Description of the condition
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease, usually causing weakness and loss of sensation in the limbs (Vallat 2010). It is caused by inflammation of the peripheral nervous system resulting in damage to the myelin sheaths which normally insulate nerve fibres. This produces a state of 'demyelination' of the nerves, which slows and may block nerve conduction. Although demyelination is the predominant pathology, the inflammation also damages the central conducting core of the nerve fibre, called the axon, resulting in axonal degeneration. The parts of the peripheral nervous system most affected are the motor and sensory spinal nerve roots and the peripheral nerves. The cranial nerves controlling eye movements and the facial, swallowing and speech muscles may also be affected. The nerves supplying the breathing muscles and the autonomic nerves which control the bladder, bowel and circulation are usually spared.
There is no single diagnostic test for CIDP. The diagnosis is made from the clinical picture, nerve conduction tests (which show evidence of demyelination), and the exclusion of other causes. Sometimes supportive tests, such as lumbar puncture and cerebrospinal fluid analysis, magnetic resonance imaging of spinal nerve roots, nerve biopsy, and therapeutic trials of immunomodulating agents, are used to help in diagnosis. Many different sets of diagnostic criteria have been proposed. Very strict research criteria require a characteristic nerve biopsy for a definite diagnosis (Ad hoc 1991). Less strict but widely accepted recent criteria rely on clinical history, examination, nerve conduction evidence and exclusion of other causes for a definite diagnosis (Van den Bergh 2010). In addition to weakness and sensory symptoms, CIDP may cause neuropathic pain and fatigue. Neuropathic pain differs from ordinary pain in that it arises spontaneously and is due to dysfunction of the nerves and not tissue injury.
The prevalence of CIDP has been between 1 and 9 per 100,000 population in different studies, with most reporting a prevalence of 2 to 3 per 100,000 (Mahdi-Rogers 2010b). It was between 1.4 and 4.7 times more common in men than women in eight population-based studies in which the sex ratio was reported. The average age of onset in four population-based studies in which the figure was given was 48 to 58 years (Mahdi-Rogers 2010b). It is uncommon in children but becomes more common with advancing age, reaching a peak prevalence in the eighth decade. In a population based study, 9 of 62 (14.5%) patients had a progressive, 44 (71%) a relapsing and remitting, and 9 (14.5%) a monophasic disease course (Mahdi-Rogers 2010b). According to Vallat 2010, 7 to 50% of patients have a monophasic or progressive course, and 20 to 35% a relapsing remitting course in different series.
CIDP is important because it can be severely disabling, although its severity is variable. On the prevalence day in the population based study (Mahdi-Rogers 2010b), 28 (68.2%) patients could walk independently, 10 (24.4%) required unilateral and three (7.3%) bilateral support to walk 10 metres. No patient needed a wheelchair. At nadir, 31 (75.6%) patients had disability in their upper limbs, 17 (41.5%) could walk independently, 11 (26.8%) needed unilateral support, 6 needed bilateral support and 7 patients used a wheelchair. Most commonly the disease causes progressive weakness leading to the need for aids to walk followed by improvement with treatment. However, treatment may need to be repeated or prolonged. In the population based study mentioned 64 (76.2%) of 84 patients had required treatment and 51 (79.7%) improved with at least one of the main line treatments, corticosteroids, intravenous immunoglobulin or plasma exchange. Less commonly the disease is so mild that treatment is not necessary. CIDP is also important because its treatment is expensive, especially when intravenous immunoglobulin (IVIg) is used. According to Blackhouse 2010 the cost per quality-adjusted life year (QALY) of using IVIg rather than corticosteroids was 696,598 USD.
The cause of CIDP is not known. Active disease sites in the spinal nerve roots and nerve trunks show inflammation and stripping of the myelin sheaths from the axons by macrophages which can be seen with the microscope in nerve biopsies or at post mortem. The inflammation is probably due to an autoimmune reaction. There is debate whether this is due to antibodies, to T cells directed against the Schwann cell or myelin, or both. There is some evidence that there is impairment of the regulatory T and B cells which normally control autoimmune responses (Vallat 2010).
Description of the interventions
Treatments aimed at the underlying disease
The most common first-line treatments for CIDP are corticosteroids, given as tablets every day or as intravenous infusions every four weeks, or immunoglobulin, usually given as intravenous infusions over two to five days for the first dose and then over one day every two to eight weeks for follow-up courses. Corticosteroids are anti-inflammatory drugs used in many types of inflammatory conditions such as asthma and arthritis. They are quite cheap but their long-term use risks serious side-effects including high blood pressure, diabetes mellitus, obesity, thinning of the bones, and cataracts (Mehndiratta 2002). Immunoglobulin is extracted from the plasma of several thousand blood donors and then purified to reduce the risk of transmitting virus and other infections. It is very expensive and often causes minor short-term side-effects such as headache and muscle aching; serious side-effects such as stroke, severe skin reactions and kidney failure do occur but are rare (Eftimov 2009).
Plasma exchange is an alternative first-line treatment. It involves drawing blood from the patient, separating the plasma from the cellular fraction and replacing the plasma with a plasma substitute. This is done with an automated machine which is able to replace the whole plasma volume in a few hours. A course of about five treatments on consecutive or alternate days is commonly used to initiate treatment, but regimes vary, and single exchanges every few weeks are sometimes used for long-term treatment. Plasma exchange is usually safe, although there are rare side-effects, such as bleeding and injuries arising from inserting large tubes into veins. Its main drawback is its inconvenience (Mehndiratta 2004).
When first-line treatments are inadequate, neurologists often prescribe immunosuppressant agents and in the past immunomodulatory agents have also been tried. The most commonly used immunosuppressants have been azathioprine, cyclophosphamide, ciclosporin and methotrexate. These can be given orally, although cyclophosphamide can also be given by intravenous infusion and methotrexate by intramuscular injection. They all reduce the white cell count and carry an increased risk of infection. Individual agents can have idiosyncratic side-effects. For instance, amongst others, azathioprine can cause hypersensitivity reactions, cyclophosphamide hair loss, ciclosporin kidney failure and methotrexate liver dysfunction. More recently-developed immunosuppressant drugs affect relatively specific components of the immune system and are beginning to be used. These include rituximab, which deletes most of the circulating B cells, and fingolimod, which prevents T cells from leaving the lymph nodes. In addition to immunosuppressant agents, an immunomodulatory agent, interferon beta, has been tested in randomised controlled trials for CIDP. Interferon beta is a naturally occurring molecule called a chemokine which can be manufactured commercially and became the first licensed treatment for multiple sclerosis. It is given by subcutaneous or intramuscular injection on one or several days a week. The potential risks of each treatment have to be balanced against the possible benefits (Mahdi-Rogers 2010a).
In addition to considering treatments aimed at the underlying disease process, this review will also provide an overview of reviews of treatments for symptoms of CIDP including those for neuropathic pain and fatigue. Trials and Cochrane reviews of such treatments generically for peripheral neuropathy do exist, but this review will focus on those reviews and trials which deal specifically with CIDP. Drugs which have been tested in trials for neuropathic pain include the tricyclic antidepressant amitriptyline (Saarto 2007) and anti-epileptic drugs such as gabapentin and pregabalin. These drugs are all given daily as tablets to try to reduce the pain. There are no trials known to us of drugs for fatigue caused by CIDP but there is a Cochrane review about exercise for fatigue in peripheral neuropathy (White 2004).
How the intervention might work
Corticosteroids, IVIg and broad spectrum immunosuppressive agents are expected to treat CIDP by inhibiting multiple components of the presumed inflammatory autoimmune response. The precise ways in which they do this in CIDP are incompletely understood, in part because the mechanisms causing nerve damage in CIDP are themselves not understood (Vallat 2010). The ways in which immunosuppressant drugs work vary from drug to drug, and will have been described or referenced in the constituent reviews. The most obvious way in which plasma exchange might work is by removing antibodies. However, it also removes other soluble plasma substances, including the small molecules called chemokines which might affect T cell function. Similarly, the most obvious action of rituximab, which engages the CD20 molecule on B cells, is to reduce the circulating B cell population, but this may in turn interfere with antigen presentation and so affect T cell function (Maloney 2002). Interferon beta has multiple actions on the immune system which tend to down-regulate harmful immune responses (Kieseier 2011). Exercise might help fatigue in CIDP by a combination of improving aerobic fitness, strengthening relevant muscle groups and having positive psychological effects.
Why it is important to do this overview
Treatment of the underlying disease in CIDP is covered by four Cochrane reviews on corticosteroids (Mehndiratta 2002), IVIg (Eftimov 2009), plasma exchange (Mehndiratta 2004) and other immunosuppressive and immunoregulatory drugs (Mahdi-Rogers 2010a). The treatment of CIDP is or might potentially be included in other Cochrane and non-Cochrane systematic reviews. There are several completed Cochrane reviews and some review protocols for treatment of neuropathic pain, for instance (Saarto 2007). There is one Cochrane review protocol of treatment for fatigue in peripheral neuropathy (White 2009), and a review of exercise for peripheral neuropathy (White 2004). Drawing together the reviews in one place will make their combined information more accessible to people with CIDP, healthcare professionals and researchers. An overview will allow some indirect comparisons of treatments which have not yet been directly compared in trials. It will be likely to draw attention to, and be a stimulus for, more research.