Abstract

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy (because it involves the nerve roots). CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. An asymmetrical variant of CIDP is known as Lewis-Sumner Syndrome.

Cause

Chronic inflammatory demyelinating polyneuropathy, also known as Vidaurri's disease, is believed to be due to immune cells, which normally protect the body from foreign infection, incorrectly attacking the nerves in the body instead. As a result, the affected nerves fail to respond, or respond only weakly, and on occasion, inordinately, to stimuli, causing numbing, tingling, pain, progressive muscle weakness, loss of deep tendon reflexes (areflexia), fatigue, and abnormal sensations. The likelihood of progression of the disease is high.

CIDP is under-recognized and under-treated due to its heterogeneous presentation (both clinical and electrophysiological) and the limitations of clinical, serologic, and electrophysiologic diagnostic criteria. Despite these limitations, early diagnosis and treatment is important in preventing irreversible axonal loss and improving functional recovery.

Lack of awareness and treatment of CIDP is also due to limitations of clinical trials. Although there are stringent research criteria for selecting patients to clinical trials, there are no generally agreed-on clinical diagnostic criteria for CIDP due to its different presentations in symptoms and objective data. Application of the present research criteria to routine clinical practice often miss the diagnosis in a majority of patients, and patients are often left untreated despite progression of their disease.

Epidemiology

In 1982 Lewis et al reported a group of patients with a chronic asymmetrical sensorimotor neuropathy mostly affecting the arms with multifocal involvement of peripheral nerves. Also in 1982 Dyck "et al" reported a response to prednisolone to a condition they referred to as chronic inflammatory demyelinating polyradiculoneuropathy. Parry and Clarke in 1988 described a neuropathy which was later found to be associated with IgM autoantibodies directed against GM1 gangliosides. This latter condition was later termed multifocal motor neuropathy This distinction is important because multifocal motor neuropathy responds to intravenous globulin alone while chronic inflammatory demyelinating polyneuropathy responds to intravenous globulin, steroids and plasma exchanges. It has been suggested that multifocal motor neuropathy is distinct from chronic inflammatory demyelinating polyneuropathy and that Lewis-Summer syndrome is a distinct variant type of chronic inflammatory demyelinating polyneuropathy.

The Lewis-Summer form of this condition is considered a rare disease with only 50 cases reported up to 2004. A total of 90 cases had been reported by 2009

Diagnosis

There are several types of immune-mediated neuropathies recognised. These include

- Chronic inflammatory demyelinating polyneuropathy (CIPD) with subtypes:

- Classical CIDP

- CIDP with diabetes

- CIDP/monoclonal gammopathy of undetermined significance

- Sensory CIDP

- Multifocal motor neuropathy

- Multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome)

- Multifocal acquired sensory and motor neuropathy

- Distal acquired demyelinating sensory neuropathy

- Guillain-Barre syndrome with subtypes:

- Acute inflammatory demyelinating polyradiculoneuropathy

- Acute motor axonal neuropathy

- Acute motor and sensory axonal neuropathy

- Acute pandysautonomia

- Miller Fisher syndrome

- IgM monoclonal gammopathies with subtypes:

- Waldenstrom's macroglobulinemia

- Mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome

- Myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS)

For this reason a diagnosis of chronic inflammatory demyelinating polyneuropathy needs further investigations.

The diagnosis is usually provisionally made through a clinical neurological examination. Patients usually present with a history of weakness, numbness, tingling, pain and difficulty in walking. They may additionally present with fainting spells while standing up or burning pain in extremities. Some patients may have sudden onset of back pain or neck pain radiating down the extremities, usually diagnosed as radicular pain. These symptoms are usually progressive and may be intermittent.

Autonomic system dysfunction can occur; in such a case, the patient would complain of orthostatic dizziness, problems breathing, eye, bowel, bladder and cardiac problems. The patient may also present with a single cranial nerve or peripheral nerve dysfunction.

On examination the patients may have weakness, and loss of deep tendon reflexes (rarely increased or normal). There may be atrophy (shrinkage) of muscles, fasciculations (twitching) and loss of sensation. Patients may have multi-focal motor neuropathy, as they have no sensory loss.

Most experts consider the necessary duration of symptoms to be greater than 8 weeks for the diagnosis of CIDP to be made.

Typical diagnostic tests include:

- Electrodiagnostics – electromyography (EMG) and nerve conduction study (NCS). In usual CIDP, the nerve conduction studies show demyelination. These findings include:

1. a reduction in nerve conduction velocities;

2. the presence of conduction block or abnormal temporal dispersion in at least one motor nerve;

3. prolonged distal latencies in at least two nerves;

4. absent F waves or prolonged minimum F wave latencies in at least two motor nerves. (In some case EMG/NCV can be normal).

- Serum test to exclude other autoimmune diseases.

- Lumbar puncture and serum test for anti-ganglioside antibodies. These antibodies are present in the branch of CIDP diseases comprised by anti-GM1, anti-GD1a, and anti-GQ1b.

- Sural nerve biopsy; biopsy is considered for those patients in whom the diagnosis is not completely clear, when other causes of neuropathy (e.g., hereditary, vasculitic) cannot be excluded, or when profound axonal involvement is observed on EMG.

- Ultrasound of the periferal nerves may show swelling of the affected nerves

- MRI can also be used in the diagnosic workup

In some cases electrophysiological studies fail to show any evidence of demyelination. Though conventional electrophysiological diagnostic criteria are not met, the patient may still respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP are critical, justifying full investigations, including sural nerve biopsy.

Treatment

First-line treatment for CIDP is currently intravenous immunoglobulin (IVIG) and other treatments include corticosteroids (e.g. prednisone), and plasmapheresis (plasma exchange) which may be prescribed alone or in combination with an immunosuppressant drug. Recent controlled studies show subcutaneous immunoglobin (SCIG) appears to be as effective for CIDP treatment as IVIG in most patients, and with fewer systemic side effects.

IVIG and plasmapheresis have proven benefit in randomized, double-blind, placebo-controlled trials. Despite less definitive published evidence of efficacy, corticosteroids are considered standard therapies because of their long history of use and cost effectiveness. IVIG is probably the first-line CIDP treatment, but is extremely expensive. For example, in the U.S., a single 65 g dose of Gamunex brand in 2010 might be billed at the rate of $8,000 just for the immunoglobulin—not including other charges such as nurse administration. Gamunex brand IVIG is the only U.S. FDA approved treatment for CIDP, as in 2008 Talecris, the maker of Gamunex, received orphan drug status for this drug for the treatment of CIDP.

Immunosuppressive drugs are often of the cytotoxic (chemotherapy) class, including rituximab (Rituxan) which targets B cells, and cyclophosphamide, a drug which reduces the function of the immune system. Ciclosporin has also been used in CIDP but with less frequency as it is a newer approach. Ciclosporin is thought to bind to immunocompetent lymphocytes, especially T-lymphocytes.

Non-cytotoxic immunosuppressive treatments usually include the anti-rejection transplant drugs azathioprine (Imuran/Azoran) and mycophenolate mofetil (Cellcept). In the U.S., these drugs are used as "off-label" treatments for CIDP, meaning that their use here is accepted by the FDA, but that CIDP treatment is not explicitly indicated or approved in the drug literature. Before azathioprine is used, the patient should first have a blood test that ensures that azathioprine can safely be used.

Anti-thymocyte globulin (ATG), an immunosuppressive agent that selectively destroys T lymphocytes is being studied for use in CIDP. Anti-thymocyte globulin is the gamma globulin fraction of antiserum from animals that have been immunized against human thymocytes. It is a polyclonal antibody.

Although chemotherapeutic and immunosuppressive agents have shown to be effective in treating CIDP, significant evidence is lacking, mostly due to the heterogeneous nature of the disease in the patient population in addition to the lack of controlled trials.

A review of several treatments found that azathioprine, interferon alpha and methotrexate were not effective. Cyclophosphamide and rituximab seem to have some response. Mycophenolate mofetil may be of use in milder cases. Immunoglobulin and steroids are the first line choices for treatment. Rarely bone marrow transplantation has been performed.

Physical therapy and occupational therapy may improve muscle strength, activities of daily living, mobility, and minimize the shrinkage of muscles and tendons and distortions of the joints.

Prognosis

As in multiple sclerosis, another demyelinating condition, it is not possible to predict with certainty how CIDP will affect patients over time. The pattern of relapses and remissions varies greatly with each patient. A period of relapse can be very disturbing, but many patients make significant recoveries.

If diagnosed early, initiation of early treatment to prevent loss of nerve axons is recommended. However, many individuals are left with residual numbness, weakness, tremors, fatigue and other symptoms which can lead to long-term morbidity and diminished quality of life.

It is important to build a good relationship with doctors, both primary care and specialist. Because of the rarity of the illness, many doctors will not have encountered it before. Each case of CIDP is different, and relapses, if they occur, may bring new symptoms and problems. Because of the variability in severity and progression of the disease, doctors will not be able to give a definite prognosis. A period of experimentation with different treatment regimens is likely to be necessary in order to discover the most appropriate treatment regimen for a given patient.