A current view of the diagnosis, clinical variants, response to treatment and prognosis of chronic inflammatory demyelinating polyradiculoneuropathy

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1 Journal of the Peripheral Nervous System 15:50 56 (2010) RESEARCH REPORT A current view of the diagnosis, clinical variants, response to treatment and prognosis of chronic inflammatory demyelinating polyradiculoneuropathy Karine Viala 1,3, Thierry Maisonobe 1,5, Tanya Stojkovic 1,2,Régine Koutlidis 1, Xavier Ayrignac 1, Lucile Musset 4, Emmanuel Fournier 1, Jean-Marc Léger 2, and Pierre Bouche 1 1 Fédération de Neurophysiologie Clinique; 2 Centre de Référence de Pathologie Neuromusculaire Paris Est; 3 Fédération des Maladies du Système Nerveux; 4 Laboratoire d immunochimie; and 5 Departement de Neuropathologie R Escourolle, AP-HP, Groupe Hospitalier Pitié Salpêtrière, Paris, France Abstract We retrospectively analyzed 146 patients fulfilling the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria for definite chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to (1) evaluate the relevance of these criteria, (2) assess the frequency of CIDP variants, and (3) determine the response to treatment and the prognosis. We found that 75% of these patients fulfilled the main EFNS/PNS clinical and electrophysiological criteria (type I). The remaining patients were diagnosed using laboratory tools as supportive criteria. The common form of CIDP represented 51% of patients. We observed a high frequency of the sensory variant (35% of patients) and the rapid onset form (18%). A positive response to treatment was observed in 87% of patients, with a similar efficacy of prednisone and IVIg. However, in the long term, 40% of treated patients remained dependent on treatment. The IVIg dependency rate was higher than the prednisone or plasma exchange dependency rate (55%, 18%, and 23%, respectively; p = ). Severe handicap was observed in 24% of patients. Key words: CIDP, diagnostic criteria, treatment dependence, treatment efficacy, somatosensory-evoked potentials Introduction Over the past 30 years the concept of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has evolved considerably. Several reports have emphasized the heterogeneity of the clinical spectrum of CIDP (Rotta et al., 2000; Saperstein et al., 2001; Busby and Donaghy, 2003; Sander and Latov, 2003). The reported lack of sensitivity of the American Academy of Neurology (AAN) criteria Address correspondence to: Karine Viala, Service de Neurophysiologie Clinique, Hôpital de la Salpêtrière, 47 bd de l Hôpital Paris cedex 13, France. Tel: ;Fax: ; karine.viala@psl.aphp.fr (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force, 1991) led to several sets of less restrictive criteria being proposed (Van den Bergh et al., 2000; Hughes et al., 2001; Nicolas et al., 2002; Thaisetthawatkul et al., 2002). Nevertheless, some patients do not fulfill the electrophysiological criteria, with the risk that the disease may go undiagnosed and the patients may not receive appropriate treatment. To improve the management of CIDP, guidelines on the definition, diagnosis and treatment of CIDP have recently been proposed, based on a consensus of experts of the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). In addition, a French CIDP Study 2010 Peripheral Nerve Society 50

2 Group has recently proposed a diagnostic strategy designed to avoid misdiagnosing atypical CIDP (The French CIDP Study Group, 2008). Both these reports recommended that the clinical definition of CIDP should include both the common and variant forms of CIDP. An elevated cerebrospinal fluid (CSF) protein count and demyelinating features on nerve biopsy are now considered as supportive but non-necessary criteria (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). Abnormalities of roots or plexuses on magnetic resonance imaging (MRI) and a positive response to immunomodulatory treatment are also proposed as new supportive criteria (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). The EFNS/PNS criteria propose three ways of diagnosing definite CIDP. The first is based on clinical criteria (including common and variant forms) and major electrodiagnostic criteria (type I); the other two use the same clinical criteria coupled with minor electrodiagnostic criteria (type II or III) and the aforementioned supportive criteria (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). The aim of this study is to give a current overview of CIDP, based on a retrospective analysis of a recent, large cohort diagnosed in a reference center for CIDP, and to try to answer the following questions: What is the relevance of the EFNS/PNS criteria? What is the clinical spectrum of CIDP and the frequency of each of the clinical variants? Is CIDP a severe disease? Are current treatments for CIDP satisfactory? Patients and Methods Between January 2005 and January 2007, 203 patients with features suggesting CIDP followed up at Salpêtrière Hospital were consecutively recorded in a database at the time of their initial electrophysiological study or, in the case of existing patients, at their first follow-up electrophysiological study during this period. We reviewed the medical records of all 203 patients up to June 2008 and included patients with definite CIDP according to the EFNS/PNS criteria (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). Exclusion criteria were those proposed by the EFNS/PNS; in particular, patients with multifocal motor neuropathy (MMN) and patients with anti-myelin associated glycoprotein (MAG) antibodies were excluded. All patients underwent a standard neurological examination and nerve conductions (Viala et al., 2004) and scored with a modified Rankin disability scale. Onset was defined as acute if symptoms developed within less than 4 weeks, subacute if they developed within 4 8 weeks and progressive if they developed over a period of more than 8 weeks. The subsequent course of the disease was classified as either progressive or relapsing-remitting. A relapsingremitting course was defined as two episodes with intervening remission and relapse unrelated to a change in treatment. Patients received one or more of the three main treatments for CIDP: IVIg (2 g/kg over 3 5 days every 4 weeks for 2 months; then we progressively increased the interval between two courses by 1 week, depending on tolerability), prednisone (1 mg/kg/day for 4 weeks, followed by slowly tapered dosages) or PE (6 PEs during the first month, followed by a progressive increase in the interval between two PEs). Some patients had also received immunosuppressive drugs. A positive response to treatment was defined as an improvement by at least two Medical Research Council (MRC) grades in any muscle and/or by a one-point improvement in the disability score (Rankin scale). Patients were considered to be non-responders to the three main treatments of CIDP if they had not improved after 2 months on full dose of corticosteroids, three courses of IVIg and six PEs. A treatment-dependent patient was a patient who needed regular administration of this treatment to maintain its benefit who could not interrupt the treatment without risking a rapid relapse. Somatosensory-evoked potentials (SSEPs) were done as described earlier (Jeanmonod et al., 1989; Lee and Seyal, 1998; Cruccu et al., 2008). Patients had a proximal conduction abnormality suggestive of demyelination if they fulfilled one major criterion or two minor criteria in at least one limb (Brown and Feasby, 1984; Petiot et al., 1999; Sinnreich et al., 2004): 1. Major criterion: significant increase in radicular conduction time (N9 N13 > 4.4 ms, N18 N22 > 5.1 ms), with normal peripheral nerve potential (PNP); 2. Minor criteria: (i) absence of spinal potential (or enhanced P9/N13 ratio > 0.98, N18/N22 ratio > 0.84), with normal PNP; (ii) abnormality of radicular waves with normal PNP: N9 latency > 11.1 ms or amplitude < 2.1 uv, N18 latency > 22.7 ms, or amplitude < 0.1 uv. All patients had undergone the following investigations and tests: blood count, urea, serum glucose, complement (hemolytic 50, C3, and C4 levels), rheumatoid factor, search for cryoglobulins, and hepatitis, HIV and Lyme serologies. Patients sera were routinely tested for monoclonal immunoglobulin by electrophoresis and immunofixation (Sebia, Evry, France). Anti-myelin antibodies (ab) were detected by indirect immunofluorescence assay on monkey peripheral nerve substrate (The Binding Site, Birmingham, UK). Anti-MAG Ab 51

3 were also detected using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Bühlmann, Basel, Switzerland). Antiganglioside Ab (including anti-gm1, -GM2, -GM3, -GD1a, -GD1b, -GT1b, and anti-gq1b Ab), from IgM and IgG isotypes, were detected by an immunodot assay as previously described (Viala et al., 2004). CSF analysis was performed in 140/203 patients. Statistical analyses were performed with Graph- Pad (Graphpad Software, San Diego, CA, USA). The response rate and the dependency rate for each treatment were compared with chi-square test for multiple comparisons. A p value < 0.05 was considered statistically significant. Results Of the 203 patients with features suggesting CIDP, 32 were excluded because further investigations and follow-up led to another disease being diagnosed. The main differential diagnoses for CIDP were Guillain- Barré syndrome (GBS) and POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. Twentyfive other patients were excluded because of insufficient data to diagnose definite CIDP. The remaining 146 patients fulfilled the criteria for definite CIDP (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006) and were included in the study. There were 53 women and 93 men, with a mean age at inclusion in the database of 55 years (range years); disease duration at inclusion in the database ranged from 0.5 to 200 months (median disease duration: 11 months). There were 97 recently diagnosed patients (diagnosis made between January 2005 and January 2007) and 49 patients who had already been diagnosed (diagnosis made before January 2005). The median follow-up was 2.9 years ( years). All patients had EFNS/PNS clinical criteria for CIDP; 110 patients (75%) had definite electrodiagnostic criteria (type I) suggestive of demyelination (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). In 36 patients the diagnosis was based on electrophysiological criteria type II or III associated with one or two supportive criteria (Table 1) (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). Among these patients, nerve biopsy contributed to the diagnosis in 17 patients. Elevated CSF protein count was used as a supportive criterion for 25/36 patients and SSEPs showed proximal conduction abnormalities in 19/36 patients. A positive response to treatment was used as a supportive criterion in six patients. The main clinical characteristics of the 146 CIDP patients are shown in Table 2. A typical clinical presentation of CIDP with symmetrical sensorimotor symptoms affecting the four limbs was observed in 74 patients (51%). Fifteen percent of patients presented asymmetrical sensory or sensorimotor symptoms predominantly located in the upper limbs (Lewis- Sumner form). A focal lumbosacral CIDP was observed in two patients (1%). Three patients (2%) had isolated cranial nerve involvement. A pure motor form was observed in 10% of patients and 35% presented a pure clinical sensory form. Among these patients we observed three groups. The first group (26 patients) had major demyelinating features in the motor conduction study but with pure clinical sensory features, such as paraesthesia and distal hypoesthesia (15 patients) or even painful symptoms (3 patients), and paraesthesia and proprioceptive ataxia (11 patients). The second group (10 patients) presented no major motor conduction abnormalities but had altered distal sensory potentials; the diagnosis of CIDP was confirmed on nerve biopsy. In this group, symptoms were predominantly distal, with pain (4 patients), paraesthesia and hypoesthesia (3 patients) with a multifocal pattern in two patients, and proprioceptive ataxia (3 patients). The third group (15 patients) had few abnormalities in the motor conduction study, normal or moderately altered distal sensory potentials and proximal conduction abnormalities on SSEP with elevated CSF protein. The predominant symptoms in this group were proprioceptive ataxia (11 patients), pain (2 patients), and distal diffuse hypoesthesia and paraesthesia (2 patients). Among the 146 patients, a rapid onset was observed in 18% of patients: 18 patients had neuropathy with a time to nadir between 4 and 8 weeks, eight patients presented with a GBS-like onset but with persistent and progressive symptoms associated with numerous features of demyelination on the follow-up electromyogram (EMG) study. Among the 146 patients, 32 patients (22%) had a monoclonal gammopathy of undetermined significance (MGUS), 19 with IgM and 13 with IgG. Six patients had antiganglioside antibodies, two with anti-gd1b antibodies, two with anti-gm2 antibodies, and two with anti-gm1 and anti-gd1b antibodies. Thirty-six patients had a concurrent illness (Table 3), of which lymphoma and diabetes mellitus were the most frequent. Sixteen patients (11%) were not treated because their neurological state was not considered severe enough. Response to treatment could be analyzed in 72 patients, most of whom (58 patients) were recently diagnosed patients. Nine of these patients (13%) were non-responders. The response rate for each therapy was: IVIg 66% (38/58), prednisone 59% 52

4 Table 1. Findings used to diagnose CIDP in 36 patients without major (type I) electrodiagnostic criteria for demyelination. Case Type of symptoms Type of electrodiagnostic criteria (Hughes et al., 2006) CSF protein level (mg/dl) Proximal conduction abnormality on SSEP Positive response to CIDP treatment Demyelinating features on nerve biopsy 1 SM, CN III NP 2 S II 65 NP + NP 3 S III SM II 80 NP NP 5 SM, CN II 50 NP + NP 6 S II 52 + NP 7 S III S III SM II 40 NP + 10 S II S II SM III NP 13 S III 138 NP S III 35 NP SM III 65 NP + 16 SM III SM II 32 NP + NP 18 M III 70 NP + NP 19 SM II 67 NP S III 65 NP S III SM III NP 23 SM III S II 72 NP + NP 25 S II 40 + NP 26 S II 65 NP + NP 27 S III 60 + NT 28 S II 62 + NP 29 S II 87 + NT NP 30 S II NP 31 S II 71 + NT NP 32 S III NP 33 S III S, CN III 75 NP S II 60 + NT NP 36 S II CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; S, sensory; M, motor; SM, sensorimotor; CN, cranial nerve involvement; NP, not performed; NT, not treated; +, present;, absent. Table 2. Characteristics of the 146 CIDP patients. Symptoms and signs % of patients Type: Sensorimotor 55 Pure motor 10 Pure sensory 35 Topography: Symmetrical 84 Upper and lower limbs 64 Lower limbs 23 Upper limbs 13 Cranial nerve 17 Temporal course: Subacute onset 12 Acute onset 9 Progressive onset 79 Relapsing-remitting course 13 Progressive course 87 Table 3. Existence of a concurrent illness in 36/146 CIDP patients (25%). Concurrent illness Number of patients Lymphoma 12 Diabetes mellitus 6 Hepatitis C 4 Lyme disease 2 HIV 2 Herpes virus 1 Solid tumor (with negative antineural 3 antibodies) Lupus 2 Sjögren s syndrome 2 Churg-Strauss syndrome 1 Central nervous system demyelination 3 53

5 Table 4. Strategies that were effective in weaning 21 patients off the treatment. Weaning strategy Number of patients Slowly reducing the 5 prednisone dose Slowly reducing the 4 frequency of IVIg courses Adding plasma exchange to 4 prednisone Adding immunosuppressant 4 (2 azathioprine, 2 drug to prednisone Adding plasma exchange and immunosuppressant drug to prednisone Adding immunosuppressant drug to IVIg mycophenolate mofetil) 2 (1 mycophenolate mofetil, 1 cyclophosphamide) 2 (mycophenolate mofetil) Administration of prednisone 1 mg/kg for 6 weeks, reduction by 5 mg/week down to one-third of the initial dose, followed by a reduction of 1 mg/week. Progressive 1-week increase in the interval between two courses, depending on tolerability. (27/46), PE 62% (13/21) (p = 0.77). Thirteen patients (18% of treated patients) responded to treatment and were able to stop treatment in the short term (<6 months) with no relapse during the follow-up. For the 50 remaining responders, various strategies were applied to try to wean them off the treatment: progressively reducing the prednisone dose or the frequency of IVIg courses, or associating two main CIDP treatments or adding immunosuppressive drugs. With these strategies, 21 patients (29% of treated patients) were able to stop the treatment after more than 12 months (mean of 15 months). The strategies that were effective in enabling these patients to be weaned off the treatment are described in Table 4. The other 29 patients (40% of treated patients) remained treatment-dependent in the long term > 18 months after the introduction of treatment and up to the end of the follow-up, which ranged from 1.8 to 10 years (median: 3 years; mean: 3.5 years).the treatment dependency rate (i.e., the percentage of responders to a treatment who became dependent) for each treatment was as follows: IVIg: 55% (21/38), prednisone: 19% (5/27), PE: 23% (3/13) (p = ). At the end of the follow-up, 40% of patients had a Rankin score < 2 and had no or non-disabling symptoms, 36% had a moderate handicap (Rankin score = 2) and 24% had a severe handicap (Rankin score > 2). Two patients died of respiratory failure following the progression of the neurological deficit. Discussion For most of the patients in our study the diagnosis of definite CIDP was based on clinical criteria (including common and variant forms) and the major electrophysiological criteria (Hughes et al., 2006; Joint Task Force of the EFNS and the PNS, 2006). The high number of patients who met the electrodiagnostic criteria (type I) may be linked to the high number of nerves examined in the electrophysiological study. However, one-fourth of the patients did not meet these criteria and the diagnosis was based on the association of clinical features, minor electrophysiological criteria of demyelination and supportive criteria. We consider that the EFNS/PNS criteria, by proposing a diagnostic category of definite CIDP based chiefly on clinical and supportive criteria, are useful in clinical practice so as to avoid overlooking this type of patient. In this cohort, a nerve biopsy was performed in 13% of patients and allowed the diagnosis in 12%. A decade ago, about two-thirds of patients with suspected CIDP underwent a nerve biopsy (Maisonobe et al., 1996; Lunn et al., 1999), which revealed demyelinating features in about half of these cases. The current trend is therefore to perform fewer nerve biopsies but to increase the diagnostic efficiency of the procedure by using it more selectively, where it is most highly indicated. SSEPs showing proximal conduction abnormalities contributed to the diagnosis in 13% of patients; they may, therefore, be added as a supportive criterion. The CSF examination, performed in 100 CIDP patients, proved useful as a supportive criterion in only 25 patients. A positive response to treatment was used as a supportive criterion in a small minority of patients (4%). Several reports have already highlighted the variety of presentations of CIDP. Our study provides the frequency of each variant of CIDP in a large cohort. We confirm previous findings that the common form occurs in half of all patients (Rotta et al., 2000). However, compared with other series (Dyck et al., 1975; McCombe et al., 1987; Barohn et al., 1989; Maisonobe et al., 1996; Gorson et al., 1997; Bouchard et al., 1999; Rotta et al., 2000; Busby and Donaghy, 2003; Rajabally et al., 2009), we found a higher frequency of the sensory variant and the rapid onset form. We identified three patterns of sensory CIDP. Half of the patients with the sensory variant had clinical sensory symptoms associated with demyelinating features on the motor conduction study, thus facilitating the diagnosis of CIDP (Oh et al., 1992; Uncini et al., 1999; van Dijk et al., 1999). One-fourth of the patients with the sensory variant had a sensory neuropathy with an axonal-like electrophysiological pattern (Vallat et al., 2003; Chin et al., 2004), and another one-fourth had a presentation suggesting a chronic immune sensory polyradiculopathy, a recently described entity (Sinnreich et al., 2004). Thus, in half of the patients with the sensory variant the motor conduction study did not show any major 54

6 demyelinating features, a situation that may have led to an underestimation of the sensory form in other series. About 18% of the patients in our study had a rapid onset. A variant of CIDP, called subacute inflammatory demyelinating polyradiculoneuropathy, has already been reported and is defined as a demyelinating neuropathy with time to nadir between 4 and 12 weeks, without relapse during the follow-up, corresponding to a monophasic entity with subacute onset (Hughes et al., 1992; Oh et al., 2003). Onlyfive of our patients corresponded to this entity. Indeed, 13 patients had a subacute onset but with spontaneous relapses (two patients) or relapses linked to a change in treatment. Eight of our patients presented a GBS-like onset. This form has already been described (Mori et al., 2002). These patients showed characteristic features of GBS in an acute phase. In some cases they partially recovered after the initial treatment, but a few months later their condition worsened, usually when they were in the rehabilitation unit. The EMG study performed at that time showed more marked demyelinating features. It is important to identify this variant of CIDP, because prednisone, a treatment not normally used when GBS has been diagnosed, can be effective (Mori et al., 2002). A few of our patients had a relapsing-remitting form. The definition of relapse differs from one study to another. As many patients are treated, thereby altering the natural course of the disease, we have chosen a restrictive definition to exclude relapses linked to a tapering of treatment. This may explain the low percentage of this variant in our study compared to other studies (Dyck et al., 1975; McCombe et al., 1987; Barohn et al., 1989; Maisonobe et al., 1996; Rajabally et al., 2009). A concurrent illness was found in one-fourth of our patients. These systemic diseases did not appear to be more than expected in a series of about 150 people attending hospital, with the possible exception of the increased frequency of lymphoma. This fact may be the consequence of a referral bias as we work closely with our hospital s hematology department. We recently reported the high frequency of CIDP in lymphoma and indicated situations in which patients with CIDP should be screened for lymphoma (Viala et al., 2008). Systemic investigations are recommended when either a severe and rapid course, a poor response to therapy with an early axonal loss, or the presence of systemic abnormalities or the presence of monoclonal gammopathy are noted in the course of CIDP. Is CIDP a severe illness? In our series, 11% of patients were not treated and may have had minimal CIDP (Uncini et al., 1996). At the end of the study, most patients had a good prognosis, since 76% of patients had a low Rankin score and were able to work and walk. However, one-fourth of the patients had a severe form. The retrospective nature of the assessment and the use of a scale with low sensitivity prevented us from making any categorical statements about treatment responses. Nevertheless, our study seems to indicate that the current issue with CIDP is not so much the efficacy of treatments as the high frequency of dependence on treatment. Indeed, most of the patients (87%) responded to treatment, with a similar efficacy of IVIg and prednisone, but 79% of our responder patients were treatment-dependent. With weaning strategies, the proportion of treatmentdependent responders fell to 46%, most of whom were receiving IVIg. In conclusion, we found that variant forms of CIDP were more frequent than expected. We also found that 25% of CIDP patients did not meet the main electrophysiological criteria for demyelination but had definite CIDP using diagnostic categories based on supplementary laboratory tools. 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