Introduction

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous group of immune-mediated neuropathies characterized by progressive, monophasic or relapsing-remitting sensorimotor neuropathy, affecting both the peripheral nerves and nerve roots. CIDP incidence ranges from 0.5 to 3.3 cases per 100,000 people, which increases with age and is more common in males.1–3 The clinical presentations of CIDP can be highly variable, encompassing both typical and atypical clinical variants. Nerve conduction studies (NCS) are the most important tool in the diagnosis of CIDP by demonstrating electrophysiological findings that support peripheral nerve demyelination. In daily practice, when NCS reveals abnormalities, it can be challenging to determine if a potentially “demyelinating” result indicates true peripheral nerve demyelination or if it stems from another cause, such as a reduced motor nerve conduction velocity (MNCV) in nerves with low compound muscle action potential (CMAP) due to the loss of large axonal fibers.3,4 The rarity, heterogeneous presentation, lack of highly specific diagnostic tests and absence of blood-based biomarkers make diagnosing CIDP challenging.5 Because CIDP is treatable6 and because under- and misdiagnosis are common, delay in treatment or overtreatment is frequently seen.7 Timely diagnosis and initiating treatment early may decrease the risk of permanent disability resulting from axonal damage.8–11 The European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) published the revised 2021 guideline on the diagnosis and treatment of CIDP.12 Despite advances in diagnostic criteria and tests, several challenges still persist. Distinguishing CIDP from other (demyelinating) neuropathies, especially in the case of a suspected CIDP variant, requires in-depth knowledge of the differential diagnosis, available diagnostic tests, and interpretation of diagnostic findings. There is ample evidence for the treatment of CIDP with immunomodulatory drugs, but tailoring the best treatment regimen to the individual patient continues to be a common challenge. Treatment response may differ between patients and timing of evaluation, as objectively as possible, is of utmost importance. Evaluating a treatment too early or underdosing can lead to dismissing a potentially effective treatment. On the other hand, evaluating a treatment too late or not using objective outcome measures can lead to overtreatment with an ineffective drug. This review aims to explore these challenges in diagnosing and treating CIDP, their implications for patient care, and potential strategies to overcome them.

Clinical Signs and Symptoms

Typical CIDP manifests as symmetrical sensorimotor neuropathy with proximal and distal limb involvement with absent or reduced tendon reflexes. Weakness must be more or less symmetric in all four limbs and the severity of proximal and distal weakness should be similar. Sensory disturbances are to be found in at least two limbs. The CIDP variants, which were formerly referred to as atypical CIDP variants,13 are specific clinical syndromes that share the same signs that are supportive of demyelination and respond to the same therapies and are therefore considered to be on the same disease spectrum as sensorimotor CIDP. The CIDP variants are divided into several groups based on the distribution of muscle weakness and sensory disturbances. Asymmetric CIDP, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) or Lewis-Sumner syndrome, is characterized by proximal and distal weakness in at least 2 limbs and sensory disturbances in the same multifocal distribution.14,15 It predominantly affects the upper limbs, although lower limbs can be affected as well, while cranial nerve deficits are more common in this phenotype.16–20 Focal CIDP is rare and similar to multifocal CIDP, but sensory and motor symptoms are limited to only one limb. In distal CIDP, also referred to as distal acquired demyelinating symmetric neuropathy (DADS), weakness and sensory disturbances are found predominantly in the lower limbs.16 Sensory CIDP presents with sensory disturbances in four limbs without weakness. If any of the motor conduction criteria are fulfilled, it would be classified as sensory-predominant CIDP.12 A long-term follow-up study revealed that 70% of patients who initially presented with a sensory CIDP phenotype, developed weakness over time and eventually evolved into a typical phenotype.21 Motor CIDP is characterized by symmetric, proximal and distal weakness in four limbs without any sensory symptoms. It is classified as motor-predominant CIDP if any sensory abnormalities are found through NCS.

Misdiagnosis is more likely to happen when a patient presents with signs that are consistent with any of the CIDP variants as opposed to typical CIDP, which is why it’s important to recognize the phenotypes and how to differentiate them from other diseases.7 Notably, length-dependent axonal neuropathies, length-dependent demyelinating anti-MAG neuropathy or genetic neuropathies can easily be misdiagnosed as distal CIDP, particularly when there is extensive axonal damage that could even result in (amplitude-dependent) conduction slowing. A more extensive overview of clinical characteristics of typical CIDP and the CIDP variants, red flags and important considerations for the differential diagnosis is presented in Table 1.

Table 1 Clinical Characteristics of CIDP Variants, Red Flags and Considerations

Diagnostic Criteria

The diagnosis of CIDP involves a combination of clinical evaluation, diagnostic tests consisting of nerve conduction studies (NCS), laboratory tests and potentially imaging, CSF examination, nerve biopsy, and treatment response. There have been many diagnostic criteria sets throughout the years, but generally the first revision of the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 criteria is regarded as the most widely used and accurate set.12,13,22,23 The second revision of this guideline by the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS), was published in 2021 and one study found a similar sensitivity and specificity for diagnosing CIDP when comparing the two guidelines in their own group of patients as compared to historical literature data.24 Another study found that the revised guideline had a lower sensitivity, but a higher specificity in their cohort of patients as compared to their control group consisting of patients with axonal peripheral neuropathy, most with diabetic polyneuropathy.25 NCS are crucial for demonstrating electrophysiological abnormalities that are supportive of peripheral nerve demyelination (Table 2). Some notable changes from the previous guideline include the removal of distinctions between “definite” and “probable” conduction blocks, consolidating them into a singular category of conduction blocks. Furthermore, tibial nerve conduction blocks are no longer included and the threshold for temporal dispersion in the tibial nerve has been adjusted to necessitate at least a 100% increase in CMAP duration. Sensory criteria have transitioned from being merely supportive to being integral to the electrodiagnostic criteria. The sensory demyelinating conduction criteria are now mandatory for possible sensory CIDP, while sensory conduction abnormalities are required for typical CIDP and other CIDP variants except for motor CIDP phenotype, where sensory conduction should be normal in at least four nerves.

Table 2 Motor and Sensory Nerve Conduction Criteria (EAN/PNS 2021 Guideline)

Additionally, the revision now introduces variant-specific electrodiagnostic criteria (Table 2), meaning that patients with a sensory or motor phenotype can meet the criteria for (possible) CIDP, despite the absence of motor or sensory conduction criteria respectively. When it comes to the supportive criteria, nerve ultrasound, which can be used to show an increase of cross-sectional area of the peripheral nerve and nerve roots,26–28 has now been included in the supportive criteria. Evidence supporting the use of somatosensory evoked potentials (SSEP) is still very limited and SSEP’s are no longer part of the supportive criteria.12 The guideline emphasizes that the diagnostic process is complex (Figure 1) and that a combination of clinical, electrophysiological, and sometimes laboratory or imaging findings are necessary for a CIDP diagnosis (Table 3).

Table 3 Laboratory and Imaging Studies

Figure 1 Visualization of the diagnostic process when following the EAN/PNS 2021 guideline.

Notes: aRegardless of supportive criteria.

Diagnostic Tests Nerve Conduction Studies

NCS remains to be the most important diagnostic tool when diagnosing CIDP. There is a strong support for demyelination if the motor conduction criteria (Table 2) are present in at least 2 nerves with distal negative peak CMAP amplitudes of 1.0 mV or higher.29 The reason for this amplitude cut-off is that axonal loss may decrease nerve conduction velocity if the fastest conducting axons are damaged. In general, any signs that are supportive of demyelination should be interpreted with caution if the distal CMAP amplitude is <1.0 mV and will therefore officially not meet the criteria of demyelination.

Nerve compression at entrapment sites can produce focal abnormalities similar to those seen in demyelinating neuropathies. Therefore, EMG abnormalities at common nerve entrapment sites should be disregarded.30,31 In some patients, this compression may even affect a larger portion of the nerve around the entrapment site. Technical difficulties, such as submaximal stimulation, costimulation with coregistration, and anastomosis (such as Martin-Gruber) can produce apparent CMAP amplitude/area reductions. These reductions can be mistakenly identified as a conduction block or they might obscure a genuine CMAP amplitude/area reduction, causing a missed conduction block. Absence of F waves can be caused by other conditions, such as radiculopathies or plexopathies,32 and is not specific for CIDP, which is why this criterion has to be present in combination with one other nerve conduction criterion in one other nerve. The many caveats in interpreting NCS findings emphasize the need for neurophysiological expertise, especially when signs that are supportive of demyelination are detected in only one or two nerves.33 The extent to which NCS are conducted can vary considerably. When too few nerves or nerve segments are tested, it may lead to missed diagnoses.33 The 2021 EAN/PNS guideline recommends testing at least the median, ulnar (with stimulation below the elbow), peroneal, and tibial nerves on one side. If the conduction criteria are not met, the suggested next step is to test the same nerves on the opposite side and to expand the ulnar and median nerve measurements by stimulating both nerves at the axilla and Erb’s point. However, it can be justified to include the median and ulnar nerve measurements up to Erb’s point from the start, inclusive of F-waves. Demyelinating features are more prevalent in the arms, especially in the proximal segments between the elbow and Erb’s point, compared to the legs.34–36 An important challenge is to interpret the NCS results in the clinical context, because the nerve conduction findings that are defined in the guidelines as strongly supportive of demyelination are not equivalent to classical demyelination as found in nerve biopsy. In essence these findings are markers for functional disruption or slowing of the salutatory conduction of the myelinated axons, which may be primarily demyelinating, but may also be primarily axonal through eg disorganization at the nodes of Ranvier.37 As such, other diseases that can meet the electrodiagnostic criteria for CIDP are autoimmune nodopathies, multifocal motor neuropathy (MMN), hereditary neuropathies with demyelinating features (demyelinating and intermediate types, hereditary neuropathy with liablity to pressure palsy), Guillain-Barré Syndrome (GBS), polyneuropathies associated with monoclonal gammopathies (anti-MAG neuropathy), amyloidosis, medication-induced neuropathies, vasculitic neuropathies, and lumbosacral radiculoplexus neuropathies.

Imaging

Nerve ultrasound and contrast-enhanced Magnetic Resonance Imaging (MRI) can be useful for assessing more proximal segments of the nerves and nerve roots, which is a region that is hard to study with NCS. Segmental or diffuse nerve hypertrophy may be visible, which is thought to be indicative of demyelination and remyelination processes and is mostly found in the brachial plexus and/or proximal median nerve segments.27 However, nerve enlargement and/or contrast enhancement are not specific for CIDP, as they can be found in other diseases, such as diabetes mellitus, amyotrophic neuralgia, vasculitis, demyelinating or intermediate Charcot-Marie-Tooth (CMT) disease.38,39

Nerve ultrasound has emerged as a valuable diagnostic tool in the evaluation of chronic inflammatory demyelinating polyneuropathy in the last decade. This non-invasive imaging can be used to measure nerve cross-sectional area (CSA) to detect nerve (root) enlargement, which has found to be the case in 69–100% of CIDP patients.40–43 Furthermore, nerve ultrasound may also be useful in guiding nerve biopsy and assisting in the monitoring of disease progression or treatment response. In a multicenter study, the inter-observer variability was good as the differences in CSA measurements between investigators were small.44 One study was able to use nerve ultrasound to identify patients who responded to treatment but did not meet the CIDP criteria.26 Nerve ultrasound can be helpful to identify CIDP patients who did not (fully) meet the electrodiagnostic criteria and can increase the diagnostic certainty.

In some cases, MRI of the brachial and lumbosacral plexus can be helpful by revealing nerve root hypertrophy, increased signal intensity, or gadolinium enhancement.27,45 MRI may be considered when patients suspected of CIDP fulfill the criteria for “possible” CIDP and ultrasounds results are non-contributory or nerve ultrasound is unavailable. Most hospitals have access to MRI, but there is a high intra-observer variability, even amongst experienced raters.46–48 The lack of objective cut-off values is also a major limitation for MRI; only a handful of studies used an objective cut-off value for abnormal nerve root diameter for the assessment of plexus MRI.49,50

CSF Examination

Cerebrospinal fluid (CSF) examination can be a very useful diagnostic tool when the diagnostic criteria are not fully met or to exclude other diagnoses. Up to 90% of patients with typical CIDP present with elevated protein levels in combination with a normal white blood cell count in their CSF.51–53 However, in patients with a CIDP variant such as multifocal CIDP, CSF protein elevation is less frequent or only slightly increased.20 On the other hand, elevated CSF protein is not specific for CIDP, as patients with diabetes mellitus or hereditary demyelinating neuropathies may also exhibit mildly elevated protein levels.54,55 CSF protein levels tend to get higher with age, so to reduce the risk of misdiagnosis, recent recommendations advice raising the CSF protein cut-off value to 0.6 g/l for patients over 50 years of age.56 One study found that with these cut-offs, the sensitivity of CSF protein elevation was 68%.57 It is yet unknown what the specificity is of higher values of CSF protein (>1.0 g/l) for the diagnosis of CIDP. If elevated leukocyte counts (>10/mm3) are detected, an infectious or malignant cause should be considered. However, slightly elevated leukocyte counts (10–50/mm3) have been reported in up to 11% of CIDP patients, indicating that this finding does not necessarily exclude the diagnosis.58–60 A leukocyte count exceeding 50/mm3 is very rare in CIDP patients, and compels further investigation for alternative causes, but it does not unequivocally rule out CIDP. One study found that 57% of patients with slightly elevated leukocytes experienced a (sub)acute disease onset, with leukocyte counts decreasing spontaneously over time.60 CSF examination in CIDP patients already meeting the clinical and electrodiagnostic criteria provides limited added value, unless there are signs of an underlying infectious or malignant disease, including a rapid onset and disease course.12

Autoantibodies

During recent years, the role of autoantibodies in inflammatory demyelinating neuropathies as diagnostic and prognostic biomarkers has been one of the most compelling laboratory research topics and the knowledge is quickly expanding. IgG antibodies against neurofascin 155 (NF155), 140 (NF140) and 186 (NF186), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) have been identified.61,62 It is estimated that 25–40% of CIDP patients carry antibodies that target certain structures of the peripheral nerve, but the target antigens for most CIDP patients remain unknown.1,61,62 Patients with (para)nodal antibodies tend to have a more aggressive and more (sub)acute course, and often respond poorly to IVIg, which is why guideline recommends testing for antibodies in patients who do not respond to first line treatments, especially if they have atypical symptoms such as pain, tremors, and severe ataxia. Routinely testing for antibodies is not yet recommended, but is becoming increasingly more common in Europe and Japan. However, it should be noted that there are different techniques used for testing auto-antibodies with different diagnostic performances and not every testing technique is widely available or meets the quality standards.63 The EAN/PNS 2021 guideline recommends a cell-based assay with mammalian expression vectors and an enzyme-linked immunosorbent assay (ELISA) or teased-nerve immunohistochemistry as a confirmatory test. An interlaboratory study is being conducted to validate these testing recommendations.63 A change in the EAN/PNS guidelines is the Task Force’s advice to classify “autoimmune nodopathies” as a separate disease from CIDP. This distinction is based on their unique clinical features, pathophysiological differences, and poor response to IVIg.

Screening for monoclonal proteins (M-protein) including immunofixation is recommended for all patients with a clinical suspicion of CIDP.12 In case of no treatment response and a distal phenotype, repeating the M-protein analysis and testing for anti-myelin-associated glycoprotein (MAG) antibodies should be considered in order to reduce the risk of a misdiagnosis. Two earlier studies, encompassing a combined total of 113 patients, identified six patients who met the diagnostic criteria for CIDP and tested positive for anti-MAG antibodies without IgM paraproteinemia.64,65 The clinical presentation and progression in these patients were similar to that of anti-MAG positive patients who had an IgM paraproteinemia. Three out of these six patients tested positive for an M-protein later during follow-up. One should note that in these studies a cut-off value of 1000 Bühlmann Titre Units (BTU) was used, which is considerably lower than the recommended threshold of 7000 BTU.66 The available evidence does not support testing for anti-MAG in patients without M-protein, pending further large-scale studies using accurate cut-off values.

Nerve Biopsy

Nerve biopsy can be helpful when CIDP is highly suspected but cannot be proven with nerve conduction studies or made more likely with the help of imaging and/or CSF examination. Generally, sensory nerves are selected such as the sural of the peroneal superficial nerve. It can also help to differentiate between CIDP and vasculitic neuropathy, amyloidosis, sarcoidosis, neurolymphatosis, or nerve sheath tumors, especially if an alternative diagnosis is being considered after limited or no treatment response. Findings that support CIDP are onion bulbs (caused by demyelination and remyelination), thinly myelinated axons and perivascular macrophage collections.67–71 However, nerve biopsy findings are often not specific or even absent in clinically moderate or mild cases, leading to a relatively low diagnostic yield.72 Another downside is that a nerve biopsy will cause damage to the nerve and this may result in sensory disturbances, which means that the severity of symptoms must be high enough to justify the potential morbidity resulting from a peripheral nerve biopsy and relatively low accuracy. In summary, a nerve biopsy should only be considered when there is a strong suspicion of CIDP despite negative NCS, CSF, and imaging results, or when other potential underlying causes necessitate a nerve biopsy.

Treatment Strategies First Line Treatments

CIDP can be managed with immunomodulatory drugs and up to 81% of patients show improvement from first-line treatments.6 These first-line treatments include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange (Table 4). 12,73 IVIg is generally well-tolerated and effective in improving disability after one month,74 but the costs are high, averaging between approximately €45,000 per year in Europe and $137,000 per year in the United States.75 Potential side effects must also be considered, such as headache, skin rash and venous thromboembolic events.76,77 Despite its efficacy, patients are often treated for years due to the low remission rate and relapsing nature of the disease, with the risk of overtreatment.78–80 Therefore, periodic weaning trials are necessary to justify long-term use. Subcutaneous immunoglobulin (SCIg) is an equally effective alternative maintenance treatment that is generally well-tolerated.81 The biggest upside is that patients or caretakers can (self-)administer SCIg outside the hospital or without a home-care nurse, relieving some of the patients burden. A recent study compared IVIg and SCIg treatments and found that they similarly impacted specific immune cells, but IVIg had a broader influence on serum cytokines than SCIg.82 It is suggested that IVIg and SCIg have distinct pharmacokinetics, leading to different post-infusion cytokine patterns in CIDP patients. However, there were no therapeutically meaningful differences. When it comes to SCIg as an induction treatment, one randomized controlled trial study has shown that SCIg and IVIg have a similar positive effect on muscle weakness when administered to treatment naïve CIDP patients.83

Table 4 First Line Treatment Options

Corticosteroids, while effective as an induction therapy, will on average take at least two to three months before improvement of symptoms takes place and may cause more severe and sometimes long-term side effects if administered for prolonged periods, such as diabetes mellitus, hypertension, osteoporosis, opportunistic infections and weight gain.79,84 For this reason, most recent studies restricted its use to relatively short period.84–87 Corticosteroids can be administered orally on a daily basis, or given in pulses, either in oral or intravenous form. There is no difference between these treatment modalities in terms of safety and efficacy.79,86 Compared to IVIg, corticosteroids show no significant difference in long-term improvement of disability, and possibly have a higher remission rate and longer duration of remission.73 Furthermore, oral administration obviates the need for intravenous treatments, negating the requirement for home care or hospital admissions. They present a much lower cost alternative compared to IVIg. Interestingly, patients with a (pure) motor CIDP variant are more likely to deteriorate when treated with corticosteroids.84,88,89

Plasma exchange is an effective treatment, particularly in severe cases.90,91 It is considered a first-line treatment, but in daily practice it is typically reserved for patients who do not respond well to one of the other first-line treatments. Improvement of symptoms can be seen within days. However, the requirement of specialized equipment and personnel, necessary expertise and invasiveness of the treatments are some of the several logistical drawbacks that limit its use. An analysis of data from a combined registry indicated that adverse events were rare and usually mild.92 Adverse events that were reported most often included access problems, hypotension, tingling, and urticaria. Plasma exchange with albumin or saline can cause a drop in blood-clotting factors, leading to a slightly prolonged clotting time, but clinically relevant hemorrhages are very rare. There is no data on the safety and effectiveness of plasma exchange as maintenance treatment.9

Evaluating Treatment Response

Timely and consistent treatment response evaluation is essential because a poor treatment response is an important reason to reconsider the CIDP diagnosis and treatment plan. It should be emphasized that stabilization of symptoms after induction treatment should generally not be regarded as proof of efficacy as one would expect symptoms to remain unchanged for longer periods of time with most other causes of (axonal) neuropathies. In a cohort of patients who were misdiagnosed with CIDP and were given immunomodulatory treatment, 85% reported that they “felt better”.7 This was without any objective measurements, merely patient-reported perception of improvement, and this shows how important it is to include objective measurements to (dis)prove a treatment response. It is recommended that treatment response is evaluated using standardized disability and impairment scales (Table 5). 12 The use of minimal clinically important differences (MCIDs) to define meaningful improvement or deterioration can be useful, but do not rule out normal daily or irrelevant fluctations.93 Optimal timing for evaluating treatment and dosing can be found in Table 4. Based on the selected treatment modality, a therapeutic response often manifests after several weeks or months. However, insufficient dosage or treatment duration can lead to therapeutic inefficacy, highlighting the importance of allowing sufficient time for treatment to take effect.94

Table 5 Tools for Objectifying Treatment Response

Discussion

There are several challenges to arrive at an early CIDP diagnosis. The diagnostic process for typical CIDP can be very straightforward, including only NCS and laboratory screening.95 However, the disease may manifest with various different phenotypes and it gets especially challenging when the electrodiagnostic criteria are not (fully) met. NCS is very helpful when it is strongly supportive of demyelination and the CIDP guidelines as reported in the EFNS/PNS 2010 first revision and the EAN/PNS 2021 second revision have a good sensitivity when used correctly, but even then, demyelination is not exclusive for CIDP. When the NCS results are weakly or not supportive, laboratory and imaging studies can be helpful to rule out other conditions or make the CIDP diagnosis more likely to allow a treatment trial, but caution should remain as most findings are not very specific for CIDP. A treatment response using objective outcome measures may upgrade the diagnostic certainty from “possible CIDP” to “CIDP”, or even from “no CIDP” to “possible CIDP” when the clinical criteria for typical sensorimotor CIDP and one other supportive criterion is met. Combining probable and definite conduction blocks leads to some simplification of the criteria but may also lead to a lower specificity for possible CIDP. Previously, one definite conduction block was required for possible CIDP. Now, a conduction block previously deemed probable is considered sufficient and increases the risk of over diagnosis and should be interpreted with caution. The inclusion of sensory criteria is another notable adjustment. Previously part of the supportive criteria, sensory conduction criteria (sural sparing, sensory nerve conduction velocities in the demyelinating range) have now been transitioned to an electrodiagnostic criterion for possible sensory CIDP. Sensory nerve conduction abnormalities, including slowing of sensory nerve conduction velocities not in demyelinating range, prolonged distal sensory latencies, and low sensory nerve action potential (SNAP) amplitudes, are now required to meet the electrodiagnostic criteria, even though they are not specific for demyelination. Furthermore, since sensory nerve conduction abnormalities were not mandatory for diagnosis with the former criteria, NCS were often limited to one or two sensory nerves. This means that some patients with prevalent CIDP would not fulfill the current criteria based on the NCS conducted at the time of diagnosis, whereas nowadays sensory measurements would be continued until also the sensory nerve conduction criteria are met in two nerves or sensory conduction must be normal in all of at least four nerves to confirm the clinical diagnosis of motor CIDP.

An important shift from the previous guideline is that auto-immune nodopathies are no longer classified as a CIDP subtype, but rather a different disease entity requiring a different disease management strategy from CIDP.96 Additionally, chronic immune sensory polyradiculopathy (CISP) is also not considered as a CIDP subtype anymore. The evolving terminology over the years reflects our deepening understanding that CIDP belongs to a spectrum of autoimmune disorders affecting the peripheral nerves, characterized by heterogeneous presentations. The term CIDP, coined in 1982, initially described the disease’s most common characteristics: timing of onset, pathophysiology, affected tissue components, and its anatomical distribution. Over time, however, it became clear that several patients who were diagnosed as CIDP did not exhibit the characteristics originally associated with CIDP. Furthermore, CIDP was initially seen as a clearly distinct disease from other chronic neuropathies such as MMN, and monoclonal gammopathies. However, some of these neuropathies would meet the supportive criteria, including treatment response, and are hard to differentiate with NCS. A more modern view is to see CIDP as part of a spectrum, which is shared with autoimmune nodopathies, CISP, MMN and even monoclonal gammopathies.96 The umbrella term “chronic autoimmune neuropathies” would adequately describe this spectrum, considering that an autoimmune etiology is a shared (suspected underlying) feature of these neuropathies, which also have similar diagnostic approaches (NCS, laboratory testing, and imaging), and may benefit from immunomodulatory treatment.5 Currently, given the absence of specific biomarkers, CIDP continues to be a clinical diagnosis, with the goal to demonstrate autoimmunity in most CIDP patients yet to be achieved. Future research should aim to develop specific immunological tests that can be added to the diagnostic work-up.

When it comes to induction treatments, corticosteroids, IVIg and plasma-exchange are proven to be effective and well-tolerated. Most patients with CIDP respond well to at least one of the first line treatments, meaning that lack of improvement by itself can be considered a “red flag” and a reason to reconsider the diagnosis. Therefore, initial assessment and monitoring of a treatment response is important and should be done with disability and impairment outcome measurements. Treatment response can easily be under- or overestimated and standardized objective outcome measurements can be very helpful in clinical practice to help monitor as objectively as possible. However, not every assessment is suitable for every patient.97 MRC sum scores are less suitable for patients with a CIDP variant with asymmetric, distal or no weakness. These patients will have fairly high MRC sum scores and due to a ceiling effect clinical improvement or deterioration will be harder to confirm. The I-RODS is not specific for CIDP and may be influenced by comorbidities, cultural differences, and lifestyle. Grip strength of the affected arm may be more helpful for these patients, but these might also fluctuate more over time.98 Therefore, changes are sometimes difficult to interpret. Utilizing MCIDs can aid in recognizing meaningful changes in impairment and disability scales. However, using the current MCIDs, it can be challenging to differentiate genuine clinical deterioration from variability over time at an individual level.93 The revised EAN/PNS 2021 guideline strongly recommends the use of at least one impairment and one disability scale to determine deterioration. While combining multiple MCIDs might enhance the accuracy, it has yet to be validated.

In conclusion, despite these many challenges, CIDP is a diagnosis based on a set of clinical criteria, electrodiagnostic features and, when in doubt, additional laboratory, and imaging studies. NCS remains to be the most useful tool for detecting features that are supportive of demyelination, as long as the tests are being conducted and interpreted correctly. IVIg, corticosteroids, and plasma exchange have proven safe and effective for treating CIDP. However, it is crucial to use objective outcome measurements for evaluating treatment efficacy. Poor treatment response gives a good reason to reconsider the CIDP diagnosis and initiating additional diagnostic testing.

Disclosure

Dr Filip Eftimov reports consultancy fees, paid to the institution from Dianthus, UCB Pharma, and Takeda, outside the submitted work. The authors report no other conflicts of interest in this work.

References

1. Broers MC, Bunschoten C, Nieboer D, Lingsma HF, Jacobs BC. Incidence and prevalence of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis. Neuroepidemiology. 2019;52(3–4):161–172. doi:10.1159/000494291

2. Van den Bergh PY, Rajabally YA. Chronic inflammatory demyelinating polyradiculoneuropathy. Presse Med. 2013;42(6 Pt 2):e203–215. doi:10.1016/j.lpm.2013.01.056

3. Johnsen B, Fuglsang-Frederiksen A. Electrodiagnosis of polyneuropathy. Neurophysiol Clin Clin Neurophysiol. 2000;30(6):339–351. doi:10.1016/S0987-7053(00)00237-9

4. Tankisi H, Pugdahl K, Johnsen B, Fuglsang-Frederiksen A. Correlations of nerve conduction measures in axonal and demyelinating polyneuropathies. Clin Neurophysiol. 2007;118(11):2383–2392. doi:10.1016/j.clinph.2007.07.027

5. Eftimov F, Lucke IM, Querol LA, Rajabally YA, Verhamme C. Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy. Brain. 2020;143(11):3214–3224. doi:10.1093/brain/awaa265

6. Cocito D, Paolasso I, Antonini G, et al. A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2010;17(2):289–294. doi:10.1111/j.1468-1331.2009.02802.x

7. Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology. 2015;85(6):498–504. doi:10.1212/WNL.0000000000001833

8. Hughes RA, Mehndiratta MM, Rajabally YA. Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2017;11(11):CD002062. doi:10.1002/14651858.CD002062.pub4

9. Mehndiratta MM, Hughes RA, Pritchard J. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2015;2015(8):CD003906. doi:10.1002/14651858.CD003906.pub4

10. Eftimov F, van Schaik I. Chronic inflammatory demyelinating polyradiculoneuropathy: update on clinical features, phenotypes and treatment options. Curr Opin Neurol. 2013;26(5):496–502. doi:10.1097/WCO.0b013e328363bfa4

11. Bouchard C, Lacroix C, Planté V, et al. Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy. Neurology. 1999;52(3):498. doi:10.1212/WNL.52.3.498

12. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/peripheral nerve society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force-second revision. Eur J Neurol. 2021;28(11):3556–3583. doi:10.1111/ene.14959

13. Van den Bergh PY, Hadden RD, Bouche P, et al. European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological societies and the peripheral nerve society - first revision. Eur J Neurol. 2010;17(3):356–363. doi:10.1111/j.1468-1331.2009.02930.x

14. Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demyelinating neuropathy with persistent conduction block. Neurology. 1982;32(9):958–964. doi:10.1212/WNL.32.9.958

15. Berg-Vos R, Berg L, Franssen H, et al. Multifocal inflammatory demyelinating neuropathy: A distinct clinical entity? Neurology. 2000;54(1):26 doi:10.1212/WNL.54.1.26.

16. Maisonobe T, Chassande B, Vérin M, Jouni M, Léger JM, Bouche P. Chronic dysimmune demyelinating polyneuropathy: a clinical and electrophysiological study of 93 patients. J Neurol Neurosurg Psychiatr. 1996;61(1):36–42. doi:10.1136/jnnp.61.1.36

17. Oh SJ, Claussen GC, Kim DS. Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy? J Peripher Nerv Syst. 1997;2(4):362–369.

18. Jeanjean AP, Duprez T, Van den Bergh PY. Massive peripheral nerve hypertrophy in a patient with multifocal upper limb demyelinating neuropathy (Lewis-Sumner syndrome). Acta Neurol Belg. 2001;101(4):234–238.

19. Weiss MD, Oakley JC, Meekins GD. Hypoglossal neuropathy in Lewis-Sumner syndrome masquerading as motor neuron disease. Neurology. 2006;67(1):175–176. doi:10.1212/01.wnl.0000223577.69111.2c

20. Rajabally YA, Chavada G. Lewis-Sumner syndrome of pure upper-limb onset: diagnostic, prognostic, and therapeutic features. Muscle Nerve. 2009;39(2):206–220. doi:10.1002/mus.21199

21. Doneddu PE, Cocito D, Manganelli F, et al. Atypical CIDP: diagnostic criteria, progression and treatment response. data from the Italian CIDP database. J Neurol Neurosurg Psychiatr. 2019;90(2):125–132. doi:10.1136/jnnp-2018-318714

22. Breiner A, Brannagan TH. Comparison of sensitivity and specificity among 15 criteria for chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2014;50(1):40–46. doi:10.1002/mus.24088

23. Rajabally YA, Fowle AJ, Van den Bergh PY. Which criteria for research in chronic inflammatory demyelinating polyradiculoneuropathy? An analysis of current practice. Muscle Nerve. 2015;51(6):932–933. doi:10.1002/mus.24496

24. Rajabally YA, Afzal S, Loo LK, Goedee HS. Application of the 2021 EAN/PNS criteria for chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatr. 2022;93(12):1247–1252. doi:10.1136/jnnp-2022-329633

25. Doneddu PE, De Lorenzo A, Manganelli F, et al. Comparison of the diagnostic accuracy of the 2021 EAN/PNS and 2010 EFNS/PNS diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg. 2022;1:329357 doi:10.1136/jnnp-2022-329357.

26. Herraets IJT, Goedee HS, Telleman JA, et al. Nerve ultrasound improves detection of treatment-responsive chronic inflammatory neuropathies. Neurology. 2020;2020:3 doi:31959710 DOI: 10.1212/wnl.0000000000008978.

27. Goedee HS, Jongbloed BA, van Asseldonk JH, et al. A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy. Eur J Neurol. 2017;24(10):1307–1313. doi:10.1111/ene.13380

28. Grimm A, Rattay TW, Winter N, Axer H. Peripheral nerve ultrasound scoring systems: benchmarking and comparative analysis. J Neurol. 2017;264(2):243–253. doi:10.1007/s00415-016-8305-y

29. Van Asseldonk JTH, Van den Berg LH, Kalmijn S, Wokke JHJ, Franssen H. Criteria for demyelination based on the maximum slowing due to axonal degeneration, determined after warming in water at 37°C: diagnostic yield in chronic inflammatory demyelinating polyneuropathy. Brain. 2005;128(4):880–891. doi:10.1093/brain/awh375

30. Padua L, Caliandro P, Aprile I, Sabatelli M, Madia F, Tonali P. Occurrence of nerve entrapment lesion in chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol. 2004;115(5):1140–1144. doi:10.1016/j.clinph.2003.12.007

31. Rajabally YA, Narasimhan M. Electrophysiological entrapment syndromes in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2011;44(3):444–447. doi:10.1002/mus.22146

32. Mondelli M, Aretini A, Arrigucci U, Ginanneschi F, Greco G, Sicurelli F. Clinical findings and electrodiagnostic testing in 108 consecutive cases of lumbosacral radiculopathy due to herniated disc. Neurophysiol Clin. 2013;43(4):205–215. doi:10.1016/j.neucli.2013.05.004

33. Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve. 2018;57(4):542–549. doi:10.1002/mus.25997

34. Lucke IM, Wieske L, van der Kooi AJ, van Schaik IN, Eftimov F, Verhamme C. Diagnosis and treatment response in the asymmetric variant of chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2019;24(2):174–179. doi:10.1111/jns.12325

35. Rajabally YA, Jacob S. Proximal nerve conduction studies in chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol. 2006;117(9):2079–2084. doi:10.1016/j.clinph.2006.05.028

36. Rajabally YA, Narasimhan M. Distribution, clinical correlates and significance of axonal loss and demyelination in chronic inflammatory demyelinating polyneuropathy. Eur J Neurol. 2011;18(2):293–299. doi:10.1111/j.1468-1331.2010.03138.x

37. Uncini A, Kuwabara S. Nodopathies of the peripheral nerve: an emerging concept. J Neurol Neurosurg Psychiatr. 2015;86(11):1186–1195. doi:10.1136/jnnp-2014-310097

38. Breiner A, Qrimli M, Ebadi H, et al. Peripheral nerve high-resolution ultrasound in diabetes. Muscle Nerve. 2017;55(2):171–178. doi:10.1002/mus.25223

39. Loewenbruck KF, Dittrich M, Bohm J, et al. Practically applicable nerve ultrasound models for the diagnosis of axonal and demyelinating hereditary motor and sensory neuropathies (HMSN). J Neurol. 2018;265(1):165–177. doi:10.1007/s00415-017-8687-5

40. Herraets IJT, Goedee HS, Telleman JA, et al. Nerve ultrasound for diagnosing chronic inflammatory neuropathy: a multicenter validation study. Neurology. 2020;95(12):e1745–e1753. doi:10.1212/WNL.0000000000010369

41. Matsuoka N, Kohriyama T, Ochi K, et al. Detection of cervical nerve root hypertrophy by ultrasonography in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Sci. 2004;219(1–2):15–21. doi:10.1016/j.jns.2003.11.011

42. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients with polyneuropathy: an ultrasound study. Muscle Nerve. 2009;40(6):960–966. doi:10.1002/mus.21431

43. Sugimoto T, Ochi K, Hosomi N, et al. Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy. J Neurol. 2013;260(10):2580–2587. doi:10.1007/s00415-013-7021-0

44. Telleman JA, Herraets IJT, Goedee HS, et al. Nerve ultrasound: a reproducible diagnostic tool in peripheral neuropathy. Neurology. 2019;92(5). doi:10.1212/WNL.0000000000006856

45. Goedee HS, van der Pol WL, Hendrikse J, van den Berg LH. Nerve ultrasound and magnetic resonance imaging in the diagnosis of neuropathy. Curr Opin Neurol. 2018;31(5):526–533. doi:10.1097/WCO.0000000000000607

46. van Rosmalen MHJ, Goedee HS, van der Gijp A, et al. Low interrater reliability of brachial plexus MRI in chronic inflammatory neuropathies. Muscle Nerve. 2020;61(6):779–783. doi:10.1002/mus.26821

47. Oudeman J, Eftimov F, Strijkers GJ, et al. Diagnostic accuracy of MRI and ultrasound in chronic immune-mediated neuropathies. Neurology. 2020;94(1):e62–e74. doi:10.1212/WNL.0000000000008697

48. Jomier F, Bousson V, Viala K, et al. Prospective study of the additional benefit of plexus magnetic resonance imaging in the diagnosis of chronic inflammatory demyelinating polyneuropathy. Eur J Neurol. 2020;27(1):181–187. doi:10.1111/ene.14053

49. Lozeron P, Lacour MC, Vandendries C, et al. Contribution of plexus MRI in the diagnosis of atypical chronic inflammatory demyelinating polyneuropathies. J Neurol Sci. 2016;360:170–175. doi:10.1016/j.jns.2015.11.048

50. Tanaka K, Mori N, Yokota Y, Suenaga T. MRI of the cervical nerve roots in the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy: a single-institution, retrospective case-control study. BMJ Open. 2013;3(8):e003443. doi:10.1136/bmjopen-2013-003443

51. Dyck PJ, Lais AC, Ohta M, Bastron JA, Okazaki H, Groover RV. Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc. 1975;50(11):621–637.

52. Prineas JW, McLeod JG. Chronic relapsing polyneuritis. J Neurol Sci. 1976;27(4):427–458. doi:10.1016/0022-510X(76)90213-6

53. McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy: a clinical and electrophysiological study of 92 cases. Brain. 1987;110(6):1617–1630. doi:10.1093/brain/110.6.1617

54. Bouché P, Gherardi R, Cathala HP, Lhermitte F, Castaigne P. Peroneal muscular atrophy. Part 1. Clinical and electrophysiological study. J Neurol Sci. 1983;61(3):389–399. doi:10.1016/0022-510X(83)90172-7

55. Kobessho H, Oishi K, Hamaguchi H, Kanda F. Elevation of cerebrospinal fluid protein in patients with diabetes mellitus is associated with duration of diabetes. Eur Neurol. 2008;60(3):132–136. doi:10.1159/000144083

56. Breiner A, Bourque PR, Allen JA. Updated cerebrospinal fluid total protein reference values improve chronic inflammatory demyelinating polyneuropathy diagnosis. Muscle Nerve. 2019;60(2):180–183. doi:10.1002/mus.26488

57. Liberatore G, Manganelli F, Cocito D, et al. Relevance of diagnostic investigations in chronic inflammatory demyelinating poliradiculoneuropathy: data from the Italian CIDP database. J Peripher Nerv Syst. 2020;25(2):152–161. doi:10.1111/jns.12378

58. Press R, Pashenkov M, Jin JP, Link H. Aberrated levels of cerebrospinal fluid chemokines in guillain-barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. J Clin Immunol. 2003;23(4):259–267. doi:10.1023/A:1024532715775

59. van Doorn PA, Vermeulen M, Brand A, Mulder PGH, Busch HFM. Intravenous Immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: clinical and laboratory characteristics associated with improvement. Arch Neurol. 1991;48(2):217–220. doi:10.1001/archneur.1991.00530140113024

60. Lucke IM, Peric S, van Lieverloo GGA, et al. Elevated leukocyte count in cerebrospinal fluid of patients with chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2018;23(1):49–54. doi:10.1111/jns.12250

61. Querol L, Siles AM, Alba-Rovira R, et al. Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy. Sci Rep. 2017;7(1). doi:10.1038/s41598-017-14853-4

62. Vural A, Doppler K, Meinl E. Autoantibodies against the node of Ranvier in seropositive chronic inflammatory demyelinating polyneuropathy: diagnostic, pathogenic, and therapeutic relevance. Front Immunol. 2018;9:1029. doi:10.3389/fimmu.2018.01029

63. Collet R, Caballero-Avila M, Querol L. Clinical and pathophysiological implications of autoantibodies in autoimmune neuropathies. Rev Neurol. 2023;179(8):831–843. doi:10.1016/j.neurol.2023.02.064

64. Sakamoto Y, Shimizu T, Tobisawa S, Isozaki E. Chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibody without any detectable M-protein. Neurol Sci. 2017;38(12):2165–2169. doi:10.1007/s10072-017-3133-0

65. Pascual-Goni E, Martin-Aguilar L, Lleixa C, et al. Clinical and laboratory features of anti-MAG neuropathy without monoclonal gammopathy. Sci Rep. 2019;9(1):6155. doi:10.1038/s41598-019-42545-8

66. Liberatore G, Giannotta C, Sajeev BP, et al. Sensitivity and specificity of a commercial ELISA test for anti-MAG antibodies in patients with neuropathy. J Neuroimmunol. 2020;345:577288. doi:10.1016/j.jneuroim.2020.577288

67. Sommer C, Koch S, Lammens M, Gabreels-Festen A, Stoll G, Toyka KV. Macrophage clustering as a diagnostic marker in sural nerve biopsies of patients with CIDP. Neurology. 2005;65(12):1924–1929. doi:10.1212/01.wnl.0000188879.19900.b7

68. Bosboom WM, van den Berg LH, Franssen H, et al. Diagnostic value of sural nerve demyelination in chronic inflammatory demyelinating polyneuropathy. Brain. 2001;124(Pt 12):2427–2438. doi:10.1093/brain/124.12.2427

69. Krendel DA, Parks HP, Anthony DC, St Clair MB, Graham DG. Sural nerve biopsy in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 1989;12(4):257–264. doi:10.1002/mus.880120402

70. Garces-Sanchez M, Laughlin RS, Dyck PJ, Engelstad JK, Norell JE, Dyck PJ. Painless diabetic motor neuropathy: a variant of diabetic lumbosacral radiculoplexus Neuropathy? Ann Neurol. 2011;69(6):1043–1054. doi:10.1002/ana.22334

71. Vallat JM, Tabaraud F, Magy L, et al. Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneuropathy: evaluation of eight cases. Muscle Nerve. 2003;27(4):478–485. doi:10.1002/mus.10348

72. Lee LY, Tan CY, Wong KT, Goh KJ, Shahrizaila N. Diagnostic yield of nerve biopsy in the evaluation of peripheral neuropathies. J Clin Neurosci. 2023;107:40–47. doi:10.1016/j.jocn.2022.11.017

73. Oaklander AL, Lunn MPT, Hughes RAC, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyeli