Acute Inflammatory Demyelinating Polyradiculoneuropathy

Background

Acute inflammatory demyelinating polyneuropathy (AIDP) is an autoimmune process that is characterized by progressive areflexic weakness and mild sensory changes. Sensory symptoms often precede motor weakness. About 20% of patients end up with respiratory failure. Many variants exist. In the West, the most common presentation is a subacute ascending paralysis. This is associated with distal paresthesias and loss of deep tendon reflexes. Progression is often maximal by the end of 4 weeks, then the condition usually plateaus before slowly improving. In 1859, Landry described 10 cases characterized by ascending paralysis and sensory changes.

During World War I, Guillain, Barré, and Strohl described a series of patients with a similar presentation and decreased or absent deep tendon reflexes. They also described albuminocytologic dissociation in the cerebrospinal fluid (CSF), ie, increased CSF protein in the absence of increased WBCs. This allowed them to differentiate AIDP from poliomyelitis, the most common acute paralytic syndrome of that era. (AIDP often is referred to as Guillain-Barré syndrome [GBS]).

Myelin breakdown and axonal degeneration were observed in nerve biopsies from patients with AIDP by Haymaker and Kernohan in 1949.^[1] An allergic etiology was suggested by Krucke in 1955 after he observed lymphocytic infiltrates within biopsy specimens.^[2] An autoimmune process was supported by Waksman and Adams when they created the experimental allergic neuritis model by injecting peripheral nerve tissue into rodents.^[3]

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Pathophysiology

Acute inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both, and the pathogenesis of these disorders remains elusive.

The recent isolation and characterization of human endoneurial endothelial cells that form the blood-nerve barrier provides an opportunity to elucidate leukocyte-endothelial cell interactions critical to the pathogenesis of inflammatory neuropathies at the interface between the systemic circulation and peripheral nerve endoneurium.

Acute inflammatory demyelinating polyneuropathy is believed to be caused by an immunologic attack that is directed against myelin components. This results in a demyelinating polyneuropathy. Both cellular and humoral immune mechanisms appear to play a role. Early inflammatory lesions consist of a lymphocytic infiltrate that is adjacent to segmental demyelination. Macrophages are more prominent several days later.

The peripheral nerve changes consist of varying degrees of perivascular edema, accumulations of mononuclear cells, and paranodal and less commonly, segmental demyelination. They are often multifocal with some predilection for the nerve roots, sites of entrapment, and distal ends. In the axonal variant of Guillain-Barré syndrome, axonal degeneration often predominates. Severe Guillain-Barré syndrome is often associated with axonal degeneration as well, which results in wallerian degeneration. Axonal degeneration occurs either as a primarily axonal process or as a bystander-type axonal degeneration, associated with demyelination. Rarely, the pathologic process extends into the central nervous system.

As the regeneration occurs, nerve sprouting and increased scarring often results.

With electron microscopy, macrophages are observed stripping off the myelin sheath. Humoral molecules such as antimyelin antibodies and complement likely contribute to the process by directing macrophages to Schwann cells by opsonization. Indeed, complement and antibodies have been found to coat the myelin sheath. The changes are observed in nerve roots, peripheral nerves, and cranial nerves. In acute motor axonal neuropathy (AMAN, an AIDP variant), deposited complement is found at the nodes of Ranvier, while myelin often is left undamaged.

Damage to the myelin sheath leads to segmental demyelination. This results in decreased nerve conduction velocity and, at times, conduction block. In this current review, AIDP refers to the more common demyelinating form unless otherwise specified.

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Epidemiology

Frequency

United States

Acute inflammatory demyelinating polyneuropathy is the most common acquired demyelinating polyneuropathy. The incidence is 0.6-1.7 cases per 100,000 per year. No significant seasonal variation has been noted.

International

Frequency is not well documented. Of 2 predominant Guillain-Barré syndrome subtypes, a demyelinating subtype (AIDP) predominates in the United States and Europe, and axonal subtype (AMAN) is the predominant form in China. Previous clinical studies suggested that AMAN also occurs in Mexican children.^[4] Similar outbreaks have been reported in Mexico, Spain, and Jordan.

Mortality/Morbidity

In 3 large studies, mortality rate ranged from 2-6%.

• In general, death is due to complications of ventilation. Causes include cardiac arrest, pulmonary embolus, sepsis, bronchospasm, pneumothorax, adult respiratory distress syndrome (ARDS), and dysautonomia.
• More than 75% of patients have complete or near-complete recovery with no deficit or only mild residual fatigue and distal weakness.
• Other patients, almost all of whom required ventilation, report severe dysesthesias or moderately severe distal weakness as residual symptoms. About 15% of patients end up with significant neurological residuals.

Race

Acute inflammatory demyelinating polyneuropathy occurs in all races and in all regions of the world.

Sex

The male-to-female ratio is 1.1-1.7:1.

Age

Patients have ranged in age from 2 months to 95 years.

• In the United States, age distribution is apparently bimodal, with most patients presenting from 15-35 years or 50-75 years.
• In China (and other countries), frequent outbreaks in children aged 2-12 years have been reported.

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History

See the list below:

• Acute inflammatory demyelinating polyneuropathy typically manifests as an ascending paralysis.
• Even in these cases, the clinical presentation and course vary. Additionally, many variants exist that differ markedly from classic AIDP in disease onset or course.^[5]
• Progressive weakness

  • The hallmark of classic AIDP is progressive weakness that usually begins in the feet before involving all 4 limbs. At presentation, 60% of patients have weakness in all 4 limbs.
  • Weakness plateaus at 2 weeks after onset in 50% of patients and by 4 weeks in over 90%. It is usually symmetric, although mild asymmetry is not uncommon early in the disease course.
  • In the arms, weakness may be worse proximally than distally. At presentation, half of patients have some facial weakness, although only 5% have varying degrees of ophthalmoplegia.
  • Oropharyngeal or respiratory weakness is a presenting symptom in 40% of patients. Improvement in strength usually begins 1-4 weeks after the plateau. About one third of patients require mechanical ventilation because of respiratory failure.

   

  

   
• Sensory symptoms

  • Mild to moderately severe paresthesias in the distal limbs are common and often precede the onset of weakness by 1 or more days.
  • Proximal sensory changes are uncommon but may occur in more severe cases of AIDP.

   

  

   
• Autonomic dysfunction

  • About two thirds of patients have one or more autonomic abnormalities. Sustained sinus tachycardia is the most common dysfunction. Postural hypotension leading to presyncope or syncope can occur.
  • Sweating dysfunction is common but rarely noted by patients. Urinary retention and constipation are more likely to occur later in the course of AIDP. Autonomic dysfunction is more common in intubated patients.

   

  

   
• Pain

  • Mild lower back and/or hip pain is very common and occasionally precedes the onset of weakness.
  • The pain is severe in about 15% of patients.

   

  

   
• AIDP may vary early in the course. More than 95% of patients eventually have the classic symptoms; other patients may have one of the characterized variants.

  • The Miller-Fisher variant, appearing with ophthalmoplegia, areflexia, and ataxia, is the most common variant and is seen in as many as 5% of patients with AIDP. Although usually seen in adults, this variant is also common in children. Most patients with the Miller-Fisher variant have antibodies against ganglioside GQ1b.
  • Regional variants of Guillain-Barré syndrome, such as pharyngeal-cervical-brachial weakness or only leg weakness, are rare and resemble AIDP in time course.
  • Pure pandysautonomia with little, if any, weakness parallels classic AIDP in time course and antecedent infections. The difference is that this variant is manifested primarily by autonomic failure. Many of these patients also have areflexia.
  • The AMAN variant is seen in China and in developing countries. It presents with weakness only.
  • Acute motor-sensory axonal neuropathy resembles classic Guillain-Barré syndrome in presentation but is related pathologically to AMAN.

   

  

   

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Physical

A detailed physical examination can help support the diagnosis of acute inflammatory demyelinating polyneuropathy and/or exclude disorders in the differential diagnosis.

• Weakness

  • Although patients often report only weakness in the legs, careful examination usually demonstrates arm weakness (proximally and distally).
  • Some patients with Miller-Fisher or other regional variants may have weakness of cranial muscles only.

   

  

   
• Deep tendon reflexes

  • Hyporeflexia or areflexia is seen in 70% of patients at presentation and eventually in all patients.
  • A progressive decrease in reflexes is a useful finding that may precede electromyographic (EMG) changes.

   

  

   
• Autonomic dysfunction

  • Fluctuations in heart rate, specifically a sustained sinus tachycardia, are seen often.
  • Some intubated patients also may have bradycardia, especially after vagal stimulation with Valsalva and/or tracheal suctioning maneuvers.
  • Orthostatic hypotension can occur and is likely due to dysfunction of the baroreceptor reflex.
  • At times, the labile blood pressure is observed with severe hypertension that may be due to dysfunction of the afferent limb of the baroreceptor reflex.
  • Urinary retention is common, especially in intubated patients. The rare patient may even develop an ileus.

   

  

   
• Findings that are inconsistent with a diagnosis of AIDP

  • Weakness that remains markedly asymmetric
  • Sharp sensory level
  • Severe bladder or bowel dysfunction at onset

   

  

   
• Diagnostic criteria for Guillain-Barré syndrome include the presence of progressive weakness and areflexia, relative symmetry, mild sensory involvement, cranial nerve involvement, at least partial recovery, autonomic dysfunction, and absence of fever. Cerebrospinal fluid features that strongly support the diagnosis are an increase in protein beyond the first week, cell count < 10 (albuminocytological dissociation). Electrophysiologic evidence of conduction slowing, block, prolonged distal latency or F-wave latencies are also strongly supportive (80% of the case), though these abnormalities may be delayed for several weeks. Marked persistent asymmetry of weakness, the presence of a sensory level, bowel/bladder involvement at onset, and a prominent pleocytosis, often cast doubt on the diagnosis, so is the presence of another cause for the neuropathy.
• In 1986, Ropper described 3 patients who experienced acute progression of oropharyngeal, neck, and shoulder weakness. Clinically, they had facial palsy, blepharoptosis, absence of sensory disturbance, and preserved tendon jerk in the legs. Based on elevated CSF protein levels and electrophysiological findings (a denervation pattern and decreased conduction velocity in peripheral nerves), he speculated that these patients had a Guillain-Barré syndrome variant, which he called pharyngeal-cervical-brachial weakness (PCB).^[6]
• Since then, PCB is considered a rare variant of Guillain-Barré syndrome. Nagashima et al identified the clinical profiles of PCB. They feel that the clinical overlapping, frequent Campylobacter jejuni infection, and common antiganglioside antibodies present in PCB, Guillain-Barré syndrome, Fisher syndrome, and Bickerstaff brainstem encephalitis provide conclusive evidence that PCB and these conditions form a continuous spectrum.^[7]

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Causes

Acute inflammatory demyelinating polyneuropathy is thought to be caused by a dysregulated immune response against myelin. This response may be triggered by several illnesses and conditions. Two thirds of patients with AIDP recall an antecedent upper respiratory or gastrointestinal infection or syndrome from 1-6 weeks prior to the onset of weakness.

• Viral

  • Infection with influenza, coxsackie, Epstein-Barr virus, or cytomegalovirus can cause upper respiratory infection. Immunoglobulin M (IgM) antibodies to each have been identified in some individuals.
  • In the winter of 2015-2016 a Zika viral infection outbreak was noted by the WHO and CDC. This outbreak was primarily centered in South and Central America and the Caribbean regions.
    • Zika virus disease is spread primarily by a bite from an Aedes species mosquito and typically causes a mild viral syndrome clinical picture.
    • However, in pregnant women Zika infection has been associated with microcephaly and other congenital abnormalities in their subsequently born children.
    • Additionally, in rare cases (approximately 0.03% risk) Zika viral infection can be associated with AIDP.^{[8, 57]}
  • Acute infection with either herpes simplex virus or human immunodeficiency virus (HIV) also has been associated with AIDP in some individuals.
    • Patients with HIV-associated AIDP often have a pleocytosis with up to 200 WBC/µL CSF.
    • Rare cases also have been reported after infection with rubella, measles, varicella-zoster, hepatitis B, Q fever, and Hantavirus.^[9]
    • Wagner at al presented a case of acute motor axonal neuropathy in a patient with previously unrecognized human immunodeficiency virus (HIV) infection. To their knowledge, this is the first case of acute motor axonal neuropathy in HIV outside of a seroconversion reaction.^[10]

   

  

   
• Bacterial

  • Strains of C jejuni that cause enteritis are associated closely with the subsequent development of AMAN.
  • Molecular mimicry between gangliosidelike epitopes of the C jejuni lipopolysaccharide and peripheral nerve gangliosides in nerve is a proposed mechanism.
  • In children, an association exists between AIDP and Mycoplasma pneumoniae infection.

   

  

   
• Other: Rare cases of AIDP in individuals infected with toxoplasma, malaria, or filaria have been reported.
• Vaccination

  • Many cases of AIDP were reported after vaccination for swine influenza (especially in 1976).
  • Several cases have been reported after immunization against rabies, influenza, measles, mumps, or rubella.

   

  

   
• Malignancies and systemic illnesses

  • Case reports document patients with AIDP associated with Hodgkin lymphoma, acute myelogenous lymphoma, Castleman disease, systemic lupus erythematosus, and hypothyroidism.
  • The rarity of these combinations raises doubts on the significance of these associations.

   

  

   
• Pregnancy: Most cases occur during the last trimester or during the first 2 weeks of the postpartum period.
• Bone marrow transplantation
• Surgery: Most patients also had an infection or blood transfusion.
• Other problems to be considered

  • Poliomyelitis: Classic poliomyelitis is very rare. However, coxsackievirus and echovirus can cause a similar, milder paralysis, especially in children.
  • Buckthorn shrub poisoning: This plant is found in the southwestern United States and Central America and bears a fruit that causes paralysis by an unknown mechanism. The CSF is usually normal.
  • Critical illness polyneuropathy: Weakness is more common in the setting of sepsis and/or multiorgan failure.
  • Diphtheria: Weakness may follow the pharyngeal infection by 2-3 weeks, beginning with palatal paralysis and, often, paralysis of accommodation. Limb weakness is not common.
  • Hypophosphatemia: An acute areflexic paralysis may follow hypophosphatemia in the setting of total parenteral nutrition, alcohol abuse, or rapid refeeding after starvation. The weakness rapidly responds to phosphate replacement.
  • Malingering and conversion reaction: Bizarre or nonphysiologic abnormalities may be seen on neurologic examination.
  • The antidepressant drug zimeldine, a serotonin reuptake blocker, was reported to be associated with Guillain-Barré syndrome and the drug has been withdrawn.

   

  

   
• Variants

  • A number of entities are related to acute demyelinating neuropathy. Although they are acute, likely inflammatory, and immune mediated, they are not necessarily demyelinating. The acute panautonomic neuropathy is characterized by widespread and severe sympathetic and parasympathetic failure. Acute motor axonal neuropathy (AMAN) results in motor axonal degeneration, with little or no demyelination or inflammation. Many follow C jejuni infection. Axonal Guillain-Barré syndrome is at the other end of the spectrum, where the illness predominantly involves the axis cylinder of the somatic nervous system, and is fairly common. Hyperacute axonal polyradiculoneuropathy has a hyperacute course with onset to respiratory failure within 48 hours. These patients have a high mortality rate. Recovery when it occurs, is delayed, very prolonged, and characteristically quite incomplete.
  • Critical illness polyneuropathy has an uncertain relationship to the acute inflammatory neuropathies. Sensory Guillain-Barré syndrome, where sensory symptoms occur in isolation, are rare.
  • The Fisher syndrome is an uncommon variant of AIDP (about 5% of the cases) characterized by the triad of ophthalmoplegia, ataxia, and areflexia. Occasionally papillary abnormalities occur, and many cases are associated with some evidence of more widespread motor involvement. Miller-Fisher variant may be associated with a particular serotype of C jejuni.
  • Other unusual variants include the pharyngeal-cervical brachial variant, with deficits limited to these regions alone, and the paraparetic variant, where the weakness is confined to the lower extremities only, as the name implies. Acute sensory neuronopathy is usually associated with autonomic failure. It is likely inflammatory-immune-mediated. The brunt of the attack is borne on the dorsal root ganglia cells.
  • The demonstration in some studies of demyelination in excess of control sera when injected into peripheral nerve, and the demonstration of IgM antibodies that bind to carbohydrate residues of peripheral nerve in 90% of Guillain-Barré syndrome patients at the onset of the disease, support of an antibody as the mechanism of Guillain-Barré syndrome.
  • Over the past decade, great progress has been made in Guillain-Barré syndrome research, and the highlights include (1) the emerging correlations between antiganglioside antibodies and specific clinical phenotypes, notably between anti-GM1/anti-GD1a antibodies and the acute motor axonal variant and anti-GQ1b/anti-GT1a antibodies and the Miller Fisher syndrome; (2) the identification of molecular mimicry between Guillain-Barré syndrome–associated C jejuni oligosaccharides and GM1, GD1a, and GT1a gangliosides as a mechanism for antiganglioside antibody induction; and (3) the development of rodent models of Guillain-Barré syndrome with sensory ataxic or motor phenotypes induced by immunization with GD1b or GM1 gangliosides, respectively.^[11]

   

  

   
• Comparison of clinical features of Guillain-Barré syndrome with CIDP

  • Patients with CIDP have a more slowly progressive weakness and a protracted course either monophasic or relapsing, and relapses are much more common with CIDP. While a history of viral infection is often obtained with Guillain-Barré syndrome, this is rather uncommon in CIDP. Occurrence of respiratory failure is very uncommon with CIDP. Both conditions are associated with areflexia, typical CSF findings of increased protein, abnormal nerve conduction studies (patchy conduction slowing with Guillain-Barré syndrome and diffuse slowing with CIDP). While prednisone therapy on its own has no proven role in Guillain-Barré syndrome, CIDP patients are sensitive to prednisone therapy.
  • Guillain-Barré syndrome and CIDP have been associated with HIV-1 infection. They are most common in infected patients who are otherwise asymptomatic. In certain cases, Guillain-Barré syndrome may occur with seroconversion. The clinical features of Guillain-Barré syndrome and CIDP in HIV-1 infected patients are similar to patients without HIV-1 infection.

   

  

   

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Laboratory Studies

Laboratory tests help to support the diagnosis of acute inflammatory demyelinating polyneuropathy (AIDP) and monitor patients with the syndrome. No associated hematologic or urinary findings are characteristic of the diagnosis. The erythrocyte sedimentation rate is normal. Serum protein electrophoresis does not show an abnormality. Hyponatremia due to inappropriate ADH secretion may occur.^[12]

Cerebrospinal fluid

Increased CSF protein without an increased WBC count (albuminocytologic dissociation) is observed classically in AIDP. However, this finding is not specific to AIDP.

About two-thirds of patients have this CSF finding during the first week of symptoms and 82% have it by 2 weeks after symptom onset.

Although protein values can be elevated by 10-fold or more, no association exists between protein level and clinical severity.

Some patients have oligoclonal banding of the CSF.

Myelin basic protein also is increased in some patients.

More than 90% of patients have fewer than 10 WBC/µL, with a mean of 3 WBC/µL. If more than 50 WBC/µL are present, an alternative diagnosis should be considered, including HIV, Lyme disease, polio, or other infections. Patients with HIV-associated AIDP often have >50 WBC/µL (mean, 23 WBC/µL).

In non-HIV cases, the cells are overwhelmingly lymphocytes, whereas a nonlymphocytic pleocytosis is seen in patients with HIV.

Blood tests

Blood tests have little role in the diagnosis of AIDP but may help to exclude other conditions and to serially monitor patients with AIDP in the hospital (especially those who are critically ill).

Recently, an association has been found between acute axonal motor variants and immunoglobulin G (IgG) directed against ganglioside GM1 and/or GD1a. Furthermore, most patients with the Miller-Fisher variant of AIDP have antibodies directed against ganglioside GQ1b. Some patients with pure sensory variants have antiganglioside GD1b antibodies. These tests are seldom beneficial in classic AIDP, but can help when patients present with variants.

Rabbit ataxic neuropathy and several case reports have suggested a close association of IgG anti-GD1b antibodies with ataxia in Guillain-Barré syndrome. However, about half of the patients with Guillain-Barré syndrome having IgG anti-GD1b antibodies with no reactivities against other gangliosides (GD1b-mono IgG) do not exhibit ataxia. Antibodies specific to ganglioside complexes (GSCs) containing GD1b have been found in sera from some patients with Guillain-Barré syndrome. IgG antibodies highly specific for GD1b may induce ataxia in Guillain-Barré syndrome.^[13]

Although not necessary for diagnosis, measurement of antiviral or antibacterial antibodies may confirm an association.

Measurement of potassium, phosphate, and porphyrin metabolism products may help exclude alternative diagnoses in atypical cases.

Some critically ill patients with AIDP develop the syndrome of inappropriate antidiuretic hormone (SIADH) with associated hyponatremia and reduced serum osmolarity.

Additionally, liver enzymes sometimes are elevated in AIDP.

If intravenous immunoglobulin (IVIg) therapy is anticipated in noncritical cases, immunoglobulin A (IgA) levels should be drawn before treatment.

Urine tests

Urine tests to exclude heavy metal intoxication may be necessary in some patients.

Stool cultures

Stool cultures may confirm C jejuni enteritis. Patients with this condition may have a more aggressive course and a slightly worse prognosis.

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Imaging Studies

Imaging is seldom necessary for diagnosing acute inflammatory demyelinating polyneuropathy, but it may be necessary to exclude alternative diagnoses and to monitor critically ill patients.

MRI of the spine is sometimes necessary to rule out spinal cord and/or nerve root processes that mimic AIDP.

• Nerve root, cauda equina, or cranial nerve enhancement is observed sometimes on T1-weighted, gadolinium-contrasted scans. This can help diagnose some atypical cases.
• Cytomegalovirus radiculitis, meningeal carcinomatosis, lymphomatosis, and sarcoidosis may have similar MRI findings.

Chest radiography in children may reveal a pattern that is consistent with mycoplasmal pneumonia. Additionally, chest and abdominal radiography may be necessary in critically ill patients to evaluate for possible pneumonia and ileus.

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Other Tests

Electrodiagnostic testing is always necessary to confirm the diagnosis of acute inflammatory demyelinating polyneuropathy.

Nerve conduction studies (NCS) can document demyelination, the hallmark of acute inflammatory demyelinating polyradiculoneuropathy. Early on, findings of NCS studies are often normal. However, 90% are abnormal within 3 weeks of symptom onset.

Patients who meet 3 of the 4 NCS criteria listed below have a clear primary demyelinating neuropathy, although patients who meet fewer than 3 criteria still may have AIDP. Severe slowing of conduction velocities may be more consistent with chronic inflammatory demyelinating polyneuropathy (CIDP). Details of electrodiagnostic criteria are provided in Cornblath.^[14]

• Reduced conduction velocity
• Conduction block or abnormal dispersion
• Prolonged distal latencies
• Prolonged F-waves

Matsumoto et al. provide electrophysiological evidence to show that the proximal segment of peripheral nerves is assumed to be involved in both demyelinating and axonal types of Guillain-Barré syndrome (GBS). They performed nerve conduction studies in 9 demyelinating GBS and 7 axonal GBS patients. Cauda equina conduction time (CECT) was obtained by subtracting S1-level latency from L1-level latency. CECT was prolonged in all the patients with demyelinating GBS who had leg symptoms, whereas motor conduction velocity (MCV) at the peripheral nerve trunk was normal in all the patients. In all the patients with axonal GBS having leg symptoms, CECT and MCV were normal and no conduction blocks were detected between the ankle and the neuro-foramina, suggesting that the cauda equina is much more frequently involved than the peripheral nerve trunk in demyelinating GBS. In axonal GBS, usually, CECT is normal and segmental lesions are absent between the ankle and the neuro-foramina. Therefore, the researchers believe that the CECT measurement should be very useful for directly detecting demyelinating lesions in GBS.^[15]

Umapathi et al. (2015), using nerve conduction studies, confirm that the  "sural-sparing pattern" of Guillain-Barré syndrome (GBS) occurs in acute inflammatory demyelinating polyneuropathy (AIDP) as well as other non-demyelinating GBS-subtypes, namely acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN) and Miller Fisher syndrome (MFS).^[16]  

Needle EMG can document the extent of denervation.

Findings of other electrophysiologic tests, such as blink reflexes, phrenic nerve conduction, and somatosensory evoked responses, may be abnormal but do not offer any advantages to typical NCS studies.

Autonomic tests such as sympathetic skin responses and cardiovagal testing may be indicated in patients with autonomic failure.

Pulmonary function tests, useful in determining the timing of intensive care unit (ICU) transfers and elective intubation, should be performed in all patients. Transfer to an ICU generally is indicated when forced vital capacity (FVC) is less than 20 mL/kg. Intubation is usually warranted when FVC drops to 15 mL/kg or negative inspiratory pressure drops to less than -25 cm H₂ O.

Electrocardiography (ECG) and cardiac monitoring can be helpful when arrhythmias occur. Other possible abnormalities include atrioventricular block, QRS widening, and T-wave abnormalities.

Jin et al measured the CSF tau protein levels in 26 patients with Guillain-Barré syndrome. The levels of the poor outcome group (Hughes grade at 6 months was between II and VI, n = 6) were higher than those of the good outcome group (0 or I, n = 20) (p < 0.0005). The higher levels of CSF tau may reflect axonal degeneration and could predict a poor clinical outcome in Guillain-Barré syndrome.^[17]

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Procedures

Lumbar puncture is performed to obtain CSF for analysis (see Lab Studies).

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Histologic Findings

Nerve biopsy is seldom required to diagnose acute inflammatory demyelinating polyradiculoneuropathy. However, in patients with prolonged clinical courses, histologic examination can help to differentiate CIDP from AIDP. Nerve biopsies in AIDP show an inflammatory infiltrate during the first few days.

Later on, macrophages are seen, sometimes with myelin stripping. Axons are usually spared. Under electron microscopy, macrophages (which are stripping myelin) are seen beneath the basement membrane and are usually advancing along the minor dense line.

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Medical Care

Advances in supportive medical care have resulted in improved survival rates in acute inflammatory demyelinating polyneuropathy (AIDP).

Mechanical ventilatory assistance is required in about one third of patients with AIDP and lasts for an average of 49 days. Intubation should be performed when FVC drops to less than 15 mL/kg or negative inspiratory pressure is worse than -25 cm H₂ O. Tracheostomy is usually recommended if mechanical ventilation will be required for more than 2-3 weeks. Bedridden patients need prophylaxis against thromboembolism. Subcutaneous heparin is the most common agent. Some may also need GI prophylaxis with an H2-blocker (or similar agent).

Enteric nutrition is necessary for patients on mechanical ventilation. Nasogastric tubes or Dubhoff tubes can be used initially. Those requiring more than 2 or 3 weeks or enteric nutrition may require gastrostomy or jejunostomy tube feedings.

Cardiac monitoring is necessary. Chronic sinus tachycardia often responds to beta-blockers or calcium channel blockers. Bradycardia requires atropine treatment, if symptomatic. Heart block may require temporary pacing. Hypertension responds well to beta-blockers. These treatments should be administered cautiously under the direction of a cardiologist or critical care specialist, since one of the main causes of death is iatrogenic hypotension, especially in patients with autonomic failure.

Constipation is common in intubated patients with AIDP, and a bowel regimen is usually necessary. Some patients may also require enemas. Ileus is rare. If it occurs, bowel rest is usually necessary and parenteral nutrition can be used during that time.

Skilled nursing care of intubated patients is necessary to avoid skin breakdown. Special mattresses are available in most intensive care or step-down units. Communication difficulties can lead to frustration and exacerbate depression. Involvement of speech therapy, physical therapy, and occupational therapy is highly recommended. Many patients may require a rehabilitation unit after being weaned off a ventilator.

Conventional immunosuppressant treatments with corticosteroids have failed to show benefit. But immunomodulation with IVIg and plasmapheresis has led to faster recovery, relatively mild disability, and shorter hospital stays. IV steroid therapy alone is not indicated for the treatment of AIDP. Treatment is less likely to be effective if initiated more than 2 weeks after the onset of symptoms. Some patients with mild weakness, especially those presenting during the plateau, may not require immunomodulatory therapy. Plasmapheresis had shown to cut the respirator time and time to independent ambulation, by about half when treatment was given during the first week of the disease.

In their study of immunotherapy in Guillain-Barr é syndrome, Alshekhlee et al. found an increasing use of IVIg over plasma exchange (PE). Older population and those with pulmonary or sepsis complications were likely treated with PE. The mortality rate was higher in patients treated with PE.^[18]

The pathogenesis of GBS is not fully understood, and the mechanism of how intravenous immunoglobulin (IVIG) cures GBS remains ambiguous. Hou et al. investigated lymphocyte subsets in patients with acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) before and after treatment with IVIG to explore the possible mechanism of IVIG action. They concluded that the changes in T- and B-lymphocyte subsets, especially in CD4+T-lymphocyte subsets, might play an important role in the pathogenesis of AIDP, and in the mechanism of IVIG action against AIDP.^[19]

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Surgical Care

Tracheostomy is necessary in many intubated patients. Those requiring long-term enteral nutrition typically require a gastrostomy or jejunostomy.

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Consultations

See the list below:

• Neurology: For patients on general medicine or other services, neurological consultation is indicated to manage diagnostic studies and to help determine appropriate treatment.
• Critical care: About one third of patients require mechanical ventilation. Any intubated patient or patient who is transferred to an ICU for monitoring should be monitored by a critical care or pulmonary specialist.
• Surgery: Some patients may require tracheostomy or a feeding tube for parenteral nutrition.
• Cardiology: Patients with arrhythmias in addition to sinus tachycardia or major cardiac rhythm abnormalities should be evaluated by a cardiologist.
• Physical medicine and rehabilitation

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Activity

Keep patients ambulatory if they are able to walk without assistance. Most patients who are admitted to the hospital require bedrest.

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Medication Summary

Immunomodulatory therapy with either IVIg or plasmapheresis has been demonstrated to result in more rapid recovery of AIDP than other treatments or no treatment. Recent large studies have demonstrated that the 2 treatments are equal in efficacy. Bedridden and critically ill patients also require treatment to prevent complications.

The mechanism of action of plasma exchange is not known. Suggested mechanisms include the removal of antibody, complement components, immune complexes, lymphokines, and acute-phase reactants. The generally recommended regimen includes every other day plasma exchange, totaling 6 exchanges in 2 weeks, with 3-3.5 L exchanged per treatment. If venous access is not of sufficient quality to ensure rapid blood withdrawal, a central line should be a consideration (in about 20% of cases).

Plasmapheresis (PE) is more frequently associated with severe adverse effects requiring cessation of therapy, including a bleeding diathesis. In addition, PE requires special, appropriate equipment and trained personnel. Also, younger children may be at risk for bleeding after insertion of wide catheters. Transient hypotension, which might occur, is corrected by adjusting the inflow-to-outflow ratio. Other common side effects include paresthesias, and rarely hypersensitivity reactions and hypocalcemia.

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Immune globulin IV (IVIg)

• Dosing, Interactions, etc.

Clinical Context:  IVIg is prepared from serum pooled from many donors by fractionation and purification. Most manufacturers include a detergent step to help prevent spread of viruses. Mechanism of action is poorly understood. However, it is believed to act by down-regulating antibody and cytokine production and by neutralizing antibodies specific for myelin. Also appears to down-regulate pro-inflammatory cytokines, such as IL-1 and gamma-IFN. Other proposed mechanisms are Fc receptor blockade and interference with complement cascade (ie, interfering with opsonization).

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Plasmapheresis or plasma exchange

Clinical Context:  This treatment entails removing blood from body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. Can be performed using either 2 large-bore peripheral IV sites or multiple lumen central line.

May not be effective if started more than 2 wk after onset of symptoms.

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Class Summary

AIDP is believed to be caused by immune dysregulation resulting from an attack against myelin. Therapy directed at the immune system can result in more rapid recovery. IVIG is especially proven highly effective in children.

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Heparin

• Dosing, Interactions, etc.

Clinical Context:  Given subcutaneously, interacts with antithrombin III to decrease clot proliferation. This can result in decreased incidence of deep venous thrombosis.

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Class Summary

Bedridden patients are at risk for deep venous thrombosis. This risk can be reduced by mild anticoagulation.

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Further Outpatient Care

Generally, all patients in whom AIDP is suspected should be admitted for further monitoring and treatment.

Patients who present with mild neurologic impairment after already reaching a plateau can be treated as outpatients with close supervision.

Upon discharge, patients require several follow-up visits to ensure that relapses do not occur and to help coordinate home-health services if necessary. Physical and occupational therapy, either in a long-term rehabilitation unit or at home, help many patients return more rapidly to their baseline level of activity.

Relapses occur (10-20%) following completion of plasma exchange, and these relapses frequently respond to a second course of treatment. Similarly, relapses that follow IVIG therapy also respond to a second course.

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Further Inpatient Care

Based on the severity of symptoms, patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) may require further inpatient services.

• Patients should have cardiac monitoring to confirm and treat arrhythmias.
• Pulmonary function tests such as FVC and negative inspiratory pressure should be performed 3-4 times a day until a patient has reached a plateau for several days.
• Transfer to an ICU is recommended for patients with worsening respiratory effort (ie, FVC < 20 mL/kg) or cardiac arrhythmias.
• Physical therapy should be initiated early to help increase patient activity and mobility. Patients who do not recover quickly benefit by transfer to an inpatient rehabilitation center before returning home.

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Transfer

Transfer patients to the ICU when respiratory failure is impending or when cardiac arrhythmias are occurring.

Transfer patients to regional or tertiary hospitals if a community hospital does not have an ICU or is unable to provide IVIg or plasmapheresis therapy.

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Complications

Critically ill patients are susceptible to the same complications as other intubated patients, including pneumonia, sepsis, skin decubiti, deep venous thrombosis, and urinary tract infections. Patients with AIDP have some unique complications that may cause significant morbidity, the most common being pain, labile blood pressure, and increased sensitivity to cardiac medications.

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Prognosis

About 75% of patients have an excellent recovery and regain their premorbid condition. Some of these patients experience easy fatigability for many years.

Almost all of the remaining patients have mild or moderately severe impairment but remain independent in most functions. Residual complaints include dysesthesias, foot drop, and intrinsic hand muscle weakness.

Severe disability occurs in fewer than 5% of patients, who do not recover full independence. Patients with residual deficits are usually those who required mechanical intubation. Improvement is usually complete by 6 months. In more serious cases, recovery may continue for 18-24 months.

Death occurs in only 2-6% of patients and is usually due to cardiac arrest, ARDS, pulmonary embolism, severe bronchospasm, pneumonia, or sepsis.

About 10% of patients have a relapse 1-6 weeks after completing immunomodulatory therapy. These patients can be treated with a second course of immunomodulation.

Fewer than 1% of patients have AIDP 1 or more years after onset of symptoms. In some cases, the recurrence follows immunization. This recurrence differs from CIDP.

Sporadic cases of recurrent Guillain-Barré syndrome^[20] and rare cases of recurrent Guillain-Barré syndrome after a long asymptomatic period^[21] have been reported. Some authors consider recurrent Guillain-Barré syndrome a variant of CIDP, while others maintain that they are 2 different entities. Martic et al describe a patient who developed Guillain-Barré syndrome as a child and experienced a full relapse after 19 years with another innocuous episode 10 years later.^[22]

Several prognostic factors have been identified, including the following:

• In general, younger patients have a better prognosis than older patients. Those patients with more severe weakness and those who are intubated have a worse prognosis than those with milder weakness.
• Diarrhea as an antecedent association often is associated with C jejuni infection. These patients may have a more prolonged recovery.
• Early improvement in strength during treatment is associated with a more rapid recovery. Low compound muscle action potential (CMAP) amplitudes (< 20% of normal) are considered a bad prognostic indicator.

In spite of therapy with plasma exchange or IVIG, the decrease in mortality has often been attributed to improved aggressive supportive treatment than to any drug treatment. This has included close monitoring with the avoidance of hypoxia, pain, and arrhythmogenic stimuli.

In the presence of dysautonomia, hypoxia can trigger cardiac arrhythmias. Tracheal suction can also at times result in cardiac arrhythmias. Ideally, these patients should be given extra oxygen before tracheal toilet.

Subcutaneous heparin to avoid venous thromboembolism, treatment of pain with analgesics including narcotics, treatment of hypotension and hypertension, as the case be and treatment of severe bradyarrhythmia all go a long way in decreasing mortality. Carbamazepine and gabapentin may help.

Persistent fatigue following Guillain-Barré syndrome is common and may be helped by a graded exercise program. C jejuni is often treated with a course of erythromycin.

Hyponatremia is due to inappropriate antidiuretic hormone secretion (SIADH) is best managed by fluid restriction coupled by the avoidance of hyponatremic fluids. Need for immunization should be reviewed on an individual basis.

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Patient Education

Guillain-Barré Syndrome Foundation International

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