Chronic inflammatory demyelinating polyneuropathy (CIDP) or chronic relapsing polyneuropathy is an acquired form of neuropathy that is characterized by non-length dependent axonal neuropathy and proximal limb weakness (feature distinguishing it from distal axonal polyneuropathies). It is an immune disorder affecting the peripheral nervous system that causes inflammation of nerve roots and axons and disrupts the myelin covering of axons. The demyelination process is symmetrical in distribution and the course of disease varies in individuals.
CIDP, in most cases, occurs in patients during the forth to sixth decade of life. Since auto-immunity to nerve components may arise in any age, younger age groups may also present with CIDP. The disease is slow in onset and progression, some consider an eight week or greater duration of symptoms for a case to be diagnosed as CIDP. 16% of cases present with acute or sub-acute onset and the majority of these are children. Some may recover spontaneously and in others, disease progresses in the following patterns:
Symptoms may affect the motor, sensory, autonomic system, may arise in combinations (two or all three components of nervous systems involved in varying proportions). Motor system involvement may develop solitary (pure motor variant) or in combination with sensory symptoms, latter being most common. Some patients may present with sensory features alone (sensory variant), however, their electrophysiological features are the same as others and they also respond to the same treatment.
Classical CIDP
In the classical form, CIDP presents with the following features:
History and clinical features
The main symptom is weakness of muscles around the shoulders, hips or phalanges. The patient presents with a history of difficulty in walking, climbing and/or of falls. In case of weakness of the hand muscles, fine movements may be affected to varying degrees. Patients may complain of reduction in mental dexterity (for example problems with buttoning a shirt). However, this problem is of muscular origin. Deep reflexes are reduced or absent and inspection may reveal muscle atrophy. Proximal limb weakness is a core feature of CIDP, differentiating this disorder from other neuropathies, which often involve more distal portion of limbs. This shows that the demyelination is non-length dependent in case of CIDP. CIDP affects the proximal musculature as severely as the distal muscles of the limb. Sensory abnormalities include pain or tingling, burning or abnormal prickling sensations. Sometimes painful parasthesia may occur [14] [15] [16] in areas supplied by affected nerves. These symptoms may be accompanied by gait disturbances, a feature seen with sensory ataxia. Limb involvement is usually symmetrical and evolves slowly over weeks (about 2 months). CIDP may arise without an antecedent illness. Other features include dysphagia, diplopia, fatigue and clumsiness.
In the head and neck region, CIDP involves face and neck flexor muscles but typically spares extra-ocular muscles. Pure motor involvement is seen in 10% of cases. Some may present with autonomic involvement, and in these cases, main symptoms comprise bladder and bowel dysfunction, orthostatic dizziness or cardiac abnormalities. Relapses and recurrences are common, and in these cases, nerve impairment is step-wise progressive, each episode adding to the previous level.
Chronic inflammatory demyelinating polyradiculoneuropathy begins with a slow onset. In 60% of the patients, the disease undergoes a progressive course and another 10% suffer from relapses, with complete recovery or progressive deterioration of nerve function with each relapse. The interval between the episodes may last weeks or months.
Important diagnostic tests that can be employed for the diagnosis of CIDP include:
CSF examination
CSF examination is one of the most important and most sensitive studies for the diagnosis of CIDP. Elevated proteins are found in CSF in around 94% of patients with normal white cell count [17] [18].
An elevated protein and a reduced white blood cell count, called albumino-cytologic dissociation and demyelination findings on electrodiagnostic testing are found in both Gullian Barre syndrome and CIDP. A WBC greater than 10/mm3 in CSF should raise the suspicion of human immuno-deficiency virus (HIV) infection, leukemia and lymphoma, as well as other autoimmune diseases like sarcoidosis and Lyme disease. A parasitic disease should be kept in mind if the CSF examination reveals an elevated white cell count.
Lumbar puncture shows an elevated CSF pressure. Oligoclonal bands are identified in 65% of the cases [19]. Similarly lymphoproliferative disorders (myelomas and lymphomas) cause an elevation of the paraprotein level in immunofixation, or an elevation of serum lambda and kappa free light chains (light chains of immunoglobulins are raised in response to myelomas as osteosclerotic myelomas).
Nerve conduction study
A reduced conduction velocity is suggestive of CIDP, on nerve conduction study and electromyography (EMG).
Nerve biopsy
This is rarely required. In cases where biopsy is taken, nerve specimen shows segmental demyelination and other characteristic features of CIDP.
Magnetic resonance imaging
This is also an important diagnostic test. On contrast enhancement, enlargement on the T2 sequence of the spinal cord nerve roots is seen. It may also show signs of inflammation.
CIDP is a treatable, acquired neuropathy and an early intervention is recommended in order to hamper the possible nerve loss and axonal damage. Treatment follows these principles:
Conventional therapy includes corticosteroids (CS), immuno-suppressive drugs, intravenous immunoglobulins (IVIG) and plasma exchange (PE) therapy or plasmapheresis. Standard therapy (CS, IVIG and PE) [20] [1] [2] has shown improvement in 50-80% of the patients.
Corticosteroids
Corticosteroids may be used alone, or in case of insufficient response, in conjunction with other therapies e.g. immunosuppressive drugs. In many cases, patients respond to corticosteroids like prednisone, but some experience adverse effects of long term use of corticosteroids, hence combined therapies are commonly employed.
Immuno-suppressive drugs
Azathioprine, cyclosporine, mycophenolate , methotrexate and cyclophosphamide are used in CIDP patients. These agents inhibit auto-immune response in patients with CIDP, but they also have an untoward effect of depressing the patient's immunity against infectious agents. Long term trials have also shown them to be less effective. Hence patients on immuno-suppressive drugs alone, or those receiving combined treatment of corticosteroids and immuno-suppressive drugs, require prophylaxes and prevention against various opportunistic organisms.
Plasma exchange/ plasmapheresis
The purpose of this procedure is to remove offending or harmful material that is present in the plasma. Many autoimmune disease treatments include this procedure in which plasma and its constituents are removed.
The patient's blood is removed and the corpuscular part is separated, leaving behind plasma, that is exchanged with normal plasma, then the blood cells are transfused back. Since normal plasma does not contain agglutinogen, an immune reaction does not occur. However, this therapy is effective only for a few weeks and the patient may require intermittent plasma exchange, in symptomatic or active phases of the disease.
Intravenous immunoglobulins
IVIG are also effective for a short term and improve the immune status of the patient. Initial treatment with IVIG may require very high doses, especially in those with severe signs and symptoms at the onset of the disease.
Physiotherapy
Physiotherapy is a rehabilitation approach that improves muscle strength and mobility, and hence preserves and improves the residual function of muscle and movement at joints. It prevents distortion of joints. It also minimizes shrinkage in muscles or tendons, and impedes atrophy.
CIDP is a treatable form of acquired neuropathy. Loss of nerve axons can be prevented by early intervention. The disease can occur either in bouts with prompt recovery or in multiple bouts with partial recovery between the relapses. Prognosis varies from patient to patient and depends on the following factors:
Relapses may occur, but about 70% of the patients recover from these. However, some may be left with numbness or partial weakness in the limbs. About 90% of the patients respond well to immuno-suppressive therapy. Gait instability and loss of limb function are significant causes of morbidity in patients with CIDP. Complete remission is likely in patients presenting with acute or sub-acute onset, symmetrical limb involvement, conduction abnormalities predominantly in distal extremities and good response to corticosteroids. These factors can also predict long term outcome in patients.
There is a strong evidence in favor of an auto-immune etiology, however the precipitating cause for auto-immunity is not known. This is due to the insidious pattern of the onset of the disease. Both respiratory and gastrointestinal illnesses have been cited to be causative in CIDP, but there is a lack of evidence suggestive of a specific infectious agent.
CIDP can affect any age group, though it is commonly seen between the fourth and sixth decade of life. The prevalence of this rare disease is around 5 to 7 cases per 100,000 population. CIDP is more common in males than females and its average age of onset is 50 years. The disease represents 20% of initially undiagnosed cases of neuropathy and 10% of cases seeking out neuromuscular clinics. The relapse rate is found to be higher in young patients, in the third and fourth decade of life. Chronic inflammatory polyradiculoneuropathy, a variant of CIDP, can occur at any age, but is more common in the 40 to 60 years age group.
CIDP is an auto-immune disease which occurs in response to cross-reacting antigens; molecules in the body that resemble some foreign protein. As compared to a normal immune response that does not attack the body's natural proteins, auto-immunity occurs when a response against harmful foreign agents creates self-reactive auto-antibodies or lymphocytes. Although incompletely understood, pathogenesis of CIDP is thought to involve both humoral and cell mediated immune responses against the myelin sheath [1] [2]. The antigen is unknown, however, like various other demyelinating diseases, CIDP presents microscopically with segmental demyelination of nerve fibers. The disease affects peripheral nerves, where T-cells and macrophages are seen to invade the epineurium and endoneurium. Another view is that these macrophages infiltrate the interstitial and perivascular spaces of the endoneurium of nerves. Macrophages sometimes invade the basement membrane of cells causing the stripping of myelin lamellae at various places along the length of the nerve fiber [3] [4], hence giving rise to segmental demyelination. Nerve biopsy specimens reveal an ongoing process of inflammation and demyelination, followed by remyelination [5] [6].
Classical CIDP:
The classical form of the disease is characterized by proximal limb weakness, sensory disturbances and loss of reflexes with a progressive or relapsing course. Electrophysiological features in this form of disease characterize:
Nerve biopsy shows areas of inflammation, demyelination and re-myelination in a skipping pattern. Laboratory tests reveal an albumino-cytological dissociation in CSF.
Chronic inflammatory demyelinating polyradiculoneuropathy:
This variant involves an immune response consisting of auto-antibodies, inflammatory T-cells and macrophages which infiltrate the interstitial and perivascular spaces of the endoneurium.
The disease is auto-immune in nature and arises in response to an unknown antigen. A prior disease may play an inciting role, however, there is a lack of scientific data in recognition of the antigen. Prevention at primary level is insignificant. Rehabilitation and disability limitation is possible and can be adequately achieved through consultation of a neurologist who evaluates the treatment of the disease and/or inciting pathologies. The patient may have to be referred to other consultants including hematologist, rheumatologist or oncologist (in case of paraneoplastic syndrome) for abolishing or treating the cause. A physical therapist and rehabilitation specialist may apply various therapies to mitigate and restore an optimum function in the affected limbs. Orthotic devices and exercises are required in patients for physiotherapy and vocational rehabilitation.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological autoimmune disorder that affects the myelin sheath (the layer of fatty tissue formed by Schwann cell, over axons that lie outside the CNS). This disease represents 20% of initially undiagnosed cases of neuropathy and 10% of cases seeking out neuromuscular clinics. Myelin is present in excess in fast conduction fibers and contributes to high speed with which action potential travels in these and other peripheral nerve fibers. A disruption of the myelin sheath in CIDP affects the speed of conduction. The disease progressively leads to a loss of axon fibers due to the damage of the protection afforded by myelin. This disease is considered to be a chronic counterpart of Gullian Barre syndrome, an acute auto-immune demyelinating disorder. Chronic inflammatory demyelinating polyradiculopathy is a variant of CIDP.
The period for the diagnosis of CIDP depends upon the severity of the immune response. As a general criterion, a period of signs and symptoms greater than 8 weeks is considered diagnostic. CIDP presents in a symmetrical fashion and affects males more commonly than females. This abnormality presents with muscle weakness, fatigue, ataxia/gait abnormalities, numbness, tingling sensations or pain, loss of deep reflexes or paralysis. The age of onset varies and spontaneous resolution can occur in few patients while others require steroidal or other medical therapy and rehabilitation interventions.
Chronic inflammatory demyelinating polyneuropathy is a chronic, acquired and treatable neurological disease. At the onset of the disease, symptoms develop slowly, over a period of two months. This disease is comparable to Gullian Barre syndrome, except that in latter, onset is sudden and paralysis ensues in ascending fashion. CIDP occurs due to an auto-immune reaction against the myelin sheath. The myelin sheath protects the nerves and maintains the high speed of conduction in the nerve fibers. Both humoral and cell mediated responses are initiated and nerve fibers undergo patchy, segmental demyelination. The severity of inflammation varies in individuals. No specific inciting cause has yet been identified.
The disease presents with progressive development of proximal and distal limb weakness; muscles of hands and feet may be involved, affecting fine movements. The patient presents with complaints like difficulty in getting up, climbing stairs or buttoning a shirt. Apart from motor function, sensory disturbances also occur and include a prickling or burning sensation, pain, numbness and ataxia (an imbalanced gait). The disease progresses in slowly ascending or relapsing fashion. Recovery is possible. However, recurring episodes may lead to progressive and permanent loss of nerve function. Diagnosis of CIDP is made by CSF examination, nerve biopsy, MRI and nerve conduction study.
Treatment includes medical treatment and rehabilitation. Corticosteroids and immuno-suppressive agents are recommended to control immune response. Response to treatment differs in patients. Physical, occupational and psychological rehabilitation is necessary to regain an optimum level of functioning in patients.