Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) is a type of acquired immune-mediated disorder that affects the peripheral nervous system. Although it has diverse clinical presentations, the classical presentation includes symmetric proximal and distal sensory and motor involvement. CIDP can be monophasic, relapsing, or progressive, which develops over more than eight weeks. The time course of 8 weeks as well as the duration to reach nadir help distinguish CIDP from Guillain-Barre syndrome (GBS) or other acute inflammatory demyelinating polyneuropathies (AIDP). The first case was described by Eichhorst Burns in 1890. About 16% of the patients present with acute GBS.
CIDP is an autoimmune disorder involving both T cell-mediated and humoral immune mechanisms by targeting myelin components of the peripheral nervous system. Classical CIDP is idiopathic. However, it has variants that can be seen in association with a neoplastic process (e.g., osteosclerotic myeloma, Waldenstrom macroglobulinemia, lymphoma, monoclonal gammopathy of undetermined significance), HIV infections, and chronic history of diabetes mellitus type II. History of anteceding infections have been commonly reported with AIDP/GBS; however, they are rare with CIDP.
A recent meta-analysis showed a crude incidence rate of 0.33 per 100,000. Overall prevalence has been reported around 0.8 to 8.9 per 100,000 and increased with advancing age with a peak incidence of 40 to 60 years of age. Due to diverse clinical presentations and diagnostic criteria used around the world, the incidence and prevalence rates also vary. CIDP predominantly affects males more than females with a ratio of 2:1.
CIDP is primarily a T cell-mediated process. However, the response to plasmapheresis suggests a possible role of B cell-mediated immune processes. The classical CIDP is idiopathic, whereas the variants are linked to the antibodies that are directed against the myelin or proteins located at the node of Ranvier. Both T cell, as well as B cell-mediated inflammation, lead to neuronal damage and dysfunction. The activated T cells, along with macrophages, act as antigen-presenting cells and bind directly to targeted structures to promote demyelination.
While many antibodies such as GD1a, GD1b, GM1, GQ1b are associated with GBS, there is no particular antibody associated with CIDP. Thus far, only a few autoantibodies have been identified in association with CIDP variants such as perinodal proteins such as neurofascin 140, 155, and 186. Additionally, gliomedin and contactin one have been shown to be targeted as well. The subtypes associated with the NF155 and contactin-1 antibodies differ from typical CIDP in terms of poor response to initial treatment with corticosteroids and intravenous immunoglobulins (IVIG) as well as at the cellular level.
At the microscopic level, demyelination and remyelination are the pathological hallmarks of CIDP. The demyelination and remyelination can be visualized on teased fibers analysis in 48% to 68% of the patients, while in 21% of patients, mixed demyelination an axonal changes are seen. The formation of ‘onion bulbs’ has also been described, which are made of concentrically oriented Schwann cell processes surrounding thinly myelinated fibers and sometimes, focally thickened myelin sheaths.
The immunopathological study of the nerve biopsy has shown inflammatory T cells and macrophages that surround the muscle units through the perivascular space in the subunits within the sarcomeres. Ultrastructural studies have demonstrated macrophages extending their processes between myelin leading to the degradation of its components. Other findings that can be seen are nerve edema, nerve fibrosis, and inflammatory infiltrates. In CIDP variants, such as DADS with Anti MAG Antibody, demyelination is seen along the large myelinated axons with separation of the myelin lamellae and depositions of IgM and C3d on myelin sheaths.
CIDP symptoms are insidious, step-wise, recurrent, progressive with a clinical course that reflects a demyelinating process that persists for greater than eight weeks. The relapsing-remitting course can be seen in up to a third of patients. The development of motor weakness is symmetric, affecting proximal or distal muscles with a predominance of large fiber neuropathy paresthesias compared to small-fiber neuropathies. This is the most typical pattern of CIDP, also known as the symmetric sensorimotor variant. Large fiber neuropathy paraesthesias include subjective complaints of tingling and pins/needles in the body with decreased vibration/position and hypotonia. Small fiber includes subjective complaints of burning, jabbing, or shooting pain with decreased sensation to pain and temperature. Typical motor findings include difficulties lifting themselves up from a chair, climbing stairs, lifting objects over their heads, difficulty with ambulation, and frequent history of falls. They may have difficulties with fine motor activities such as dressing, opening jars, and dropping objects at home. Diffuse areflexia or hyporeflexia, and a positive Romberg are common. Allodynia, cervical/lumbar dorsalgia, and multiple cranial nerve neuropathies may be present. Rapidly progressive symptoms may resemble an acute onset CIDP. However, it has to fall within the eight weeks or more time course with relapsing or progressive course.
Severe or atypical variants may have additional symptoms. Bulbar and autonomic symptoms may include dysarthria, dysphagia, dyspnea, dysrhythmias, hypotension or hypertension, anhidrosis or hyperhidrosis, urinary retention, impotence, and constipation. Lumbar radiculopathy and cauda equina symptoms may be present in the setting of root nerve hypertrophy. Bilateral phrenic nerve palsy has also been reported, but are rare. Tremors, sensory ataxia, neuropathic pain, cramps, and fatigue can be seen in the asymmetric multifocal, purely motor, or purely sensory predominant forms. Atypical symptoms should prompt the clinician to rule out alternate diagnoses.
A good longitudinal and careful history recorded across time with serial physical examinations before and after immunomodulatory treatment can clinically help confirm the diagnosis to CIDP. A long-standing history of uncontrolled diabetes mellitus should also raise suspicion for CIDP. Ancillary testing, which will be discussed in the following section, is essential to distinguish typical from atypical variants.
Atypical Variants (Clinical)
The diagnosis of CIDP can be very challenging, especially with distinct clinical presentations. Therefore, making the correct diagnosis is very important as CIDP is amenable to treatment. While early diagnosis and treatment will prevent the progression of the disease to axonal damage, but CIDP is also commonly overdiagnosed in almost 50% of the patients. Due to a lack of consensus, the diagnosis is essentially based on clinical features followed by electrophysiological criteria. The laboratory, cerebrospinal fluid analysis, and nerve biopsy are ancillary testings.
Electrophysiological Findings of Classical CIDP
Electrophysiological studies/Nerve conduction study (NCV) helps to differentiate a demyelinating process from an axonal. Axonal can be primary or secondary to demyelination and does not exclude CIDP. There are 15 different sets of diagnostic criteria to diagnose CIPD. Of all, the European fenestration of neurological societies and peripheral nerve SocietyEFNS/PNS 2010 diagnostic criterion. has 83% sensitivity and 97% specificity. Based on this criterion, CIDP can be diagnosed as definite, probable, possible.
A. For the definite, the following demyelination changes on NCV have required in at least two nerves.
B. For probable
C. For possible CIDP, the findings described in A that need to be there in a single nerve
Atypical Variant Electrophysiology
CIDP is idiopathic; therefore, appropriate labs to evaluate for other causes of acquired, inflammatory, and demyelinating neuropathies such as Lyme borreliosis, West Nile, HIV/AIDS infection, lymphoma, or sarcoidosis, hemoglobin A1c, thyroid function testing, vasculitic markers should be done. Sometimes, serum immunofixation is done to evaluate for IgM neuropathies such as Anti-MAG, POEMS.
Similar to GBS where albuminocytological dissociation is seen. Most patients (around 85-90%) with CIDP have elevated protein and mild pleocytosis of less than 10/µL. WBC, more than 50/µL, should raise suspicion for alternate diagnoses. Elevated CSF protein is considered as ancillary testing more than a diagnostic criterion; therefore, a normal CSF protein does not exclude the diagnosis.
It is ancillary with high specificity. The features of CIDP are described earlier under the histopathological section. It's particularly useful in challenging cases. Nerve biopsy can exclude other causes of neuropathy such as amyloidosis, vasculitis, toxic or hereditary neuropathies.
With more understanding of this entity and advancement, nerve and root imaging is incorporated in aiding the diagnosis. The breach in the blood-brain barrier due to inflammatory cells can be seen as gadolinium enhancement on magnetic resonance imaging. Hypertrophy of the nerves can provide a clue of active inflammation. More recently, ultrasound techniques are being utilized to support the diagnosis of CIDP. The high-resolution ultrasound helps to visualize the gross anatomy of the nerves and perhaps has the potential to monitor disease activity.
The first-line treatment options for CIDP include corticosteroids, intravenous immunoglobulins (IVIG), and plasma exchange (PLEX). Given long-term adverse effects, corticosteroids are used as bridge therapies; serial IVIG and plasmapheresis are the mainstays of therapy. Both of them have similar efficacy. However, the long-term adverse effects, as well as the cost-effectiveness, needs to be weighed against the benefits of continuing any maintenance therapy. Steroid-sparing immunosuppressive agents may be used as maintenance therapy (e.g., Azathioprine, Cyclosporine, Tacrolimus, Mycophenolate).
Steroid Sparing Agents for Maintenance Therapy
Differential diagnosis includes the following:
The long-term prognosis depends on the age at onset, clinical course, and the initial response to treatment. About 90% of the patients with CIDP improve with immunosuppressive treatment with a 50% relapse rate. Overall long-term prognosis is good for patients with CIDP diagnosed at a younger age and with a monophasic or a relapsing course.
In a study reported in South England, 54% of patients were severely disabled by CIDP at some stage of their disease. Usually, these patients are followed up for years, the longer they are followed up the more are the chances of relapses. Based on clinical examination and nerve conduction study, if there is no worsening seen then the immunosuppressive therapy can be eventually be tapered off. A study with 40 patients by Dyck et al demonstrated 72% of patients required immunosuppressive therapy while 27% achieved remission off therapy.
About 54% of the patients are misdiagnosed as CIDP. Such patients are committed to long-term immunosuppressive therapy. Despite the availability of several immunosuppressive therapies, a majority of the CIDP patients have some form of disability. Furthermore, the patients suffer from several treatment-related side effects such as hypertension, thromboembolic events, risks of infections, bone marrow suppression, nephrotoxicity, and malignancies such as lymphoma.
CIDP is commonly misdiagnosed or overdiagnosed. Patients need to know that early diagnosis and treatment can prevent the progression as well as disabling deficits. The patients need to be aware of the diverse symptoms and the need for timely evaluation by a neurologist or a neuromuscular specialist. The long course of the disease, the side effects of medications, and medical expenses that come along can sometimes be discouraging to the patients for continuing therapy. However, there are several therapeutic options available that can not only prevent relapses but some patients also achieve complete remission.
The diagnosis and management of CIDP are complex, requiring an interprofessional inpatient and outpatient team that includes a general neurologist, neuromuscular specialist, intensivist, physical and rehabilitation specialist, pain management specialist, physical therapist, occupational therapist, psychiatrist, social workers, and case management staff. Aggressive immunomodulatory therapy combined with physical neurorehabilitation is essential for a long-term favorable outcome. Some of the barriers that may hinder clinical improvement include social determinants of health, pain control, aggressive clinical variants, among others. An interprofessional team approach will result in the best outcomes. [Level 1]
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