Acute Inflammatory Demyelinating Polyradiculoneuropathy

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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]

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.

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%.

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.

History

See the list below:

Physical

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

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.

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.[11]

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.[12]

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.

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.

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.

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.[13]

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.[14]

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).[15]  

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.[16]

Procedures

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

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.

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.[17]

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.[18]

Surgical Care

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

Consultations

See the list below:

Activity

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

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.

Immune globulin IV (IVIg)

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).

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.

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.

Heparin

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

Class Summary

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

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.

Further Inpatient Care

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

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.

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.

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[19] and rare cases of recurrent Guillain-Barré syndrome after a long asymptomatic period[20] 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.[21]

Several prognostic factors have been identified, including the following:

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.

Patient Education

Guillain-Barré Syndrome Foundation International

Author

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Richard A Sater, MD, PhD, MD, PhD,

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE, Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Disclosure: Nothing to disclose.

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