Journal of the Peripheral Nervous System 19:2–13 (2014)

2013 PERIPHERAL NERVE SOCIETY MEETING PNS PRESIDENTIAL LECTURE

Chronic inflammatory demyelinating polyradiculoneuropathy and variants: where we are and where we should go Eduardo Nobile-Orazio Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, 2nd Neurology, IRCCS Humanitas Research Hospital, Milan, Italy

Abstract

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and often disabling sensory motor neuropathy postulated as caused by an immune attack against peripheral nerve myelin. In addition to a classic sensory–motor polyneuropathy, other phenotypes of CIDP have been described including the LewisSumner syndrome, distal acquired demyelinating symmetric (DADS) neuropathy, pure motor CIDP, pure sensory CIDP including chronic immune sensory polyradiculopathy (CISP), and focal CIDP. These phenotypes are currently considered to be variants of CIDP, even if the possibility that they represent different demyelinating neuropathies cannot be fully excluded considering differences in their response to therapy. Several data support the role of the immune system in the pathogenesis of CIDP even if the precise targets and actors (antibodies and lymphocytes) of this immune response remain uncertain. Recent studies have shown that the therapeutic response may differ in patients with peculiar clinical presentations supporting the hypothesis that different pathogenetic mechanisms may underlie the heterogeneity of CIDP. The majority of patients with CIDP show improvement after immune therapies including corticosteroids, plasma exchange, and high-dose intravenous immunoglobulin (IVIg). It remains unclear why none of the other immune therapies that were reported to be variably effective in other immune disorders proved to be effective also in CIDP.

Key words: antibodies, autoimmunity, chronic inflammatory demyelinating polyradiculoneuropathy, CIDP, corticosteroids, immune therapy, IVIg, Lewis-Sumner syndrome, myelin, plasma exchange

¨ 1975 ; Hahn et al ., 2005 ; Koller et al ., 2005 ; Said , 2006 ; Vallat et al ., 2010). The prevalence of CIDP ranges from 0.8/100,000 in Japan (Kusumi et al ., 1995), to 1.32 (Lunn et al ., 1999) to 2.84/100,000 (Mahdi-Rogers and Hughes, 2013) in south-east England, 1.9/100,000 in New South Wales, Australia (McLeod et al ., 1999), 3.5/100,000 in Piedmont, Italy (Chio` et al ., 2007), and 8.9/100,000 in Olmstead County, United States (Laughlin et al ., 2009), while the incidence ranges from 0.2 (McLeod et al ., 1999) to 1.60 per 100,000 (Laughlin et al ., 2009). Even if these differences may suggest

Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare peripheral nerve disorder that often responds to immune therapies (Dyck et al .,

Address Correspondence to: Eduardo Nobile-Orazio, MD, PhD, FAAN, Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Milan University, 2nd Neurology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, Milan 20089, Italy. Tel: +390282242209; Fax: +390282242298; E-mail: [email protected]. © 2014 Peripheral Nerve Society

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a geographical diversity in the prevalence of CIDP, recent studies suggested that they probably reflect the use of different diagnostic criteria. It was shown for instance that in Leicestershire and Rutland, UK, the prevalence of CIDP ranged from 1.97 to 4.77/100,000 depending on the diagnostic criteria used (Rajabally et al ., 2009b). This variability may also derive from the fact that, being a treatable disorder, a few different clinical phenotypes have been included under this term, allowing the use of expensive therapies also in these variants (Busby and Donaghy , 2003 ; Rotta et al ., 2003 ; Joint Task Force of the EFNS and the PNS , 2010). It remains, however, unclear whether these phenotypes represent indeed variants of CIDP or different demyelinating neuropathies with a different pathogenesis and response to therapy. This might be clarified when a better understanding of the immune pathogenesis of CIDP and its variants will become available. This was the case, for instance, of neuromyelitis optica that was considered for years to be a variant of multiple sclerosis but is now considered a separate disease (Wingerchuk et al ., 2007) or, to remain in peripheral nerve disorders, of multifocal motor neuropathy (MMN), that was initially considered a variant of CIDP but it is now considered a separate disease (Nobile-Orazio et al ., 2005 ; Vlam et al ., 2011).

are now considered to have a GBS-like onset (or acute onset) CIDP (Ruts et al ., 2010). Typically most patients with CIDP present with sensory and motor symptoms with over 90% of patients having weakness that may be severe enough to lead to marked disability and total dependence (Simmons et al ., 1993) while over 80% have sensory symptoms or loss. Pain at onset is rare even if it may occasionally be the presenting symptom (Boukhris et al ., 2007). Proximal weakness is one of the clues to the clinical diagnosis of CIDP even if distal weakness is usually more common and severe than proximal weakness. Reflexes are historically deemed to be absent in CIDP even if total areflexia only occurs in 70% of patients while the rest have a mixture of decreased and absent reflexes with ankle reflexes being most often absent. Gait imbalance and upper limb tremor may occur in some patients. Cranial nerve symptoms occur in a minority of patients (Dyck et al ., 1975 ; McCombe et al ., 1987 ; Barohn et al ., 1989 ; Simmons et al ., 1993). Respiratory failure seldom occurs in CIDP (Henderson et al ., 2005). When asked, over 80% of the patients reported fatigue as a major symptom (Merkies et al ., 1999), and this may occasionally be the presenting symptom when weakness is not present (Bissay et al ., 2008). Symptoms of dysautonomia are uncommon (McCombe et al ., 1987), even if a usually mild autonomic dysfunction has been reported in 65% of the patients (Stamboulis et al ., 2006). CIDP is a severe disease with over 50% of the patients having at least temporary severe disability in the course of the disease, including temporary restriction to a wheelchair or inability to walk without support, while 10% of them eventually become persistently disabled or die because of the illness (Lunn et al ., 1999 ; Chio` et al ., 2007). A few patients have, however, a disturbing but functionally indolent course with minimal weakness and minor sensory symptoms and are considered to have a clinically minimal and sometimes asymptomatic CIDP (Uncini et al ., 1999).

Clinical Presentation: One or More Diseases? Typical CIDP CIDP may have either a chronic progressive or a relapsing course (Dyck et al ., 1975 ; Hahn et al ., 2005 ; ¨ Koller et al ., 2005 ; Said , 2006 ; Vallat et al ., 2010). As in the case of multiple sclerosis, younger patients tend to have a relapsing course while older patients more frequently have a chronic progressive course (Hattori et al ., 2001). This distinction is becoming, however, difficult with available current therapies as patients with a progressive course may deteriorate after therapy suspension or dose reduction mimicking a relapse while this is really only a wear-off effect of therapy. Initial symptoms may progress over several weeks to months even if a more rapid progression may initially lead to the diagnosis of Guillain-Barre´ syndrome (GBS). This was reported to occur in 16% of the patients with CIDP (Ruts et al ., 2010) and can be suspected if deterioration continues for more than 2 months from onset, if there are three or more treatment-related fluctuations (Ruts et al ., 2010), or when prominent sensory symptoms are present at onset (Dionne et al ., 2010). These patients were initially considered to have GBS evolving into a chronic form of CIDP while they

Sensory CIDP Some patients with CIDP may present with a pure sensory syndrome with a proportion in different series ranging from 5% to 15% (Busby and Donaghy , 2003 ; Rotta et al ., 2003). Even if these patients have normal strength, most of them have electrodiagnostic abnormalities on motor nerve conduction studies (Oh et al., 1992a; 1992b; Simmons and Tivakaran, 1996 ; Van Dijk et al., 1999 ; Said, 2006 ; Ayrignac et al., 2013b). Some patients subsequently develop weakness (Berger et al ., 1995 ; Van Dijk et al ., 1999 ; Said , 2006), while others maintain a pure sensory impairment during the follow-up (Said , 2006 ; Rajabally and Wong , 2012). Few 3

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patients have, however, a clinically and electrodiagnostically pure sensory neuropathy (Rubin and Mackenzie, 1996 ; Rajabally and Wong , 2012) and probably represent a minority among patients with sensory CIDP. Even in a recent series of patients with a cryptogenetic sensory neuropathy who were found to have pathological features of CIDP on sural nerve biopsy, motor abnormalities were found on nerve conduction studies (Chin et al ., 2004). A particular form of sensory CIDP is chronic immune sensory polyradiculopathy (CISP) (Sinnreich et al ., 2004; Caporale et al ., 2011). This entity was first reported by Sinnreich et al. ( 2004) who described 15 patients who had only sensory symptoms for a few years with normal nerve conduction studies. In these patients, somatosensory evoked potentials were delayed, cerebrospinal fluid (CSF) proteins were increased, and lumbar magnetic resonance imaging (MRI) revealed an enlargement of lumbar roots. Root biopsy confirmed the inflammatory nature of the process, and all treated patients improved with intravenous immunoglobulin (IVIg) or corticosteroids. Very few data are available on the response to therapies in patients with sensory CIDP even if most patients were reported to respond to the same therapies effective in CIDP (Oh et al ., 1992a; 1992b; Simmons and Tivakaran, 1996 ; Van Dijk et al ., 1999 ; Said , 2006 ; Ayrignac et al ., 2013b). Two patients were, however, reported to deteriorate after plasma exchange (Larue et al ., 2008), and one deteriorated with oral corticosteroids but improved after IVIg (Rajabally and Wong , 2012). It is quite difficult to delineate the boundaries of sensory CIDP as the criteria for this diagnosis have not been established. In particular, it is unclear whether this group should include patients without weakness or only those with a purely clinical and electrophysiological sensory impairment. In the latter case, the recent diagnostic criteria of the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) for CIDP (Joint Task Force of the EFNS and the PNS , 2010) might not even allow the diagnosis of possible CIDP due to the absence of any abnormalities on motor nerve conduction studies.

mentioned in series of patients with CIDP. Patients with motor CIDP were reported to deteriorate with corticosteroids (Donaghy et al ., 1994) even if some of these patients had MMN. This deterioration is also mentioned in the EFNS/PNS guidelines (Joint Task Force of the EFNS and the PNS , 2010), and probably mainly derives from the opinion of the experts. In one study, some patients had an asymmetric presentation with partial conduction block and no slowing of motor conduction, which is reminiscent of MMN (Sabatelli et al ., 2001). In this series of young patients, reduced amplitude of the sensory action potentials (SAPs) in the upper limbs was found, raising some doubts on the selective motor impairment. In another series of five patients with motor dominant CIDP, two had mildly reduced sensory conduction velocities but SAP amplitudes were not reported (Kimura et al ., 2010). In both series, patients were also reported to worsen after corticosteroids and to improve with IVIg. This has led to the exclusion of patients with the purely motor variant from some controlled trials of CIDP. Even if this form is classically considered a variant of CIDP, the peculiar response to therapy may also suggest that it might represent a diffuse variant of MMN, a disorder where patients also deteriorate with corticosteroids. In addition, it remains unclear whether the diagnosis of motor CIDP should be only based on clinical findings or on the presence of normal sensory nerve conduction studies.

Focal CIDP Some patients have been reported with a restricted distribution of weakness and sensory loss restricted to one or both upper limbs. Thomas et al. ( 1996) reported nine patients, including five who had a sensorimotor impairment in one or both upper limbs, one with sensory monomelic impairment and three with a purely motor impairment in one or two upper limbs. One of the patients with pure motor impairment deteriorated after steroids and improved after IVIg, similar to what was observed in MMN. An additional patient with a chronic monomelic sensory neuropathy that did not spread to other limbs and did not involve strength after 30 years has been recently reported (Ayrignac et al., 2013a). Several clinical and laboratory features suggested a diagnosis of possible CIDP, and the patient improved after therapy with IVIg. In other patients an upper-limb predominant multifocal CIDP was reported even if in some of them some features suggested a diagnosis of LewisSumner syndrome (LSS) (Gorson et al ., 1999). The improvement observed in these patients after therapy with corticosteroids or IVIg led to their inclusion under the term of focal CIDP. The reason for this selective focal impairment remains unclear considering

Motor CIDP A few patients have been reported to have a pure or predominant motor impairment throughout the course of the disease (Donaghy et al ., 1994; Sabatelli et al ., 2001; Kimura et al ., 2010). They represented in one series (Busby and Donaghy , 2003) 4% of the patients with chronic demyelinating neuropathy, similar to what was observed in our series of CIDP patients. However, very few reports are centered on patients with motor CIDP as most of them are briefly 4

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clinical phenotype corresponds to what is typically observed in patients with neuropathy associated with IgM monoclonal gammopathy and antibodies to the myelin-associated glycoprotein (MAG) (Latov et al ., 1988 ; Nobile-Orazio, 1998). However, not all patients with this phenotype have IgM monoclonal gammopathy (Katz et al ., 2000) or anti-MAG antibodies (Larue et al ., 2011). This clinical pattern is now considered a clinical phenotype more than a definite syndrome and patients without IgM monoclonal gammopathy or antiMAG antibodies are considered to have a DADS variant of CIDP (Joint Task Force of the EFNS and the PNS , 2010 ; Larue et al ., 2011). Similar to what was observed in patients with anti-MAG neuropathy, these patients were reported to have a less satisfactory response to the therapy than patients with CIDP (Katz et al ., 2000 ; Saperstein et al ., 2001). Even if the term DADS is currently used, the criteria that permit the distinction between CIDP and DADS in the absence of IgM monoclonal gammopathy are not well defined. Sensory impairment, ataxia, and tremor may also be found in patients with CIDP as well as a predominant distal impairment. A progression from DADS to a severe CIDP has also been reported (Leitch et al ., 2013). No specific trial has assessed the treatment response in patients with DADS without monoclonal gammopathy even if a recent retrospective study showed a positive response to immune therapy in most patients.

the current view that CIDP is caused by a systemic immune reaction against nerve myelin. We should also consider, however, that while response to immune therapy may support the diagnosis of CIDP, other neuropathies including neuropathy associated with IgM monoclonal gammopathy or vasculitis may also improve with immune therapies.

Lewis-Sumner syndrome In 1982, Lewis et al. ( 1982) described five patients with a chronic, acquired, asymmetric sensorimotor demyelinating polyneuropathy which clinically resembled a multiple mononeuropathy syndrome. Electrodiagnostic studies demonstrated multifocal conduction block in motor nerves. CSF protein was normal to mildly elevated. Two patients were treated with prednisone and improved. Several similar patients have been subsequently reported under the name of LewisSumner syndrome (LSS) or other terms including multifocal acquired demyelinating sensory and motor neuropathy (MADSAM neuropathy) (Oh et al ., 1997 ; Saperstein et al ., 1999 ; Van den Berg-Vos et al ., 2000 ; Verschueren et al ., 2005 ; Viala et al ., 2004). Even if this syndrome is considered to be a multiple mononeuropathy variant of CIDP, several patients maintain a multifocal distribution for years. In one series, 50% of affected patients evolved into CIDP within 4 years, while the remaining 50% maintained a multifocal distribution (Viala et al ., 2004). In another series, 80% of the patients maintained a multifocal and asymmetric impairment after a mean follow-up of 10 years (Attarian et al ., 2011). In addition, the upper limbs are usually involved before the lower limbs (Viala et al ., 2004; Rajabally and Chavada, 2009). CSF protein levels are usually normal but may be mildly elevated in one-third of the patients, even if very high levels have been seldom reported. Response to therapy is similar to CIDP (Viala et al ., 2004), even if some patients were reported to deteriorate after therapy with corticosteroids (Attarian et al ., 2011). In addition, patients with a predominant impairment in upper limbs were reported to have a more frequent response to corticosteroids than to IVIg (74% vs. 52%) while the reverse occurred in patients more impaired in lower limbs (25% vs. 80%) (Rajabally and Chavada, 2009).

Immune Pathogenesis of CIDP There is a general consensus that CIDP is an immune-mediated disorder affecting peripheral nerve myelin even if this has not been formally ¨ et al ., 2005 ; Hughes et al ., 2006 ; proved (Koller Said , 2006 ; Vallat et al ., 2010). This hypothesis is strongly supported by the fact that the vast majority of patients improve after receiving immune therapies, but it is also sustained by other data. The onset and relapses of CIDP are sometimes triggered by infections or immunizations, which have been reported in 20%–30% of the patients, including upper respiratory infections, gastroenteritis, other infections, vaccinations, surgery, and trauma (Dyck et al ., 1975 ; Pollard and Selby , 1978 ; McCombe et al ., 1987 ; Barohn et al ., 1989 ; Simmons et al ., 1993 ; Hughes et al ., 1996 ; Gorson et al ., 1997 ; Kuitwaard et al ., 2009). Other studies showed, however, that the prevalence of antecedent infection is around 10% and does not differ from that observed in the control population (Chio` et al ., 2007). Patients who developed CIDP after vaccination were, however, reported to have an increased risk of relapse after vaccination

Distal acquired demyelinating symmetric neuropathy The term distal acquired demyelinating symmetric (DADS) neuropathy was introduced by Katz et al. ( 2000) to describe a group of patients with predominantly distal symmetric sensory ataxic demyelinating neuropathy. Most of these patients have markedly slowed motor conduction velocities and even more prolonged motor distal latencies. This 5

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(Hughes et al ., 1996). In any instance, these figures are consistently different from that observed in GBS, where antecedent events occur in at least two-thirds of the patients (van Doorn et al ., 2008). Antibodies against different tissues and antigens (extensively reviewed in Hughes et al ., 2006 ), including myelin (Koski et al ., 1985), the glycolipids GM1 (Ilyas et al ., 1992), LM1 (Fredman et al ., 1991) and LM1-containing ganglioside complexes (Kuwahara et al ., 2011), asialoGM1 (McCombe et al ., 1992), sulfatide (Fredman et al ., 1991), galactocerebroside (Hughes et al ., 1984) and chondroitin sulfate (Melendez-Vazquez et al ., 1997), the proteins P2 (Khalili-Shirazi et al ., 1993), P0 (Yan et al ., 2001) and a P0-related glycoprotein (NobileOrazio et al ., 1995 ; Allen et al ., 2005), PMP22 (Sanvito et al ., 2009a) and β-tubulin (Connolly et al ., 1993 ; Khalili-Shirazi et al ., 1993 ; Manfredini et al ., 1995), and, more recently, the combination of GM1 with galactocerebroside (Nobile-Orazio et al ., 2013b), have been reported in a variable proportion of patients with CIDP (usually less than 30% of the patients). Data from our laboratory show that antibodies to each of these antigens ranges from 3% to 29% in patients with CIDP while almost 50% of them have one or more of these antibodies. In most studies, these reactivities were not significantly more frequent in CIDP than in controls and were rarely associated with specific clinical features (Kuwahara et al ., 2013). These data suggest that these reactivities may represent the marker of an ongoing immune response more than the initial immune response responsible for demyelination in CIDP. More recently, attention has been devoted to the presence of antibodies directed against myelin or axonal proteins at the node of Ranvier (Pollard and Armati , 2011). Antigens at these locations would be indeed an ideal target in a disease where conduction block is one of the main features. In addition, it was recently shown that early abnormalities in myelinated fibers in the skin biopsy of patients with CIDP occurred around the node of Ranvier (Doppler et al ., 2013). Despite these promising preliminary observations, antibodies against these proteins have been found in a minority of patients with CIDP, similar to what was observed with the other antibodies associated with CIDP. Devaux et al. ( 2012) showed, for instance, that antibodies against any of the antigens gliomedin, contactin, Neurofascin-186 (NF-186), and NrCAM were present in 24% of the patients with CIDP. Ng et al. ( 2012) later reported antibodies to NF-155 in 4% of patients with CIDP while none of them had antibodies to NF-186. More recently, Querol et al. ( 2013) found that sera from 4 of 46 (8.6%) patients with CIDP reacted with hippocampal neurons and paranodal structures on nerves, including three patients (6.5%) with antibodies to contactin-1. The most important

aspect of this study was the fact that these patients had some distinctive features from the rest of patients with CIDP, including the higher age, more severe, mostly motor neuropathy with early axonal loss and poor response to IVIg. In a more recent study, antibodies to NF were more frequently found in patients with central and peripheral demyelination than in patients with CIDP and were frequently associated with a positive response to IVIg and plasma exchange (Kawamura et al ., 2013). These data raise the suspicion that different antibodies may underlie different clinical forms of CIDP. It would be advisable in future studies to carefully correlate the presence of antibodies against different antigens to the clinical features of the patients. Despite the well known evidence from pathological studies on nerve biopsy of affected patients showing the presence of macrophages and T-cell infiltrates and of deposits of immunoglobulins (Hahn et al ., 2005) in the last years, only a few studies have addressed the possible role of cellular immunity in CIDP (reviewed in Hughes et al ., 2006 ; Sanvito et al ., 2009b; Chi et al ., 2010 ). It was recently shown that the T-cell receptor repertoire of cells infiltrating peripheral nerve have a strong monoclonal or polyclonal restriction that corresponds to that of circulating T cells (Schneider-Hohendorf et al ., 2012). These data support the hypothesis of an antigen-driven T-cell attack against nerve, even if the target of this immune response remains unclear. This hypothesis is also supported by the finding in patients with CIDP of an oligoclonal restriction of the T-cell repertoire of circulating CD8+ T cells and that this pattern was corrected by treatment with IVIg (Mausberg et al ., 2013). This therapy was, however, also reported to inhibit the production of the B-cell activating factor (BAFF), that contributes to B-cell homeostasis and antibody production, and that BAFF levels were increased in patients with CIDP (Bick et al ., 2013). Even if both studies may cast some light on the possible mechanism of action of IVIg in CIDP, their combination does not help to clarify what might be the final effector mechanism in CIDP.

Diagnosis of CIDP Even if the diagnosis of CIDP is often easy in clinical practice, the use of expensive therapies for this disease and the description of a number of clinical variants has led to the necessity to define the clinical boundaries of this neuropathy in order to avoid the inappropriate use of expensive therapies but at the same time to include under this diagnosis the largest proportion of patients who might benefit from treatment. This is why, even if CIDP is not a common disease, at least 15 diagnostic criteria sets for 6

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CIDP (Bromberg , 2011; Breiner and Brannagan, 2013) have been proposed. For the same reason, despite the presence of a number of differences, variants of CIDP were variably included under the term of CIDP to allow affected patients to receive the same therapies. Most of these criteria have similar clinical features but differ in terms of the electrophysiological criteria necessary for its diagnosis (Bromberg , 2011). Recently, Koski et al. ( 2009) proposed another set of criteria which allowed the diagnosis of CIDP on clinical grounds only. The presence of a symmetric neuropathy affecting four limbs with proximal weakness in at least one limb in the absence of a serum paraprotein or documented genetic abnormality was considered sufficient for the diagnosis. It was recently shown (Rajabally et al ., 2009a) that the sensitivity of these criteria for the diagnosis of CIDP was higher than that of the criteria of the American Academy of Neurology (Ad Hoc Subcommittee, 1991) but lower than that of the EFNS/PNS (Joint Task Force of the EFNS and the PNS , 2010) with a comparable specificity. Similar data were derived from a recent study where the sensitivity and specificity of 15 diagnostic criteria used in CIDP was calculated in a series of 56 patients with a diagnosis of CIDP and controls with diabetic neuropathy or amyotrophic lateral sclerosis (Breiner and Brannagan, 2013). The EFNS/PNS criteria appeared to have the best combination of sensitivity (73%) and specificity (90%) for the diagnosis of CIDP compared with the other criteria. These criteria also have the advantage of including patients with typical and atypical presentation and, in comparison with most other criteria, to allow the diagnosis of CIDP even in patients with demyelinating abnormalities in a single nerve when other supportive criteria for the diagnosis of CIDP are present.

Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) (Donofrio et al ., 2009) and in the guideline of the American Academy of Neurology (AAN) on the use of IVIg in neurological diseases (Patwa et al ., 2012), and, for plasma exchange, in the guideline of the AAN on the use of plasma exchange in neurological diseases (Cortese et al ., 2011). It is often difficult to decide what therapy should be first used in CIDP. This decision should consider the efficacy, cost, and side effects of each of these therapies. A few randomized trials have shown comparable short-term efficacy of IVIg and oral corticosteroids (Hughes et al ., 2001) and of IVIg and plasma exchange (Dyck et al ., 1994) in CIDP. More recent trials have shown that both IVIg (Hughes et al ., 2008 ; Merkies et al ., 2009) and corticosteroids (van Schaik et al ., 2010 ; Eftimov et al ., 2012) have prolonged efficacy in CIDP. A recent randomized controlled trial comparing the 6-month efficacy of IVIg and intravenous methylprednisolone (IVMP) showed that IVIg was more frequently effective and tolerated (87.5%) than corticosteroids (47.6%) during the first 6 months of treatment, although, when effective, corticosteroids were less frequently associated with deterioration than IVIg in the 6 months following therapy discontinuation (Nobile-Orazio et al ., 2012). In the follow-up extension of this study (Nobile-Orazio et al ., 2013a), a similar proportion of patients who discontinued IVIg (87%) and IVMP (79%) eventually worsened and required further therapy even if the median time to deterioration was longer after discontinuing IVMP (14 months) than IVIg (4.5 months). There were not significant differences in the proportion of patients experiencing adverse events. This data may somehow balance the more frequent response to IVIg than to IVMP observed in the original study as also probably does the lower cost of corticosteroid than of IVIg (McCrone et al ., 2003 ; Blackhouse et al ., 2010). It is likely, however, that a more prolonged use of corticosteroids may eventually lead to a higher frequency of adverse events than observed during 6 months of therapy (Dukes, 1996). The possibility to reduce the cost and the inconvenience of repeated hospital admissions for chronic IVIg therapy in CIDP was addressed with the use of subcutaneous immunoglobulin (SCIg). A few patients with CIDP were reported to maintain the improvement achieved with IVIg assuming the same dose subcutaneously at home during the week (Lee et al ., 2008 ; Cocito et al ., 2011b). These observations were confirmed in a small, randomized, placebocontrolled study on 15 patients that showed that SCIg was safe and as effective as IVIg in most CIDP patients (Markvardsen et al ., 2013). SCIg may improve the quality of life of the patients who do not need

Treatment of CIDP Several controlled studies and retrospective series on large series of patients and a few randomized controlled trials have shown the efficacy of corticosteroids, plasma exchange, and IVIg in CIDP as summarized in recent Cochrane reviews (Mehndiratta and Hughes, 2012 ; Mehndiratta et al ., 2012 ; Eftimov et al ., 2013). Approximately 50%–70% of the patients respond to each of these therapies, and an additional 50% of patients not responding to one of these therapies respond to one of the others so that about 80% of the patients respond to these therapies (Cocito et al ., 2010 ; Viala et al ., 2010). The efficacy of these therapies has also been highlighted in the Guidelines of the EFNS/PNS (Joint Task Force of the EFNS and the PNS , 2010), for IVIg in a Consensus statement of the American 7

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to suspend their daily activities to receive periodic infusions. An alternative to SCIg could be home-based IVIg therapy. This therapy was reported to be effective in observational studies (Cats et al ., 2011; Souayah et al ., 2011; Katzberg et al ., 2013). This therapy has the same advantage of SCIg to perform the therapy at home without having the inconvenience of SCIg that require repeated subcutaneous therapies during the week. Unfortunately, the possibility to perform IVIg therapy at home is not yet allowed in all countries. Even if similarly effective to IVIg, plasma exchange is usually considered the third choice as it is more invasive for the patient and has a higher prevalence of side effects, mostly related to hemodynamic changes, that makes it less suitable for long-term treatment (Joint Task Force of the EFNS and the PNS , 2010). It is now often reserved for patients who have an insufficient response to IVIg or corticosteroids. Several anecdotal reports have shown the efficacy of other immune therapies that have been used to reduce the cost and frequency of IVIg, the side effects of corticosteroids, or to treat patients not responding or becoming resistant to these therapies. These studies have been summarized in a recent Cochrane Review (Mahdi-Rogers et al ., 2013). None of the randomized controlled trials with these therapies confirmed their efficacy. Oral azathioprine (2 mg/kg) in addition to oral prednisone (120 mg on alternate day tapered to 0 mg) given for 9 months to 27 patients with CIDP was not more effective than prednisone alone (Dyck et al ., 1985). The dose and duration of treatment with azathioprine was, however, smaller and shorter compared with what was later reported to be effective in a trial in patients with myasthenia gravis (Palace et al ., 1998). In addition, only the adjunctive effect of azathioprine was analyzed and not its capability to reduce the dosage of corticosteroids. A second randomized study was performed with oral methotrexate in addition to IVIg or corticosteroids (RMC Trial Group, 2009). This therapy was well tolerated but was not more effective than placebo in reducing the dose of corticosteroids or IVIg used to maintain the improvement in 60 patients with CIDP. In particular, 52% of the patients taking oral methotrexate, 15 mg weekly, and 44% of those on placebo reduced by at least 20% the associated initial dose of IVIg or corticosteroids by the end of the 40 weeks of the study. Similar negative results were obtained in two trials with intramuscular interferon beta-1a (IM IFNb-1a) on a total of 77 patients (Hadden et al ., 1999 ; Hughes et al ., 2010). In the larger study on 67 patients with CIDP on chronic IVIg therapy (Hughes et al ., 2010), treatment for 32 weeks with either 30 or 60 mg of IM IFNb-1a once or twice weekly was not more effective than placebo in reducing

the mean dose of IVIg with 47% of the patients in both groups not needing to restart IVIg after their suspension after 16 weeks of therapy with IFNb-1a. The subgroup of patients severely affected or taking high baseline dose of IVIg, could, however, reduce more IVIg after IM IFNb-1a than after placebo. Both the study with methotrexate and IM IFNb-1a showed that a consistent proportion of patients with CIDP are probably over treated with corticosteroids or IVIg as more than 40% of them could reduce or suspend the therapy without worsening. It is not possible, however, to exclude that the scales used in these trials might not have captured the modifications in some disturbing symptoms like fatigue or sensory loss that usually lead the physician to resume therapy. This consideration highlights the need for better evaluation scales in trials on CIDP (Vanhoutte et al ., 2013). Despite the negative results from these randomized studies, immunosuppressive agents are still widely used in the treatment of CIDP. This derives from the results of uncontrolled or retrospective series of patients showing a variable efficacy in patients treated with cyclosporin (82% of patients improved), cyclophosphamide (75%), Rituximab (75%), Methotrexate (70%), Azathioprine (64%), Interferon alfa (64%), Alentuzumab (57%), mycophenolate mofetil (46%), Interferon b 1a (35%), Etanercept (30%), tacrolimus, and autologous hematopoietic stem cell transplantation (reviewed in Mahdi-Rogers et al ., 2013 ). These figures should be considered, however, in light of the above-mentioned consistent proportion of patients not worsening after therapy discontinuation even when taking placebo. In a more recent retrospective multicenter study on 110 patients with CIDP not adequately responsive to IVIg, corticosteroids, or plasma exchange, the proportion of patients responding to these therapies ranged between 20% and 30%, with 10%–20% of treated patients having adverse events related to the use of these therapies (Cocito et al ., 2011a). In a recent session on the use of immune suppressive agents in CIDP at the Periph¨ eral Nerve Society Meeting held in Wurzburg in 2009, the majority of the experts supported the use of oral azathioprine in patients with mild to moderate CIDP and of cyclophosphamide in severely affected patients. These data highlight the fact that transferring the data deriving from clinical trials to the clinical practice might not always be an easy task.

Conclusions Several advances have been made in the last few years in the diagnosis, pathogenesis, and therapy of CIDP. Several issues should, however, be further 8

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characterized. These include the real boundaries of CIDP and whether it should be considered a single disease with a few variants or a group of diseases that may differ not only in the clinical presentation but also in their pathogenesis and possibly therapy. Similarly unclear is whether our ignorance in the pathogenesis of CIDP derives from the fact that we are still looking for a single immune mechanism underlying this disease while different pathogenetic mechanisms might be involved and possibly underlie the different clinical presentations. In addition, even if we now have a few consistent therapies in CIDP, it remains unclear why none of the immunosuppressive agents used in CIDP beside corticosteroids, IVIg, and plasma exchange have been proven to be effective in a randomized trial in CIDP. It would be also important to fill in the gap between our evaluation parameters and the subjective feeling of the patients that may worsen in symptoms that are not assessed in our scale but that for the patients may represent a real limitation in their life (Vanhoutte et al ., 2013).

Berger AS, Herskovitz S, Kaplan J (1995). Late motor involvement in cases presenting as ‘‘chronic sensory demyelinating polyradiculoneuropathy’’. Muscle Nerve 18:440–444. Bick S, Tschernatsch M, Karg A, Fuehlhuber V, Trenczek TE, Faltermeier K, Hackstein H, Kaps M, Blaes F (2013). Intravenous immunoglobulin inhibits BAFF production in chronic inflammatory demyelinating polyneuropathy - a new mechanism of action? J Neuroimmunol 256:84–90. Bissay V, Flamez A, Schmedding E, Ebinger G (2008). Fatigue as the presenting symptom of chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 38:1653–1657. Blackhouse G, Gaebel K, Xie F, Campbell K, Assasi N, Tarride JE, O’Reilly D, Chalk C, Levine M, Goeree R (2010). Costutility of intravenous immunoglobulin (IVIG) compared with corticosteroids for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in Canada. Cost Eff Resour Alloc 17:14. Boukhris S, Magy L, Khalil M, Sindou P, Vallat JM (2007). Pain as the presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). J Neurol Sci 254:33–38. Breiner A, Brannagan TH III (2013). Comparison of sensitivity and specificity among 15 criteria for chronic inflammatory demyelinating polyneuropathy. Muscle Nerve Oct 6. (Epub ahead of print). Bromberg MB (2011). Review of the evolution of electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 43:780–794. Busby M, Donaghy M (2003). Chronic dysimmune neuropathy. A subclassification based upon the clinical features of 102 patients. J Neurol 250:714–724. Caporale CM, Staedler C, Gobbi C, Bassetti CL, Uncini A (2011). Chronic inflammatory lumbosacral polyradiculopathy: a regional variant of CIDP. Muscle Nerve 44:833–837. Cats EA, van der Pol WL, Bertens AS, van den Berg LH (2011). Home-based IVIg treatment is convenient and time-saving in patients with multifocal motor neuropathy. J Peripher Nerv Syst 16:147–149. Chi LJ, Xu WH, Zhang ZW, Huang HT, Zhang LM, Zhou J (2010). Distribution of Th17 cells and Th1 cells in peripheral blood and cerebrospinal fluid in chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst 15:345–356. Chin RL, Latov N, Sandr HW, Hays AP, Croul SE, Magda P, Brannagan TH (2004). Sensory CIDP presenting as cryptogenetic sensory polyneuropathy. J Peripher Nerv Syst 9: 132–137. Chio` A, Cocito D, Bottacchi E, Buffa C, Leone M, Plano F, Mutani R, Calvo A, The PARCIDP (2007). Idiopathic chronic inflammatory demyelinating polyneuropathy: an epidemiological study in Italy. J Neurol Neurosurg Psychiatry 78:1349–1353. Cocito D, Paolasso I, Antonini G, Benedetti L, Briani C, Comi C, Fazio R, Jann S, Mata` S, Mazzeo A, Sabatelli M, NobileOrazio E (2010). A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 17:289–294. Cocito D, Grimaldi S, Paolasso I, Falcone Y, Antonini G, Benedetti L, Briani C, Fazio R, Jann S, Mata` S, Sabatelli M, Nobile-Orazio E (2011a). Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis. Eur J Neurol 18:1417–1421.

Acknowledgements Eduardo Nobile-Orazio reports personal compensation for serving in the Steering or Advisory Board of Baxter-Italy, CSL Behring-Italy, Kedrion-Italy, and Novartis-Switzerland. He has received honoraria for lecturing from Baxter, CSL Behring, Grifols-Spain, and Kedrion and travel support for Scientific Meetings from Baxter and Kedrion. All compensation and support is outside the submitted work.

References Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (1991). Criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 41:617–618. Allen D, Giannopoulos K, Gray I, Gregson N, Mokowska A, Pritchard J, Hughes RA (2005). Antibodies to peripheral nerve myelin proteins in chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst 10:174–180. Attarian S, Verschueren A, Franques J, Salort-Campana E, Jouve E, Pouget J (2011). Response to treatment in patients with Lewis-Sumner syndrome. Muscle Nerve 44:179–184. Ayrignac X, Bienvenue S, Morales R, Renard D, Labauge P (2013a). Focal CIDP presenting as chronic progressive monomelic sensory neuropathy. Muscle Nerve 47:143–144. Ayrignac X, Viala K, Morizot Koutlidis R, Taieb G, Stojkovic T, ´ Musset L, Leger J-M, Fournier E, Maisonobe T, Bouche P (2013b). Sensory chronic inflammatory demyelinating polyneuropathy: an under-recognized entity? Muscle Nerve 48:727–732. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR (1989). Chronic inflammatory demyelinating polyradiculoneuropathy: clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 46:878–884.

9

Nobile-Orazio

Journal of the Peripheral Nervous System 19:2–13 (2014)

demyelinating polyradiculoneuropathy react with ganglioside LM1 and sulphatide of peripheral nerve myelin. J Neurol 238:75–79. Gorson KC, Allam G, Ropper AH (1997). Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 48:321–328. Gorson KC, Ropper AH, Weinberg DH (1999). Upper limb predominant, multifocal chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 22:758–765. Hadden RDM, Sharrack B, Bensa S, Soudain SE, Hughes RA (1999). Randomized trial of interferon b1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 53:57–61. Hahn AF, Hartung H-P, Dyck PJ (2005). Chronic inflammatory demyelinating polyradiculoneuropathy. In: Peripheral Neuropathy, 4th Edn. Dyck PJ, Thomas PK (Eds). Elsevier Saunders, Philadelphia, pp 2221–2253. Hattori N, Misu K, Koike H, Ichimura M, Nagamatsu M, Hirayama M, Sobue G (2001). Age of onset influences clinical features of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 184:57–63. Henderson RD, Sandroni P, Wijdicks EF (2005). Chronic inflammatory demyelinating polyneuropathy and respiratory failure. J Neurol 252:1235–1237. Hughes RA, Gray IA, Gregson NA, Kadlubowski M, Kennedy M, Leibowitz S, Thompson H (1984). Immune responses to myelin antigens in Guillain-Barre´ syndrome. J Neuroimmunol 6:303–312. Hughes RA, Choudhary PP, Osborne M, Rees JH, Sanders EA (1996). Immunization and risk of relapse of GuillainBarre´ syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 19:1230–1231. Hughes RA, Bensa S, Willison HJ, van den Bergh P, Comi G, Illa I, Nobile-Orazio E, van Doorn P, Dalakas M, Bojar M, Swan A, the Inflammatory Neuropathy Cause and Treatment (INCAT) group (2001). Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 50:195–201. Hughes RA, Allen D, Makowska A, Gregson NA (2006). Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst 11:30–46. Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, Merkies IS, van Doorn PA, ICE Study Group (2008). Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol 7:136–144. Hughes RA, Gorson KC, Cros D, Griffin J, Pollard J, Vallat JM, Maurer SL, Riester K, Davar G, Dawson K, Sandrock A, for the Avonex CIDP Study Group (2010). Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 74:651–657. Ilyas AA, Mithen FA, Dalakas MC, Chen ZW, Cook SD (1992). Antibodies to acidic glycolipids in Guillain-Barre´ syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 107:111–121. Joint Task Force of the EFNS and the PNS (2010). European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report

Cocito D, Serra G, Falcone Y, Paolasso I (2011b). The efficacy of subcutaneous immunoglobulin administration in chronic inflammatory demyelinating polyneuropathy responders to intravenous immunoglobulin. J Peripher Nerv Syst 16:150–152. Connolly AM, Pestronk A, Trotter JL, Feldman EL, Cornblath DR, Olney RK (1993). High-titer selective serum anti-βtubulin antibodies in chronic inflammatory demyelinating polyneuropathy. Neurology 43:557–562. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A (2011). Evidence-based guideline update: Plasmapheresis in neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 76:294–300. Devaux JJ, Odaka M, Yuki N (2012). Nodal proteins are target antigens in Guillain-Barre´ syndrome. J Peripher Nerv Syst 17:62–71. Dionne A, Nicole MW, Hahn AF (2010). Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy. Muscle Nerve 42:202–207. Donaghy M, Mills KR, Boniface SJ, Simmons J, Wright I, Gregson N, Jacobs J (1994). Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 57:778–783. Donofrio PD, Berger A, Branaga TH III, Bromberg MB, Howard JF, Latov N, Quick A, Tandan R (2009). Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions. Report of the AANEM Ad Hoc Committee. Muscle Nerve 40:890–900. van Doorn PA, Ruts L, Jacobs BC (2008). Clinical features, pathogenesis, and treatment of Guillain-Barre´ syndrome. Lancet Neurol 7:939–950. Doppler K, Werner C, Sommer C (2013). Disruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies. J Peripher Nerv Syst 18:168–176. Dukes MN (1996). Meyler’s Side Effects of Drugs. Elsevier, New York, pp 1193–1209. Dyck PJ, Lais AC, Ohta M, Bastron JA, Okazaki H, Groover RV (1975). Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 50:621–637. Dyck PJ, O’Brien P, Swanson C, Low P, Daube J (1985). Combined azathioprine and prednisone in chronic inflammatory demyelinating polyneuropathy. Neurology 35:1173–1176. Dyck PJ, Litchy WJ, Kratz KM, Suarez GA, Low PA, Pineda AA, Windebank AJ, Karnes JL, O’Brien PC (1994). A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 36:838–845. Eftimov F, Vermeulen M, van Doorn PA, Brusse E, van Schaik IN, On behalf of the PREDICT Study Group (2012). Long-term remission of CIDP after pulsed highdose dexamethasone or short term prednisolone treatment. Neurology 78:1079–1084. Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN (2013). Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 12:CD001797. Fredman P, Bedeler CA, Nyland H, Aarli JA, Svennerholm L (1991). Antibodies in sera from patients with inflammatory

10

Nobile-Orazio

Journal of the Peripheral Nervous System 19:2–13 (2014)

of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society-First Revision. J Peripher Nerv Syst 15:1–9. (Erratum in: J Peripher Nerv Syst 2010;15:373). Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ (2000). Distal acquired demyelinating symmetric neuropathy. Neurology 54:615–620. Katzberg HD, Rasutis V, Bril V (2013). Home IVIG for CIDP: a focus on patient centred care. Can J Neurol Sci 40:384–388. Kawamura N, Yamasaki R, Yonekawa T, Matsushita T, Kusunoki S, Nagayama S, Fukuda Y, Ogata H, Matsuse D, Murai H, Kira J (2013). Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 81:714–722. Khalili-Shirazi A, Atkinson P, Gregson N, Hughes RA (1993). Antibody responses to P0 and P2 myelin proteins in Guillain-Barre´ syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol 46:245–251. Kimura A, Sakurai T, Koumura A, Yamada M, Hayashi Y, Tanaka Y, Hozumi I, Yoshino H, Yuasa T, Inuzuka T (2010). Motor-dominant chronic inflammatory demyelinating polyneuropathy. J Neurol 257:621–629. ¨ Koller H, Kieseier BC, Jander S, Hartung H-P (2005). Chronic inflammatory demyelinating polyneuropathy. N Engl J Med 352:1343–1356. Koski CL, Humphrey R, Shin ML (1985). Anti-peripheral myelin antibody in patients with demyelinating neuropathy: quantitative and kinetic determination of serum antibody by complement component 1 fixation. Proc Natl Acad Sci U S A 82:905–909. Koski CL, Baumgarten M, Magder LS, Barohn RJ, Goldstein J, Graves M, Gorson K, Hahn AF, Hughes RA, Katz J, Lewis RA, Parry GJ, van Doorn P, Cornblath DR (2009). Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 277:1–8. Kuitwaard K, Bos-Eyssen ME, Blomkwist-Markens PH, van Doorn PA (2009). Recurrences, vaccinations and longterm symptoms in GBS and CIDP. J Peripher Nerv Syst 14:310–315. Kusumi M, Nakashima K, Nakayama H, Takahashi K (1995). Epidemiology of inflammatory neurological and inflammatory neuromuscular diseases in Tattori Prefecture, Japan. Psychiatry Clin Neurosci 49:169–174. Kuwahara M, Suzuki S, Takada K, Kusunoki S (2011). Antibodies to LM1 and LM1-containing ganglioside complexes in Guillain-Barre´ syndrome and chronic inflammatory demyelinating polyneuropathy. J Neuroimmunol 239:87–90. Kuwahara M, Suzuki H, Samukawa M, Hamada Y, Takada K, Kusunoki S (2013). Clinical features of CIDP with LM1-associated antibodies. J Neurol Neurosurg Psychiatry 84:573–575. ´ Larue S, Dashi F, Demeret S, Leger JM (2008). Two patients with CIDP deteriorated after plasma exchange. J Peripher Nerv Syst 13:307. Larue S, Bombelli F, Viala K, Neil J, Maisonobe T, Bouche P, ´ Musset L, Fournier E, Leger JM (2011). Non-anti-MAG DADS neuropathy as a variant of CIDP: clinical, electrophysiological, laboratory features and response to treatment in 10 cases. Eur J Neurol 18:899–905. Latov N, Hays AP, Sherman WH (1988). Peripheral neuropathy and anti-MAG antibodies. Crit Rev Neurobiol 3:301–332. Laughlin RS, Dyck PJ, Melton LJ III, Leibson C, Ransom J, Dyck PJ (2009). Incidence and prevalence of CIDP and the associations with diabetes mellitus. Neurology 73:39–45.

Lee D-Y, Linker RA, Paulus W, Schneider-Gold C, Chan A, Gold R (2008). Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 37:406–409. Leitch MM, Sherman WH, Brannagan TH III (2013). Distal acquired demyelinating symmetric polyneuropathy progressing to classic chronic inflammatory demyelinating polyneuropathy and response to fludarabine and cyclophosphamide. Muscle Nerve 47:292–296. Lewis RA, Sumner AJ, Brown MJ, Asbury AK (1982). Multifocal demyelinating neuropathy with persistent conduction block. Neurology 32:958–964. Lunn MPT, Manji H, Choudhary PP, Hughes RA, Thomas PK (1999). Chronic inflammatory demyelinating polyradiculoneuropathy: a prevalence study in south east England. J Neurol Neurosurg Psychiatry 66:677–680. Mahdi-Rogers M, Hughes RA (2013). Epidemiology of chronic inflammatory neuropathies in southeast England. Eur J Neurol May 17. (Epub ahead of print). Mahdi-Rogers M, Swan AV, van Doorn PA, Hughes RA (2013). Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 6:CD003280. Manfredini E, Nobile-Orazio E, Allaria S, Scarlato G (1995). Anti-alpha and beta-tubulin IgM antibodies in dysimmune neuropathies. J Neurol Sci 133:79–84. Markvardsen LH, Debost JC, Harbo T, Sindrup SH, Andersen H, Christiansen I, Otto M, Olsen NK, Lassen LL, Jakobsen J, Danish CIDP and MMN Study Group (2013). Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 20:836–842. ¨ Mausberg AK, Dorok M, Stettner M, Muller M, Hartung HP, ¨ Dehmel T, Warnke C, Meyer Zu Horste G, Kieseier BC (2013). Recovery of the T-cell repertoire in CIDP by IV immunoglobulins. Neurology 80:296–303. McCombe PA, Pollard JD, McLeod JG (1987). Chronic inflammatory demyelinating polyradiculoneuropathy: a clinical and electrophysiological study of 92 cases. Brain 110:1617–1630. McCombe PA, Wilson R, Prentice RL (1992). Anti-ganglioside antibodies in peripheral neuropathy. Clin Exp Neurol 29:182–188. McCrone P, Chisholm D, Knapp M, Hughes R, Comi G, Dalakas M, Illa I, Kilindireas C, Nobile-Orazio E, Swan A, Van den Bergh P, Willison HJ, the INCAT Study Group (2003). Cost-utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eur J Neurol 10:687–694. McLeod JC, Pollard JD, Macaskill P, Mohamed A, Spring P, Khurana V (1999). Prevalence of chronic inflammatory demyelinating polyneuropathy in New South Wales, Australia. Ann Neurol 46:910–913. Mehndiratta MM, Hughes RA (2012). Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 8:CD002062. Mehndiratta MM, Hughes RA, Agarwal P (2012). Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 9:CD003906. ´ Melendez-Vazquez C, Redford J, Choudhary PP, Gray IA, Maitland P, Gregson NA, Smith KJ, Hughes RA (1997). Immunological investigation of chronic inflammatory

11

Nobile-Orazio

Journal of the Peripheral Nervous System 19:2–13 (2014)

demyelinating polyradiculoneuropathy. J Neuroimmunol 73:124–134. Merkies IS, Schmitz PI, Samijn JP, van der Meche´ FG, van Doorn PA (1999). Fatigue in immune-mediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Neurology 53:1648–1654. Merkies IS, Bril V, Dalakas MC, Deng C, Donofrio P, Hanna K, Hartung HP, Hughes RA, Latov N, van Doorn PA, ICE Study Group (2009). Health-related quality-of-life improvements in CIDP with immunoglobulin IV 10%: the ICE study. Neurology 72:1337–1344. Ng JKM, Malotka J, Kawakami N, Derfuss T, Khademi M, Olsson T, Linington C, Odaka M, Tackenberg B, Pruss H, Schwab JM, Harms L, Harms M, Sommer C, Rasband MN, EshedEisenbach Y, Peles E, Hohlfeld R, Yuki N, Dornmair K, Meinl E (2012). Neurofascin as target for auotoantibodies in peripheral neuropathy. Neurology 79:2241–2248. Nobile-Orazio E (1998). Neuropathies associated with antiMAG antibodies and IgM monoclonal gammopathies. In: Immunological and Infectious Diseases of the Peripheral Nerve. Latov N, Wokke JH, Kelly JJ (Eds). Cambridge University Press, Cambridge, pp 169–189. Nobile-Orazio E, Manfredini E, Sgarzi M, Spagnol G, Allaria S, Quadroni M, Scarlato G (1994). Serum IgG antibodies to a 35kDa P0-related glycoprotein in motor neuron disease. J Neuroimmunol 53:143–151. Nobile-Orazio E, Cappellari A, Priori A (2005). Multifocal motor neuropathy: current concepts and controversies. Muscle Nerve 31:663–680. Nobile-Orazio E, Cocito D, Jann S, Uncini A, Beghi E, Messina P, Antonini G, Fazio R, Gallia F, Schenone A, Francia A, Pareyson D, Santoro L, Tamburin S, Macchia R, Cavaletti G, Giannini F, Sabatelli M, for the IMC Trial Group (2012). Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 11:493–502. Nobile-Orazio E, Cocito D, Jann S, Uncini A, Messina P, Antonini G, Fazio R, Gallia F, Schenone A, Francia A, Pareyson D, Santoro L, Tamburin S, Macchia R, Beghi E, Cavaletti G, Giannini F, Sabatelli M, for the IMC Study Group (2013a). Frequency and time to relapse after therapy discontinuation in CIDP patients treated for six months with IVIg or IV Methylprednisolone (IMC follow-up study). J Peripher Nerv Sys 18:S80–S81. ´ Nobile-Orazio E, Giannotta C, Musset L, Messina P, Leger JM (2013b). Sensitivity and predictive value of antiGM1/galactocerebroside IgM antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry Aug 1. (Epub ahead of print). Oh SJ, Joy JL, Kuruoglu R (1992a). ‘‘Chronic sensory demyelinating neuropathy:’’ chronic inflammatory demyelinating polyneuropathy presenting as a pure sensory neuropathy. J Neurol Neurosurg Psychiatry 55:677–680. Oh SJ, Joy JL, Sunwoo I, Kuruoglu R (1992b). A case of chronic sensory demyelinating neuropathy responding to immunotherapies. Muscle Nerve 15:255–256. Oh SJ, Claussen GC, Kim DS (1997). Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy? J Peripher Nerv Syst 2:362–369. Palace J, Newsom-Davis J, Lecky B (1998). A randomized double-blind trial of prednisolone alone or with azathioprine

in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 50:1778–1783. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT (2012). Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders. Neurology 78:1009–1015. Pollard JD, Armati PJ (2011). CIDP - the relevance of recent advances in Schwann cell/axonal neurobiology. J Peripher Nerv Syst 16:15–23. Pollard JD, Selby G (1978). Relapsing neuropathy due to tetanus toxoid: report of a case. J Neurol Sci 37:113–125. Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez ´ E, Diaz-Manera J, Suarez-Calvet X, Navas M, Araque J, Gallardo E, Illa I (2013). Antibody to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 73:370–380. Rajabally Y, Chavada G (2009). Lewis-Sumner syndrome of pure upper limb onset prognostic, diagnostic and therapeutic features. Muscle Nerve 39:206–220. Rajabally YA, Wong SL (2012). Chronic inflammatory pure sensory polyradiculoneuropathy: a rare CIDP variant with unusual electrophysiology. J Clin Neuromuscul Dis 13:149–152. ´ Rajabally YA, Nicolas G, Pieret F, Bouche P, Van den Bergh PY (2009a). Validity of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy: a multicentre European study. J Neurol Neurosurg Psychiatry 80:1364–1368. Rajabally YA, Simpson BJ, Beri S, Bankart J, Gosalakkal JA (2009b). Epidemiologic variability of chronic inflammatory demyelinating polyneuropathy with different diagnostic criteria: study of UK population. Muscle Nerve 39:432–438. RMC Trial Group (2009). Pilot randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC Trial). Lancet Neurol 8:158–164. Rotta FT, Sussman AT, Bradley WG, Ayyar DR, Sharma KR, Shebert RT (2003). The spectrum of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 173:129–139. Rubin M, Mackenzie CR (1996). Clinically and electrodiagnostically pure sensory demyelinating polyneuropathy. Electromyogr Clin Neurophysiol 36:145–149. Ruts L, Drenthen J, Jacobs BC, van Doorn PA, on behalf of the Dutch GBS Study Group (2010). Distinguishing acute onset CIDP from fluctuating Guillain-Barre´ syndrome. A prospective study. Neurology 74:1680–1686. Sabatelli M, Madia F, Mignogna T, Lippi G, Quaranta L, Tonali P (2001). Pure motor chronic inflammatory demyelinating polyneuropathy. J Neurol 248:772–777. Said G (2006). Chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord 16:293–303. Sanvito L, Makowska A, Mahdi-Rogers M, Hadden RD, Peakman M, Gregson N, Nemni R, Hughes RA (2009a). Humoral and cellular response to myelin protein peptides in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry 80:333–338. Sanvito L, Makowska A, Gregson N, Nemni R, Hughes RA (2009b). Circulating subsets and CD4(+)CD25(+) regulatory T cell function in chronic inflammatory demyelinating polyradiculoneuropathy. Autoimmunity 42:667–677. Saperstein DS, Amato AA, Wolfe GI, Katz JS, Nations SP, Jackson CE, Bryan WW, Burns DK, Barohn RJ (1999). Multifocal acquired demyelinating sensory and motor

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Nobile-Orazio

Journal of the Peripheral Nervous System 19:2–13 (2014)

neuropathy: the Lewis-Sumner syndrome. Muscle Nerve 22:560–566. Saperstein DS, Katz JS, Amato AA, Barohn RJ (2001). Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve 24:311–324. van Schaik IN, Eftimov F, van Doorn PA, Brusse E, van den Berg LH, van der Pol WL, Faber CG, van Oostrom JC, Vogels OJ, Hadden RD, Kleine BU, van Norden AG, Verschuuren JJ, Dijkgraaf MG, Vermeulen M (2010). Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind randomised controlled trial. Lancet Neurol 9:245–253. ¨ Schneider-Hohendorf T, Schwab N, Uc¸eyler N, Gobel K, Sommer C, Wiendl H (2012). CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 78:402–408. Simmons Z, Tivakaran S (1996). Acquired demyelinating polyneuropathy presenting as a pure clinical sensory syndrome. Muscle Nerve 19:1174–1176. Simmons Z, Albers JW, Bromberg MB, Feldman EL (1993). Presentation and initial clinical course in patients with chronic inflammatory demyelinating polyradiculoneuropathy: comparison of patients without and with monoclonal gammopathy. Neurology 43:2202–2209. Sinnreich M, Klein CJ, Daube JR, Engelstad J, Spinner RJ, Dyck PJB (2004). Chronic immune sensory polyradiculopathy. A possibly treatable sensory ataxia. Neurology 63:1662–1669. Souayah N, Hasan A, Khan HM, Yacoub HA, Jafri M (2011). The safety profile of home infusion of intravenous immunoglobulin in patients with neuroimmunologic disorders. J Clin Neuromuscul Dis 12:S1–S10. Stamboulis E, Katsaros N, Koutsis G, Iakovidou H, Giannakopoulou A, Simintzi I (2006). Clinical and subclinical autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 33:78–84. Thomas PK, Claus D, Jaspert A, Workman JM, King RHM, Larner AJ, Anderson M, Emerson JA, Ferguson IT (1996). Focal upper limb demyelinating neuropathy. Brain 119:765–774. Uncini A, Di Muzio A, De Angelis MV, Gioia S, Lugaresi A (1999). Minimal and asymptomatic chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol 110:694–698.

Vallat J-M, Sommer C, Magy L (2010). Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 9:402–412. Van den Berg-Vos RM, Van den Berg LH, Franssen H, Vermeulen M, Witkamp TD, Jansen GH, van Es HW, Kerkhoff H, Wokke JH (2000). Multifocal inflammatory demyelinating neuropathy: a distinct clinical entity? Neurology 54:26–32. Van Dijk GW, Notermans NC, Franssen H, Wokke JH (1999). Development of weakness in patients with chronic inflammatory demyelinating polyneuropathy and only sensory symptoms at presentation: a long-term follow-up study. J Neurol 246:1134–1139. Vanhoutte EK, Faber CG, Merkies IS, the PeriNomS study group (2013). 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies. 8–10 February 2013, Naarden, The Netherlands. Neuromuscul Disord 23:924–933. Verschueren A, Azulay JP, Attarian S, Boucraut J, Pellissier JF, Pouget J (2005). Lewis-Sumner syndrome and multifocal motor neuropathy. Muscle Nerve 31:88–94. ´ ´ Viala K, Renie´ L, Maisonobe T, Behin A, Neil J, Leger JM, Bouche P (2004). Follow-up study and response to treatment in 23 patients with Lewis-Sumner syndrome. Brain 127:2010–2017. Viala K, Maisonobe T, Stojkovic T, Koutlidis R, Ayrignac X, ´ Musset L, Fournier E, Leger JM, Bouche P (2010). A current view of the diagnosis, clinical variants, response to treatment and prognosis in chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst 15:50–56. Vlam L, van der Pol WL, Cats EA, Straver DC, Piepers S, Franssen H, van den Berg LH (2011). Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat Rev Neurol 8:48–58. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007). The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815. Yan WX, Archelos JJ, Hartung HP, Pollard JD (2001). P0 protein is a target antigen in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 50:286–292.

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