Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Pathogenesis and Pathophysiology. CIDP is an apparent immune-mediated disorder of the PNS. The term CIDP was coined to emphasize that the disorder is a chronic process that results in demyelination as well as an inflammatory cell response in peripheral nerves and spinal nerve roots; typically, there is a mononuclear cell infiltration involving the endoneurium and epineurium of peripheral nerve fibers. y The predominant pathological feature is SD, although usually there is some degree of axon loss as well (iF|gs..ii,.4,9.-.3 and 49-4. ). These pathological changes have been found to involve roots, plexuses, proximal nerve trunks, and occasionally, cranial nerves and sympathetic trunks, as well as some autonomic nerves.y The predilection for CIDP to involve roots and proximal nerve trunks is responsible for the prominent proximal weakness that may be encountered in this disorder and helps distinguish it from most other generalized polyneuropathies. The predominant involvement of myelin in CIDP results in a characteristic pattern of findings on EDX testing, including

Figure 49-3 Electron microscopy of sural nerve in CIDP. A normal myelinated fib(left) adjacent to a myelinated fiber that has thin and partially absent mye(right).

Figure 49-4 Teased nerve fiber preparation showing segmental demyelination in a sural nerve in CIDP.

slowed nerve CV and conduction block; the latter process correlates with the clinical deficits. Also, the distinctive distribution of NCS abnormalities that may occur with acquired SD polyradiculopathies (already described) is often seen. y

The evidence that CIDP is immune mediated is compelling although still somewhat inconclusive. In many respects, it is similar to the evidence advanced for AIDP being an immune-mediated disorder. The onset or relapses of CIDP on occasion seem to be triggered by a preceding event, such as an infection or vaccination that could initiate an immune-mediated response. In addition, most patients with CIDP respond to corticosteroids and other immunosuppressants, plasma exchange, and IVIg, therapies designed to treat immune-mediated disorders. Furthermore, CIDP shares many clinical and pathological features with experimental models of immune-mediated peripheral neuropathy, particularly EAN. This has led to speculation that the pathogenesis of CIDP is similar to that of AIDP and EAN. Lastly, the presence of immune-effector cells and the deposition of antibody and complement on myelinated fibers is impressive but indirect evidence of an immunemediated process in which both cellular and humoral immune systems are operative. y

A disorder clinically similar to CIDP but with pathological and EDX features, indicating an axon loss process, has been reported. y Whether this actually represents a so-called axonal form of CIDP similar to the axonal form of GBS remains to be established.

Epidemiology and Risk Factors. The age of onset of CIDP has been reported to range from 1 year through the eighth decade or later, with a mean in the fourth decade. Both sexes are affected, although there is a slight male predominance. With the mean age of onset being in the fourth decade, women of childbearing age may develop CIDP. Furthermore, there is evidence that the disorder may relapse or worsen during pregnancy and in the postpartum period. y Patients with certain histocompatibility antigens have an increased risk of developing CIDP. In

particular, there is an increased incidence of histocompatibility locus antigens AW30, AW31, A1, B8, and DR w3. Furthermore, CIDP, GBS, and multiple sclerosis have all been associated with the presence of the M3 allele of the alpha-1 antitrypsin system located on chromosome 14. y

Clinical Features and Associated Disorders. By definition, CIDP is a chronic disorder that typically evolves slowly, almost always requiring a period of 8 weeks or longer for symptoms to reach their peak, and they typically do so over many months. CIDP can follow either a slowly progressive monophasic course, which occurs in approximately two-thirds of patients, or a cyclical relapsing course seen in the remainder. y , y

The symptoms of CIDP can be variable, but usually weakness tends to predominate over sensory symptoms.y , y The distribution of weakness often conforms to a typical peripheral neuropathy pattern of symmetrical involvement, with the lower extremities being affected more than the upper extremities and distal muscles being affected more than proximal muscles. However, in many patients, the weakness is asymmetrical, and in others, it is more prominent proximally. The degree of weakness varies markedly from patient to patient. In the majority of patients, it is mild to moderate in degree, but rarely, the weakness can be severe and generalized, sometimes associated with respiratory failure necessitating ventilatory support. Muscle cramping and fasciculations are infrequent symptoms. [5 , y , y

Sensory symptoms are usually confined to mild paresthesia or modest sensory loss. However, in those patients with chronic progressive courses, sensory symptoms may become more prominent. In addition to numbness and paresthesia, pain sometimes is reported, although this occurs in less than 20 percent of patients. Very infrequently, CIDP may present with predominate sensory symptoms, including numbness, paresthesia, and sensory ataxia. In a subset of these patients, this PNS disorder appears essentially confined to sensory fibers, prompting speculation that the apparent immune-mediated response is directed at a unique antigen in the myelin of sensory fibers. However, in most instances in which the disorder begins as a sensory neuropathy, it later evolves to a more typical pattern of sensory and motor involvement. On occasion, the cranial nerves may be affected, causing symptoms of diplopia, facial weakness or numbness, dysarthria, and dysphagia. Autonomic symptoms are uncommon, although incontinence and erectile impotence have been reported. y , y , y

The physical signs noted in CIDP reflect the clinical symptoms. Distal symmetrical weakness, with the lower extremities more severely affected than the upper extremities, is the rule. However, asymmetrical involvement and more prominent proximal involvement can occur, and they serve as important clinical clues to the diagnosis of CIDP. Generalized hyporeflexia or areflexia is characteristic. Sensory loss often conforms to a distal to proximal gradient, in the so-called stocking-glove pattern, with all modalities affected to a nearly equal extent. Occasionally, sensory ataxia may be observed. Cranial nerve findings may include signs of facial, bulbar, and neck weakness. Papilledema is an unusual clinical feature, and its precise pathophysiology is unclear. It has been attributed to altered resorption of CSF over the arachnoid villi due to elevations of CSF protein or to increased intracranial pressure. y Rather rare clinical features include pupil abnormalities consistent with parasympathetically denervated pupil, Horner's syndrome, and postural or cerebellar-type tremors. y Occasionally, hypertrophied nerves may be palpated in patients with very chronic CIDP. Rarely, the spinal nerve roots may be hypertrophied to such an extent that they act as masses, compressing the spinal cord and may produce a syndrome of spinal cord compression. y

Some patients with CIDP have abnormalities on MRI scans of the head that are considered to be consistent with multiple sclerosis. y Whether these isolated patients represent the coincidental occurrence of two disorders or whether an immune-mediated disorder of both central and peripheral myelin is operative remains unclear.

There is no conclusive evidence that CIDP patients have a higher incidence of other medical conditions, including autoimmune disorders. However, associated disorders, including systemic lupus erythematosus, Hashimoto's thyroiditis, thyrotoxicosis, chronic active hepatitis, inflammatory bowel disease, urticaria, eczema, and psoriasis do occur in some CIDP patients.y A CIDP-like disorder may occur in the setting of monoclonal gammopathies of uncertain significance (MGUS), as well as with multiple myeloma, osteosclerotic myeloma and other lymphoproliferative disorders. These disorders are discussed as distinct entities in the following sections.

Differential Diagnosis. On purely clinical grounds, CIDP may be confused with a wide variety of chronic sensorimotor polyneuropathies, including those related to diabetes, uremia, hypothyroidism, acromegaly, toxins, and alcoholic-nutritional mechanisms. Although CIDP may produce distinguishing clinical features, such as predominant motor symptoms and signs, asymmetrical involvement, proximal motor involvement, and cranial nerve symptoms and signs, the paramount factor in separating CIDP and related disorders from the rather large group of nonspecific, chronic axon loss sensorimotor polyneuropathies is the presence of acquired SD features on EDX testing. Thus, EDX evaluation is the key step in identifying the acquired SD polyneuropathies, including CIDP. The differential diagnosis of this category includes not only CIDP but the CIDP-like disorders that may be associated with multiple myeloma, osteosclerotic myeloma (including the POEMS syndrome, an acronym which stands for polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), MGUS, and Waldenstrom's macroglobulinemia. These disorders may be distinguished from CIDP by the presence of an M-protein in the serum or urine, the presence of lytic or sclerotic lesions on skeletal bone survey, or both. A disorder essentially identical to CIDP can result from HIV infection. Consequently, testing for HIV is indicated in patients at risk. CIDP may be a presenting feature of HIV infection, preceding seroconversion for up to 6 months. For this reason, repeating HIV testing 6 months after the onset of a CIDP-like disorder is appropriate in patients at risk.

Familial hypertrophic polyneuropathies that produce EDX features of SD along with axon loss may sometimes be confused with CIDP. With the familial disorders, a positive family history typically is recorded, but in some instances, it is not. CIDP can usually be distinguished on clinical grounds by its more rapid tempo of evolution and

a cyclical or relapsing course. The EDX findings may also be helpful in differentiating CIDP from these disorders. In the familial disorders, the SD features on NCS tend to be symmetrical, with uniform involvement of all nerves. Focal conduction block and focal conduction slowing usually are not observed. Despite these numerous distinguishing features, occasionally it still may be difficult to distinguish a long-duration CIDP from a familial hypertrophic SD polyneuropathy. In such circumstances, a trial of therapy is usually indicated.

On occasion, CIDP may be difficult to differentiate from AIDP. Patients with more subacute courses of CIDP have been described, and sometimes CIDP may begin with a relatively acute onset. Over time, CIDP usually declares itself by a typical chronic relapsing course or a more slowly progressive monophasic course. The distinction between AIDP and CIDP is significant because the ultimate course, prognosis, and treatment are different. y , y

Evaluation. As noted earlier, the performance of a comprehensive EDX evaluation to uncover findings consistent with acquired SD is key in the evaluation and diagnosis of CIDP and related disorders. These EDX findings clearly distinguish CIDP and related disorders from the vastly more common group of clinically similar axon loss sensorimotor polyneuropathies.

The general laboratory features of CIDP are relatively nonspecific and are not particularly useful in confirming the diagnosis. Routine laboratory tests typically are normal. The CSF protein, however, is frequently elevated to a moderate degree; in one series, it ranged from 23 to 600 mg/dl with a mean of 138 mg/dl. Nonetheless, it should be emphasized that in 10 percent of patients with CIDP, the CSF protein may be normal. [5 Even sural nerve biopsies generally do not provide specific or diagnostic features, although in the majority of patients they will document the presence of inflammation and demyelination, two features that characterize CIDP. However, these findings are not pathognomonic. Furthermore, the sural nerve biopsy may be normal in nearly 25 percent of patients. y It is important to appreciate that a normal CSF protein and sural nerve biopsy are not necessarily inconsistent with the diagnosis of CIPD. On the other hand, a normal EDX examination essentially excludes this diagnosis.

The critical component in the evaluation of a patient with suspected CIDP is to exclude the CIDP-like disorders. This requires careful screening of the serum and urine for the presence of M-proteins. Because a small amount of M-protein may still be undetected by routine serum protein electrophoresis testing, the search for M-protein should include an assessment incorporating immunoelectrophoresis or immunofixation techniques. The presence of an M-protein in the setting of a CIDP-like disorder may signify a polyneuropathy associated with multiple myeloma, osteosclerotic myeloma, MGUS, Waldenstrom's macroglobulinemia, or another lymphoproliferative disorder. Also, a skeletal x-ray study is indicated, because a significant percentage of patients with osteosclerotic myeloma may not disclose an M-Protein on immunofixation. HIV testing should also be performed in all patients at risk with a CIDP-like disorder.

Management. CIDP is a very treatable disorder, with most patients showing favorable responses to one of the many therapeutic modalities available. Some of the earliest reports of CIDP indicated that it was often steroid responsive. y Subsequently, a controlled clinical trial clearly established the value of corticosteroids in the treatment of CIDP, regardless of whether the course was monophasic and progressive, or cyclical and relapsing. y Other forms of immunosuppression, including azathioprine and cyclophosphamide, also have been reported to be effective therapies for CIDP, but none has been confirmed by a randomized or controlled trial. In addition, plasma exchange therapy and IVIg are efficacious and of comparable value in the treatment of CIDP. y , y

When constructing a treatment plan for patients with CIDP, it is important to balance clinical symptoms against the risks and potential benefits of the therapy. Clearly, patients with rather modest or minimal symptoms may not require treatment. Instead, they should be followed and observed closely. However, in those with a progressive course or with substantial clinical symptoms, treatment may begin with IVIg, plasma exchange therapy, or corticosteroids. Although both IVIg and plasma exchange are relatively expensive therapeutic modalities, either is justified as an initial treatment. Their advantage is that they obviate the need for chronic corticosteroid or other immunosuppressant treatment, and thus avoid the associated side effects and complications of these therapies. Both IVIg and plasma exchange are comparable in efficacy and expense. Nonetheless, IVIg may have certain advantages over plasma exchange. It may require fewer treatments, it is somewhat less invasive, and it may be administered at home. It is imperative, however, that patients considered for IVIg therapy be assessed for IgA deficiency, because anaphylactic reactions have occurred following the administration of IVIg in patients with IgA deficiency. Furthermore, caution should be exercised in administering IVIg to patients who have underlying renal dysfunction, because the risk of renal failure is increased following IVIg treatment. Traditionally, IVIg therapy is administered at a dose of 400 mg/kg/day over 5 consecutive days. y An alternative recommendation is to use IVIg at 400 mg/kg/day once per week over 6 to 8 consecutive weeks.y Plasma exchange therapy requires expertise in its use and is clearly more technically demanding than is IVIg treatment. Plasma exchange usually is administered twice weekly for the first 3 weeks and then once or twice weekly for an additional 3 weeks. y Patients typically respond to IVIg or plasma exchange within the first several weeks of treatment and may demonstrate sustained improvement for many weeks or months. Relapses may require periodic isolated treatments with a single dose of IVIg or single plasma exchange. If a patient responds successfully to infrequent booster treatments of either IVIg or plasma exchange, it is reasonable to maintain this form of treatment rather than adding corticosteroids or other immunosuppressants.

In patients who are not candidates for either IVIg or plasma exchange, or in whom responses are not satisfactory, chronic immunosuppressive therapy must be considered. Corticosteroids typically are used at relatively high doses initially and then slowly tapered while monitoring the clinical response. Most patients who respond will do so during their first few months of treatment. In those patients who cannot tolerate corticosteroids and in those who do not

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obtain a satisfactory clinical response to them, a trial of other immunosuppressants, including azathioprine or cyclophosphamide, may be a reasonable alternative. y

In addition to these various immunosuppressive therapies, patients should undergo a thorough physical therapy assessment to determine if they require aids to ambulation, including orthotic devices such as ankle-foot-orthosis for footdrop. Other physical therapy modalities, including stretching and range of motion exercises, may be helpful while a patient is responding to medical therapy.

Prognosis and Future Perspectives. The prognosis is favorable for most patients with CIDP who are properly diagnosed and treated. In one large group of patients whose disease-duration averaged 5.7 years and who were followed for a minimum of 24 months, nearly 40 percent were asymptomatic and nearly 50 percent had either minor symptoms that did not have any impact on their level of function or had only very modest restrictions in lifestyle. y Future research objectives will focus on the specific immune-mediated mechanisms and pathophysiology of CIDP. From a purely clinical perspective, further trials are needed to better define optimal therapeutic protocols using the modalities that have already proved effective, including IVIg, plasma exchange, and corticosteroids.

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