratory effort (IF) (force generated by a maximal  inhalation) less than 15 cm H2O. Values > 25 are usually safe;
• Decreased vital capacity (VC) (measured as a full expiration  after a deep inspiration), of < 15-20 ml/kg;
• Rapid fall, e.g., > 30%, of IF or VC within 24 hours;
• In the fatigued patient even a VC fall to 18 ml/kg may suffice  to ventilate;
• A drop of 500 ml in VC;
• Inability to count to over 10 with one breath provides a quick  bedside marker of a VC down to 1 liter, signaling  impending  failure. A normal VC allows counting to twenty17 (Ropper); and
• Inconsistent or falling values of VC or IF at a single test session.

Intubation:
• Endotracheal intubation is more difficult in patients with GBS than in other patients requiring emergency airway control, because of dysautonomia which can cause sudden arrhythmia or hypotension during airway manipulation.
• Tracheal intubation is also required if laryngeal reflex are impaired
• Endotracheal tubes currently available require low cuff pressures to maintain adequate seal.
• For prolonged intubation tracheostomy is recommended once the need for prolonged mechanical ventilation is apparent. Tracheostomy should be considered in the second weeks
• Succinylcholine should be avoided when invasive airway management becomes necessary. The technique of rapid sequence intubation may required.

Mode of ventilation:
• The commonest mode of mechanical ventilation used in other patients with GBS is SIMV.
• This mode is comfortable for the patient, assures a minimum level of minute ventilation, and allows variation in respiratory support from near total to minimal.
• Pressure support ventilation is often combined with SIMV to reduce work of breathing during spontaneous breaths and minimize desynchronization with the ventilator.

Weaning:
• The time to wean patients from mechanical ventilation is when criteria necessitating respiratory support are no longer present.
• Weaning from mechanical ventilation should be guided by improvement in strength and serial pulmonary function tests (PFTs). As muscle strength improves, gradual reduction in either the SIMV rate or the level of pressure support will progressively increase patient contribution towards the work of breathing.
• Discontinuing ventilator support is a two step process.
o First  determine readiness to wean and then initiate weaning.  Monitor for returning strength, such as the presence of head,  eye and shoulder movement, as a clue to weaning readiness.
o Prior to weaning the patient should be hemodynamically stable and  medications with sedating properties, e.g., opiates and anxiolytics, should be discontinued. Daily interruption of these agents (sedation  vacation), as clinically deemed safe, has been found to shorten  duration of ventilation. Sedation vacation allows for assessment of  neurologic status and measurement of vital capacity, key factors in  determining the GBS patient’s readiness for weaning.
• Common methods for weaning include a T tube trial and pressure  support ventilation.  In a T tube trial, intervals of spontaneous breathing off ventilatory  support are provided through a T tube circuit. Limit the trial to two  hours or less to determine if the patient is ready for extubation. If  the patient fails they should be returned to full ventilatory support  for 24 hours prior to reattempting weaning.
• To begin the weaning process with PSV, set the ventilator to  an initial optimal level of pressure that will enable the patient  to generate a tidal volume of 10-12 ml/kg with a decreased  respiratory rate.
o Accomplish this by increasing the PSV level,  starting at a baseline value of 15 to 20 cm H20, in increments  of 3 to 5 cm.
o Continue the incremental increase until the patient  shows a decrease in respiratory rate while maintaining the tidal  volume of 10 to 12 ml/kg.
o Gradually reduce pressure support, based on the patient’s clinical tolerance, by 3-8 cm water/H20 while monitoring that the patient is maintaining their tidal  volume. This method slowly transfers the work of breathing from  the ventilator to the patient.
o Once the patient is stable on low  pressure support, an extubation trial should be initiated.

• Noninvasive ventilation.
o Patients with hypercapnic (elevated CO2)  respiratory failure can benefit from noninvasive positive pressure  ventilation.
o Several trials have suggested that the use of inspiratory  and expiratory or bilevel positive airway pressure (BiPAP) post  extubation lowers mortality rate, lessens duration of ventilation  and lowers the rate of nosocomial pneumonia.

For patients on a ventilator additional care guidelines may apply:
• Stress ulcers: to reduce the risk of this and other causes  of upper gastrointestinal bleeding, use an H2 receptor blocker (e.g., famotidine [Pepcid®]) or proton pump inhibitor  (e.g., pantoprazole )
• Urine retention: prevent this with an indwelling bladder  catheter (Foley);
• Decubitus and foot drop prevention: use modalities as listed  in section 10, e.g., alternating pressure mode of specialty bed, frequent repositioning-e.g., every 2 hours, heel off-loading,  ankle-foot orthosis, etc.
• Oxygen desaturation: if this occurs look for causes, such as  atelectasis, mucous plug, endotracheal tube migration into a main stem bronchus, pulmonary embolism, pneumothorax,  or new infiltrate;
• Atelectasis: treat with chest physical therapy, postural  drainage, etc. and
• Tracheostomy: plan for this in the event that ventilation  beyond two weeks is required.

ii.Cardiovascular management:
• Common manifestations include paroxysmal fluctuations in blood pressure, and tachy and bradyarrhythmias, while less frequent manifestations include myocardial involvement ranging from myocarditis to heart failure.
• Cardiac rhythm and blood pressure monitoring for patients in the progressive phase of GBS. Monitoring should be instituted at time of admission and continued until ventilatory support is no longer necessary or until recovery is underway in patients not needing mechanical ventilation.
• Practical tips for the management of patients with GBS include the following:
o Quadriplegic patients should not be left unattended in the sitting position without assessment of orthostatic hypotension
o Intravascular volume should be maintained, particularly during positive-pressure ventilation
o Drugs with hypotensive side effects should be avoided if possible
o Arrhythmias frequently occur during suctioning
o Plasma exchange can cause hypotension and electrolyte disturbances

iii.Blood pressure:
• Intraarterial monitoring should be instituted in the presence of significant blood pressure fluctuations.
• Hypotension can usually be treated with fluids, but low-dose phenylephrine can be used if fluids are not effective. In the presence of dysautonomia, only low doses of carefully titrated short-acting vasoactive agents should be used for treatment of hypotension and hypertension because of the potential to overshoot the target blood pressure in the setting of possible denervation hypersensitivity.
• Episodes of severe hypertension (mean arterial pressure >125 mmHg) can be treated with labetalol, esmolol, or nitroprusside.
• In cases of autonomic cardiovascular dysfunction, other conditions must be excluded, such as pulmonary thromboembolism, hypoxemia, sepsis, gastrointestinal bleeding, and fluid and electrolyte disturbances.

iv.Arrhythmias:
• Sustained sinus tachycardia is the most common cardiac arrhythmia, affecting 25 to 38 percent of patients with GBS, and usually requires no treatment. Bradyarrhythmias are also fairly common.
• Additional arrhythmias and electrocardiogram (ECG) changes that have been reported with GBS include atrial fibrillation, atrial flutter, paroxysmal tachycardia, ventricular tachycardia, elevated or depressed ST segments, flat or inverted T waves, Q-T interval prolongation, axis deviation, and various conduction blocks.
• Serious or life-threatening cardiac arrhythmias, including atrioventricular block and asystole, can occur with GBS and require intervention with administration of atropine and cardiac pacing

v. Autonomic dysfunction :
• Autonomic dysfunction may result in features such as refractory orthostatic hypotension, paroxysmal hypertension, bradycardia, ventricular tachyarrhythmias, ileus and urinary retention.
• Close monitoring of  blood pressure, fluid status, and cardiac rhythm is essential to the management of patients with GBS.
• Careful consideration should be given to the use of suxamethonium and inotropic and vasopressor agents may produce markedly atypical responses in heart rate and blood pressure. 

vi.Nutrition :
• Gastrointestinal support should include nasogastric feeding wherever possible.
• Total parenteral nutrition may occasionally be necessary when enteral measures prove inadequate.

vii.Immobility :
• Musculoskeletal features may include limb/girdle pain, for which simple analgesics, quinine, anti-depressants and opioids have all been used successfully.
• Physiotherapy should continue throughout the illness to prevent the sequelae of limb disuse, with careful attention given to pressure area care.
• Deep-vein thrombosis prophylaxis is considered a priority with Heparin.

viii.Bowel and bladder care:
• Additional autonomic problems associated with GBS include adynamic ileus and urinary retention.
• Daily abdominal auscultation to monitor for bowel silence and the development of adynamic ileus is recommended, as is monitoring of opioid administration. For treating ileus, erythromycin or neostigmine may be effective.

ix.Pain control:
• Pain occurs in about two-thirds of patients during the course of GBS and often requires treatment. 
• Gabapentin or carbamazepine may be used for intensive care unit pain control during the acute phase of GBS.
• Simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) may be tried, but they often do not provide adequate pain relief.
• Appropriate narcotic analgesics may be used but require careful monitoring for adverse effects in the setting of autonomic denervation.
• Epidural morphine also can be useful.
• For the long-term management of neuropathic pain, tricyclic antidepressants, gabapentin, carbamazepine, or pregabalin may be useful.

x.Rehabilitation:
• Acute-phase rehabilitation should include an individualized program of gentle strengthening, involving isometric, isotonic, isokinetic, and manual resistive and progressive resistive exercises.
• Rehabilitation should emphasize proper limb positioning, posture, and orthotics as well as nutrition.
• A device to help with communication may be necessary.
• After the acute phase, disabled patients should be treated by a multidisciplinary rehabilitation team.
• An exercise program may be beneficial for persistent fatigue.

xi. Psychological issues :
• GBS patients frequently require a great deal of psychological support, given the extremely disabling and frightening aspects of the condition and its sequelae..

xii. Medication:
• Prompt treatment of infection eg, urinary,respiratory etc
• Treatment of cardiovascular abnormalities appropriate

Prognostic factors:
• Factors associated with a poor prognosis for recovery from GBS include:
• Older age
• Rapid onset (less than seven days) prior to presentation
• Severe muscle weakness on admission
• Need for ventilatory support
• An average distal motor response amplitude reduction to <20 percent of normal
• Preceding diarrheal illness
(Ref: Morgan+ Stolting+uptodate.com)