Continuing Education Activity

Chronic inflammatory demyelinating polyradiculoneuropathy can be caused by multiples diseases, from infectious as well as immunology diseases. It is one of the most challenging diagnoses, and sometimes underdiagnosis for variable presentation. To avoid high mortality as well as morbidity, it must be promptly diagnosed and treated. This activity reviews the evaluation, diagnosis, and treatment of neuropathy, demyelinating polyradiculoneuropathy, chronic, inflammatory, and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology, of chronic inflammatory demyelinating polyradiculoneuropathy.
• Review the risk factors for developing chronic inflammatory demyelinating polyradiculoneuropathy.
• Summarize the management options available for chronic inflammatory demyelinating polyradiculoneuropathy.

Introduction

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.[1] 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).[2] The first case was described by Eichhorst Burns in 1890.[3] About 16% of the patients present with acute GBS.

Etiology

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.

Epidemiology

A recent meta-analysis showed a crude incidence rate of 0.33 per 100,000.[4] 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.[5][1]

Pathophysiology

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.[6] 

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.[5]

Histopathology

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.[7] 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.[8] 

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.[5] 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.[6] 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.[8]

History and Physical

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.[9] 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.[10] 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.[11]

Typical Variants

• Symmetric Sensorimotor variant (motor 94%> sensory 89% symptoms)

Atypical Variants (Clinical)

• Distal acquired demyelinating symmetric neuropathy variant  (DADS)- distal predominant dysesthesias, can overlap with CISP variant with sensory ataxia, motor weakness appears late in advance stages of the disease.
• Multifocal acquired demyelinating sensory and motor neuropathy variant 6% to 15% (MADSAM or Lewis-Sumner syndrome)- Asymmetric, mixed sensorimotor clinical symptoms.
• Proximal radiculopathy variant (brachial or lumbosacral plexopathy)- Bilateral motor-sensory deficits that follow a root/plexus distribution, predominant in upper or lower extremities depending on the plexus affected
• Pure motor variant 7% to 10%- A relapsing-remitting focal or diffuse motor weakness
• Pure sensory variant- 5% to 35%- lower extremity predominant dysesthesias with or without sensory ataxia
• Chronic immune sensory polyradiculopathy (CISP) variant- Clinically similar to the pure variant except that the sensory ataxia is predominant given the disruption of dorsal column nerve conduction

Evaluation

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.[12] 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.[13][14]  has 83% sensitivity and 97% specificity. Based on this criterion, CIDP can be diagnosed as definite, probable, possible.[13][14][15]

A. For the definite, the following demyelination changes on NCV have required in at least two nerves. 

1. Prolonged distal CMAP latencies more than 50% above the upper limit of normal value (excluding the median nerve)
2. Reduction of motor conduction velocity more than 30% below the lower limit of normal value (independent of the compression site)
3. Prolongation of F wave latency more than 30% about the upper limit of normal value
4. Absence of F waves in 2 or more nerves, if these nerves have distal negative peak CMAP amplitudes ≥20% of LLN + ≥1 other demyelinating parameter in ≥1 other nerve,
5. Partial motor conduction block with at least 50% amplitude reduction of proximal CMAP relative to the distal negative peak
6. Abnormal temporal dispersion (prolongation of proximal motor response duration by 30% or more)
7. Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) increase in ≥1 nerve (median ≥ 6.6 ms, ulnar ≥ 6.7 ms, peroneal ≥ 7.6 ms, tibial ≥ 8.8 ms) + ≥1 other demyelinating parameter in ≥1 other nerve 

B. For probable

• At least 30% reduction of the amplitude of the proximal negative peak CMAP relative to distal, if the distal negative peak CMAP at least 20% of the lower limit of normal values, in 2 nerves OR in one nerve + at least one other demyelinating parameter in one or more other nerves. 

C. For possible CIDP, the findings described in A that need to be there in a single nerve

Atypical Variant Electrophysiology

• Distal acquired demyelinating symmetric neuropathy variant  (DADS)- initially, the sensory conduction is affected, with some overlap of posterior column deficits, as seen in the CISP variant. Often there are conduction deficits on motor potentials. A unique feature is that more than half of the patients generate IgM gamma antibodies against anti-myelin-associated glycoprotein (anti-MAG) in CSF.[16]
• Multifocal acquired demyelinating sensory and motor neuropathy variant 6 to 15% (MADSAM or Lewis-Sumner syndrome)- abnormal nerve conduction studies (NCS), including multi-focal sensory and motor conduction blocks within one or both upper extremities. In a later course, the lower extremities may develop the typical CIDP pattern.[17]
• Proximal radiculopathy variant (brachial or lumbosacral plexopathy)- proximal and distal sensory and motor nerve conduction is affected, usually affecting upper or lower extremities, depending on the plexus affected. Advanced imaging can help distinguish this variant from other by gross hypertrophy of the plexus affected. 
• Pure motor variant 7% to 10%- minimal or absent sensory electrophysiological deficits.[18]
• Pure sensory variant- 5% to 35%- pure sensory conduction abnormalities are rare. most often, there is evidence of motor-axonal demyelination in advanced stages.[19][20] 
• Chronic immune, sensory polyradiculopathy (CISP) variant-may have a normal distal NCS sensory potentials with focal damage to the posterior columns and large fibers.[21]

Laboratory Finding 

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.[1] Sometimes, serum immunofixation is done to evaluate for IgM neuropathies such as Anti-MAG, POEMS.[8]

CSF Criteria

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.[2]

Nerve Biopsy

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.[2]

Imaging

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.[22] The high-resolution ultrasound helps to visualize the gross anatomy of the nerves and perhaps has the potential to monitor disease activity.[23]

Treatment / Management

The first-line treatment options for CIDP include corticosteroids, intravenous immunoglobulins (IVIG), and plasma exchange (PLEX).[7] 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.[24] 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).

Corticosteroids 

• The usual induction dose of prednisone is 60 to 100 mg per day. This can be tapered after steroid-sparing medications reach a steady-state in patients/.[25]
• Studies have shown no difference between using high dose monthly dexamethasone to daily oral prednisone.[26]
• Corticosteroids are rather much cheaper and easier to use.
• Serious side effects of corticosteroids are hypertension, diabetes, moon facies, osteoporosis and fractures, myopathy, sleep and mood disturbances, cataract, skin and hair changes, immunosuppression, and risk of infections.[27]

IVIG

• The ICE (Immune Globulin Intravenous for Chronic Inflammatory Demyelinating Polyneuropathy) trial in 2008 was the largest reported study of CIDP treatment that showed the efficacy and the safety of IVIG as the initial and maintenance therapy for CIDP to prevent frequent relapses.[28] 
• The relapse rate with IVIG is reported at around 45%, whereas corticosteroids are around 50%.[29]
• The median time to deterioration was delayed or slowed after chronic administration of corticosteroids and IVIG.
• Dosing: IVIG is administered as an initial induction dose of 2 g/kg over 2 to 5 days, followed by a maintenance dose of 0.4 g/kg (0.2 to 1 g/kg) every 3 to 4 weeks.
• More recently, the PATH study reported the safety and efficacy of subcutaneous IG for maintenance therapy of CIDP given for 24 weeks. The study showed equal efficacy with fewer generalized side effects as compared to IVIG.[30][31][30]
• Some adverse effects related to IVIG are infusion reactions, fever, chills, hypotension, thrombotic events, aseptic meningitis.[32]

Plasma Exchange

• Plasma exchange is typically used in severe cases or if patients do not respond to corticosteroids and IVIG. It usually requires 5-10 sessions over 2-4 weeks, and the response is faster compared to IVIG or steroids. The main caveat is the requirement of central venous catheter placement and the associated risk of infections. Some other adverse effects are hypotension, hypocalcemia, allergic reaction to albumin infusion, citrate toxicity.[33]

Steroid Sparing Agents for Maintenance Therapy

• There is no clinical guideline about the duration of maintenance therapy. Based on the clinical response and relapses, maintenance therapy is usually given for about six months. 
• Patients requiring chronic therapies with high-risks of developing serious adverse effects from corticosteroids or IVIG can be switched to other immunosuppressive agents such as methotrexate, cyclosporine, cyclophosphamide, rituximab, mycophenolate. There are no major randomized trials for most of these therapies; however, they have shown benefits in smaller case studies or anecdotal reports.
• Azathioprine (2 mg/kg) offers unclear benefits. Methotrexate (15 mg weekly) has no benefit. Rather can cause serious adverse effects compared to placebo.[34] Similarly, intramuscular interferon–beta–1A (Avonex) at low (30 µg weekly), intermediate (30 µg twice weekly), and high dose (60 µg twice weekly) compared to IVIG did not show any additional benefit.[35][36]
• Mycophenolate mofetil has been used alone or in combination with prednisone to treat various autoimmune conditions, including CIDP. Similar to Azathioprine, it can cause bone marrow suppression and is contraindicated in pregnant females.[15][25][15]
• Approximately 25% of patients are refractory to first-line treatment. These patients require further investigations to evaluate for CIDP variants or other causes of acquired demyelinating chronic neuropathies. In such cases, targeted therapies such as rituximab and alemtuzumab can be used.

Differential Diagnosis

Differential diagnosis includes the following:

• Toxic and metabolic neuropathy
  • Diabetic lumbosacral radiculopathy-plexopathy
  • Non-diabetic lumbosacral radiculopathy-plexopathy
  • Chemotherapy-induced demyelinating neuropathy (e.g. TNF alpha)
• Acute inflammatory demyelinating polyneuropathy
• Infectious Neuropathy (Lyme disease, diphtheria, HIV)
• Hereditary demyelinating neuropathy and hereditary CIDP mimics
  • Charcot-Marie-Tooth (CMT) disease, especially CMT1
  • Hereditary neuropathy with liability to pressure palsies
  • Transthyretin (TTR) familial amyloid polyneuropathy (FAP)
• Multifocal motor neuropathy (MMN)
• Distal acquired demyelinating symmetric neuropathy (DADS) with IgM monoclonal gammopathy with antibodies to myelin-associated glycoprotein (MAG)
• Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD)
• PNS lymphoma
• Systemic amyloidosis
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes-POEMS syndrome/osteosclerotic myeloma

Prognosis

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.[1][37] 

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.[38] A study with 40 patients by Dyck et al demonstrated 72% of patients required immunosuppressive therapy while 27% achieved remission off therapy.[39]

Complications

About 54% of the patients are misdiagnosed as CIDP.[12] 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.[40][15]

Deterrence and Patient Education

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.

Pearls and Other Issues

• CIDP is a type an immune-mediated disorder that affects the myelinated structures of the peripheral nervous system
• It can be monophasic, progressive, relapse-remitting developing over more than 8 weeks which distinguishes it from AIDP and GBS variants 
• It is typically symmetric, affecting proximal and distal sensorimotor patterns, with a demyelinating nerve conduction pattern that includes a focal or multi-focal distal latency prolongation, decreased or block in conduction, prolonged or absent F-wave latency, temporal dispersion, and increased duration.
• Atypical variants include DADS, CISP, MADSAM/Lewis-Sumner syndrome, focal/diffuse brachial or lumbosacral plexopathy, pure motor, and pure sensory.
• The pathophysiology includes a chronic, maladaptive self-targeting of myelinated components of the neurons by the coordinated activation of innate (macrophages) and adaptive immune system, including humoral (B and T cell) and cell (T-cell) based mechanisms.
• Typical symptoms include symmetric large> small fiber paresthesias, paraparesis, diffuse fatigue, and areflexia.
• Atypical symptoms include asymmetric allodynia, painful cervical/lumbar radiculomyelopathies, multiple cranial nerve neuropathies, bulbar (dysarthria, dysphagia, dyspnea), and autonomic symptoms (e.g. dysrhythmias, urinary retention, and constipation), tremors, and spasticity.
• Uncontrolled diabetes mellitus type II is a strong risk factor to develop CIDP.
• Alternate differential diagnosis includes toxic, metabolic, systemic, infectious, iatrogenic, hereditary, neoplastic, and multifocal motor neuropathies.
• Supporting ancillary testing include a CSF with albumocytological dissociation, gadolinium-enhancing hypertrophy of the neuroaxis, delayed somatosensory evoked potentials, or biopsy with unequivocal evidence of demyelination/remyelination.
• Treatment includes acute and chronic immunomodulatory treatments such as serial IVIG, plasmapheresis, prednisone, mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, and in special cases, rituximab
• Complications of therapy include infusion reaction, headaches, infections, renal failure, and hypercoagulability.
• Prognosis is variable and can depend on the age, clinical course, responsiveness to treatment, and electrophysiological findings.
• Aggressive rehabilitation is instrumental for the long-term recovery of CIDP patients

Enhancing Healthcare Team Outcomes

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]