Chronic inflammatory demyelinating polyneuropathy (CIDP)



Background

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder, which is sometimes called chronic relapsing polyneuropathy, is caused by damage to the myelin sheath of the peripheral nerves. Although it can occur at any age and in both genders, CIDP is more common in young adults, and in men more so than women. It often presents with symptoms that include tingling or numbness (beginning in the toes and fingers), weakness of the arms and legs, loss of deep tendon reflexes (areflexia), fatigue, and abnormal sensations.  CIDP is considered when patients have a symmetric proximal and distal motor predominant disorder.It is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart of that acute disease. Left untreated, 30% of CIDP patients will progress to wheelchair dependence. Early recognition and treatment can avoid a significant amount of disability.The incidence of new cases is estimated to be between 1.5 and 3.6 in a million people.

Antecedent events are more frequent with Guillain-Barré syndrome than in CIDP. Approximately 70 percent of AIDP cases are preceded by an infectious illness, vaccination, or surgery by three to four weeks prior to the onset of clinical symptoms. In contrast, most studies have found an antecedent event prior to CIDP in no more than 30 percent of patients.

Classification

Whether CIDP is a disease or a syndrome remains controversial. The following neuropathies all have chronicity, demyelination, inflammation, or immune-mediation in common:

  • CIDP
  • Multifocal motor neuropathy (MMN)
  • Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)
  • Distal demyelinating neuropathy with IgM paraprotein, with or without anti-myelin associated glycoprotein (anti-MAG)
  • Demyelinating neuropathy with IgG or IgA paraprotein (the terms paraprotein and monoclonal gammopathy of undetermined significance [MGUS] are used synonymously in this setting)
  • POEMS syndrome (osteosclerotic myeloma: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
  • Sensory predominant demyelinating neuropathy
  • Demyelinating neuropathy with central nervous system demyelination
  • Demyelinating neuropathy associated with systemic disorders, including:
  • Hepatitis B or C
  • HIV infection
  • Lymphoma
  • Diabetes mellitus
  • Systemic lupus erythematosus or other collagen vascular disorders
  • Thyrotoxicosis
  • Organ or bone marrow transplants
  • Inherited neuropathies
  • Nephrotic syndrome
  • Inflammatory bowel disease

While there is no established consensus regarding the classification of all these neuropathies, there is general agreement that MMN, POEMS, and the MAG-related neuropathies are separate from CIDP and the other neuropathies on the basis of clinical, electrodiagnostic, and therapeutic distinctions.

Most investigators consider the remaining disorders to be variants of CIDP since they have many clinical and electrodiagnostic features in common and treatment response with immunotherapy appears to be similar. The classification of inflammatory demyelinating neuropathies will continue to evolve as specific immune mechanisms are elucidated.

Pathogenesis

Although the cause of CIDP and its variants is unknown, there is evidence to support the hypotheses that the disorder(s) are immunologically based and have multiple triggers. Both the cellular and humoral components of the immune system appear to be involved in the pathogenesis of CIDP and its variants.

  • Cellular immunity involvement is supported by evidence of T-cell activation, crossing of the blood-nerve barrier by activated T-cells, and by expression of cytokines, tumor necrosis factor, interferons, and interleukins.
  • Humoral immunity is implicated by the demonstration of immunoglobulin and complement deposition on myelinated nerve fibers, and by passive transfer experiments that induce conduction block and demyelination by injecting serum or purified IgG from CIDP patients into rats.

However, the immunologic cause(s) of CIDP remain unclear, since specific provoking antigens have not been identified

Epidemiology

The estimated prevalence of CIDP in populations from the UK, Australia, Italy, Japan, and the US is 0.8 to 8.9 per 100,000. CIDP can affect all ages but is more common in older males. It is thought that the disease is more likely to be progressive in the older age group and relapsing-remitting in younger patients.

No specific predisposing factors for CIDP have been identified. There have been conflicting studies on human leukocyte antigen (HLA) type associations, but no clear genetic predisposition has been found. In several case reports, treatment with tumor necrosis factor-alpha inhibitors has been associated with the subsequent development of chronic demyelinating neuropathies

Clinical Manifestations

The classic form of CIDP is fairly symmetric and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles, and this pattern is a hallmark of acquired demyelinating polyneuropathy. Cranial nerve and bulbar involvement occur in 10 to 20 percent of patients.

Most patients with CIDP also have sensory involvement and globally diminished or absent reflexes. Sensory impairment in CIDP is usually greater for vibration and position sense than for pain and temperature sense, reflecting the involvement of larger myelinated fibers. Unlike the motor involvement, the sensory involvement tends to follow a distal to proximal gradient, although finger involvement is frequently seen as early as toe and foot involvement. Painful dysesthesias can occur in some patients.

Constipation and urinary retention are not usually early symptoms of CIDP, but may occur in more severe cases. Back pain may be present. Symptoms of lumbar spinal stenosis and cauda equine syndrome can occur rarely if there is marked nerve root hypertrophy, and may require surgical intervention.

Most patients with CIDP exhibit a slowly progressive course, but a relapsing-remitting course is noted in at least one-third, and may be more common in younger patients. The advent of early treatment for CIDP has made the temporal progression of the disease more difficult to characterize, since remissions may be related to therapy rather than to the natural course of the disease.

Pathology

The characteristic pathologic features of CIDP include segmental demyelination and remyelination, and onion bulb formation. The term “onion-bulb formation” refers to the appearance of affected nerves when viewed under the microscope in transverse section. As a result of repeated episodes of demyelination and remyelination, such nerves are enlarged due to whorls of overlapping and proliferating Schwann cell processes encircling bare axons. Some degree of axonal degeneration is usually present as well.

Varying degrees of interstitial edema and endoneurial inflammatory cell infiltrates, including lymphocytes and macrophages, are additional pathologic features of CIDP. The macrophages are thought to initiate the demyelination by unraveling and degrading the myelin . Unfortunately, this is not commonly found on most biopsy specimens.

While the exact mechanism of axonal degeneration in CIDP is not known, it has been considered to be a secondary bystander product of the inflammatory demyelinating process.

Diagnostics

Electrodiagnostic testing is recommended for all patients with suspected CIDP . Additional studies that may be indicated in select patients include:

  • Cerebrospinal fluid analysis
  • Nerve biopsy
  • MRI of spinal roots, brachial plexus, and lumbosacral plexus
  • Laboratory studies
  • Evaluation for inherited neuropathies

Electrodiagnostic testing — A critical component of the CIDP evaluation, electrodiagnostic testing is used to determine if there is demyelination, which causes reduced conduction velocity, prolonged distal motor latencies, dispersion and distance-dependent reduction of compound motor action potential (CMAP) amplitude, and delay or disappearance of F waves.

Most, but not all, patients with CIDP will have electrodiagnostic evidence of primary demyelination. However, other focal or generalized nerve diseases (eg, diabetic neuropathy) can also result in slow conduction velocities or apparent block in neural conduction. As already mentioned, various sets of electrodiagnostic criteria for demyelinating neuropathy have been established to address this problem . While these criteria can be helpful to the clinician, none have ideal sensitivity and specificity.

Extensive studies of the upper limbs or all four limbs, rather than unilateral or lower limb studies, may improve the electrodiagnostic yield.

Cerebrospinal fluid analysis — A lumbar puncture is supportive of the diagnosis of CIDP when the cerebrospinal fluid (CSF) protein is elevated and the CSF white cell count is normal (ie, the classic albuminocytologic dissociation). This finding is present in over 90 percent of patients with CIDP. CSF protein elevations as high as 10 times the upper limits of normal are occasionally seen in patients with CIDP.

An increased CSF white cell count of >10 cells/mm^3 should suggest a diagnosis other than CIDP. An exception to this general rule is that patients with HIV infection may have a cerebrospinal fluid pleocytosis, although the CSF white cell count in patients with CIDP and HIV infection is generally <50/mm^3.

Nerve biopsy — The diagnostic utility of nerve biopsy (typically of the sural nerve) for suspected CIDP is controversial. Nerve biopsy is used mainly when other studies fail to clearly establish the diagnosis of CIDP, particularly when electrophysiologic criteria for demyelination are not met.

A major limitation of nerve biopsy is suboptimal sensitivity and specificity. CIDP is a multifocal disorder, and motor nerve fibers tend to be more affected than sensory nerves (the usual nerves used for biopsy). As a result, the biopsy sample may not demonstrate the demyelination. In addition, the inflammatory component of CIDP may not be prominent and thus may not be apparent on biopsy.

Despite these drawbacks, nerve biopsy can provide solid evidence of demyelination. In addition, biopsy occasionally reveals other neuropathies that mimic CIDP, such as those due to amyloidosis, sarcoidosis, and vasculitis.

The nerve selected for biopsy should be one that is clinically and electrophysiologically affected by the disorder . However, care should be taken to choose a nerve that has either electrophysiologic or clinical evidence of functionality, as completely devastated nerves usually convey limited information. Typically, the sural nerve is biopsied, but other candidate nerves include the superficial peroneal, superficial radial, and gracilis motor nerve. Electron microscopy and teased fiber analysis of nerve biopsy specimens is highly desirable.

Supportive features for CIDP on nerve biopsy include the following:

  • Endoneurial edema
  • Macrophage-associated demyelination
  • Demyelinated and remyelinated nerve fibers
  • Onion bulb formation (see ‘Pathology’ above)
  • Endoneurial mononuclear cell infiltration
  • Variation between fascicles

MRI — MRI with gadolinium of the spinal roots, cauda equina, brachial plexus, lumbosacral plexus, and other nerve regions can be used to look for enlarged or enhancing nerves. MRI abnormalities are useful as supportive criteria for CIDP in the EFNS/PNS guideline. The MRI results can also guide selection of abnormal nerves for biopsy.

Laboratory studies — There are no blood tests that specifically point to CIDP. However, a number of studies are useful to look for disorders that are either associated with or mimic CIDP. These include:

  • Fasting serum glucose and/or oral glucose tolerance test
  • Glycated hemoglobin
  • Thyroid function studies
  • Hepatitis profiles
  • HIV antibody
  • Serum and urine immunofixation electrophoresis to detect paraprotein
  • Complete blood count
  • Renal function tests
  • Liver function tests
  • Borrelia burgdorferi serology
  • C reactive protein
  • Antinuclear antibodies
  • Extractable nuclear antigen antibodies
  • Angiotensin converting enzyme
  • Chest radiograph
  • Skeletal survey, if a paraprotein is found.

Genetic considerations — Certain genetic disorders of peripheral nerve myelin have characteristics that can mimic the clinical or electrodiagnostic features of CIDP or its variants. These include:

  • Hereditary neuropathy with liability to pressure palsies
  • Charcot-Marie-Tooth (CMT) disease, particularly CMT1A, adult-onset CMT1B, and CMT1X

 

A careful family history and examination of parents and siblings is important if these disorders are a consideration . Appropriate genetic testing should be considered in select patients, particularly for PMP22 gene duplication or deletion and connexin 32 mutations