guideline-CIDP-2021.pdf

Received: 16 May 2021 | Accepted: 28 May 2021 DOI: 10.1111/ene.14959 GUIDELINES 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 Peter Y. K. Van...

Received: 16 May 2021 | Accepted: 28 May 2021 DOI: 10.1111/ene.14959 GUIDELINES 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 Peter Y. K. Van den Bergh1 | Pieter A. van Doorn2 | Robert D. M. Hadden3 | Bert Avau4 | Patrik Vankrunkelsven5 | Jeffrey A. Allen6 | Shahram Attarian7 | 8 9 10 Patricia H. Blomkwist-­Markens | David R. Cornblath | Filip Eftimov | | Thomas Harbo12 | Satoshi Kuwabara13 | H. Stephan Goedee11 14 15 16 Richard A. Lewis | Michael P. Lunn | Eduardo Nobile-­Orazio | Luis Querol17 | Yusuf A. Rajabally18 | Claudia Sommer19 | Haluk A. Topaloglu20 1 Neuromuscular Reference Centre, Department of Neurology, University Hospital Saint-­Luc, Brussels, Belgium 2 Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands 3 Department of Neurology, King's College Hospital, London, UK 4 Cochrane Belgium, CEBAM, Leuven, Belgium and CEBaP, Belgian Red Cross, Mechelen, Belgium 5 Cochrane Belgium, CEBAM, Leuven, Belgium 6 Department of Neurology, University of Minnesota, Minneapolis, Minnesota 7 Centre de Référence des Maladies Neuromusculaires et de la SLA, APHM, CHU Timone, Marseille, France 8 Patient Representative GBS/CIDP Foundation International, International Office, Philadelphia, Pennsylvania, USA 9 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 10 Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 11 Department of Neuromuscular Disorders, University Medical Centre Utrecht, Utrecht, The Netherlands 12 Department of Neurology, Århus University Hospital, Århus, Denmark 13 Department of Neurology, Chiba University Hospital, Chiba, Japan 14 Department of Neurology, Cedars-­Sinai Medical Center, Los Angeles, California, USA 15 Department of Neurology and MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK 16 Neuromuscular and Neuroimmunology Service, IRCCS Humanitas Clinical and Research Center, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy 17 Neuromuscular Diseases Unit—­Neurology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain 18 19 Regional Neuromuscular Service, Neurology, Queen Elizabeth Hospital Birmingham, Birmingham, UK Neurology Clinic, University Hospital Würzburg, Würzburg, Germany 20 Department of Pediatrics, Yeditepe University, İstanbul, Turkey Correspondence Peter Y. K. Van den Bergh, Neuromuscular Reference Centre, Department of Neurology, University Hospital Saint-­Luc, Brussels, Belgium. Email: [email protected] Abstract Objective: To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome This article is co-published by the European Journal of Neurology and the Journal of the Peripheral Nervous System. © 2021 European Academy of Neurology and Peripheral Nerve Society Eur J Neurol. 2021;00:1–28.  wileyonlinelibrary.com/journal/ene | 1 2 | Funding information European Academy of Neurology (EAN); GAIN Charity UK; GBS/CIDP Foundation International; Peripheral Nerve Society (PNS) Van den Bergh et al. (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Results: Statements were prepared according to the GRADE Evidence-­to-­Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term “atypical CIDP” was replaced by “CIDP variants” because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-­line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point). KEYWORDS CIDP, diagnosis, GRADE, guideline, treatment O B J EC TI V E S A N D S CO PE most closely linked to electrodiagnostic criteria for detection of peripheral nerve demyelination. Comparison of different published The EFNS/PNS consensus guideline on the diagnosis and manage- diagnostic criteria sets for CIDP showed that the 2010 EFNS/PNS ment of chronic inflammatory demyelinating polyradiculoneuropathy guideline criteria [3,4] have very good diagnostic accuracy [6–­8]. (CIDP) was published first in 2005 [1,2] and revised in 2010 [3,4]. The World-­wide acceptance and use of these criteria in CIDP research aim of this second revision is to update the 2010 guideline accord- have been documented [9]. Nevertheless, misdiagnosis commonly ing to the Grading of Recommendations Assessment, Development occurs, particularly in those classified as CIDP variants [10–­12]. and Evaluation (GRADE) methodology [5] and to formulate evidence-­ Although this may be related to errors in the interpretation of diag- based recommendations and consensus-­based Good Practice Points nostic test results [11,13] and to non-­compliance or lack of aware- for clinical practice. The target population for the diagnostic part con- ness of guidelines [14], some patients fulfilling diagnostic criteria sists of patients of any age, presenting with clinical features suggestive based on correctly interpreted test results do not have CIDP [10,13]. of CIDP. Patients with any comorbidity are considered excluding those The current guideline revision attempts to improve specificity of the with a confirmed alternative cause of their neuropathy. The treatment criteria. The evidence from randomized clinical therapeutic trials has recommendations apply to patients diagnosed with CIDP. This guide- significantly increased since 2010 and allows evidence-­based rec- line revision is intended for neurologists and paediatric neurologists in ommendations about treatments according to GRADE. secondary and tertiary care settings. The aim is to optimise diagnostic accuracy and to improve patient outcomes. BAC KG RO U N D M E TH O D S The methodology for the development of this guideline followed the frameworks provided by AGREE II [15] and GRADE [5], and the rec- The diagnosis of CIDP rests upon a combination of clinical, elec- ommendations of the EAN on the development of a neurological man- trodiagnostic, and laboratory features with exclusions to eliminate agement guideline [16]. Twelve research questions were constructed other disorders that may mimic CIDP. Criteria for CIDP have been in the Population/Intervention/Comparison/Outcome question | EAN/PNS GUIDELINE ON DIAGNOSIS AND TREATMENT 3 BOX 1 Population/Intervention/Comparison/Outcome questions (PICOs) DIAGNOSTIC PICOS (systematic literature search and consensus—­except GRADE for PICO 1) PICO 1. Electrodiagnosis—­In patients with suspected CIDP, does the use of electrophysiology/electrodiagnosis (motor and sensory nerve conduction studies, somatosensory evoked potentials, root stimulation, triple stimulation technique, nerve excitability studies, and electromyography), compared to not using electrodiagnosis, influence diagnostic accuracy and patient outcome? PICO 2. Response to treatment as diagnostic criterion—­In patients with suspected CIDP, does the use of patients' response to treatment (subjective vs objective), compared to not considering response to treatment, influence diagnostic accuracy, and patient outcome? PICO 3. MRI or ultrasound—­In patients with suspected CIDP, does the use of imaging—­MRI (thickening or abnormal enhancement of cervical/lumbar nerve roots or brachial/lumbar plexus) or nerve ultrasound (increased cross-­sectional area of peripheral nerves or roots compared with normal values), compared to no imaging, influence diagnostic accuracy and patient outcome (treatment response and clinical course)? PICO 4. CSF—­In patients with suspected CIDP, does the use of CSF examination compared to not using CSF examination, influence diagnostic accuracy and patient outcome? Are thresholds for raised protein different in children <16 years old or in any patient, or in subgroups with diabetes, or previous spinal surgery? PICO 5. Antibodies—­In patient with suspected CIDP, does testing for the presence of serum auto-­antibodies, including anti-­nodal and paranodal antibodies (contactin1, contactin1/contactin-­associated protein1 complex, neurofascin155, neurofascin140/neurofascin186, contactin-­associated protein1), anti-­ganglioside antibodies, and anti-­MAG antibodies, compared to not testing for antibodies, influence diagnostic accuracy and patient outcome? PICO 6. Nerve biopsy—­In patients with suspected CIDP, does nerve biopsy (looking for macrophage-­associated demyelination, onion bulb formation, demyelinated and to a lesser extent remyelinated nerve fibres, endoneurial oedema, endoneurial mononuclear cell infiltration, loss of transverse bands or paranodal loop detachment, teased fibre analysis), compared to no nerve biopsy, influence diagnostic accuracy and patient outcome? PICO 7. Monoclonal gammopathies—­In patient with suspected CIDP, does testing for the presence of IgG, IgA, IgM, or light chain monoclonal gammopathies, compared with not testing for monoclonal gammopathies and patient outcome? TREATMENT PICOS (systematic literature search and GRADE -­except consensus for PICO 12) PICO 8. Corticosteroids—­In patients with CIDP, does treatment with corticosteroids, compared to no treatment with corticosteroids or corticosteroids in a different dose/timing influence impairment, disability, and quality of life? Are treatment effects different in CIDP variants and in children (<16 years)? PICO 9. Immunoglobulin—­In patients with CIDP, does treatment with IV or SC immunoglobulins, compared to no treatment with immunoglobulins or immunoglobulins in a different dose/timing, influence impairment, disability, and quality of life? Are treatment effects different in CIDP variants and in children (<16 years)? PICO 10. Plasma exchange—­In patients with CIDP, does treatment with plasma exchange, compared to no treatment with plasma exchange or plasma exchange in a different dose/timing, influence impairment, disability, and quality of life? Are treatment effects different in children (<16 years)? PICO 11. Other immune treatments—­In patients with CIDP, does treatment with immunomodulatory drugs other than corticosteroids, immunoglobulins and plasma exchange, compared to no treatment with immunomodulatory drugs or immunomodulatory drugs in a different dose/timing, influence impairment, disability, and quality of life? Are treatment effects different in children (<16 years)? PICO 12. Pain treatment—­In patients with CIDP, do drugs for pain relief (anti-­epileptic, antidepressant, opiates or opiate analogues, cannabinoids, acetaminophen, NSAIDs or other typical or atypical analgesia), compared to no pain relief or other analgesia influence pain, fatigue, and quality of life? (PICO) format during a kick-­off meeting in March 2018 (Box 1). The Reviews; the Database of Abstracts of Reviews (DARE); and the following databases were searched for identification of eligible stud- Cochrane Central Register of Controlled Clinical Trials. The litera- ies for each PICO, according to predefined selection criteria: Medline, ture search for each PICO was conducted between June 2018 and via the PubMed interface; Embase, via the embase.com interface; the July 2019 without restrictions regarding publication date. The Task Cochrane Library, consisting of the Cochrane Database of Systematic Force (TF) additionally included relevant papers published during the 4 | preparation of this Guideline. Unpublished data known to the TF was Van den Bergh et al. TA B L E 1 Clinical criteria for CIDP not used. Data were extracted and summarized in GRADE summary Typical CIDP of findings tables (treatment PICOs) or evidence tables (diagnostic All the following: PICOs). To reach consensus, the TF members prepared draft state- • Progressive or relapsing, symmetric, proximal and distal muscle weakness of upper and lower limbs, and sensory involvement of at least two limbs ments about definition, diagnosis, and treatment, according to the elements of the GRADE Evidence-­to-­Decision frameworks [17,18]. The TF made a strong recommendation (for or against an interven- • Developing over at least 8 weeks tion) when it judged that almost all informed people would make the • Absent or reduced tendon reflexes in all limbs recommended choice [19]. A weak recommendation was made when CIDP variants it judged that most informed people would choose the recommended One of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in unaffected limbs): course of action, but a substantial number would not, either because it was applicable (or available) only to a subgroup, or the evidence had low certainty, or the risk/benefit ratio might not be favourable for all patients. For diagnostic PICOs, a formal GRADE approach to all evidence was not considered useful, because of limited evidence. The TF reached consensus and offered advice as Good Practice Points [20]. Only PICO 1 on electrodiagnosis was subjected to GRADE, which led to the decision to treat the other diagnostic PICOs as consensus-­ based PICOs, supported by a systematic literature search without formal GRADE assessment. The recommendations and Good Practice Points were revised and collated into a single document, which was then revised iteratively by the TF until consensus was reached. The patient representative from the GBS/CIDP Foundation International • Distal CIDP: distal sensory loss and muscle weakness predominantly in lower limbs • Multifocal CIDP: sensory loss and muscle weakness in a multifocal pattern, usually asymmetric, upper limb predominant, in more than one limb • Focal CIDP: sensory loss and muscle weakness in only one limb • Motor CIDP: motor symptoms and signs without sensory involvement • Sensory CIDP: sensory symptoms and signs without motor involvement Abbreviation: CIDP, chronic inflammatory demyelinating polyradiculoneuropathy. reviewed all recommendations and Good Practice Points and participated in consensus votes in her capacity as TF member. A de- commonly between 40 and 60 years. Onset during infancy and child- tailed protocol of the guideline development can be found in suppo​ hood can occur [27–­30]. Typical CIDP may present acutely (acute-­ rting​infor​mation. It is planned to update the guideline every 5 years. onset CIDP [A-­CIDP]) in up to 13% of patients, who rapidly progress within 4 weeks and initially may be diagnosed with GBS [31,32]. R E S U LT S Diagnostic criteria for CIDP Therefore, distinguishing A-­CIDP from GBS can be challenging as 5% of patients initially diagnosed with GBS are later reclassified as A-­ CIDP [32]. In contrast with GBS patients, A-­CIDP patients continue to deteriorate more than 8 weeks after onset or do relapse at least three times after initial improvement. Often, A-­CIDP patients re- Clinical criteria main able to walk independently, are less likely to have facial weakness, respiratory or autonomic nervous system involvement, and are The TF refined the clinical criteria for defining CIDP into “typical more likely to have sensory signs [32,33]. Although these features CIDP” and “CIDP variants”. Since they are more a matter of definition may favour the diagnosis of A-­CIDP, there are no specific clinical than research questions, these criteria are formulated as consensus features or laboratory tests that can distinguish GBS from A-­CIDP in expert opinion. The TF replaced the label “atypical CIDP,” used in the the acute stage of the disease. 2010 EFNS/PNS guideline [3,4], by “CIDP variants” because these are now well characterized entities, each presenting with a specific CIDP variants clinical and electrodiagnostic phenotype (Table 1, Flowchart 1). Clinical presentations different from typical CIDP are considered CIDP variants because they share the common features of demyeli- Typical CIDP nation and response to immune therapy. Whether their pathogenic Most commonly, the disease begins with paraesthesia and weakness mechanisms are different is not clear since there are indications in the distal limbs as well as difficulty walking. The clinical examina- that CIDP variants may evolve over time into typical CIDP [34–­36]. tion shows progressive symmetric proximal and distal muscle weak- Recognition of the clinical phenotype of the variants is crucial since ness, sensory loss, and decreased or absent deep tendon reflexes. the diagnostic workflow and the differential diagnosis may differ The disease course is steadily progressive for more than 8 weeks, but compared to typical CIDP. can be relapsing-­remitting. In contrast with Guillain-­Barré syndrome (GBS), cranial nerves are less frequently affected and respiratory • Distal CIDP, also known as distal acquired demyelinating symmet- [21,22] or autonomic involvement is exceptional [23–­26]. Typical ric neuropathy [37], presents with sensory loss in the distal upper CIDP is more common in males and can occur at any age, but most and lower limbs as well as gait instability. Weakness may occur | EAN/PNS GUIDELINE ON DIAGNOSIS AND TREATMENT 5 and is usually distally accentuated in lower more than upper limbs. contactin-­associated protein 1 [Caspr1], and neurofascin isoforms Approximately two thirds of patients with this phenotype have NF140/186) have been discovered in a small subset of patients ful- IgM paraproteinaemic neuropathy, often with antibodies against filling 2010 EFNS/PNS criteria for CIDP [3,4] (PICO 5, Flowchart 1). myelin-­associated glycoprotein (MAG) [38–­40]. Distal neuropathy Patients with these antibodies often have specific clinical character- with an IgM paraprotein and anti-­MAG antibodies, anti-­MAG neu- istics [65,66]. Antibodies against CNTN1 were reported in patients ropathy, is considered outside the scope of CIDP as the majority diagnosed with CIDP, who presented with acute or subacute disease of patients have specific electrodiagnostic and pathologic find- onset, motor or ataxic features, and had no or poor response to IVIg ings and do not respond to intravenous immunoglobulin (IVIg) or treatment [67–­69]. Antibodies against NF155 were observed in pa- corticosteroids. tients diagnosed with CIDP who were younger at onset, and had a • Multifocal CIDP (synonyms: multifocal demyelinating neuropa- subacute or chronic disease course, distal weakness, ataxia, tremor, thy with persistent conduction block, Lewis-­Sumner syndrome and no or poor response to IVIg treatment [70–­72]. Antibodies against [LSS] [41]; multifocal acquired demyelinating sensory and motor Caspr1 present as an acute/subacute neuropathy frequently associ- neuropathy [MADSAM] [42]; multifocal inflammatory demyelin- ated with ataxia, neuropathic pain, cranial nerve involvement and poor ating neuropathy [43]) usually affects the upper limbs first. Lower response to IVIg [73–­75]. Antibodies to all neurofascin isoforms lead limbs may become involved later or sometimes are affected from to a severe phenotype, in particular when of the IgG3 isotype [76,77]. the onset. [42,43] Cranial nerves, including oculomotor, trigemi- The TF proposed to name these conditions “auto-­immune nodopa- nal, facial, vagal, and hypoglossal nerves, are probably more fre- thies” and not to regard them as CIDP variants because they have dis- quently involved than in other CIDP forms [38,44–­49]. tinct clinical features, no overt inflammation or macrophage-­mediated • Focal CIDP is rare and usually affects the brachial or lumbosacral plexus, but can affect individual peripheral nerves as well [50,51]. demyelination [68,78,79] and do poorly respond to CIDP treatment, IVIg in particular. Rituximab, however, may be effective [73,76,80]. • Motor CIDP presents as relatively symmetric proximal and distal CIDP has been associated with numerous conditions (eg, diabe- weakness but with normal sensation clinically and electrodiag- tes mellitus, IgG or IgA monoclonal gammopathy of undetermined nostically [52,53]. This is in contrast to both typical CIDP, where significance [MGUS], IgM monoclonal gammopathy without an- sensation is abnormal, and multifocal motor neuropathy (MMN), tibodies to MAG, HIV infection, malignancies) [81]. There is insuf- where the pattern of weakness is asymmetric and mainly affect- ficient evidence to consider CIDP associated with these diseases ing the upper limbs [54]. If sensory nerve conduction is abnormal different from idiopathic CIDP. In some cases, CIDP may occur as in clinically motor CIDP [55], the diagnosis is motor-­predominant an immune-­related adverse event induced by drugs or biologics [82–­ CIDP. Patients with motor CIDP may deteriorate after corticoste- 84]. In those cases, most physicians would stop the drug/biologic roids (PICO 8) [36,52,55,56]. but this decision should be based on the individual clinical situation. • Sensory CIDP is usually characterized by gait ataxia, impairment In most published reports, treatment has not differed from that used of vibration and position sense and changes in cutaneous sensa- in idiopathic CIDP. The differential diagnosis of typical CIDP and tion [35,57,58]. By definition, muscle weakness is not present. If CIDP variants is extensive and needs to be carefully addressed by motor nerve conduction slowing or motor conduction block are appropriate investigations (Tables 4 and 5, Flowchart 2). present [57,59,60], the diagnosis is sensory-­predominant CIDP. Long-­term follow-­up studies have shown that sensory CIDP is often a transient clinical stage that precedes the appearance of Electrodiagnostic criteria (PICO 1) weakness in about 70% of patients [36,61]. The TF strongly recommended electrodiagnosis (nerve conduction Disorders not classified as CIDP studies) to support the clinical diagnosis of typical CIDP and CIDP Chronic immune sensory polyradiculopathy (CISP): Patients sus- variants (Tables 2 and 3). The TF decided to reduce the levels of pected to have clinically sensory CIDP, but with normal motor electrodiagnostic certainty, as used in the 2010 EFNS/PNS guide- and sensory nerve conduction studies may have CISP [62–­6 4]. line [3,4], from three (definite, probable, possible CIDP) to only two Somatosensory evoked potentials may be absent or show very (CIDP and possible CIDP), because of empirical evidence showing proximal slowing in CISP because sensory axons proximal to the that the sensitivity and specificity of electrodiagnostic criteria for dorsal root ganglia are affected. Because the sensory neurons probable and definite CIDP do not significantly differ [8,92]. Since in the dorsal root ganglia remain intact, standard sensory nerve there is no gold standard for the diagnosis of CIDP, the TF decided conduction studies are normal. Although most likely immune-­ to avoid the label “definite CIDP.” The TF decided to require not only mediated and responding to immune treatment, there is not motor but also sensory conduction studies to define the diagnostic enough evidence to determine if CISP is demyelinating or related categories of typical CIDP and CIDP variants (Table 6, Flowchart 1). to sensory CIDP, and has therefore not been included in the CIDP variant classification (see Flowchart 2). Recommendation 1—­Typical CIDP Autoimmune nodopathies: Antibodies against nodal-­paranodal cell-­ • To confirm the clinical diagnosis of typical CIDP, at least two adhesion molecules (contactin-­1 [CNTN1], neurofascin-­155 [NF155], motor nerves must have abnormalities which fulfil the motor 6 | Van den Bergh et al. TA B L E 2 Motor nerve conduction criteria (1) Strongly supportive of demyelination: At least one of the following: (a) Motor distal latency prolongation ≥50% above ULN in two nerves (excluding median neuropathy at the wrist from carpal tunnel syndrome), or (b) Reduction of motor conduction velocity ≥30% below LLN in two nerves, or (c) Prolongation of F-­wave latency ≥20% above ULN in two nerves (≥50% if amplitude of distal negative peak CMAP <80% of LLN), or (d) Absence of F-­waves in two nerves (if these nerves have distal negative peak CMAP amplitudes ≥20% of LLN) + ≥1 other demyelinating parametera in ≥1 other nerve, or (e) Motor conduction block: ≥30% reduction of the proximal relative to distal negative peak CMAP amplitude, excluding the tibial nerve, and distal negative peak CMAP amplitude ≥20% of LLN in two nerves; or in one nerve + ≥ 1 other demyelinating parametera except absence of F-­waves in ≥1 other nerve, or (f) Abnormal temporal dispersion: >30% duration increase between the proximal and distal negative peak CMAP (at least 100% in the tibial nerve) in ≥2 nerves, or (g) Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) prolongation in ≥1 nerveb + ≥1 other demyelinating parametera in ≥1 other nerve • (LFF 2 Hz) median > 8.4 ms, ulnar > 9.6 ms, peroneal > 8.8 ms, tibial > 9.2 ms • (LFF 5 Hz) median > 8.0 ms, ulnar > 8.6 ms, peroneal > 8.5 ms, tibial > 8.3 ms • (LFF 10 Hz) median > 7.8 ms, ulnar > 8.5 ms, peroneal > 8.3 ms, tibial > 8.2 ms • (LFF 20 Hz) median > 7.4 ms, ulnar > 7.8 ms, peroneal > 8.1 ms, tibial > 8.0 ms (2) Weakly supportive of demyelination As in (1) but in only one nerve. Note 1. These criteria have been established by using a frequency filter bandpass of 2 Hz to 10 kHz for all parameters, except for distal CMAP duration prolongation where separate criteria were defined for four different LFFs of 2, 5, 10, and 20 Hz. Skin temperature should be maintained to at least 33°C at the palm and 30°C at the external malleolus. Note 2. Extensiveness of motor nerve conduction studies (number of nerves to be studied and proximal studies): •T  o apply motor nerve conduction criteria, the median, ulnar (stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial nerves on one side are tested. • I f criteria are not fulfilled, the same nerves are tested at the other side, and/or the ulnar and median nerves are stimulated at the axilla and at Erb's point. • Motor conduction block or slowing is not considered in the ulnar nerve across the elbow or the peroneal nerve across the knee. •B  etween Erb's point and the wrist, at least 50% CMAP amplitude reduction is required for conduction block in the ulnar and median nerves. Proximal studies of the median nerve may require collision techniques to avoid ulnar nerve components in the median nerve CMAP when recorded from the abductor pollicis brevis muscle (but not when recorded from the flexor carpi radialis muscle) [3,4,49,85,86]. •F  or ulnar motor conduction block in the forearm, a Martin-­Gruber anastomosis should be ruled out with stimulation of the median nerve at the elbow recording over the abductor digiti minimi muscle. •F  or median motor conduction block in the forearm, co-­stimulation of the ulnar nerve at the wrist must be ruled out. Stimulation of the median nerve at the wrist while simultaneously recording over the abductor pollicis brevis muscle and the abductor digiti minimi muscle can detect ulnar nerve co-­stimulation; stimulation should be adapted so that no CMAP is recorded from the ulnar nerve-­innervated abductor digiti minimi muscle. • I f distal CMAP amplitudes are severely reduced (<1 mV), recording from more proximal muscles innervated by the peroneal, median, ulnar or radial nerve. Abbreviations: CMAP, compound muscle action potential; LFF, low frequency filter; LLN, lower limit of normal values; ULN, upper limit of normal values. a Any nerve meeting any of the criteria (a-­g). b Mitsuma et al. [87] conduction criteria. If criteria are fulfilled in only one nerve, the Recommendation 2—­Distal CIDP diagnosis is possible typical CIDP. • Motor conduction criteria fulfilment is required in at least two • Sensory conduction abnormalities must be present in at least two nerves. upper limb nerves to confirm the clinical diagnosis of distal CIDP. The distal negative peak CMAP amplitude should be at • In patients suspected of having typical CIDP because they fulfil least 1 mV. When criteria are fulfilled in two lower limb but not clinical criteria but not minimal electrodiagnostic criteria, the di- upper limb nerves or if criteria are fulfilled in only one upper agnosis of possible typical CIDP may be made if there is objective limb nerve, the maximum diagnostic certainty is possible distal improvement following treatment with IVIg, corticosteroids or plasma exchange and if at least one additional supportive criterion (PICO 2-­4, 6) is fulfilled. CIDP. • Sensory conduction abnormalities must be present in at least two nerves. | EAN/PNS GUIDELINE ON DIAGNOSIS AND TREATMENT TA B L E 3 Sensory nerve conduction criteria (1) CIDP • Sensory conduction abnormalities (prolonged distal latency, or reduced SNAP amplitude, or slowed conduction velocity outside of normal limits) in two nerves. (2) Possible CIDP • As in (1) but in only one nerve. • Sensory CIDP with normal motor nerve conduction studies needs to fulfil a. or b: a. sensory nerve conduction velocity <80% of LLN (for SNAP amplitude >80% of LLN) or <70% of LLN (for SNAP amplitude <80% of LLN) [85] in at least two nerves (median, ulnar, radial, sural nerve), or b. sural sparing pattern (abnormal median or radial sensory nerve action potential [SNAP] with normal sural nerve SNAP) (excluding carpal tunnel syndrome) [88–­90]. Note 1. Skin temperature should be maintained to at least 33°C at the palm and 30°C at the external malleolus. 1. Since these criteria do not permit to identify normal reference values compatible with sensory nerve demyelination, sensory CIDP cannot be more than a possible diagnosis as based on clinical and electrophysiological criteria. Note 2. Decline in sural nerve action potential amplitude occurs with age and use of age-­dependent reference values after age 60 is advised [91]. Abbreviations: CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; LLN, lower limit of normal; SNAP, sensory nerve action potential. 7 • Sensory CIDP with motor conduction criteria fulfilled in one nerve is diagnosed as possible sensory-­predominant CIDP. If motor conduction criteria are fulfilled in two nerves, the diagnostic certainty increases to sensory-­predominant CIDP. Considerations supporting the Recommendations (suppo​r ting​infor​ mation) Evidence summary: Data extracted from 38 cohort studies assessing the usefulness of a total of 27 electrodiagnostic parameters or criteria sets were subjected to GRADE analysis. The certainty of the evidence of effect estimates was low to very low for all outcomes. Rationale: The recommendation of the TF for electrodiagnostic testing in patients with clinically suspected CIDP is based on the very good diagnostic accuracy of 2010 EFNS/PNS electrodiagnostic criteria [3,4] with high sensitivity/specificity for CIDP of 95%/96% [6], 81%/96% [7], and 73%/91% [8] reported in different patient populations. The advantages of electrodiagnostic testing include the long history of clinical experience, availability, inexpensiveness, and low burden for the patient. The TF expanded the 2010 EFNS/PNS electrodiagnostic criteria [3,4] by including sensory nerve conduction studies and by defining criteria specific for CIDP variants (Tables 2 and 3). Since up to 20% of patients with clinically typical CIDP do not fulfil minimal electrodiagnostic criteria, the TF considered that such patients may be diagnosed as possible typical CIDP as proposed by Koski et al. [93] if there is an objective response to a trial with any of the three proven CIDP treatments (PICO 2) Recommendation 3—­Multifocal and focal CIDP and if at least one other supportive criterion is fulfilled. • Motor conduction criteria fulfilment is required in at least two nerves in total in more than one limb to confirm the clinical diagnosis of multifocal CIDP and in at least two nerves in one limb for Supportive criteria the diagnosis of focal CIDP. When criteria are fulfilled in only one nerve, the maximum diagnostic certainty is possible multifocal or Response to treatment (PICO 2), imaging (PICO 3), cerebrospinal possible focal CIDP. fluid (CSF) (PICO 4), or nerve biopsy (PICO 6) may support the di- • Sensory conduction abnormalities must be present in at least two agnosis of CIDP in patients who fulfil clinical criteria for CIDP, but nerves of the affected limbs for the diagnosis of multifocal or whose electrodiagnostic criteria only allow for possible CIDP. Since focal CIDP and in one nerve of the affected limb for the diagnosis sensory nerve conduction studies are now part of the electrodiag- of possible focal CIDP. nostic criteria set, they have been removed as general supportive criterion, except for diagnosing patients with sensory CIDP without Recommendation 4—­Motor CIDP (and motor-­predominant CIDP) motor nerve conduction abnormalities, in whom fulfilment of the • Motor CIDP must fulfil motor conduction criteria in at least two sensory conduction criteria is required. nerves and sensory conduction must be normal in all of at least four nerves (median, ulnar, radial, and sural) to confirm the clinical (a) Response to treatment (PICO 2) diagnosis of motor CIDP. If criteria are fulfilled in only one motor nerve, the diagnosis is possible motor CIDP. • Motor CIDP with sensory conduction abnormalities in two nerves is diagnosed as motor-­predominant CIDP. Good Practice Points • The TF considered that an objective response to treatment with immunomodulatory agents (IVIg, plasma exchange, corticosteroids) supports the clinical diagnosis of CIDP in patients in whom Recommendation 5—­Sensory CIDP (and sensory-­predominant CIDP) clinical, electrodiagnostic and other supportive criteria allow only a diagnosis of possible CIDP. • Sensory CIDP must fulfil sensory conduction criteria and • Objective response to treatment requires improvement on at least motor conduction must be normal in all of at least four nerves one disability and one impairment scale. Lack of improvement fol- (median, ulnar, peroneal, and tibial) to confirm the clinical di- lowing treatment does not exclude CIDP and a positive response is agnosis. The maximum diagnostic certainty is possible sensory not specific for CIDP. Many outcome scales are used in CIDP. Some CIDP. examples of disability and impairment scales are given: 8 | Van den Bergh et al. ○ Disability can be assessed by the Inflammatory Rasch-­built nerve enlargement* of at least two sites in proximal median nerve Overall Disability Scale (I-­RODS) [94–­96] and the Inflammatory segments and/or the brachial plexus (see NOTE below on exclud- Neuropathy Cause and Treatment (INCAT) disability scale ing mimics). [97,98]. *Cross-­sectional area median nerve >10 mm2 at forearm, >13 mm2 ○ Impairment can be assessed by the MRC sum score [96,98,99], the Modified INCAT Sensory Sum scale (mISS) [98,100], the Neuropathy Impairment Score [101], and by measuring grip strength using handheld dynamometry [98,102–­104]. upper arm, >9 mm2 interscalene (trunks) or >12 mm2 for nerve roots. • There is currently no evidence to support ultrasound in paediatric patients. • The changes required to define improvement have not been adequately validated. The following which have been used in clinical Considerations supporting the Good Practice Points (suppo​ trials can serve as a guide: rting​infor​mation) ○ I-­RODS: + ≥4 centile points Evidence summary: Data extracted from 12 cohort studies assessing ○ INCAT disability scale: − ≥1 point the usefulness of ultrasound were analysed. Enlargement mainly of ○ mISS: − ≥2 points proximal nerve segments in arm nerves and spinal nerve roots are ○ MRC sum score (0-­60): + ≥2 to 4 points* the most characteristic feature in CIDP [109–­112]. The yield of strin- ○ Grip strength: gent cut-­off values using a practical sonographic protocol (brachial • Martin Vigorimeter: + ≥8 to 14 kPa* plexus and proximal median nerve segments bilaterally) has been • Jamar hand grip dynamometer: + ≥10%** validated in a prospective cohort of patients with suspected chronic *higher values may improve diagnostic specificity. inflammatory neuropathies [113,114]. In contrast to the adult pop- **values averaged over 3 consecutive days improve diagnostic ulation, systematic studies on yield of ultrasound in children with specificity [104]. suspected CIDP are lacking. Only a few smaller studies reported on reference values for sonographic nerve sizes in different age catego- Considerations supporting the Good Practice Points (suppo​ ries [115–­117], but stringent cut-­off values based on disease controls rting​infor​mation) are lacking. Evidence summary: Data from six cohort studies assessing response to Rationale: Since in children inherited demyelinating neuropathies are treatment with IVIg, plasma exchange, or corticosteroids were extracted much more prevalent than CIDP and since rater experience on nerve and analysed in evidence tables. There is moderate certainty evidence ultrasound in children is limited, the TF suggested not to use ultra- that corticosteroids and plasma exchange and high certainty evidence sound to support the diagnosis in children. Ultrasound is a low-­cost, that IVIg improves impairment [105] (PICO 8-­10). Uncontrolled studies widely available, non-­invasive procedure with moderate diagnostic report a positive response to IVIg, plasma exchange, or corticosteroids accuracy. in variable proportions of patients (68%-­99%) [35,49,106–­108]. Reasons for therapeutic failure likely include inadequate treatment dosing or du- MRI ration [12]. Misdiagnosis is also an important consideration for patients who do not respond to first line CIDP treatment [10–­12]. Good Practice Points Rationale: Current immunomodulatory treatments are not specific • The TF suggested not to use MRI in adult patients to diagnose for CIDP, since other auto-­immune conditions may also respond to CIDP except in patients fulfilling diagnostic criteria for possible these. Treatment response therefore needs to be carefully consid- CIDP but not for CIDP. CIDP may be more likely if there is en- ered in the clinical and electrophysiological context to avoid overdi- largement and/or increased signal intensity of nerve root(s) on agnosis. If patients have an objective response to treatment, the T2 weighted MRI sequences (DIXON/STIR, coronal + sagittal probability of the diagnosis of CIDP increases. A minority of non-­ planes)* (see NOTE below on excluding mimics). responders to at least one of the three proven effective treatments *preferably quantitative assessment of the spinal nerve root (PICO 8-­10) still may have CIDP. These patients would require addi- sizes (nerve root diameter right next to the ganglion, measured tional testing to rule out other disorders which mimic CIDP before as height in coronal plane with cut-­off value >5 mm), or semi-­ considering other immunosuppressive treatment strategies. quantitative scoring of abnormalities of the spinal nerve roots and trunks using the following categories: normal, possibly abnormal, (b) Imaging (PICO 3) clearly abnormal. • There is currently no evidence to support MRI in paediatric Ultrasound patients. Good Practice Points Considerations supporting the Good Practice Points (suppo​ • The TF suggested to use ultrasound in adult patients to diagnose rting​infor​mation) CIDP in patients fulfilling diagnostic criteria for possible CIDP but Evidence summary: Data from 18 studies assessing the useful- not for CIDP. The diagnosis of CIDP may be more likely if there is ness of MRI were extracted and analysed. MRI of the brachial | EAN/PNS GUIDELINE ON DIAGNOSIS AND TREATMENT 9 and lumbosacral plexus may aid in the diagnosis of CIDP by Considerations supporting the Good Practice Points (suppo​ showing nerve root hypertrophy, increased signal intensity or rting​infor​mation) contrast enhancement [109,118–­1 21]. Advanced MRI sequences Evidence summary: From 42 clinical cohort studies identified, 9 were in- have improved tissue discriminating properties [122]. Most MRI cluded for data extraction and analysis. CSF protein is often increased studies only evaluated patients with established CIDP, using in CIDP patients (sensitivity of 42%-­77%), but with unknown specificity different study designs (with/without control group), whereas to discern CIDP from CIDP mimics [7,47]. In suspected CIDP with unu- only a few investigated its added diagnostic value that would sual features or in the presence of systemic symptoms and signs, CSF approach a more routine clinical setting [123,124]. An important analysis is suggested to exclude an underlying malignancy or infection limitation is the lack of objective cut-­o ff values for abnormal- [129]. There is a risk of misdiagnosis in cases where electrodiagnosis is ity. Two studies found low reproducibility of results in patients non-­confirmatory and only CSF protein is increased [11]. Specificity for with chronic inflammatory neuropathies and disease controls, CIDP is uncertain using newly established higher normative cut-­off val- even among experienced raters [125–­1 27]. Only a few studies ues for CSF protein elevation in older subjects (>0.6 g/L above age 50) used objective cut-­o ffs for abnormal nerve root sizes (>5 mm) to [130]. Liberatore et al. [131] found that, using cut-­offs of ≥0.5 g/L under improve performance and consistency of plexus MRI [123,128]. the age of 50 years and >0.6 g/L over the age of 60 years, sensitivity of Rationale: Conditions under which MRI may be considered in pa- CSF protein elevation for CIDP was 68%. In children, the interpretation tients fulfilling only possible electrodiagnostic criteria include of CSF protein levels is complex and validated reference values for dif- unavailability of ultrasound or when ultrasound results are non-­ ferent ages categories are lacking. contributory. In children with suspected CIDP, systematic stud- Rationale: The independent diagnostic value of CSF testing remains ies on MRI are lacking, inherited demyelinating neuropathies are unproven. When CSF protein levels are normal, doubt may unnec- more prevalent than CIDP and can also show nerve size increase, essarily be cast upon the diagnosis. In selected cases, where the and rater experience in children is limited. The low inter-­r ater re- clinical diagnosis and electrodiagnostic results are not fully confir- liability, lack of objective cut-­off values and high cost of MRI con- matory, CSF analysis could either support the diagnosis or exclude tribute to the statement against using MRI. alternative diagnoses. The sensitivity of CSF in CIDP variants is un- NOTE: Before concluding that ultrasound or MRI abnormalities certain. It may be advisable to consider more extensive electrodiag- are supportive of CIDP, there should be no laboratory/clinical fea- nostic testing prior to performing a lumbar puncture. tures that suggest other diseases such as MMN, demyelinating Charcot-­Marie-­Tooth (CMT) disease, IgM paraproteinaemic neu- (d) Nerve biopsy (PICO 6) ropathy (especially with anti-­MAG antibodies), polyneuropathy-­ organomegaly-­endocrinopathy-­M-­protein-­skin changes (POEMS) Good Practice Points syndrome, diabetic radiculoplexus neuropathy, amyloid neu- The TF suggested not to perform nerve biopsy as a routine proce- ropathy, neuralgic amyotrophy, leprosy, neurofibromatosis or dure to diagnose CIDP, but only in specific circumstances: neurolymphomatosis. • In cases where CIDP is suspected but cannot be confirmed with (c) CSF analysis (PICO 4) the clinical, laboratory, imaging, and electrodiagnostic studies. • In cases where CIDP is suspected, but there is little or no re- Good Practice Points sponse to treatment, such that an alternative diagnosis such as • The TF suggested not to perform CSF analysis if diagnostic crite- CMT, amyloidosis, sarcoidosis, or nerve sheath tumours/neurofi- ria are already met. • CSF analysis should be considered to exclude other diagnoses or to support the diagnosis of CIDP in the following circumstances: ○ Patients fulfilling diagnostic criteria for possible CIDP but not CIDP. ○ In cases of acute or subacute onset. ○ When an infectious or malignant aetiology is suspected or possible. ○ CSF protein elevation should be interpreted cautiously in the presence of diabetes. bromatosis might be considered. • Nerve biopsies should be considered only when: ○ skilled (neuro)surgeons and neuropathologists and specialized and experienced pathology laboratory facilities are available. ○ symptoms are severe enough to justify the potential morbidity associated with a nerve biopsy. ○ the low accuracy of the test is fully understood by the patient before undergoing the biopsy. • When a nerve biopsy is taken: ○ current expert consensus on minimal standards for processing and evaluating nerve biopsies should be observed [132]. ○ In view of higher normative values for CSF protein in individ- ○ most often the sural or the superficial peroneal nerve is biop- uals older than 50 years, higher levels are required to support sied but biopsy of a clinically affected nerve is more likely to a diagnosis of CIDP; there is insufficient research to date to establish rigorous cut-­offs. provide useful information. ○ factors probably supporting the diagnosis of CIDP may be: 10 | Van den Bergh et al. • thinly myelinated axons and small onion bulbs [133] Measurement of serum free light chains (SFLC) may detect an ab- • thinly myelinated or demyelinated internodes in teased fibres normality not otherwise detected. Note that relevant monoclonal [134] proteins may still have normal light chain and ratio measurements • perivascular macrophage clusters [135] in SFLC assays. If a gammopathy is found, further evaluation may • supportive features of demyelination on electron microscopy. be required and haematology-­oncology consultation should be [136] strongly considered. • In patients with distal CIDP, if no IgM paraprotein is found or Considerations supporting the Good Practice Points (suppo​ anti-­MAG antibody testing is negative, repeat testing should be rting​infor​mation) considered. Evidence summary: Data from 26 studies identified for assessing the • Testing of vascular endothelial growth factor (VEGF) serum levels usefulness of nerve biopsy were extracted and analysed to reach is indicated in patients with a distal and painful CIDP phenotype, consensus. Several studies tried to estimate nerve biopsy accuracy in whom a lambda light chain associated IgA or IgG paraprotein is in diagnosing CIDP, but the variability between them was huge and found, when POEMS syndrome is suspected. they could not be combined because of the wide range of outcomes used. Even when using the same parameters, there is an important Considerations supporting the Good Practice Points (suppo​ level of heterogeneity in the sensitivity for findings suggestive of rting​infor​mation) CIDP, which can be due to the subjectivity in studying the biopsies, Evidence summary: Data from 35 observational studies assessing the timing of the biopsy in the disease course, and comorbidities the presence and significance of monoclonal proteins and anti-­ [137]. Several studies assessed the clinical outcomes when initiat- MAG antibodies were extracted and summarized in evidence tables. ing treatment after a nerve biopsy. Clinical outcomes in patients Neuropathies with MGUS may behave like typical CIDP [146–­148]. with suspected CIDP, treated with immunomodulating agents after However, monoclonal gammopathies may be associated with neu- a biopsy-­guided diagnosis of CIDP, have been successful [137–­139]. ropathies mimicking CIDP, such as anti-­MAG IgM neuropathy However, lacking a control group, these data could not be used for [37,149], POEMS syndrome [150–­152], multiple myeloma or AL-­ analysis. Since nerve biopsy can reveal findings suggestive of a dif- amyloidosis [151]. ferent or differential diagnosis, a biopsy may save patients from the Rationale: In patients with suspected CIDP and a monoclonal gam- unnecessary complications of immune treatment and lead to ap- mopathy, correct diagnosis of both the neurological and oncological propriate therapy. Nerve biopsies have poor sensitivity and speci- condition is of paramount importance because of the implications ficity, and their contribution to the diagnosis is limited by these for management and treatment. Patient burden is negligible. These inaccuracies. tests are low cost and are available in most hospitals. Rationale: The statement on nerve biopsy is intended to reduce the number of unnecessary biopsies for suspected CIDP, given the low Antibody testing (PICO 5) diagnostic accuracy and invasive nature. The TF expects that only a Good Practice Points small number of carefully selected nerve biopsies will contribute to a • The TF suggested to consider testing for nodal and paranodal an- more accurate diagnosis of CIDP and to a lower probability of misdi- tibodies in all patients with clinical suspicion of CIDP: agnosis, especially in unusual cases when all other investigations are ○ when nodal and paranodal (anti-­NF155, anti-­CNTN1, anti-­ non-­diagnostic, including some patients considered to have CIDP Caspr1) and possibly anti-­NF140/186 antibody testing is avail- who have not responded to treatment. Sural nerve biopsy is asso- able and meeting quality standards. ciated with numbness in the area of innervation [140–­142]. Other ○ testing of nodal and paranodal antibodies is advised in CIDP complications include acute pain [143], chronic pain [142], allodynia patients with the following features: [144], dysaesthesia [145], neuroma formation [143], infections, and • resistance to standard therapy with IVIg and corticosteroids. wound dehiscence [144]. • acute or subacute aggressive onset, previous diagnosis of GBS or A-­CIDP. • low-­frequency tremor, ataxia disproportionate to the sen- Criteria for immunological testing sory involvement or other cerebellar features or predominantly distal weakness. Monoclonal gammopathy testing (PICO 7) • respiratory failure and cranial nerve involvement. Good Practice Points • associated nephrotic syndrome. • The TF strongly advised testing for serum monoclonal proteins in • very high CSF protein levels. adult patients with a clinical suspicion of CIDP. • Testing should include serum protein electrophoresis and immunofixation (to increase sensitivity to detect relevant low level • The TF advised using for nodal and paranodal autoantibody testing: paraproteins and identify paraprotein class and light chain), spot ○ a cell-­based assay using mammalian expression vectors en- urine immunofixation for light chains (Bence Jones protein). coding human NF155, CNTN1, NF186/NF140, and Caspr1. | EAN/PNS GUIDELINE ON DIAGNOSIS AND TREATMENT Expression vectors should avoid the use any protein tag at 11 TA B L E 4 Differential diagnosis (see Flowchart 2)a Typical CIDP the N-­terminal site, any protein tag at the C terminal site for CNTN1 and avoid the use, in general, of GFP-­t agged expres- • AL amyloidosis, ATTRv polyneuropathy sion vectors. • Chronic ataxic neuropathy ophthalmoplegia M-­protein agglutination disialosyl antibodies (CANOMAD) proteins) or teased-­nerve immunohistochemistry. The order • Guillain-­Barré syndrome of assays can be interchanged. The application of additional • Hepatic neuropathy confirmatory tests to the protocol is strongly recommended • HIV-­related neuropathy for low titre sera or dubious staining on the cell-­based assay • Multiple myeloma to avoid false positives. • Osteosclerotic myeloma • POEMS syndrome • Uremic neuropathy • Vitamin B12 deficiency—­actual or functional (eg, nitrous oxide poisoning) ○ a confirmatory test with ELISA (using human recombinant • The TF advised anti-­MAG antibody testing in all patients with an IgM paraprotein fulfilling CIDP diagnostic criteria (especially distal CIDP) because a high titre of anti-­MAG antibodies (>7000 Bühlmann Titre Units, BTU) [153] would strongly imply a different Distal CIDP diagnosis than CIDP. • The TF advised for anti-­MAG antibody testing: ○ Bühlmann test ELISA, or • Anti-­MAG IgM neuropathy • Diabetic neuropathy • Hereditary neuropathies (CMT1, CMTX1, CMT4, metachromatic leukodystrophy, Refsum disease, adrenomyeloneuropathy, ATTRv polyneuropathy) • POEMS syndrome • Vasculitic neuropathy ○ Locally validated ELISA, Western blot or immunohistochemistry assays. Considerations supporting the Good Practice Points (suppo​ Multifocal and focal CIDP rting​infor​mation) • Diabetic radiculopathy/plexopathy • Entrapment neuropathies • Hereditary neuropathy with liability to pressure palsies (HNPP) • Multifocal motor neuropathy (MMN) dence is needed for anti-­NF155 IgM [154], anti-­nodal NF140/186 • Neuralgic amyotrophy IgG [76,77], and anti-­MAG without an apparent paraprotein [155]. • Peripheral nerve tumours (such as lymphoma, perineurioma, schwannoma, neurofibroma) • Vasculitic neuropathy (mononeuritis multiplex) Evidence summary: Data from 16 cohort studies assessing the presence of nodal-­paranodal and anti-­MAG antibodies were extracted and analysed. Diagnostic utility seems strong for anti-­NF155 and anti-­CNTN1 IgG [67,69,72], and anti-­C aspr1 IgG [73–­75]. More evi- For autoantibodies against CNTN1 and NF155, replication studies and a systematic review [156] are available with clear associations Motor CIDP to clinically relevant features and a high diagnostic specificity. For • Hereditary motor neuropathies (such as distal hereditary motor neuropathies, spinal muscular atrophy, porphyria) tibody detection may inform treatment remains anecdotal. Several • Inflammatory myopathies case reports and case series associate the detection of nodal-­ • Motor neurone disease paranodal antibodies, especially anti-­NF155 and anti-­CNTN1 with • Neuromuscular junction disorders (such as myasthenia gravis, Lambert-­Eaton syndrome) autoantibodies against Caspr1, nodal NF, and MAG, only small case series or anecdotal cases have been reported. Evidence that autoan- poorer responses to conventional therapies [66,156]. There is an- Sensory CIDP ecdotal evidence that these patients may respond well to rituximab • Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) ent cohorts and the magnitude of the effect is, at least for a subset • Chronic immune sensory polyradiculopathy (CISP) of patients, very significant. • Dorsal column lesions (such as syphilis, paraneoplastic, copper deficiency, vitamin B12 deficiency) sidered in patients who fulfil criteria for CIDP, when they present • Hereditary sensory neuropathies with particular characteristics (Flowchart 1) and when they do not • Idiopathic sensory neuropathy respond well to proven effective treatments for CIDP. Anti-­MAG an- • Sensory neuronopathy tibodies are relevant, if associated with a distal CIDP phenotype and • Toxic neuropathies (such as chemotherapy and vitamin B6 toxicity) [80,157]. Although the evidence is weak due to the low numbers of patients, the response to rituximab has been replicated in independ- Rationale: Nodal-­paranodal or MAG antibody testing should be con- an IgM paraprotein. The antibody testing has a low cost and positive results have significant implications for diagnosis and treatment. Access to antibody testing requires specialized laboratory procedures that are not available worldwide and standardization of the Abbreviation: CIDP, chronic inflammatory demyelinating polyradiculoneuropathy. a The differential diagnosis includes the disorders listed but is not limited to these. 12 | Van den Bergh et al. TA B L E 5 Investigations to be considered Investigations strongly advised in typical CIDP and in CIDP variants: • Electrodiagnosis including motor and sensory nerve conduction studies • Serum and urine monoclonal protein detection by immunofixation • Fasting blood glucose • Complete blood count • Renal function • Liver function Investigations to be performed if indicated, in typical CIDP and in CIDP variants: assays through interlaboratory validation needs to be performed. Patient burden is negligible. Advised strategy for the diagnosis of CIDP CIDP should be considered in any patient with a progressive symmetric or multifocal polyradiculoneuropathy in whom the clinical course is relapsing and remitting or progresses for more than 8 weeks, especially if there are sensory symptoms, proximal weakness, areflexia without wasting, or preferential loss of vibration or joint position sense (Flowcharts 1 and 2, Table 6). Electrodiagnostic • Ultrasound of the brachial plexus and cervical nerve roots in adult patients • MRI of cervical and lumbosacral nerve roots in adult patients • Cerebrospinal fluid examination including cells and protein • Nerve biopsy • Glycosylated haemoglobin (HbA1c) not met initially, a repeat study at a later date should be consid- • Borrelia burgdorferi serology ered. Supportive criteria (PICOs 2-­4, 6) can be used to confirm the • C reactive protein diagnosis of CIDP in patients with a possible diagnosis as based • Antinuclear antibody antibodies (ANA) on clinical and electrodiag