Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder characterized by chronic inflammation of the peripheral nerves, resulting in loss of the myelin sheath that insulates these nerves.¹ Early diagnosis and effective treatment are paramount, because untreated CIDP can result in axonal loss and permanent nerve damage.² CIDP has heterogeneous features, but its most common clinical presentation is symmetric progressive proximal and distal muscle weakness with distal numbness evolving over at least 8 weeks. Its clinical course can be progressive, monophasic, or relapsing-remitting.³

Epidemiology

The incidence of CIDP is estimated to be between 0.15 and 1.6 cases per 100,000 person-years, and the overall prevalence ranges between 0.67 and 10.3 per 100,000 individuals.⁴ On average, the mean age at onset is around 40 to 60 years, and men are more frequently affected than women (2:1 ratio).⁵ Contrary to acute demyelinating neuropathies, regional differences have not been identified.⁵

Etiology and Pathogenesis

CIDP is thought to be primarily autoimmune.³ The clinical heterogeneity and variability of response to treatment suggest different immunologic mechanisms.⁵ In CIDP, the immune system attacks the myelin sheath of the peripheral nerves, which is followed by segmental demyelination, and, in certain cases, secondary axonal degeneration.^2,6–8 The immunopathogenesis of CIDP is complex and beyond the scope of this article.⁷ Briefly, it is thought to be a combination of cell-mediated and humoral immunity responses against antigens within the peripheral nerves.⁹ This results in inflammation and macrophage-induced demyelination.⁷ The factors that trigger these aberrant immune responses remain unknown.

Clinical Presentation

CIDP has a wide spectrum of clinical presentation. The most recent classification divides the spectrum into typical CIDP, CIDP variants, and autoimmune nodopathies.¹⁰

Typical CIDP

Typical CIDP, which comprises just over half of CIDP cases,³ usually starts with paresthesia and weakness in the distal limbs and gait difficulties. Symptoms steadily progress for longer than 8 weeks. Most commonly, there is a progressive symmetric proximal and distal weakness, sensory loss (typically proprioception and vibration sense), and diminished or absent reflexes. In contrast to Guillain-Barré syndrome, cranial nerves, respiratory muscles, and the autonomic nervous system are rarely affected.^3,7,10

CIDP Variants

Distal Acquired Demyelinating Symmetric Neuropathy. Distal acquired demyelinating symmetric (DADS) neuropathy presents with sensory loss distally in all 4 limbs. Gait disturbances are common. Weakness may occur distally as well, more in the lower than upper limbs, but proximal involvement is lacking. Two-thirds of individuals with DADS neuropathy have immunoglobulin M (IgM) paraproteinemia, and within this subgroup, most have antibodies to myelin-associated glycoprotein (MAG).

Anti-MAG neuropathy differs in clinical course, electrodiagnostic characteristics, pathology, and response to treatment, and is considered a separate entity from CIDP.^3,7,10 This disorder comprises 2% to 17% of all CIDP cases.³ The clinical course usually is slowly progressive, and tremors of high amplitude and low frequency are common.

Multifocal CIDP. The prevalence of multifocal CIDP is 6% to 15% of CIDP cases.³ Multifocal CIDP is also known as multifocal demyelinating neuropathy with persistent conduction block (Lewis-Sumner syndrome), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and multifocal inflammatory demyelinating neuropathy. The upper limbs frequently are affected first, with subsequent lower limb involvement. Cranial nerves (including oculomotor, facial, and vagal, among others) are more frequently involved in multifocal CIDP than in other CIDP subtypes.^7,10

Focal CIDP. Focal CIDP is rare (1% of CIDP cases) and usually affects the brachial or lumbosacral plexus. Individual nerves also can be affected.³ Focal CIDP has been conceptualized as one end of a spectrum of disease (localized MADSAM or CIDP).^10,11

Motor CIDP. The prevalence of motor CIDP is between 4% and 10% of CIDP cases.³ Motor CIDP is similar to typical CIDP, but with preserved sensation, including on sensory conduction studies. This contrasts with multifocal motor neuropathy (MMN), in which the pattern of weakness is asymmetric, and mostly affects the upper limbs. If sensory conduction study results are abnormal, the term motor-predominant CIDP is used.¹⁰

Sensory CIDP. Sensory CIDP is characterized by impairment of vibration and joint position sense and gait ataxia with preserved muscle strength. The prevalence is estimated to be 4% to 35% of CIDP cases.³ If motor conduction abnormalities are noted, the term sensory-predominant CIDP is used. However, studies have shown that sensory CIDP is a transient stage and precedes onset of weakness in 70% of cases.¹⁰

Disorders Not Classified as CIDP by European Academy of Neurology/Peripheral Nerve Society Task Force¹⁰

Chronic inflammatory sensory polyneuropathy. Chronic inflammatory sensory polyneuropathy (CISP) constitutes 5% to 12% of CIDP cases. CISP is considered a pure sensory CIDP, with the distinct feature of preganglionic nerve root involvement. This results in normal sensory conduction studies because the postganglionic fibers are intact. In CISP, somatosensory evoked potentials (SSEPs) are helpful and show slowing of responses, most commonly at N13 (cervical) latencies or N9 through N13 interpeak latencies (segments that include cervical roots).^10-12 Protein in cerebrospinal fluid (CSF) has been shown to be elevated in 92% of cases and MRI of the spine can show root enhancement.¹²

Autoimmune Nodopathies. The most recently described subtype within CIDP, autoimmune nodopathies involve autoantibodies targeting specific molecules within the nodes of Ranvier.¹³ Antibodies against neurofascin 155 (NF155), neurofascin 186 (NF186), contactin 1 (CNTN1), and contactin-associated protein 1 (CASPR1) have been identified in individuals within this group.¹³ The majority of these antibodies are immunoglobulin G4, which cannot activate complement or bind to immunoglobulin receptors (Fcγ receptors).⁹ This may explain the lack of response to intravenous immunoglobulin (IVIg).

There is some overlap among these antibody-related conditions, but specific clinical characteristics have been identified for each antibody.^9,10 Ataxia and poor response to IVIg are common features across all of them.¹⁰ Anti-NF155 antibodies occur in younger individuals with distal weakness. These individuals may develop a low-frequency, high-amplitude tremor, which can be debilitating. People with anti-CNTN1 antibodies can present with acute to subacute severe weakness, and tremors and glomerulonephritis can occur in this disorder. In the case of anti-CASPR1 or anti-CNTN1/CASPR1 complex antibodies, individuals may have an acute presentation resembling Guillain-Barré syndrome (GBS) with cranial nerve involvement. Neuropathic pain can also occur.¹³

Differential Diagnosis

The differential diagnosis of demyelinating neuropathies is relatively narrow, with inherited demyelinating neuropathies, paraproteinemic neuropathies, and MMN being the main considerations. In addition, whereas GBS typically involves a rapid neurologic decline with nadir by 4 weeks, and follows a distinct clinical course, there are instances where it may be the initial presentation of CIDP. The Figure illustrates differential diagnoses. These alternative diagnoses are discussed in the following section.

Paraproteinemic Neuropathies

Paraproteinemic neuropathies are a group of neuropathies associated with the presence of a paraprotein in the serum. Briefly, paraproteins are immunoglobulins overproduced by an abnormal clonal proliferation of plasma cells. Paraproteins be heavy chains or immunoglobulins (such as immunoglobulin A [IgA], IgM, or immunoglobulin G [IgG]) or light chains (kappa or lambda). This could occur in the setting of hematologic premalignancy or malignancy, such as lymphoma, multiple myeloma, or primary amyloidosis. However, paraproteinemia most commonly occurs as monoclonal gammopathy of undetermined significance (MGUS). The incidence of MGUS increases with advancing age, and involves the accumulation of bone marrow plasma cells from a single abnormal clone without malignant proliferation.¹⁴ There are different presentations within paraproteinemic neuropathies; the most common ones are detailed in the following.

Anti-MAG Neuropathy. Anti-MAG neuropathy usually has slow progression, and is clinically similar to distal acquired demyelinating symmetric neuropathy. Anti-MAG neuropathy involves predominantly distal sensory symptoms with minimal weakness. Individuals usually have tremors of high amplitude and low frequency. Anti-MAG antibodies in addition to an IgM paraprotein are present. People with proximal disease usually show response to rituximab.¹⁴

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) is a multisystemic syndrome in the setting of a plasma cell proliferative disorder, most commonly lambda-restricted. People with POEMS syndrome have a severe subacute demyelinating neuropathy, usually distal, that can progress rapidly and cause severe pain.¹⁵ The associated monoclonal protein is almost always lambda light chain, with either IgG or IgA heavy chain, in contrast to the more commonly associated IgM in MGUS and anti-MAG neuropathy. The presence of demyelinating neuropathy and monoclonal gammopathy constitute major criteria for establishing the diagnosis. Vascular endothelial growth factor levels are often elevated. They are associated with increased microvascular permeability resulting in papilledema and dependent lower-extremity edema. Osteosclerotic myeloma is a common association as well, and requires X-ray skeletal survey, low-dose total-body CT scan, or MRI.¹⁶ Diabetes and thyroid disorders are not sufficient to qualify as endocrinopathy for the minor diagnostic criteria of POEMS syndrome. Individuals may exhibit distinct skin changes, such as hyperpigmentation, hypertrichosis, or hemangiomas, and may have thrombocytosis or leukocytosis. Organomegaly, particularly hepatomegaly or splenomegaly, is common in POEMS syndrome.^15,16

Chronic Ataxic Neuropathy With Ophthalmoplegia, IgM Paraprotein, Cold Agglutinins, and Disialosyl Antibodies. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD) is a rare disorder that clinically resembles chronic Miller Fisher syndrome, with ataxia, areflexia, and ophthalmoplegia. Ataxia in CANOMAD is usually disabling. The antibodies present in CANOMAD are anti-ganglioside, anti-GD1b, and anti-GQ1b.⁹

Multifocal Motor Neuropathy

MMN presents with asymmetric weakness, and most commonly affects the upper limb. MMN can be described as a pure motor multiple mononeuropathy. Muscle atrophy is a common finding, even early in the disease course. One-third of individuals present with foot drop that precedes upper limb involvement.¹⁷ Men are more commonly affected, and age at onset is somewhat younger than that of typical CIDP (The median age of onset for MMN is 40 years versus over 50 years in CIDP).^4,18 Cramps and fasciculations can be seen in 40% of cases, and cold aggravates weakness. Electrodiagnostic studies show conduction block, which is the key neurophysiological criterion in the diagnosis of MMN. Anti-GM1 antibodies are present in 40% of cases.¹⁷ IVIg is the first line of treatment and is usually required long-term.

Diagnostic Criteria

The diagnosis of CIDP is made using a combination of clinical (Table) and electrodiagnostic criteria as defined by the 2021 European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) Guideline.^3,10

Electrodiagnostic Criteria

Electrodiagnostic studies are key to supporting the clinical diagnosis. A report by Van den Bergh et al contains a detailed overview of the motor and sensory electrodiagnostic criteria from the 2021 EAN/PNS Guideline.¹⁰ CIDP confirmation is predominantly based on motor nerve conduction findings. However, there are important pitfalls in interpreting electrodiagnostic studies¹⁹: the reduction in compound muscle action potential amplitude leads to loss of faster conducting fibers, so conduction should be significantly slower than the lower limit of normal to be considered primarily demyelinating; cool temperatures (<30° for lower limbs and <32° for upper limbs) can falsely appear as slowing distal latencies and velocities; and coexisting disorders such as diabetic polyneuropathy, entrapment neuropathies, or radiculopathies can confound the interpretation of electrodiagnostic studies.

In anti-MAG neuropathy, motor distal latencies are much more severely prolonged than slowing of conduction velocity.¹⁴ Electrodiagnostic features of POEMS and CIDP are indistinguishable.¹⁶

Supportive Criteria

Imaging, CSF, and response to treatment can support the diagnosis of CIDP. Nerve biopsy is rarely indicated.

Imaging. MRI can add value in assessing proximal nerves and the brachial and lumbosacral plexuses, showing nerve hypertrophy and gadolinium enhancement. Ultrasound can be used to evaluate for nerve hypertrophy, and may be helpful in cases of diagnostic uncertainty, such as in possible CIDP.¹⁰ However, nerve hypertrophy can be present in hereditary neuropathies,²⁰ and nerve enhancement, especially of the cauda equina, can be seen in carcinomatosis, lymphoma, sarcoidosis, and infections.²¹

Cerebrospinal Fluid. Albuminocytologic dissociation in CSF (normal leukocytes, <10 cells/µL, with elevated protein) is often seen (sensitivity of 42%-77%) in people with CIDP.¹⁹ However, mild protein elevations can be found in people with diabetes.¹ Furthermore, protein levels in CSF increase with age. Therefore, a cutoff of .6 g/L has been established for individuals older than 50 years.²² If leukocytes are elevated (>50 cells/µL), an alternative diagnosis, such as infection or malignancy (lymphoma or carcinomatosis) should be considered. A small subset of people with CIDP can have >10 cells/µL.²³

Response to Treatment. In cases where the highest diagnostic certainty is limited to possible CIDP, response to treatment (IVIg, plasmapheresis, or corticosteroids) can support the diagnosis of CIDP. A significant response to treatment is based on improvement in neurologic examination results and improvement on at least 1 established disease-monitoring scale. The most frequently used scales are the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (a >1-point improvement is considered relevant) and the Medical Research Council sum score (a >10% change is considered relevant).¹⁰ The Inflammatory Rasch-Built Overall Disability Scale (I-RODS), an outcome measure focused on the effects of disease on daily activity as rated by the individual, is also useful.²⁴ The Inflammatory Rasch-built Overall Disability Scale (I-RODS) is solely based on individual report; the INCAT assesses functionality based on a physical examination, which may not always reflect the true disability experienced by the individual.

Nerve Biopsy. Nerve biopsies are rarely needed in diagnosis of CIDP, and are reserved for specific cases of diagnostic uncertainty, particularly when conditions such as vasculitis are considered in the differential diagnosis.²⁵ Nerve biopsies should be limited to severely affected nerves (clinically or on electrodiagnostic studies) to prevent additional functional loss and secondary complications (eg, pain, neuroma formation). Histopathologic features supporting CIDP diagnosis are thin myelinated axons and small onion bulbs, thin myelinated or demyelinated internodes in teased fibers, and perivascular macrophage clusters.

Serologic Testing. Assessment for serum monoclonal proteins using serum protein electrophoresis with immunofixation should be performed in every individual with suspected CIDP. Serum free light chains, which are unbound and not detected by serum protein electrophoresis or immunofixation, could also help identify an abnormality. If results of any of these tests are abnormal, further evaluation with hematology-oncology is advised.¹⁰ Anti-MAG antibodies should be tested in distal CIDP.^10,26 Repeat testing for an IgM monoclonal component or anti-MAG antibody is indicated if not initially present. In distal, painful CIDP, POEMS is high in the differential, and vascular endothelial growth factor levels should be checked. POEMS is associated with IgA or IgG lambda paraprotein.¹⁵

Nodal and paranodal antibodies (ie, anti-NF155, NF140/186, anti-CNTN1, anti-CASPR1) should be tested, if available, in every individual suspected to have CIDP. This has prognostic implications, because these disorders do not respond well to conventional therapies, and individuals may benefit from early rituximab use.^10,13 These antibodies should be checked in first-line testing especially in treatment-refractory cases, and in people with aggressive onset, prominent tremor, ataxia, respiratory failure, cranial nerve involvement, very high CSF protein, or nephrotic syndrome.

Additional Testing. SSEPs use is limited in diagnosis of CIDP, but can be very helpful in diagnosing pure sensory CIDP. Studies have shown that up to 100% of individuals with CISP who did not meet EDX criteria for CIDP had involvement of the nerve roots based on SSEPs.¹

Treatment

CIDP is an autoimmune disease and treatment is focused on immunosuppressive and immunomodulatory therapies. The primary goals are to reduce symptoms and disability. There is no single first-line therapy, and therapeutic choices differ based on regional and provider preferences and treatment availability.

IVIg and steroids are first-line therapies, with demonstrated benefit in multiple studies.^26,27 The seminal randomized, double-blind, placebo-controlled Intravenous Immune Globulin for the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy study (ICE study) showed significant improvement in Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score in participants with CIDP treated with IVIg vs placebo.²⁷ The placebo response in phase I was 21%, but the placebo effect in phase II was 58%.²⁷ IVIg has different immunomodulatory effects, including downregulation of cytokines, neutralization and clearance of antibodies, and complement regulation, among others.²⁶ The usual regimen is an initial loading dose of 2 g/kg divided over 2 to 5 days followed by maintenance doses of 1 to 2 g/kg every 4 to 8 weeks.²⁶ Subcutaneous immunoglobulin (SCIg) is an alternative to maintenance IVIg, typically dosed weekly. The randomized, double-blind, placebo-controlled Polyneuropathy and Treatment with Hizentra (PATH) study demonstrated that SCIg was effective in preventing relapses when compared with placebo in participants with CIDP, and SCIg was better tolerated than IVIg.^28,29 In general, individuals experience treatment response within weeks of initiating IVIg, but in some cases, it may take up to 6 to 12 months for a substantial response to occur. IVIg is also first-line therapy in MMN.²

Corticosteroids have similar efficacy to IVIg.³⁰ Multiple dosing strategies have been described, typically starting high (60 to 100 mg/day) with progressive taper over time (typically months).^26,30 Pulse corticosteroids have shown similar results to IVIg and oral prednisone, with lower frequency of weight gain and development of Cushingoid features.³¹

Plasma exchange, which removes circulating antibodies and immune factors associated with demyelination, has been shown to be effective.³² An induction phase with 6 sessions over a 2-week period is followed by maintenance therapy of at least 1 session every 6 to 8 weeks. This is a more invasive treatment, and is used as a second-line therapy for refractory and severe cases.^10,26

Other second-line agents for refractory cases or for steroid- and IVIg-sparing treatments are cyclophosphamide, methotrexate, azathioprine, or mycophenolate, among other immunosuppressive drugs.^5,11,26 Their efficacy has not been demonstrated in clinical trials. Rituximab, an anti-CD20 monoclonal antibody, has been shown to be effective in treatment of refractory CIDP, particularly in individuals with nodal and paranodal antibodies.³³ Rituximab has been shown to be effective in up to 30% to 50% of treated individuals.^14,34 Additionally, rituximab is most often used as first-line therapy in anti-MAG neuropathy.⁵

For the most refractory CIDP cases, stem cell transplant has been suggested.³²

Prognosis and Long-Term Treatment

Given the heterogeneity of CIDP, there is a paucity of studies assessing treatment duration and prognosis. A recent meta-analysis estimated a favorable prognosis overall, with 47.1% of individuals having good outcomes without long-term disability, although 8.2% of individuals were nonambulatory.³⁵ The remission rate (ie, treatment-free stable condition for 1 year after initial treatment) from this study was estimated to be 40.8%. It has been suggested that if disease is stable for 6 to 12 months, a substantial proportion of individuals can stop treatment without relapsing. Withdrawal of therapy should be attempted with caution, with a slow taper of treatment and close monitoring. No specific taper method has been established. In general, tapering is performed by lowering dosage every 6 to 12 months. If the individual declines neurologically, the dose should be increased. Reassessment of the need for continuous treatment should be done every 1 to 2 years.^10,32 Conversely, escalation of therapy should be performed if neurologic deficits worsen or response is incomplete, especially in nodopathies.¹⁰

Development of New Therapies

The armamentarium to treat autoimmune disorders continues to grow. Two ongoing trials aim to expand the treatment options in CIDP (A Study to Assess the Efficacy, Safety and Tolerability of Rozanolixizumab in Subjects With Chronic Inflammatory Demyelinating Polyradiculoneuropathy [MyCIDPchoice], NCT03861481; A Study to Assess the Safety and Efficacy of a Subcutaneous Formulation of Efgartigimod in Adults With Chronic Inflammatory Demyelinating Polyneuropathy [CIDP, an Autoimmune Disorder That Affects the Peripheral Nerves] [ADHERE], NCT04281472). Neonatal Fc receptor (FcRn) inhibitors are a new and promising group of biologics that target FcRn, resulting in increased degradation of IgG.³⁶ Preliminary results have shown some benefit.³⁷ Complement inhibitors are being investigated in another clinical trial (Proof-of-Concept Study for SAR445088 in Chronic Inflammatory Demyelinating Polyneuropathy, NCT04658472). Other potential therapies are proteasome inhibitors (bortezomib) and Bruton tyrosine kinase inhibitors (Imbruvica [ibrutinib]; Janssen Biotech, Inc., Horsham, PA, and Pharmacyclics LLC, Sunnyvale, CA).³²

Immune Checkpoint Inhibitor–Related Immune Neuropathies

Immune checkpoint inhibitors are a new class of drugs targeting PD-1 and CTL-4 pathways to enhance immune-mediated tumor control. They carry the risk of autoimmune side effects, including neuropathies such as GBS and CIDP.³⁸ Among these, nivolumab in monotherapy or in combination with ipilimumab has been linked to CIDP.³⁸ Treatment depends on the severity of the symptoms, but usually involves discontinuation of immune checkpoint inhibitors in addition to IVIg or steroids.³⁹

Conclusion

CIDP is a complex disease with heterogeneous presentation. Diagnosis is not always straightforward, and proper interpretation of the clinical and diagnostic data is crucial to avoid misdiagnosis. There is no standardized treatment and assessing response can be difficult. Careful clinical evaluation and the use of standardized scales such as INCAT, I-RODS, and manual muscle testing can aid in assessing disease progression, treatment response, and disease relapses. Navigating the complexities of CIDP demands a multidimensional approach and continuous research efforts are essential to improve the understanding of this disease as well as to optimize treatment.