CIDP demystified: From diagnosis to management

CIDP and diagnostic barriers

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating neuropathy that has the potential to cause permanent disability.¹ Prompt diagnosis and initiation of therapy are essential to prevent prolonged disability and neural damage.²

The pathophysiology of CIDP is intricate, although phagocytosis of myelin by macrophages plays an important role in the pathogenesis of both typical and atypical cases of CIDP, by driving demyelination of nerves within the peripheral nervous system.³ Myelin damage is primarily attributed to activation of complement-dependent antibodies, although antibody-dependent phagocytosis by macrophages can occur independently of complements.³ Specific factors triggering this process have not yet been identified.⁴

People with CIDP commonly present with progressive muscle weakness, sensory loss, and impaired deep tendon reflexes.⁵ In severe cases, autonomic symptoms may arise, including constipation and urinary retention.⁵

Epidemiology

Historical differences in diagnostic criteria are potentially driving geographical variability in the estimated prevalence of CIDP^6,7

The prevalence and incidence of CIDP varies considerably between different geographic locations, likely due to historical differences in diagnostic criteria.^6,7 The observed prevalence of CIDP is estimated to be 0.7–10.3 cases per 100,000 people, highlighting the rarity of the disease.⁶ CIDP is more commonly diagnosed in males, with a female-to-male ratio of 1.5:4.⁶ Children are less likely to develop CIDP, with an estimated prevalence of 0.22 cases per 100,000 people.⁸

The diagnostic paradigm

A study from the Netherlands found that 26% of people experienced a diagnostic delay of more than 12 months⁹

Diagnostic delays and misdiagnosis are recognized challenges in CIDP; reported delays in diagnosis range from 2 to 64 months.⁹

Key barriers to diagnosis

Delays in diagnosis and misdiagnosis are commonly attributed to:

• Phenotypic variability³
• Overlap with other neurological disorders⁹
• Absence of specific biomarkers¹⁰

Phenotypic variability

The phenotypic heterogeneity of CIDP makes it difficult to diagnose.³

Clinical presentations that deviate from typical CIDP are categorized as CIDP variants due to their shared characteristics of demyelination and their response to immunotherapy.¹¹ Variations in lesion distribution and Schwann cell repair processes may underlie the differences between subtypes.³

Clarification of the CIDP definition was a key modification in the 2021 European Academy of Neurology/Peripheral Nerve Society guidelines (Figure 1).

Figure 1. Types of CIDP, including typical, distal, multifocal/focal, motor, and sensory.¹¹ CIDP, chronic inflammatory demyelinating polyneuropathy.

Up to 50% of people referred with a CIDP diagnosis are misdiagnosed, primarily those with atypical symptoms.¹² Diagnosis is considered more straightforward in those with a typical presentation of proximal and distal weakness, highlighting the importance of considering CIDP in those with an atypical presentation.¹²

Overlap with other neurological disorders

Misdiagnosis is frequent due to the overlap of symptoms with other neurological conditions. For example, a UK retrospective study of 60 people with CIDP found a strikingly high initial misdiagnosis rate of 68.3%, with Guillain–Barré syndrome the leading alternative diagnosis, followed by genetic neuropathy (Figure 2).⁹

Figure 2. Percentage of pre-referral diagnoses at initial assessment. Image licensed CC 4.0 BY from Chaudhary and Rajabally.⁹ CIAP, chronic idiopathic axonal polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; CNS, central nervous system; GBS, Guillain–Barré syndrome; MS, multiple sclerosis; TM, transverse myelitis.

Comparatively, rates of underdiagnosis due to prior misdiagnosis were lower in a Dutch retrospective study, in which 20% of 81 people with a final diagnosis of CIDP received an incorrect diagnosis before their referral to the study clinic.⁷ Within this cohort of “underdiagnosed” patients, all had experienced proximal muscle weakness, 50% had clinically atypical CIDP, 100% fulfilled the electrodiagnostic criteria for CIDP, and 25% had an increased cerebrospinal fluid (CSF) protein level.⁷

In addition to underdiagnosis of CIDP, people can be incorrectly diagnosed with CIDP (overdiagnosis).⁷ In the Dutch study, 32.3% of 96 people with a referral diagnosis of CIDP were considered overdiagnosed. Within this cohort, 97% of people diagnosed with CIDP had another type of neuropathy, 74% had an elevated CSF protein level, 65% did not fulfill the electrodiagnostic criteria for CIDP, 48% of people lacked proximal muscle weakness, 29% only had distal muscle weakness, and 20% had asymmetric muscle weakness.⁷

Existing comorbidities, such as diabetes mellitus type 2, and malignancies can also lead to delays in diagnosis as the polyneuropathy experienced by the person with CIDP may be attributed to these initial diagnoses only.²

Absence of specific biomarkers

The absence of a specific biomarker adds a layer of complexity to the diagnosis of CIDP, and the number of tests required for diagnosis can potentially extend the time to diagnosis.¹⁰

Multiple disease activity targets have been explored, including autoantibodies, cytokines, complement proteins, Fc receptor modulators, immunoglobulin G levels, pathologic markers, and electrophysiological and imaging measures.¹⁰ Finding a reliable biomarker could revolutionize CIDP diagnosis and monitoring, and ongoing studies fuel hopes that a dependable biomarker will be discovered.¹⁰

To minimize the risk of underdiagnosis:⁷ 

• Consider proximal muscle weakness as a diagnostic hallmark of CIDP
• Avoid overreliance on CSF protein levels
• Adhere to electrodiagnostic criteria
• Consider other causes of polyneuropathy

CIDP misdiagnosis brings many detrimental consequences, including severe disability and poor quality of life.⁹ Find out more about how the guidelines help overcome barriers to diagnosis.

References

1. Brun, 2022. CIDP: Current treatments and identification of targets for future specific therapeutic intervention. https://www.mdpi.com/2673-5601/2/1/9
2. Quint, 2024. Preventing long-term disability in CIDP: The role of timely diagnosis and treatment monitoring in a multicenter CIDP cohort. https://www.doi.org/10.1007/s00415-024-12548-1
3. Dziadkowiak, 2021. Pathophysiology of the different clinical phenotypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). https://www.doi.org/10.3390/ijms23010179
4. Koike and Katsuno, 2020. Pathophysiology of chronic inflammatory demyelinating polyneuropathy: Insights into classification and therapeutic strategy. https://www.doi.org/10.1007/s40120-020-00190-8
5. Ponnala, 2023. Chronic inflammatory demyelinating polyneuropathy (CIDP): Overview, treatment, and a case study. https://www.doi.org/10.7759/cureus.47475
6. Ariana, 2024. Chronic inflammatory demyelinating polyneuropathy. A case description. https://www.doi.org/https://doi.org/10.1002/ccr3.9217
7. Broers, 2021. Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy. https://www.doi.org/https://doi.org/10.1111/ene.14796
8. Łukawska, 2021. Pediatric CIDP: Diagnosis and management. A single-center experience. https://www.doi.org/10.3389/fneur.2021.667378
9. Chaudhary and Rajabally, 2021. Underdiagnosis and diagnostic delay in chronic inflammatory demyelinating polyneuropathy. https://www.doi.org/10.1007/s00415-020-10287-7
10. Allen, 2020. The misdiagnosis of CIDP: A review. https://www.doi.org/10.1007/s40120-020-00184-6
11. Van den Bergh, 2021. 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. https://www.doi.org/10.1111/jns.12455
12. Eftimov, 2020. Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy. https://www.doi.org/10.1093/brain/awaa265

Navigating diagnostic barriers: Guidelines

Eduardo Nobile-Orazio (University of Milan, Italy) highlights diagnostic technologies that support the accurate diagnosis of CIDP. View transcript.

Chronic inflammatory demyelinating polyneuropathy (CIDP) should be considered in people with progressive symmetric or multifocal polyradiculoneuropathy that relapses and remits or progresses for more than 8 weeks, particularly if there are any of the following:¹

• Sensory symptoms
• Proximal weakness
• Areflexia without muscle atrophy
• Preferential loss of vibration or joint position sense

In 2021, an update to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines provided additional recommendations to enhance diagnostic accuracy and improve patient outcomes for people living with CIDP.¹

The updated guidelines outline a diagnostic approach to CIDP that encompasses assessment of clinical, electrodiagnostic, and laboratory features, and list additional exclusion criteria that can help to rule out other disorders that may resemble CIDP.¹

Improved outcomes have been identified in people with CIDP who fulfilled the EAN/PNS 2021 diagnostic criteria, likely due to various factors, including:²

• Quicker diagnosis following disease onset
• Earlier treatment initiation

Adoption of EAN/PNS 2021 guidelines for CIDP within the clinical setting is essential for minimizing the risk of misdiagnosis and improving prognostic outcomes²

Initial testing should assess for patterns of weakness and sensory disturbance to facilitate identification of the type of CIDP the patient may have (Figure 1). It is important to repeat electrodiagnostic tests if criteria are not initially met.¹

Figure 1. Differences in electrodiagnostic and clinical criteria, according to CIDP type.^{1 *}CIDP variant. CIDP, chronic inflammatory demyelinating polyneuropathy.

Additional supportive criteria

Treatment response, imaging results, cerebrospinal fluid (CSF) analysis, and nerve biopsy may support the diagnosis of CIDP in people who meet the clinical criteria for CIDP but whose electrodiagnostic criteria suggest only possible CIDP.¹

Treatment response

In people where the clinical, electrodiagnostic, and other supportive criteria indicate CIDP but are not sufficient to make a definitive diagnosis, an objective response^† following treatment with immunomodulatory agents (i.e., intravenous immunoglobulin, plasma exchange, and corticosteroids) can validate the clinical diagnosis of CIDP.¹

However, a lack of improvement following treatment does not rule out CIDP, and a positive response is not exclusively indicative of CIDP.¹

Imaging results

In adult patients meeting the diagnostic criteria for possible CIDP, ultrasound is recommended; nerve enlargement in a minimum of two regions in the proximal median nerve segments and/or the brachial plexus further increases the likelihood of CIDP.¹

To note, the use of ultrasound or magnetic resonance imaging in pediatric patients is not recommended due to concerns about diagnostic accuracy in this population.¹

CSF analysis

While in atypical CIDP, protein elevation may be insignificant or absent, 90% of people with typical CIDP have elevated protein in the CSF with normal leucocytes; it is therefore considered a hallmark feature of the disease.³

However, as increased CSF protein levels are also seen with other conditions, such as hereditary demyelinating neuropathies, it is important to consider other diagnostic tests.³

The latest guideline revision suggests CSF testing:¹

• Is not performed if diagnostic criteria have already been met
• Should only be used to support a CIDP diagnosis or exclude possible differential diagnosis
• Should not be solely relied upon given the absence of data supporting a precise cut-off

Nerve biopsy

Given the low diagnostic accuracy and invasive nature of nerve biopsy, guidelines recommend it only in specific cases of suspected CIDP, such as:¹

• Inconclusive results from clinical, laboratory, imaging, and electrodiagnostic studies
• Minimal or no response to treatment

In a small number of cases, nerve biopsy may support a more accurate diagnosis of CIDP and lower the chances of misdiagnosis.¹

^†Objective treatment response is defined as improvement on at least one disability and one impairment scale.

References

1. Van den Bergh, 2021. 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. https://www.doi.org/10.1111/jns.12455
2. Loser, 2024. Characteristics and outcome of chronic inflammatory demyelinating polyradiculoneuropathy patients according to their diagnostic certainty based on the 2021 EAN/PNS criteria. https://www.doi.org/https://doi.org/10.1016/j.jns.2024.123259
3. Eftimov, 2020. Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy. https://www.doi.org/10.1093/brain/awaa265

Living with CIDP: Long-term complications

Eduardo Nobile-Orazio (University of Milan, Italy) discusses the long-term challenges faced by people with CIDP, including delays in diagnosis and treatment-related side effects. View transcript.

Beyond physical ability, chronic inflammatory demyelinating polyneuropathy (CIDP) can also impair social interaction and mental health.¹ Challenges with work, daily tasks, leisure activities, and dependency are common social functioning issues, often associated with disability.¹

What matters most to people with CIDP?

In a survey of 184 people with CIDP, individuals were asked to select what their top priorities would be should they achieve disease remission; multiple options could be selected. The survey respondents highlighted the following:²

• Reduction of fatigue (60.3%)
• Better balance (58.2%)
• Reduction of pain (39.1%)
• Better use of hands (28.3%)
• Elimination of need for steroids (25%)
• None of the above (3.8%)

People were also asked to consider which burdens associated with CIDP impact their lives (Figure 1).² Fatigue, not being able to do a favorite activity, and anxiety about the future were identified as the most influential factors on quality of life (QoL).²

Figure 1. Life-impacting burdens identified by people with CIDP.²

In a nationwide US patient survey, 475 people with CIDP identified loss of balance/coordination (51%), weakness in the hips/legs (41%), and pain (40%) as the most bothersome symptoms at the time of starting medication.³

How does CIDP influence physical burden?

Fatigue is prevalent in CIDP irrespective of disease activity⁴

Fatigue is a significant symptom experienced by people with CIDP; it has been reported to affect people (n=85) with both active disease (54%) and those in remission (46%).⁴ Sedative medication use significantly contributes to the level of fatigue, and sleep quality remains poor regardless of disease activity. Depression is more common in those with active CIDP.⁴

Reducing sedative medications, enhancing sleep quality, and addressing depression may help alleviate CIDP-related fatigue.⁴

Fatigue was experienced by 38% of people with pain, compared with 17% of those without pain⁵

Pain is also a common symptom of CIDP – affecting 62% of patients – and it compromises both QoL and emotional wellbeing.⁵ People experiencing pain exhibit more sensory abnormalities on the Inflammatory Neuropathy Cause and Treatment Sensory Sumscore compared with those without pain.⁵ Additionally, their physical QoL, as measured by SF-36, is worse.⁵

Living with CIDP can lead to time being missed from school or work, with 20% (n=95) of people reporting absences due to symptoms and 28% (n=133) due to infusion treatments (US nationwide survey; N=475).³ Figure 2 illustrates the breakdown of the 20% and 28% of the population who have missed school or work due to symptoms and infusions, respectively.

Figure 2. Distribution of time (days) missed from school or work in the past month by people with CIDP that were unable to attend work/school due to (1) symptoms (n=95) and (2) infusions (n=133).³

How does CIDP influence mental burden?

CIDP can also impact mental health. A study of Dutch people with CIDP (n=76) assessed 36-Item Short Form Survey Instrument (SF-36) scores for two of the domains of the mental component Vitality and Social Functioning. The normative value is 50, and SF-36 scores in people with CIDP were as follows:⁶

• Vitality: 41.2
• Social Functioning: 46.2
• Role Emotional: 50
• Mental Health: 50.1

Addressing QoL with a multidisciplinary approach

Occupational therapy, physical therapy, and physiatry are essential in optimizing functional status for people with CIDP, and multidisciplinary interventions can aim to boost mobility, strength, coordination, and independence in daily activities, thus improving overall QoL.⁷

Existing guidelines provide recommendations to support symptom control, including considering different treatment options and a multidisciplinary approach.⁸

Find out more about recommendations from the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) on the management of long-term complications.⁸

References

1. Englezou, 2023. Impact of social-functioning and sleep on quality of life in chronic inflammatory demyelinating polyneuropathy. https://www.doi.org/10.1016/j.clineuro.2023.108017
2. Fix, 2022. Voice of the patient. https://www.gbs-cidp.org/wp-content/uploads/2022/08/GBSCIDP-Voice-of-the-Patient-Report_Final.pdf
3. Allen, 2024. CIDP disease burden — Results of a US nationwide patient survey. https://www.gbs-cidp.org/wp-content/uploads/2019/03/Allen-CIDP-Survey-banner_Oct-24.pdf
4. Gable, 2020. Fatigue in chronic inflammatory demyelinating polyneuropathy. https://www.doi.org/10.1002/mus.27038
5. Mork, 2022. Prevalence and determinants of pain in chronic inflammatory demyelinating polyneuropathy: Results from the German INHIBIT registry. https://doi.org/10.1111/ene.15341
6. Querol, 2021. Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP). https://www.doi.org/10.1007/s00415-020-09998-8
7. Gogia, 2024. Chronic inflammatory demyelinating polyradiculoneuropathy. https://www.ncbi.nlm.nih.gov/books/NBK563249/
8. Van den Bergh, 2021. 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. https://www.doi.org/10.1111/jns.12455

In people with chronic inflammatory demyelinating polyneuropathy (CIDP), the main objectives of treatment should be to:¹

• Alleviate symptoms such as weakness, sensory impairment, imbalance, and pain
• Enhance functional abilities by minimizing disability
• Sustain long-term remission (if feasible)

Treatment initiation should only be considered in people with CIDP or suspected CIDP who experience impairment of activities of daily living and present with clear objective signs that may be improved²

Selecting an induction and maintenance treatment

Decision-making when selecting an induction treatment should consider a number of patient-specific factors, such as a patient’s age and any possible contraindications. Additionally, it may be necessary to switch between different maintenance treatments if an objective response is not achieved following initial treatment with an induction therapy (Figure 1).²

Figure 1. Steps to follow when using induction and maintenance treatment in people with CIDP, as per clinical guidelines.² CIDP, chronic inflammatory demyelinating polyneuropathy; IVIg, intravenous immunoglobulin; PE, plasma exchange; SCIg, subcutaneous immunoglobulin.

Guidelines recommend the following induction and maintenance treatment options following a diagnosis of CIDP or possible CIDP:²

• Corticosteroids
• Intravenous immunoglobulin (IVIg)
• Plasma exchange (PE)

Please note: Licensed IVIg products include human normal immunoglobulin.

Subcutaneous immunoglobulin (SCIg) is also strongly recommended for maintenance treatment in people with CIDP.²

Subsequent treatment decisions should be based on the objective response to induction treatment:²

• If there is no objective response to three induction treatments but CIDP is still suspected, rituximab, cyclophosphamide, or ciclosporin may be considered, despite limited supporting evidence
• If there is an objective response, maintenance treatment can be initiated

Please note: Use of corticosteroids, rituximab, cyclophosphamide, and ciclosporin is off-label for people with CIDP.

Treatment considerations: Corticosteroids

Corticosteroids are recommended as a suitable induction and maintenance treatment.² However, prolonged high-dose corticosteroids may be contraindicated in some people with CIDP, and other treatment options may need to be considered when selecting an induction treatment.²

In people with CIDP receiving corticosteroids, treatment response should be closely monitored in the weeks and months after initiation.² Periodic dose reductions can help assess whether the high dose remains necessary or if the patient is in remission.²

In some people with low-disability CIDP, corticosteroid use may lead to side effects that outweigh the benefits derived from the treatment, such as:²

• Osteoporosis
• Gastric ulceration
• Diabetes
• Cataracts
• Avascular necrosis of long bones
• Arterial hypertension

Treatment considerations: Immunoglobulin

In people with CIDP at high risk of osteoporosis or diabetes, immunoglobulin is a suitable first-line treatment option.²

However, intravenous treatments may be less tolerable for children than oral tablets, and this should be considered when selecting a first-line treatment option; the potential impact on growth should also be taken into account when selecting a treatment for this patient population.²

Treatment considerations: Plasma exchange

PE is recommended as a suitable induction and maintenance treatment; however, its effectiveness depends on specialized equipment and good vascular access.² To address challenges with PE:²

• A non-peripheral vein catheter can be a viable solution for people with problematic vascular access who require multiple exchanges quickly
• Tunneled catheters can be used for single exchanges during long-term maintenance treatment

Non-pharmaceutical recommendations

Provide advice for people with CIDP on foot care, exercise, diet, driving, and lifestyle management.² Depending on individual patient needs, orthotic support, physiotherapy, occupational therapy, psychological assistance, and referrals to rehabilitation specialists should also be considered.²

Research suggests that strength training and physiotherapy can positively impact muscle strength in people with CIDP.³ Other strategies, such as neurostimulation or electrostimulation, may also be beneficial, although there are currently only controlled studies testing these approaches in other polyneuropathies and central nervous system diseases.³

References

1. Grifols, 2020. Your guide to caring for someone with CIDP. https://www.gbs-cidp.org/wp-content/uploads/2020/09/Your-Guide-to-Caring-for-Someone-with-CIDP.pdf
2. Van den Bergh, 2021. 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. https://www.doi.org/10.1111/jns.12455
3. Fisse, 2020. Comprehensive approaches for diagnosis, monitoring and treatment of chronic inflammatory demyelinating polyneuropathy. https://www.doi.org/10.1186/s42466-020-00088-8

Interview with Eduardo Nobile-Orazio

“It is important to always consider the patient as a whole and not just the symptoms of the disease.” Eduardo Nobile-Orazio (University of Milan, Italy) discusses chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and highlights the values of a patient-centric approach in diagnosis, treatment, and long-term management.

View transcript.

Chapters
00:04 The role of early symptoms in diagnostic delay
01:30 Symptoms that support the diagnosis of CIDP
03:24 Clinical features that differentiate CIDP
05:34 Technologies for the diagnosis of CIDP
07:52 Long-term complications associated with CIDP
12:55 Determining appropriate initial treatment
14:38 Involving patients in treatment plan decisions
17:26 Non-pharmaceutical disease management for CIDP
18:27 Current treatment options for CIDP
21:17 Emerging therapies and research areas in CIDP