Deb Ellis, RN, MSN, NP-C

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.

2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.

3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.

4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.

5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.

6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.

7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.

8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.

9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.

10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.

11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.

12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.

13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.

14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.

15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.

16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.

17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.

18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.

19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.

20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neuro­crit Care. 2006;5(3)235-242.

21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.

22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.

23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.

24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.

25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]

26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.

27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.

28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.

29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.

30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.

31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.

32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.

33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.

34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.

35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.

36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.

37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.

38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.

39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.

40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.

41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.

42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.

43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.

44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.

45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.

46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.

47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.

48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.

49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.

2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.

3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.

4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.

5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.

6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.

7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.

8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.

9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.

10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.

11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.

12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.

13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.

14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.

15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.

16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.

17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.

18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.

19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.

20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neuro­crit Care. 2006;5(3)235-242.

21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.

22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.

23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.

24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.

25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]

26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.

27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.

28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.

29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.

30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.

31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.

32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.

33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.

34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.

35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.

36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.

37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.

38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.

39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.

40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.

41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.

42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.

43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.

44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.

45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.

46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.

47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.

48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.

49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

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