Challenges in the Early Diagnosis and Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy in Adults: Current Perspectives

Figures & data

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

Phenotype	Weakness	Sensory Disturbances	Red Flags	Differential Diagnosis
Typical CIDP	Symmetric in 4 limbs	In ≥2 limbs	Onset < 4 weeks	Guillain-Barré syndrome
			Motor > sensory and/or weakness distal > proximal	Auto-immune nodopathies (anti-NF155, anti-CNTN1, anti-CASPR1)
			Ataxia	CANOMAD (in combination with ophthalmoplegia), anti-NF155, anti-CNTN1
			Cranial nerve or bulbar involvement	Anti-NF140/NF186, anti-CASPR1
			M-protein presence	Monoclonal gammopathy (POEMS, AL amyloidosis, multiple myeloma)
			Poor response to IVIg	Reassess CIDP diagnosis; prompt further testing and evaluate differential diagnoses based on other red flags
Multifocal/focal variant	In ≥2 limbs in multifocal distribution	In ≥2 limbs in multifocal distribution	Diabetes mellitus	Diabetic radiculopathy or plexopathy
			Pain	Vasculitic neuropathy (mononeuritis multiplex), diabetic polyradiculopathy or plexopathy, amyotrophic neuralgia, cryoglobulinemia
			No sensory disturbances	MMN, motor neuron disease
			Close to entrapment sites	Entrapment neuropathies, HNPP (in case of multiple entrapments and/or family history of HNPP)
	Only 1 limb	In distribution of affected nerve(s)	Single nerve	Peripheral nerve tumors (schwannoma, perineurioma, lymphoma, neurofibroma), nerve entrapment
Distal variant	Distal, predominantly in lower limbs	In ≥2 limbs	M-protein and/or anti-MAG presence	Anti-MAG IgM neuropathy, POEMS, multiple myeloma, cryoglobulinemia
			Diabetes mellitus	Diabetic neuropathy
			Family history of neuropathy	Hereditary neuropathies with demyelinating features (CMT1, CMTX1, CMT4, metachromatic leukodytrophy, Refsum disease, adenomyeloneuropathy, ATTR-v polyneuropathy),
			Pain and/or asymmetry	Vasculitic neuropathy, cryoglobulinemia
Motor variant	Symmetric in 4 limbs	None	Asymmetry	Motor neuron disease
			Bulbar weakness	Motor neuron disease, myasthenia gravis
			Family history of neuropathy	Hereditary motor neuropathies (spinal muscular atrophy, porphyria)
			Elevated CK, normal tendon reflexes	Inflammatory myopathies
			Fluctuation of symptoms	Neuromuscular junction disorders (myasthenia gravis, Lambert-Eaton)
Sensory variant	None	Symmetric in 4 limbs	Pain	Small-fiber neuropathy
			Family history of neuropathy	Hereditary sensory neuropathies
			Ataxia	CANVAS, dorsal column lesions (vitamin B12 deficiency, paraneoplastic, syphilis, copper deficiency)
			Normal motor and sensory conduction	CISP
			Diabetes mellitus	Diabetic polyneuropathy
			Chemotherapy or other neurotoxic treatments/ supplements	Toxic neuropathies (eg chemotherapy, vitamin B6 toxicity)
			Slow progression	Idiopathic sensory neuropathies

Abbreviations: ATTR-v, amyloid transthyretin variant; CANOMAD, chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies; CANVAS, cerebellar ataxia, neuropathy and vestibular areflexia; CASPR1, contactin-associated protein-1; CISP, chronic immune sensory polyradiculopathy; CMT, Charcot-Marie-Tooth; CNTN-1, contactin-1; MAG, myelin-associated glycoprotein; MMN, multifocal motor neuropathy; NF-155/186/140, neurofascin-155/186/140; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes.

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

Motor nerve conduction criteria
Strongly supportive of demyelination	At least one of the following:
	a. Motor distal latency prolongation of ≥50% above ULN in ≥2 nerves ^a
	b. Motor conduction velocity decrease ≥30% below LLN in ≥2 nerves
	c. F-wave latency prolongation: ≥20% above ULN (≥50% if amplitude is <80% LLN) in ≥2 nerves
	d. Absent F-waves: In two nerves if distal amplitude ≥20% LLN plus ≥1 other demyelinating parameter in ≥1 other nerve
	e. Motor conduction block: ≥30% reduction of the proximal-to-distal amplitude as long as distal amplitude is >20% LLN in ≥2 nerves (excluding tibial nerve) or in 1 nerve plus ≥1 other demyelinating parameter except absent F waves
	f. Abnormal temporal dispersion: >30% increase between the proximal and distal duration (≥100% in the tibial nerve) in ≥2 nerves
	g. Distal CMAP duration prolongation in ≥1 nerve plus ≥1 other demyelinating parameter in ≥1 other nerve
Weakly supportive of demyelination	As in “strongly supportive of demyelination” but only in one nerve, excluding criterion g
Sensory conduction criteria
Sensory conduction abnormalities	At least one of the following in ≥2 nerves: ● Prolonged distal latency ^a ● Reduced SNAP amplitude ● Conduction velocity slowing outside of normal limits
Sensory conduction criteria ^b	● Sensory nerve conduction velocity <80% of LLN (for SNAP amplitude >80% of LLN) or <70% of LLN (for SNAP amplitude <80% of LLN) in in ≥2 nerves ● Sural sparing pattern: abnormal median or radial SNAP with normal sural nerve SNAP, excluding carpal tunnel syndrome
Variant-specific criteria
Typical CIDP	Motor conduction criteria, sensory conduction abnormalities
Multifocal/focal variant	Motor conduction criteria, sensory conduction abnormalities ● If in 1 nerve in 1 limb only: maximum diagnostic certainty is possible focal CIDP ^c
Distal variant	Motor conduction criteria (in upper limbs), sensory conduction abnormalities ● If motor conduction criteria only present in lower limbs, maximum diagnostic certainty is possible distal CIDP ^c
Sensory(-predominant) variant	Motor conduction criteria, sensory conduction abnormalities ● Pure sensory: sensory conduction criteria, motor conduction criteria normal in ≥4 nerves ^c
Motor(-predominant) variant	Motor conduction criteria, sensory conduction abnormalities ● Pure motor: motor conduction criteria, sensory conduction normal in ≥4 nerves

Notes: ^aExcluding median neuropathy at the wrist caused by carpal tunnel syndrome. ^bFor possible sensory CIDP only. ^cDiagnostic certainty not upgradable with fulfillment of 2 supportive criteria.

Abbreviations: CMAP, compound muscle action potential; SNAP, sensory nerve action potential; LLN, lower limit of normal; ULN, upper limit of normal.

Table 3 Laboratory and Imaging Studies

Diagnostic Test	Typical Findings in CIDP	Which Patients to Test?	Pitfalls & Cautions
Lumbar puncture	Elevated CSF protein and normal white blood cell count	● When infectious or malignant causes are suspected ● Helpful when NCS findings are weakly supportive and clinical criteria are met	● Mildly elevated protein also found in patients with diabetes mellitus and can increase with age ● Unnecessary when diagnostic criteria already met ● No additional diagnostic value when NCS and clinical criteria are not met
Nerve ultrasound	Enlargements of cross-sectional area of peripheral nerves or cervical nerve roots/ brachial plexus	● Suspicion of focal nerve compression ● Helpful when NCS findings are weakly supportive and clinical criteria are met, or to exclude CIDP	● Does not differentiate between CIDP and other inflammatory neuropathies or hereditary neuropathies (MMN, CMT, vasculitis) ● Availability of institutional nerve imaging expertise ● No additional diagnostic benefit when NCS and clinical criteria are not met
MRI	Enlargement or abnormal contrast enhancement of cervical/lumbar nerve roots or brachial/lumbar plexus	● Helps differentiate when spinal cord pathology is suspected	● Nerve imaging expertise necessary, high inter-rater variability ● No additional diagnostic benefit when NCS and clinical criteria are not met
Nerve biopsy	Onion bulbs, macrophage-associated demyelination, signs of demyelinated and remyelinated nerve fibers	● High (clinical) suspicion of CIDP, but unable to prove through electrodiagnostic, laboratory or nerve imaging tests ● When vasculitis, amyloidosis, sarcoidosis, nerve (sheath) tumors is suspected	● High risk of permanent damage of biopsied nerve ● Signs of demyelination often not seen in a biopsy leading to a low diagnostic yield
M-protein screening	None (no monoclonal antibodies, including immunofixation)	● All patients suspected of CIDP ● Repeat in case of no treatment response, especially in case of a distal phenotype or ataxia	● Monoclonal proteins are common and not always relevant (MGUS)
Autoantibodies	None ^a	● In case of clinical “red flags” (tremor, ataxia) ● No or insufficient treatment response ● In case of IgM(+), consider anti-MAG testing	● Not helpful for patients who have a good treatment response ● Antibody analysis needs to be done in a laboratory with paranodal antibody testing experience
SSEP	None, limited evidence for the usage of SSEP in CIDP	● Clinical sensory CIDP, especially with predominant sensory ataxia, with normal motor and sensory NSC who may have CISP	● Sensitivity for CIDP unknown, not recommended unless CISP is considered

Notes: ^a(Para)nodal antibodies are specific for autoimmune (para)nodopathies, which are not classified as CIDP but as a different disease entity.¹²

Abbreviations: CISP, chronic immune sensory polyradiculopathy; CMT, Charcot-Marie-Tooth; MAG, myelin-associated glycoprotein; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; SSEP, somatosensory evoked potentials.

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

Notes: ^aRegardless of supportive criteria.

Table 4 First Line Treatment Options

Treatment	When to Start	How to Dose	When to Evaluate	Notable Side Effects & Cautions
IVIg	● Loading dose followed by maintenance treatment, especially when there is significant disability due to symptoms and swift improvement is essential ● Contra-indications for corticosteroids	● Loading dose 2.0 g/kg over 2–5 days ● Maintenance 0.4–1.0 g/kg every 3 weeks	●Induction treatment after 3–6 weeks ● Maintenance treatment after 2–5 treatments ● Periodic weaning justification of long-term use (every 6–12 months first 2–3 years, then 1–2 years)	● Risk of VTE, especially in patients with previous VTEs without anti-coagulant therapy, skin reactions, headache
SCIg	Alternative to IVIg maintenance treatment, consider in case of: ● Debilitating wearing-off symptoms ● Infusion-related adverse events, such as skin reactions ● If IVIg home treatments are not available or feasible ● Patient preference, more autonomy	● 0.4 g/kg per week or 1:1 conversion from IVIg treatment dose divided by dose interval for weekly SCIg dose. ● Administration frequency may vary from 1–3 times per week to once every 14 days	● Periodic weaning justification of long-term use (every 6–12 months first 2–3 years, then 1–2 years)	● Fewer systemic side effects compared to IVIg ● Patients or a caretaker need to administer the treatment themselves ● Not proven to be a suitable induction treatment option
Corticosteroids	● As induction and maintenance treatment ● Contra-indications IVIg	● Pulsed dexamethasone (40 mg on 4 consecutive days every 4 weeks) for 6 months ● Pulsed IV methylprednisolone (1 g every 3 weeks) for 6 months ● Daily prednisone: starting with 60 mg daily and slowly taper over 6–8 months	● Two to three months	● Ample long-term side effects ● Prophylactic treatment of osteoporosis necessary ● Motor CIDP can deteriorate after corticosteroids, IVIg preferred
Plasma exchange	● No response to other first line treatments, fast progression ● Auto-immune nodopathies	● No established protocol for CIDP	● After 2–4 weeks	● Relatively safe, but risk of central-line infections and thrombosis with prolonged use ● Not suitable as long-term maintenance treatment, logistical and financial constraints

Abbreviations: IVIg, intravenous immunoglobulins; SCIg, subcutaneous immunoglobulins; VTE, venous thromboembolism.

Table 5 Tools for Objectifying Treatment Response

Scale	Measurement	Modality (Range)	Minimal Clinically Important Difference^a
Disability	I-RODS	Questionnaire (0–48)	↑ ≥4 centile points
	INCAT-DS	Investigator reported arm (0–5) and leg (0–5) disability score (1–10)	↓ ≥1 point
Impairment	mISS scale	Investigator reported score (0–33)	↓ ≥2 points
	Grip strength	Handheld dynamometry	Martin Vigorimeter: ↑ ≥8-14 kPa ^b Jamar Hand grip dynamometer: ↑ ≥10%
	MRC Sum score	Sum of MRC scores (0–60) ^c	↑ ≥2-4 points ^b

Notes: ^a Changes to objectify improvement have not been sufficiently validated yet, but these cut-offs for improvement are commonly used in CIDP trials. ^b Higher values improve specificity. ^c Including shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension and foot dorsiflexion.

Abbreviations: I-RODS, Inflammatory Rasch-built Overall Disability Scale; INCAT-DS, Inflammatory Neuropathy Cause and Treatment disability scale; mISS, Modified INCAT Sensory Sum; MRC, Medical Research Council.

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

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