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. An allergic etiology was suggested by Krucke in 1955 after he observed lymphocytic infiltrates within biopsy specimens. An autoimmune process was supported by Waksman and Adams when they created the experimental allergic neuritis model by injecting peripheral nerve tissue into rodents.

Pathophysiology: AIDP 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 GBS, axonal degeneration often predominates. Severe GBS 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.

Frequency:

• In the US: AIDP 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.

• Internationally: Frequency is not well documented. In rural China, the AMAN variant occurs in clusters during the late summer. Similar outbreaks have been reported in Mexico, Spain, and Jordan.

Mortality/Morbidity: In 3 recent 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: AIDP 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.

Treatment
Medical Care: Advances in supportive medical care have resulted in improved survival rates in 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 H₂O. 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.

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

Consultations:

• 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

Diet: No special diet is required.

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

Medication
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.

Drug Category: Immunomodulatory agents -- 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.

Drug Name	IV Immunoglobulin (IVIg) or gamma globulin (many manufacturers) -- 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).
Adult Dose	0.4 g/kg/d for 5 d has been used most often Alternative regimen is 1-2 g/kg/d for 2 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; IgA immunodeficiency (if present, low-IgA preparations available) Severe congestive heart disease is relative contraindication
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include headache and itching—pretreatment with acetaminophen and diphenhydramine help prevent these effects Patients with prior cardiac history are at risk for pulmonary edema—if it occurs, furosemide is drug of first choice Rarer adverse effects include aseptic meningitis, stroke, skin rashes, renal tubular necrosis; hepatitis C has been transmitted by IVIg in past, but current preparations include detergent step Can artificially decrease serum sodium and elevate ESR

Drug Name	Plasmapheresis or plasma exchange -- 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.
Adult Dose	Typical protocol: 200-250 mL/kg for each of 4 or 5 exchanges during an 8- to 10-d period
Pediatric Dose	Administer as in adults
Contraindications	Recent myocardial infarction; coronary artery disease; arrhythmias; severe renal failure; severe hepatic failure; bleeding disorder
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Back-to-back plasmapheresis sessions may remove clotting factors and can alter coagulation test results Common adverse effects include headaches Rare cases of myocardial infarction and stroke have been reported

Drug Category: Anticoagulant agents -- Bedridden patients are at risk for deep venous thrombosis. This risk can be reduced by mild anticoagulation.

Drug Name	Heparin -- Given subcutaneously, interacts with antithrombin III to decrease clot proliferation. This can result in decreased incidence of deep venous thrombosis.
Adult Dose	5000 U SC tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Some preparations contain benzyl alcohol as preservative and, when used in large amounts, may be associated with fetal toxicity (ie, gasping syndrome); preservative-free heparin recommended in neonates Use with caution in patients with shock or severe hypotension