doi:10.1093/brain/awaa265 BRAIN 2020: 143; 3214–3224 | 3214 UPDATE Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy Filip Eftimov,1 Ilse M. Lucke,1 Luis A. Querol,2,3 Yusuf A. Rajabally4 and Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 Camiel Verhamme1 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consists of a spectrum of autoimmune diseases of the periph- eral nerves, causing weakness and sensory symptoms. Diagnosis often is challenging, because of the heterogeneous presentation and both mis- and underdiagnosis are common. Nerve conduction study (NCS) abnormalities suggestive of demyelination are man- datory to fulfil the diagnostic criteria. On the one hand, performance and interpretation of NCS can be difficult and none of these demyelinating findings are specific for CIDP. On the other hand, not all patients will be detected despite the relatively high sensitiv- ity of NCS abnormalities. The electrodiagnostic criteria can be supplemented with additional diagnostic tests such as CSF examin- ation, MRI, nerve biopsy, and somatosensory evoked potentials. However, the evidence for each of these additional diagnostic tests is limited. Studies are often small without the use of a clinically relevant control group. None of the findings are specific for CIDP, meaning that the results of the diagnostic tests should be carefully interpreted. In this update we will discuss the pitfalls in diagnos- ing CIDP and the value of newly introduced diagnostic tests such as nerve ultrasound and testing for autoantibodies, which are not yet part of the guidelines. 1 Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 3 Centro para la Investigación en Red en Enfermedades Raras (CIBERER), Madrid, Spain 4 Aston Medical School, Aston University, Birmingham, UK Correspondence to: Camiel Verhamme, MD, PhD Department of Neurology and Clinical Neurophysiology Amsterdam UMC – location AMC Meibergdreef 9 1105 AZ Amsterdam The Netherlands E-mail: c.verhamme@amsterdamumc.nl Keywords: CIDP; diagnostic pitfalls; diagnostic accuracy; misdiagnosis; underdiagnosis Abbreviations: CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CMAP = compound muscle action potential; EFNS/PNS = European Federation of Neurological Societies/Peripheral Nerve Society; NCS = nerve conduction studies; SSEP = somatosensory evoked potential neuropathies, causing weakness and sensory symptoms in a Introduction progressive, relapsing-remitting or monophasic fashion (Van Chronic inflammatory demyelinating polyradiculoneuropa- den Bergh et al., 2010). Early diagnosis is important, as in- thies (CIDPs) consists of a spectrum of immune-mediated duction of treatment can prevent axonal damage and Received April 8, 2020. Revised June 7, 2020. Accepted June 17, 2020. Advance access publication November 6, 2020 C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Diagnostic challenges in CIDP BRAIN 2020: 143; 3214–3224 | 3215 permanent disability (Bouchard et al., 1999; Eftimov et al., Table 1 Sensitivities and specificities of different 2013; Mehndiratta et al., 2015; Hughes et al., 2017). diagnostic criteria sets Diagnosis is often challenging, because of the heterogeneous Criteria Sensitivity Specificity presentation. Clinical presentation and nerve conduction EFNS/PNS, 2010 studies (NCS) play a major role in diagnosing CIDP, supple- Definite 73% (59.7–84.2%) 88% (78.7–94.4%) mented with diagnostic tests such as CSF examination, MRI, Probable 77% (63.6–87.0%) 84% (74.0–91.6%) nerve biopsy and somatosensory evoked potentials (SSEP) Possible 91% (80.4–97.0%) 65% (54.0–76.3%) (Van den Bergh et al., 2010). Recently, nerve ultrasound Van den Bergh and Piéret and testing for autoantibodies were introduced (Goedee Definite 63% (48.5–75.1%) 86% (77.1–93.5%) et al., 2017b; Vural et al., 2018). Despite diagnostic guide- Probable 66% (52.2–78.2%) 78% (68.1–87.5%) lines, in clinical practice both mis- and underdiagnosis are AAN common. Misdiagnosis is a major problem, leading to the Definite 4% (0.4–12.3%) 100% (95.3–100%) inappropriate use of expensive and potentially harmful treat- Probable 13% (5.2–24.1%) 100% (95.3–100%) Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 ment; underdiagnosis means that patients may not get effect- Possible 25% (14.4–38.4%) 100% (95.3–100%) ive treatment (Boukhris et al., 2004; Ayrignac et al., 2013; Koski 50% (36.3–63.7%) 84% (74.0–91.6%) Allen and Lewis, 2015; Lucke et al., 2019a). In this update AAN = American Academy of Neurology; EFNS/PNS = European Federation of we will discuss the frequent pitfalls in diagnosing CIDP and Neurological Societies/Peripheral Nerve Society. Adapted from Breiner and Brannagan (2014). the value of newly introduced diagnostic tests such as nerve ultrasound and testing for autoantibodies. the van den Bergh and Piéret criteria (2004), the AAN criteria (American Academy of Neurology, 1991) and the Koski crite- Clinical signs and symptoms ria (Koski et al., 2009) in 151 CIDP patients and 162 patients Typical CIDP is defined as proximal and distal weakness with axonal neuropathies as control subjects. The EFNS/PNS and sensory dysfunction of all extremities, with absent or electrodiagnostic criteria had the highest sensitivity of 81% reduced tendon reflexes in all four limbs, with a progressive, for definite or probable CIDP, with specificities ranging from relapsing-remitting or monophasic course, typically progress- 79% to 96%, depending on the extent of the NCS. The spe- ing over months. Atypical CIDP may be divided, based on cificity of the criteria sets are likely overestimated, as all stud- clinical presentation, in the asymmetric, focal, distal, pure ies used control patients with clear clinical phenotypes of motor and pure sensory variants (Van den Bergh et al., axonal neuropathies or motor neuron diseases instead of the 2010). Misdiagnosis is common and is reported in up to ideal control population with initially suspected CIDP with al- 50% of patients referred with a CIDP diagnosis, mainly in ternative diagnosis. As the EFNS/PNS 2010 criteria seem the patients with an atypical presentation (Allen and Lewis, most accurate and widely used set of criteria, this review will 2015). In patients with a typical presentation of proximal further mainly focus on this set (Rajabally et al., 2014). All and distal weakness, diagnosing CIDP is often straightfor- diagnostic tests have their pitfalls and should be interpreted in ward. It was even suggested to base diagnosis on a typical the clinical context, including considering alternative causes presentation without further investigations (Koski et al., of a demyelinating neuropathy (Table 2). 2009). However, none of the typical findings are specific for CIDP. Diagnostic tests Diagnostic criteria sets Consensus on the diagnostic criteria for CIDP has proven Nerve conduction studies difficult, which led to many different sets throughout the The diagnosis of CIDP relies heavily on identification of years. One North American study (Breiner and Brannagan, demyelinating features on motor NCS. The electrophysio- 2014) compared 15 diagnostic criteria sets, including the logical demyelinating features are not equivalent to classical revised European Federation of Neurological Societies/ demyelination as found in nerve biopsy, but rather are Peripheral Nerve Society (PNS/PNS) criteria (Van den Bergh markers for functional disruption or slowing of the saltatory et al., 2010), the van den Bergh and Piéret criteria (2004), conduction of the myelinated axons. Based on the amount the American Academy of Neurology (AAN) criteria and certainty of demyelinating features, this will lead to a (American Academy of Neurology, 1991) and the Koski cri- definite, probable or possible electrodiagnosis according to teria (Koski et al., 2009) in 57 CIDP patients and 37 the EFNS/PNS 2010 criteria (Van den Bergh et al., 2010). A patients with diabetic neuropathy and 39 patients with definite electrodiagnostic diagnosis requires at least two amyotrophic lateral sclerosis as control subjects (Table 1). demyelinating features in two different nerves. A probable The EFNS/PNS criteria had the highest sensitivities, with diagnosis requires two probable blocks or a probable block good specificities. Another European study (Rajabally et al., and one other demyelinating feature in a different nerve, 2009) investigated the specific electrodiagnostic criteria, while a possible diagnosis requires one demyelinating feature including the 2006 EFNS/PNS criteria (Hughes et al., 2006), in one nerve. Recent studies highlighted the importance of 3216 | BRAIN 2020: 143; 3214–3224 F. Eftimov et al. Table 2 Diagnostic pitfalls Diagnostic test Pitfall Nerve conduction studies Misdiagnosis Other diseases that can meet electrodiagnostic criteria MMN Hereditary neuropathies with demyelinating features - CMT (demyelinating and intermediate types) HNLPP IgM monoclonal gammopathy associated with anti-MAG antibodies POEMS syndrome Amyloidosis Vasculitic neuropathy Lumbosacral radiculoplexus neuropathy Neurolymphomatosis Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 Misinterpretation Increased distal latencies and slowed velocities due to severe axonal loss (low CMAP ampli- tudes), especially for the fibular nerve Demyelinating signs over segments prone to compression [median nerve (carpal tunnel), ulnar nerve (elbow), fibular nerve (fibular head)] interpreting CMAP reduction (abductor digiti minimi muscle) in forearm as a conduction block, without excluding Martin-Gruber anastomosis Uncertainties in determination of motor conduction block in segment axilla to Erb’s point Absence of F-waves Distal CMAP duration prolongation with improper cut-off values Non-stringent interpretation of proximal CMAP amplitude reductions and temporal dispersion in the legs, especially for the tibial nerve Underdiagnosis Testing too few (proximal arm) nerve segments Proximal leg nerves, including lumbosacral plexus, and partly brachial plexus are not accessible Criteria mainly based on motor nerves Lumbar puncture Misdiagnosis Elevated CSF protein also found in diabetes mellitus and CMT CSF protein can increase with age Underdiagnosis Normal CSF protein in atypical CIDP variants Imaging Misdiagnosis Enlarged nerves also found in diseases such as vasculitis, diabetes mellitus, amyotrophic neural- gia, demyelinating and intermediate CMT Cut-off values for enlargement need critical attention High inter- and intra-observer variability of qualitative MRI assessment Underdiagnosis Sensitivity of MRI is unknown High inter- and intra-observer variability of qualitative MRI assessment Evoked potentials Misdiagnosis Prolonged SSEP not specific for CIDP Underdiagnosis Sensitivity of SSEPs is unknown Nerve biopsy Misdiagnosis Biopsy findings do not differentiate between CIDP and differential diagnoses such as axonal neu- ropathies or vasculitis Underdiagnosis Demyelination is often not seen in biopsy Autoantibodies Misdiagnosis Autoantibodies are regarded as specific; however, better standardization of techniques and esti- mates of the diagnostic accuracy are warranted Underdiagnosis Sensitivity is currently low CMT = Charcot-Marie-Tooth disease; HNLPP = hereditary neuropathy with liability to pressure palsy; MMN = multifocal motor neuropathy; POEMS = polyneuropathy, organome- galy, endocrinopathy, monoclonal protein, skin changes. correct interpretation of NCS and electrodiagnostic criteria, amplitudes 51 mV, with particular focus on the clinical as this often led to misdiagnosis (Allen and Lewis, 2015; context (Van Asseldonk et al., 2005). Recordings of more Allen et al., 2018). A pitfall is that the electrophysiological proximal muscles, such as the flexor carpi radial muscle to criteria are sensitive to diagnose a demyelinating neuropathy, test the median nerve, can sometimes be of added value in but they are also fulfilled in other diseases (Table 2). case of profound distal axonal loss. Another frequent pitfall is severe axonal loss that can have Demyelinating features in segments prone to compression or a profound influence on nerve conduction velocity if the entrapment should not be considered as supportive for CIDP. largest, fastest conducting axons are involved. For this rea- The most important reason is that compression or entrapment son, several criteria have additional fulfilments for the com- itself can give demyelinating features. More severe demyelin- pound muscle action potential (CMAP) amplitude (Van den ation was not observed at entrapment sites as compared with Bergh et al., 2010). In general, demyelinating features should that observed at other nerve segments in CIDP (Padua et al., be identified with caution in measurements with CMAP 2004; Rajabally and Narasimhan, 2011b). Diagnostic challenges in CIDP BRAIN 2020: 143; 3214–3224 | 3217 Interpretation of CMAP amplitude reductions as conduc- Erb’s point, including F-waves, as demyelinating features tion blocks should be done with care in trajectories of nerves may more often be found in the arms, including the more that are adjacent to each other, as co-stimulation and proximal (above) elbow to axilla and axilla to Erb’s point co-registration may occur. Moreover, physiological anasto- segments, than in the legs (Rajabally et al., 2005; Rajabally moses, such as the Martin-Gruber anastomosis, have to be and Narasimhan, 2011a; Lucke et al., 2019b). CMAP ampli- considered. These reasons should be ruled out prior to tudes of distal leg muscles are often too low for proper inter- concluding that (apparent) CMAP reductions are due pretation, while the proximal parts of the leg nerves are not to conduction blocks, especially in the lower arm segment of accessible for NCS. Moreover, proximal CMAP amplitude the median or the ulnar nerve. reductions and temporal dispersion in the legs should be Both severely lengthened minimal F-wave latencies and ab- interpreted more stringently, taking into account physiologic- sent F-waves may be classified as demyelinating features, but al phenomena, especially in the tibial nerve. One study dem- these findings are not specific, especially in case of the fibu- onstrated that conduction blocks at the axilla and Erb’s lar nerve (Puksa et al., 2003; Argyriou et al., 2006; Pastore- point were highly specific for CIDP and that proximal inves- Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 Olmedo et al., 2009). However, F-wave analysis may be of tigations improved the sensitivity of the diagnostic criteria diagnostic utility when more distal NCS are found normal (Rajabally and Jacob, 2006). This study defined a block at in presence of clinical features suggestive of the diagnosis Erb’s point as an amplitude reduction of 450% between (Rajabally and Varanasi, 2013). wrist and Erb’s point (Rajabally and Jacob, 2006). However, The distal CMAP duration criterion in the guideline has determining a block at Erb’s point may be challenging, with been debated as it does not take differences in filter settings a higher risk of submaximal stimulation at Erb’s point due between centres into account (Isose et al., 2009), which can to the depth of the nerves, and no more proximal sites to ver- greatly influence the duration (Rajabally et al., 2012; ify CMAP amplitude reduction. Optimal stimulation at Erb’s Mitsuma et al., 2015). However, when cut-off values are point is especially of importance, as CMAP amplitude reduc- adjusted based on the filter settings used in the individual tions in normal control subjects may be substantial over lon- centre, it is a useful criterion that can aid diagnosis with lim- ger arm nerve trajectories due to physiological temporal ited testing. dispersion (Johnsen et al., 2006). Sensory NCS are not included in the electrodiagnostic cri- teria but can support sensory involvement and may be of value as one of the supportive criteria in the ENFS/PNS CSF examination guidelines. Currently, a normal sural with abnormal median Elevated protein in the CSF with normal leucocytes is found (excluding median neuropathy at the wrist from carpal tun- in up to 90% of patients with typical CIDP and is thought nel syndrome) or radial sensory nerve action potential to be one of the hallmark features of the disease (Dyck (SNAP) and/or a conduction velocity of 580% of lower et al., 1975; Prineas and McLeod, 1976; McCombe et al., limit of normal (570% if SNAP amplitude 580% of lower 1987). In atypical CIDP variants such as the asymmetric limit of normal) are included as supportive criteria (Van den subtype, protein elevation might be less pronounced, or ab- Bergh et al., 2010). Additional review of the literature does sent (Rajabally and Chavada, 2009). Elevation of the CSF not justify a more prominent position for sensory NCS in protein is not specific for CIDP and especially patients with the guidelines and suggests that the evidence for the current- diabetes mellitus or hereditary demyelinating neuropathies ly included supportive criteria, is limited with particularly (CMT1) can have slightly elevated protein levels (Bouche low sensitivity levels (Kimura et al., 1986; Kincaid et al., et al., 1983; Kobessho et al., 2008). To prevent misdiag- 1988; Tamura et al., 2005; Rajabally and Narasimhan, nosis, it was recently suggested to increase the cut-off value 2007; Bragg and Benatar, 2008; Rajabally and for CSF protein to 0.6 g/l in patients older than 50 (Breiner Samarasekera, 2010). Patients with clinically pure sensory et al., 2019). If an elevated leucocyte count (410/mm3) is involvement often also have motor abnormalities at NCS found, infections or malignancies should be considered. that can lead to the diagnosis of CIDP. However, an uncer- However, slightly elevated leucocyte counts (410 mm3) tain proportion of these patients with pure sensory involve- have been reported in up to 11% of CIDP patients (van ment do not fulfil the electrophysiological criteria for at least Doorn et al., 1991; Press et al., 2003; Lucke et al., 2018), possible CIDP, as these are based on motor NCS (Van den meaning that this does not automatically exclude the diagno- Bergh et al., 2010). Some studies have proposed alternative sis. One study found that 8 of 14 (57%) patients with ele- diagnostic criteria for this specific CIDP phenotype vated leucocytes (410 mm3) had a (sub)acute onset of (Ayrignac et al., 2013). disease and that leucocytes spontaneously decreased over In clinical practice the order and extensiveness of NCS time (Lucke et al., 2018). vary widely. If too few nerve segments are tested, this may lead to underdiagnosis. The guideline advises to first test the median and ulnar nerve at one forearm and the fibular and Imaging tibial nerve of one lower leg (Van den Bergh et al., 2010). MRI and nerve ultrasound can be a valuable addition in the However, in case of CIDP suspicion, there are arguments to diagnostic work-up, as proximal segments such as the prox- initiate the study with the median and the ulnar nerves up to imal part of the brachial plexus and the lumbosacral plexus 3218 | BRAIN 2020: 143; 3214–3224 F. Eftimov et al. can be assessed, while NCS cannot study these regions. In more recent single centre study that included 100 patients both techniques, one of the main parameters is nerve hyper- clinically suspected of an acquired inflammatory neuropathy trophy. It is noteworthy that this is not an exclusive phe- found a high sensitivity (97%) for nerve ultrasound, but the nomenon for acquired inflammatory neuropathies such as specificity was lower than previously reported (69%) CIDP and may be seen in other relatively prevalent diseases (Herraets et al., 2020). In addition, ultrasound identified such as diabetes mellitus, hereditary demyelinating neuropa- patients that responded to treatment but did not meet the thies and neuralgic amyotrophy (Breiner et al., 2017; Padua electrodiagnostic criteria (Herraets et al., 2020). et al., 2018; van Rosmalen et al., 2019). A good inter-observer variability of the nerve ultrasound Multiple studies were carried out to evaluate MRI in was shown in a multicentre study, including acquired in- CIDP with widely varying results: nerve hypertrophy was flammatory neuropathies (Telleman et al., 2019). An advan- found in 37–100% of cases (Tazawa et al., 2008; Sinclair tage of nerve ultrasound over MRI is that nerve ultrasound et al., 2011; Lozeron et al., 2016; Goedee et al., 2017a; is a relatively easy, quick, patient-friendly tool. Jongbloed et al., 2017), hyperintensity ranged from Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 56–100% (Adachi et al., 2011; Sinclair et al., 2011; Shibuya et al., 2015; Goedee et al., 2017a; Jongbloed Evoked potentials et al., 2017) and enhancement after gadolinium adminis- SSEP and triple stimulation technique (TST) may be of help tration was reported in 0–69% (Midroni et al., 1999; in diagnosing CIDP. SSEPs are used to assess the functioning Adachi et al., 2011; Goedee et al., 2017a). Most cohorts of the whole sensory pathway, including the nerve roots. had small sample sizes and consisted of prevalent cases The evidence that supports the use of SSEP in diagnosing with a typical presentation, who met the electrophysio- CIDP is limited. Proximal sensory nerve involvement as logical criteria for definite CIDP. Only few studies investigated with SSEP was found in 38–100% of CIDP included a clinically relevant control group, leading to less cases (Pineda et al., 2007; Yiannikas and Vucic, 2008; generalizable results for the daily practice where distin- Tsukamoto et al., 2010; Salhi et al., 2014). Sample sizes of guishing CIDP from its differential diagnoses is often diffi- these studies were often small. None of the studies investi- cult. A recent study has evaluated the diagnostic gated the diagnostic utility of SSEP in treatment-naı̈ve performance of MRI in differentiating CIDP and multi- patients or with the use of SSEP as a primary investigation. focal motor neuropathy from disease controls (segmental The role of the SSEP in diagnosing CIDP is clearly limited if spinal muscular atrophy) and healthy control subjects the electrodiagnostic criteria are met. However, studies (Oudeman et al., 2020). In that study, intra- and inter- showed that in up to 100% of patients with a pure sensory observer agreement for qualitative assessment of nerve presentation, who did not meet the electrophysiological crite- hypertrophy and hyperintensity as scored on STIR varied ria, SSEP showed involvement of the nerve roots (Sinnreich widely. This was also the case for qualitative scoring on et al., 2004; Ayrignac et al., 2013). In clinical practice, SSEP magnetic resonance neurography, a newer sequence should be considered in patients with predominant sensory technique. ataxia and areflexia, if the electrodiagnostic criteria are not Several studies showed changes in diffusion tensor imaging fulfilled. in CIDP, a technique that enables quantitative measurements Another potential method to overcome the challenges of of water diffusivity within nerve tissue, but the diagnostic assessing demyelination in proximal parts might be motor contrast seems relatively small and may not be useful in clin- evoked potentials. Several explorative studies using motor ical practice (Kakuda et al., 2011; Markvardsen et al., 2016; evoked potentials in CIDP showed (very) prolonged periph- Kronlage et al., 2017; Oudeman et al., 2020). Given the eral conduction times and, less often, changes in central con- rapid development of MRI techniques, the aim may be to duction times, but formal diagnostic accuracy studies have develop other preferably quantitative measures suited to per- not been performed (Takada and Ravnborg, 2000; Pineda ipheral nerve tissue in health and disease. et al., 2007). TST is a specialized diagnostic tool to examine Increases in nerve cross-sectional area on nerve ultrasound the nerve roots proximal of Erb’s point, and includes the use have been reported in several studies. Nerve enlargement of motor evoked potentials. It may demonstrate proximal was found in 69–100% of CIDP patients (Matsuoka et al., motor conduction blocks, even if patients do not meet the 2004; Zaidman et al., 2009; Sugimoto et al., 2013). Studies electrodiagnostic criteria (Attarian et al., 2015; Cao et al., showed that the CSA of the brachial plexus and the median 2018), indicating that TST can probably increase sensitivity. nerve were the most adequate measurements to distinguish However, specificity is yet unknown and there is very limited between CIDP and axonal neuropathy (Grimm et al., 2014; experience with this technique. Goedee et al., 2017b). A recent single centre study provided cut-off values based on the upper limits for axonal neuropa- thies and found a 100% specificity for enlargement of one Nerve biopsy or more segments of the median nerve or the cervical trunci/ Whether nerve biopsy has additional value in diagnosing roots (Goedee et al., 2017b). However, also in this study, CIDP has long been a matter of debate. Usually, the nerve only patient controls with a clear-cut diagnosis of axonal selected for biopsy is the sural nerve, as it is easily accessible. neuropathy or amyotrophic lateral sclerosis were studied. A The pathological findings are segmental demyelination and Diagnostic challenges in CIDP BRAIN 2020: 143; 3214–3224 | 3219 remyelination, onion bulb formation and inflammatory infil- Table 3 Characteristics of patients with autoantibodies trates (Krendel et al., 1989). These findings were reported in in CIDP 48–71% of the biopsies in patients that met diagnostic Characteristics criteria (Barohn et al., 1989; Krendel et al., 1989; Neurofascin 155 (NF155) Subacute onset, fast progression Molenaar et al., 1998; Bouchard et al., 1999). However, sam- (Querol et al., 2014; Younger age ple sizes of the studies were small and few studies compared Devaux et al., 2016) Distal motor involvement biopsy results from CIDP patients with disease controls. One Ataxia study suggested that none of the biopsy findings were specific Prominent, low-frequency tremor for CIDP, as these findings were also found in vasculitis, Neurofascin 140 and 186 Subacute onset, fast progression axonal and demyelinating hereditary neuropathies and mono- (NF140 and NF186) Cranial nerve deficits (Delmont et al., 2017; Ataxia clonal gammopathies (Krendel et al., 1989). Other studies Stengel et al., 2019) also showed that nerve biopsies failed to differentiate between CIDP and axonal neuropathies or diabetic neuropathies Contactin-1 (CNTN1) Subacute onset, fast progression Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 (Querol et al., 2013; Axonal involvement at onset (Molenaar et al., 1998; Uncini et al., 1999; Bosboom et al., Ataxia Miura et al., 2015) 2001). Some studies suggested that there might be some value in atypical CIDP cases (Vallat et al., 2003; Ayrignac et al., Contactin-associated Severe pain protein 1 (CASPR1) 2013). The recent discovery of specific nodal and paranodal (Doppler et al., 2016) abnormalities in the ultrastructural analysis of the nerve in patients with antibodies against node of Ranvier cell adhesion molecules may have diagnostic utility in specific patients (Koike et al., 2017; Vallat et al., 2017; Uncini and Vallat, clinical significance of antibodies other than those targeting 2018). Nerve biopsy is considered invasive and will lead to nodal and paranodal proteins is unclear. persisting sensory loss in most patients, while persisting pain, The optimal technical approach to test for nodal/parano- infections and dysaesthesias have also been reported in a mi- dal antibodies is currently under investigation. However, nority of patients (Gabriel et al., 2000; Ruth et al., 2005). most published studies use cell-based assays (either immuno- cytochemistry or flow-cytometry) performed with HEK293 cells transfected with the human recombinant protein target Autoantibodies of the antibodies, ELISAs using human recombinant proteins Autoantibody search has been an important topic of re- as the protein substrate or immunohistochemistry on teased- search in CIDP in the last decades, but just recently, sub- nerve fibres to detect the typical nodal or paranodal staining. groups of CIDP patients with antibodies targeting the nodes Considering that the detection of these autoantibodies usual- of Ranvier and paranodal regions have been described ly leads to the use of therapeutic algorithms that includes (Querol et al., 2017a; Vural et al., 2018). The discovery of therapies (e.g. rituximab) that are not first line therapies in these antibodies, associating with antibody-specific clinical CIDP, it seems reasonable to try to confirm the detected features, boosted interest in the role of antibodies as diag- antibodies with at least two different techniques to increase nostic and prognostic biomarkers. Up to 25% of patients diagnostic specificity (Martı́n-Aguilar et al., 2020). with CIDP show evidence of circulating autoantibodies tar- Two independent series, in which in a total of 113 patients geting antigens of the peripheral nerve structures, including were included, described six patients fulfilling the diagnostic nodal and paranodal regions (Querol et al., 2017b; Vural criteria for CIDP, in which anti-MAG antibodies were et al., 2018; Broers et al., 2019). Autoantibodies specifically detected in the absence of IgM paraproteinaemia. These targeting the nodal and paranodal regions are found in patients presented and progressed similar to anti-MAG-posi- 10% of CIDP patients. Antibodies to neurofascin 155 tive patients with IgM paraproteinaemia (Sakamoto et al., (NF155) are the most frequent, while antibodies to neurofas- 2017; Pascual-Go~ ni et al., 2019) and two of them developed cin 140 (NF140) and neurofascin 186 (NF186), contactin-1 detectable paraproteinaemia years after disease-onset, sug- (CNTN1) and contactin-associated protein 1 (CASPR1) are gesting that a subset of patients classified as distal CIDP less common (Querol et al., 2017a; Vural et al., 2018; could indeed be patients with early anti-MAG-positive Bunschoten et al., 2019). Most are of the IgG4 isotype. A monoclonal gammopathy of undetermined significance systematic review reported a very low sensitivity of these related polyneuropathy (MGUSP) (Allen and Lewis, 2015). autoantibodies but specificities of 100% in CIDP (Hu et al., It is important to take this into account to avoid misdiag- 2018). Specific clinical phenotypes have been described in nosis, especially in patients with the distal phenotype. patients with autoantibodies to the nodes and paranodes Testing for antibodies should be considered in treatment (Table 3). In general, antibodies to nodal and paranodal unresponsive patients, especially in the presence of atypical proteins, regardless of the autoantibody, associate with a symptoms such as a subacute onset, severe ataxia, pain or a subacute onset and more progressive CIDP phenotypes, ini- tremor. In case of the distal phenotype and treatment unre- tially often classified as Guillain-Barré syndrome, and poorer sponsiveness, M-protein reanalysis and anti-MAG antibodies responses to immunoglobulins than patients without these may be considered. International, multicentric studies are autoantibodies (Hu et al., 2018; Vural et al., 2018). The currently underway, which focus on standardization of 3220 | BRAIN 2020: 143; 3214–3224 F. Eftimov et al. measuring autoantibodies, but also on providing better esti- neuropathies meet various supportive criteria, including mates of the diagnostic accuracy of autoantibody testing in treatment response, but not the electrophysiological criteria patients suspected of CIDP. If autoantibody testing is shown (Lucke et al., 2019a; Herraets et al., 2020). However, the to be widely reliable and reproducible, it can be introduced best examples are the recently discovered nodal and parano- for standard clinical practice. dal neuropathies that are caused by autoantibodies. Some are autoantibodies to axonal nodal structures, such as CNTN1, so that it became clear that autoimmunity can be primarily directed to axonal antigens, and not only to mye- Discussion lin antigens. In case of anti-CNTN1, electron microscopy CIDP has a very heterogeneous presentation, and consists of examination showed a selective loss of the septate-like junc- a spectrum of autoimmune diseases of the peripheral nerves tions at the paranodes and a detachment of the paranodal based on presumed breach of tolerance leading to auto- myelin loops from the axon, but there was an absence of in- immunity against nerve antigens. Different pathophysiologic- flammation and classical macrophage-induced demyelination Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 al mechanisms have been identified, often sharing clinical (Kouton et al., 2020). Importantly, this disorganization of features, which makes diagnosis challenging. the nodes of Ranvier disrupts the saltatory conduction, The term CIDP was introduced in 1982 describing some which leads to electrophysiological findings that are trad- of the most common features of the disease in four different itionally interpreted as demyelinating features. The electro- domains, namely time of onset, pathophysiology, tissue com- physiological criteria for CIDP were originally intended to ponent involved and anatomical distribution. However, the be able to detect the physiological substrate of demyelin- use of this term has evolved over time to try to incorporate ation, as this was the only known underlying pathology. other patients with primary chronic immune-mediated neu- However, in essence they are markers for functional disrup- ropathies susceptible to disease-modifying therapies that tion or slowing of the saltatory conduction of myelinated share but do not necessarily include all of the original fea- axons. In the context of CIDP, conduction block can result tures. More importantly, as our knowledge of the disease from paranodal abnormalities of the myelin sheath, but also deepens, it has become increasingly difficult to unite all clin- from primary dysfunction of the axon at the nodes of ical presentations and pathophysiological mechanisms under Ranvier. Considering that inflammation and demyelination this term, some even contradicting the original terminology. as core features are not present in all CIDP patients, while First, CIDP may have an acute onset, that initially resembles an autoimmune aetiology is presumed in all patients, the Guillain-Barré syndrome (Vural et al., 2018). Also, some umbrella term ‘chronic autoimmune neuropathies’ may fit Figure 1 A conceptual framework for a diagnostic work-up in chronic autoimmune neuropathies. A conceptual framework for a diagnostic work-up in chronic auto-immune neuropathies, assuming future emphasis on immunological tests with high specificity to show evi- dence for autoimmunity. Combinations and number of tests required for diagnosis depend on specificity of clinical phenotypes, of immunological tests and of supportive tests, such as nerve conduction studies, imaging, CSF examination, pathology and response to treatment. NCS currently have the best diagnostic accuracy. Diagnostic challenges in CIDP BRAIN 2020: 143; 3214–3224 | 3221 better (Fig. 1). Further discussion will be needed on whether introduction of the nerve ultrasound and the discovery of to include other entities such as multifocal motor neuropathy autoantibodies in CIDP, the update of the EAN/PNS diag- and anti-MAG neuropathy within this term. Recent studies nostic guidelines is much awaited. suggested that anti-MAG antibodies can be present in few patients with CIDP without the presence of IgM paraprotei- naemia. However, in an overwhelming majority of patients there is also IgM paraproteinaemia, suggesting that the Funding underlying pathomechanism is plasma cell dyscrasia rather No funding was received towards this work. than breach of tolerance. Moreover, further studies are needed to determine the diagnostic cut-off of anti-MAG anti- bodies in those patients without IgM paraproteins as these can also be found in low quantities in other conditions. Competing interests Regardless of the nomenclature, if we consider the auto- Downloaded from https://academic.oup.com/brain/article/143/11/3214/5957444 by guest on 19 October 2023 F.E. reports grants from ZonMw (Dutch Governmental immune aetiology as the hallmark of the disease, in the fu- Agency) and Prinses Beatrix Spierfonds. He also reports ture we should also probably focus more on introducing grants from CSL Behring, Kedrion, Terumo BCT and specific immunological tests in our diagnostic work-up. This Takeda Pharmacetical Company, outside the submitted would be in line with the diagnostic approaches of other, work. Grants were paid to institution and are used for inves- similarly heterogeneous, autoimmune diseases, in which ac- tigator initiated studies within INCbase, an international cess to tissue is difficult, such as autoimmune encephalopa- CIDP registry. He also received consultancy fees from UCB thies (Graus et al., 2016). Unfortunately, despite recent pharma, paid to institution, outside the submitted work. I.L. progress, finding proof of autoimmunity is currently difficult has nothing to disclose. L.Q. has provided expert testimony as antibodies in blood/CSF are only found in a minority of for Grifols, Sanofi-Genzyme, Novartis, UCB, Roche and patients, while unambiguous pathology results from nerve CSL Behring and received research funds from Novartis biopsy supporting an autoimmune origin are uncommon. Spain, Sanofi-Genzyme and Grifols, outside the submitted However, other autoantibody reactivities or markers of work. Y.R. has received speaker/consultancy honoraria from autoimmunity, including immunity-related genes, may be CSL Behring, LFB, Grifols, BPL, Octapharma and Kedrion, identified in the future (Nevo et al., 2013; Staudt et al., has received educational sponsorships from LFB, CSL 2017). Behring and Baxter and has obtained research grants from Despite desirable future advances to prove autoimmunity CSL Behring and LFB, outside the submitted work. C.V. is a in more patients, the diagnosis of CIDP currently remains a member of a clinical advisory board (CAB) of Inflectis clinical one, with greater complexity and concurrently France; payment was made to his organization for attending increased uncertainty for atypical versus typical forms. The a CAB meeting, outside the submitted work. absence of a golden standard challenges proper evaluation of diagnostic accuracy of tests. Still, taking surrogate stand- ards, such as fulfilment of consensus criteria and treatment response, partially overcomes this problem. Recognizing the References technical difficulties and caveats as outlined in this review, Adachi Y, Sato N, Okamoto T, Sasaki M, Komaki H, Yamashita F, will hopefully reduce the number of patients with misdiag- et al. 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