Chronic Inflammatory Demyelinating Polyneuropathy Case File

Chronic Inflammatory Demyelinating Polyneuropathy Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 38

A 64-year-man is referred by his primary care physician to a neurologist for a 3-year history of progressive weakness in his lower extremities resulting in frequent falls, difficulty standing from a chair, and painful burning in his feet and finger tips. The patient has a past medical history of high blood pressure. His physical examination is significant for weakness in his lower extremities, specifically of the hip flexors and ankle/foot muscles. He also has mild weakness of his finger extensors. The sensory examination is significant for loss of sensation in his extremities that is worse in the toes and fingers and extends above the knee and the wrist. When he stands with his eyes closed, he becomes very unstable (Rhomberg sign). The deep tendon reflexes are absent in the upper and lower extremities. The rest of the neurologic examination is normal. His extensive laboratory studies are normal, including a normal blood glucose and a normal glycosylated hemoglobin level. Magnetic resonance imaging (MRI) of his brain is normal, and MRI of his spine shows minimal arthritis, but no cord or nerve compression. Electrodiagnostic study of his muscle (electromyography [EMG]) and nerve (nerve conduction study [NCS]) confirms a sensory and motor polyneuropathy involving both his lower extremities and upper extremities.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 38:

Chronic Inflammatory Demyelinating Polyneuropathy                           

Summary: This 64-year-old man with a medical history of hypertension has a slowly progressive condition that causes weakness and sensory loss of his extremities. His examination reveals absent reflexes, proximal (hips) and distal (fingers, ankle/feet) weakness, a stocking-and-glove distribution of sensory loss in his upper and lower extremities, and a positive Rhomberg’s sign. The diabetic screen is negative. His studies confirm that his symptoms are caused by a neuropathy involving both of his arms and legs. Thus, this patient has a symmetric, bilateral sensory and motor polyneuropathy.

• Most likely diagnosis: Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Next diagnostic step: Analysis of the cerebrospinal fluid (CSF)
• Next step in therapy: Immunosuppressive therapy such as corticosteroids or intravenous immunoglobulins

ANALYSIS

Objectives

1. Know the diagnostic approach to polyneuropathy, including laboratory and pathologic studies and electrodiagnostic tests.
2. Be familiar with the common etiologies of chronic polyneuropathy.
3. Be familiar with the management of chronic demyelinating polyneuropathy.

Considerations

This is a 64-year-old man with progressive weakness and sensory loss. This patient likely has a chronic polyneuropathy. The term polyneuropathy describes nerve dysfunction (neuropathy) involving multiple nerves (>3-4) of the legs and arms. He presents with a slowly progressive symmetrical weakness and sensory abnormalities of the hands and legs. This patient’s examination is consistent with a peripheral nervous system process, as reflected by weakness that is flaccid or associated with decreased or absent reflexes. The sensory deficits point toward peripheral nerve involvement, rather than that of motor neuron cells, nerve-muscle junction, or solely muscle, since disorders of these structures result in pure motor involvement. Other conditions that can cause a peripheral neuropathy include toxins such as lead, arsenic, thallium, chemotherapy drugs, and certain antiretroviral therapy; metabolic conditions, classically diabetes mellitus, with an estimated 50% of diabetics having some form of neuropathy, although many are asymptomatic.

Chronic polyneuropathies without an underlying etiology are considered primary or idiopathic, although these can be associated with a number of conditions, such as malignancy and human immunodeficiency virus (HIV). Chronic acquired inflammatory demyelinating polyneuropathy is a neurologic disorder characterized by progressive weakness and impaired sensory function in the legs and arms caused by damage to the myelin sheath (the fatty covering that wraps around and protects nerve fibers) and is one of the treatable peripheral neuropathies. In this case, the patient’s presentation is consistent with CIDP. EMG and NCS can help confirm the diagnosis.

APPROACH TO:

Chronic Inflammatory Demyelinating Polyneuropathy                                  

DEFINITIONS

MYELIN: An electrically insulating phospholipid layer that surrounds the axons of many neurons. It is an outgrowth of Schwann cells, a glial cell that supplies the myelin for peripheral neurons, whereas oligodendrocytes supply it to those of the central nervous system.

AXON: Nerve fiber projection of a motor or sensory neuron that conducts electrical impulses away from the neuron cell body or soma.

CLINICAL APPROACH

Clinical Features and Epidemiology

The prevalence of CIDP is approximately 0.9 to 8.9 per 100,000 population. The estimated annual incidence is 0.15 per 100,000 population. However, the true incidence of CIDP is likely underestimated because of stringent diagnostic criteria and clinical and pathologic variability of the disorder.

In neuromuscular disease referral centers, however, CIDP represents approximately 20% of undiagnosed neuropathies and accounts for approximately 10% of all patients referred.

CIDP can occur at any age, including childhood in 10% of cases. However, the mean age of onset is approximately 47.6 (median, 53.5 years). Males are more affected than females by 2:1.

CIDP is an acquired peripheral neuropathy with an extremely variable clinical presentation and course. At symptom onset, patients usually present with a generalized pattern of numbness and weakness in upper and lower extremities and spontaneous pain that develops gradually over several weeks. Some patients present with a progressive sensory ataxia; in other patients motor deficits predominate. Proximal and distal limbs are commonly affected in a roughly symmetrical pattern. Yet occasionally, the demyelinating neuropathy is focal, leading to focal or multifocal motor dysfunction. Motor deficits occur in 83% to 94%, sensory deficit in 72% to 89%, loss of tendon reflexes in 86% to 94%, and facial palsy in 4% to 15% of patients. Symptoms typically develop gradually in 84% but can occur more acutely in 16% of patients, who reach maximal disability within 4 weeks. Often, these rapidly progressing patients are initially diagnosed with Guillain-Barré syndrome or acute inflammatory demyelinating polyneuropathy (see Case 39), but the diagnosis is usually changed to CIDP or CIDP-variant when symptoms progress beyond 8 weeks. A variable proportion of cases follow a relapsing course, with many of these patients, often younger, developing a secondarily progressive course, similar to that observed in multiple sclerosis patients.

Etiology and Pathogenesis

CIDP is immunologic in origin. It is characterized by long-standing multifocal demyelination that predominantly affects spinal roots, major plexuses, and proximal nerve trunks. Although no genetic susceptibility genes or factors have been identified, there are certain predisposing factors reportedly linked to the disease, including a history of vaccination or infection within 6 weeks of symptom onset, pregnancy or postpartum period, and surgery.

Pathologically, lesions consist of patchy regions of demyelination and edema with variable inflammatory infiltrates of macrophages and T cells, which are diagnostic of CIDP. Both cell-mediated mechanisms and antibody-mediated responses to major glycolipid or myelin protein antigens have been implicated. CD4+ and CD8 T cells can be demonstrated in nerve biopsy specimens, but macrophages constitute the major cell component of the inflammatory infiltrate.

Diagnosis

CIDP should be considered in patients with a progressive symmetrical or asymmetrical polyneuropathy that is relapsing and remitting or progresses for more than 2 months. Sensory symptoms, proximal weakness, areflexia without wasting, or preferential loss of vibration or joint position sense are especially suggestive. The major diagnostic tests for CIDP are electrophysiologic studies (EMG/NCV), CSF examination, and nerve biopsy.

Increased CSF protein content in association with less than 10 cells/mm3, cytoalbuminologic dissociation, is also a feature of CIDP. EMG is useful to differentiate other causes of muscle weakness, such as myopathy, axonal neuropathies, and disorders of nerve muscle transmission. NCS will often show a reduction or block in nerve conduction velocities, which is consistent with demyelination. These studies, however, may be nonspecific.

In many instances, the electrophysiologic tests for the diagnosis of a demyelinating neuropathy will provide mixed results because of the accompanying secondary nerve axon degeneration that can occur with demyelination. A nerve biopsy should be considered in patients when a clinical suspicion of an inflammatory demyelinating neuropathy remains even if they fail to meet the proposed criteria for CIDP. The nerve biopsy may show only nonspecific lesions when the demyelination and inflammation are proximal to the site of the biopsy (sampling error). MRI can be supportive in difficult diagnostic cases, can show hypertrophy and contrast enhancement of nerve roots and nerve plexi, and is helpful in ruling out infiltrative processes or spinal disease.

Laboratory studies should also be performed to rule out other causes or associated conditions including a fasting glucose or glucose tolerance test to rule out diabetes or prediabetic state, thyroid dysfunction, vitamin deficiencies (B12, folate), rheumatologic disorders, leukemia or paraproteinemias, and infection (HIV).

Although this patient does not have diabetes mellitus, many diabetics will develop a chronic progressive symmetric polyneuropathy. However, these patients usually develop a predominantly motor and ataxic polyneuropathy, and the NCSs usually show more severe axonal loss.

Treatment and Management

Corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressive drugs are the main treatments used in this condition. Nearly all patients with CIDP will show an initial response to immunomodulatory therapy but often require long-term therapy to maintain clinical response. Historically, evaluation of response to treatment is hampered by the lack of objective measures, poor correlation with electrophysiologic data, variable incidence of axonal degeneration, which is unlikely to respond quickly to treatments, and variability of the disease course. A 5-year retrospective review of patients treated for CIDP showed subacute onset, symmetrical symptoms, and good initial response to corticosteroids as positive prognostic factors. However, a landmark study (the ICE trial 2008) showed that intravenous immunoglobulin (IVIg) therapy was effective for initial treatment of CIDP compared to placebo as well as for maintenance therapy with associated improved quality of life, motor scores, sensory perception, and electrophysiologic measures of nerve function in treated patients.

Patients with very mild symptoms that do not or only slightly interfere with activities of daily living may be monitored without treatment. Urgent treatment with corticosteroids or IVIg should be considered for patients with moderate or severe disability—for example, when hospitalization is required or ambulation is severely impaired. Contraindications to corticosteroids will influence the choice toward IVIg and vice versa. For pure motor CIDP, IVIg treatment should be the first choice. If corticosteroids are used, patients should be monitored closely for adverse events related to steroid therapy. Occupational and physical therapy are often helpful in maintaining muscle conditioning and safe mobility.

CASE CORRELATION

• See also Case 39 (Guillain-Barré Syndrome) and Case 40 (Dermatomyositis)

COMPREHENSION QUESTIONS

38.1 Which of the following test results is most supportive of the diagnosis of definite CIDP?

A. Cytoalbuminologic dissociation

B. Decreased nerve conduction velocities

C. Hypertrophy of nerve roots

D. Segmental demyelination of nerve axons

38.2 Which patient will often present with relapsing CIDP?

A. Older patients

B. Diabetic patients

C. HIV-infected patients

D. Younger patients

38.3 Which of the following therapies is effective in treating CIDP?

A. Corticosteroids, physical therapy, radiation therapy

B. Corticosteroids, physical therapy, immunoglobulin

C. Corticosteroids, plasma exchange, surgery

D. Corticosteroids, immunoglobulin, nerve growth factor

ANSWERS

38.1 D. Segmental demyelination of nerve axons is diagnostic of CIDP.

38.2 D. Younger patients are more prone to a relapsing course.

38.3 B. Corticosteroids, physical therapy, and immunoglobulins are effective therapy in CIDP.

    CLINICAL PEARLS    

▶ CIDP is the second most frequently diagnosed neuropathy in patients age 70 to 79. ▶ Clinical diversity in presentation and course is the most remarkable feature of CIDP. ▶ Cranial nerves can be involved, particularly cranial nerve VII resulting in diplopia. ▶ Papilledema with pseudotumor cerebri syndrome is rarely observed in patients with CIDP and is caused by high CSF protein levels (usually >1000 mg/mL).

REFERENCES

European Federation of Neurological Societies; Peripheral Nerve Society. Guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006;13(8):809-818. 

Hughes RA, Donofrio P, Bril V, et al; ICE Study Group. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol. 2008;7(2):136-144. 

Kuwabara S, Misawa S, Mori M, Tamura N, Kubota M, Hattori T. Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow-up of 38 cases. J Neurol Neurosurg Psych. 2006;77:66-70. 

Rajabally YA, Simpson BS, Beri S, Bankart J, Gosalakkal JA. Epidemiologic variability of chronic inflammatory demyelinating polyneuropathy with different diagnostic criteria: study of a UK population. Muscle Nerve. 2009;39(4):432-438. 

Said G. Chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord. 2006;16(5):293-303.

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