2010--EFNS副蛋白血症性脱髓鞘性神经病

Journal of the Peripheral Nervous System 15:185–195 (2010) EFNS/PNS PDN GUIDELINE European Federation of Neurological Societies/Peripheral Nerve Society Guideline* on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision Joint Task Force of the EFNS and the PNS† Abstract The aim of this guideline is to update the 2006 EFNS/PNS guideline on management of patients with a demyelinating neuropathy and a paraprotein (paraproteinemic demyelinating neuropathy [PDN]) by review of evidence and expert consensus. In the absence of adequate evidence, the panel agreed on good practice points: (1) patients with PDN should be investigated for a malignant plasma cell dyscrasia; (2) a monoclonal gammopathy of undetermined significance is more likely to be causing the neuropathy if it is immunoglobulin (Ig)M, anti-neural antibodies are present, and the clinical phenotype is chronic distal sensory neuropathy; (3) patients with IgM PDN usually have predominantly distal sensory impairment, prolonged distal motor latencies, and often anti-myelin-associated glycoprotein antibodies; (4) IgM PDN may respond to immunomodulatory therapies. Their potential benefit should be balanced against possible side effects and the usually slow disease progression; (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy; and (6) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes syndrome is a multi-system malignant PDN. Key words: demyelinating, guidelines, MAG, monoclonal gammopathy, neuropathy, paraprotein, POEMS, treatment Address correspondence to: Dr. Robert Hadden, PhD, FRCP, Department of Neurology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel: +44-20-3299-8343; Fax: +44-20-3299- 8358; E-mail: robert.hadden@nhs.net *Anticipated date for updating this guideline: Not later than October 2013. †Membership of Task Force: Robert D. M. Hadden, UK; Eduardo Nobile-Orazio, Italy; Claudia L. Sommer, Germany; Angelika F. Hahn, Canada; Isabel Illa, Spain; Enrica Morra, Italy; John D. Pollard, Australia; Michael P. T. Lunn, UK; Pierre Bouche, France; David R. Cornblath, USA; Eileen Evers, UK; Carol Lee Koski, USA; Jean-Marc Le´ger, France; Peter Van den Bergh, Belgium; Pieter A. van Doorn, The Netherlands; Ivo N. van Schaik, The Netherlands. Objectives Our objective was to construct clinically use- ful guidelines for the diagnosis, investigation, and treatment of patients with both a demyelinating neu- ropathy and a paraprotein (paraproteinemic demyeli- nating neuropathy [PDN]), based on the available evidence and, where evidence was not available, consensus. This is the first revision of the original 2006 guideline (Joint Task Force of the EFNS and the PNS, 2006). © 2010 Peripheral Nerve Society 185 www.medlive.cn EFNS/PNS PDN Guideline Journal of the Peripheral Nervous System 15:185–195 (2010) Background The neuropathies associated with paraproteins are complex and difficult to classify because of hetero- geneity in the clinical and electrophysiological features of the neuropathy, the class, immunoreactivity and pathogenicity of the paraprotein, and the malignancy of the underlying plasma cell dyscrasia (Yeung et al., 1991; Ropper and Gorson, 1998). In the absence of an agreed diagnostic classification, specific diagnostic criteria are available for only a few of these disor- ders, and treatment trials are therefore difficult to interpret. Both demyelinating and axonal neuropathies may be associated with paraproteins, but this guideline concentrates on the demyelinating neuropathies. Many patients with PDN have a neuropathy that is indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and there is no consensus as to whether these should be considered as the same disease or as different diseases. Paraproteinemic axonal neuropathies are mentioned briefly in the section on Other Neuropathy Syndromes Associated with Paraproteinemia. As both paraproteins and neuropathies are common, it often remains uncertain whether the paraprotein is causing the neuropathy or is coincidental. Search Strategy We searched MEDLINE and the Cochrane Library on May 1, 2009 for articles on (‘paraprotein(a)emic demyelinating neuropathy’ AND [‘diagnosis’ OR ‘treatment’ OR ‘guideline’]) and used the personal databases of Task Force members. Methods for Reaching Consensus Evidence was classified as Class I–IV and recommendations as Level A–C (Brainin et al., 2004). When only Class IV evidence was available but consensus could be reached, the Task Force has offered advice as good practice points. The original 2006 guideline (Joint Task Force of the EFNS and the PNS, 2006) was revised iteratively until unanimous consensus was reached. Results Any diagnostic classification of PDN must take account of the dimensions of clinical phenotype, immunoglobulin (Ig) class, presence of malignancy, antibodies to myelin-associated glycoprotein (MAG), electrophysiological phenotype, and causal relationship of the paraprotein to the neuropathy. There is no consensus as to which should take precedence in classification. This guideline distinguishes IgM from IgG and IgA PDN because IgM PDN tends to have a typical clinical phenotype, pathogenic antibodies, a causal relationship between paraprotein and neuropathy, and a different response to treatment. Nevertheless, there is a significant overlap between the clinical and electrophysiological features of the neuropathy with different types of paraprotein. Investigation and Classification of the Paraprotein Background While some paraproteins (monoclonal gammopa- thy, monoclonal Ig) are detected by standard serum protein electrophoresis (SPEP), both serum immuno- electrophoresis (SIEP) and serum immunofixation elec- trophoresis (SIFE) are more sensitive techniques which detect lower paraprotein concentrations (Vrethem et al., 1993; Keren, 1999). Heavy (IgM, IgG, or IgA) and light chain (kappa or lambda) classes should be identified. A paraprotein indicates an underlying clonal B-cell expansion, usually in bone marrow, which may be malignant (and may itself require treatment) or a monoclonal gammopathy of undetermined signifi- cance (MGUS) (Table 1) (International Myeloma Work- ing Group, 2003). Most bone lesions causing neuropathy are sclerotic or mixed lytic–sclerotic, most commonly in the vertebral bones or pelvis. Although there is limited evidence on imaging of sclerotic lesions, skeletal survey (or computed tomography [CT]), magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT are complementary imaging modalities and more than one may be needed if the index of suspicion is high (Dimopoulos et al., 2009). Table 1. Classification of hematological conditions with a paraprotein. I. Malignant monoclonal gammopathies 1. Multiple myeloma (overt, asymptomatic [smoldering], non-secretory, or osteosclerotic) 2. Plasmacytoma (solitary, extramedullary, multiple solitary) 3. Malignant lymphoproliferative disease: a. Waldenstro¨m’s macroglobulinemia b. Malignant lymphoma c. Chronic lymphocytic leukemia 4. Heavy chain disease 5. Primary amyloidosis (AL) (with or without myeloma) II. Monoclonal gammopathy of undetermined significance 186 www.medlive.cn EFNS/PNS PDN Guideline Journal of the Peripheral Nervous System 15:185–195 (2010) Table 2. Investigation of a paraprotein. The following should be considered in patients with a paraprotein: 1. Serum immunofixation electrophoresis 2. Physical examination for peripheral lymphadenopathy, hepatosplenomegaly, macroglossia, and signs of POEMS syndrome (see section on the Other Neuropathy Syndromes Associated with Paraproteinemia) 3. Full blood count, renal and liver function, calcium, phosphate, erythrocyte sedimentation rate, C-reactive protein, uric acid, beta 2-microglobulin, lactate dehydrogenase, rheumatoid factor, and serum cryoglobulins 4. Total IgG, IgA, and IgM concentrations 5. Serum free light chains 6. Random urine collection for the detection of Bence-Jones protein (free light chains), and, if positive, 24-h urine collection for protein quantification 7. Radiographic X-ray skeletal survey (including skull, pelvis, spine, ribs, and long bones) to look for lytic or sclerotic lesions. Part or all of this may be replaced by CT, which is more sensitive but involves greater radiation exposure except where low-dose whole body CT is available. If the index of suspicion is high, CT and/or MRI of the spine, pelvis, or whole body, and perhaps whole body FDG-PET/CT, may be considered 8. Ultrasound or CT of chest, abdomen, and pelvis (to detect lymphadenopathy, hepatosplenomegaly, or malignancy) 9. Serum VEGF levels if POEMS syndrome suspected 10. Consultation with a hematologist and consideration of bone marrow examination CT, computed tomography; FDG, F18-fluorodeoxyglucose; Ig, immunoglobulin; MRI, magnetic resonance imaging; PET, positron emission tomography; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes; VEGF, vascular endothelial growth factor. Recommended investigations Table 2 suggests investigations to be considered in patients with a paraprotein. SIFE should be performed in patients with a known paraprotein to define the heavy and light chain types, in patients with acquired demyelinating neuropathies, and in patients in whom a paraprotein is suspected but not detected by SPEP. Definition of MGUS The definition of IgM MGUS is different from that for IgG and IgA MGUS (Table 3). Patients with IgM MGUS have alternatively been classified as either ‘IgM-related disorders’ if they have clinical features attributable to the paraprotein (such as neuropathy), or ‘asymptomatic IgM monoclonal gammopathy’ if not (Owen et al., 2003). Typical Syndromes of PDN The most common types of PDN are those with demyelinating neuropathy and MGUS, without non- neurological symptoms. The neuropathy is defined as demyelinating if it satisfies electrophysiological criteria for CIDP (Joint Task Force of the EFNS and the PNS, 2010). If there are subtle features of demyelination not meeting these criteria, further investigations should be considered to clarify the possible pathogenic link between the paraprotein and the neuropathy (see section on the Cerebrospinal Fluid and Nerve Biopsy). IgM paraproteinemic demyelinating neuropathy Clinical phenotype Most patients with IgM PDN have predominantly distal, chronic (duration over 6 months), slowly pro- gressive, symmetric, predominantly sensory impair- ment, with ataxia, relatively mild or no weakness, and often tremor (Class IV evidence) (Yeung et al., 1991; Maisonobe et al., 1996; Chassande et al., 1998; Simovic et al., 1998; Capasso et al., 2002; Magy et al., 2003). This phenotype is most strongly associated with IgM anti-MAG antibodies. Some patients have more prominent ataxia with impairment predominantly of vibration and joint position sense. However, the clinical features do not correlate exactly with the paraprotein type: a few patients with IgM PDN have proximal weak- ness more typical of IgG/IgA PDN, and some CIDP patients have distal weakness without a paraprotein (Katz et al., 2000). Electrophysiology Patients with IgM PDN may meet the definite electrophysiological criteria for CIDP (Joint Task Force of the EFNS and the PNS, 2010). They may also have additional specific electrophysiological features in one or more nerves which help to distinguish from CIDP, typically uniform symmetrical, and predominantly distal reduced conduction velocity (terminal latency index <0.25) without conduction block (Table 4, adapted Table 3. Definition of MGUS. 1. IgM MGUS is defined by the presence of both of the following: a. No lymphoplasmacytic infiltration on bone marrow biopsy, or equivocal infiltration with negative phenotypic studies b. No signs or symptoms suggesting tumor infiltration (e.g., constitutional symptoms, hyperviscosity syndrome, organomegaly) 2. IgG or IgA MGUS is defined by the presence of all of the following: a. Serum monoclonal component ≤30 g/l b. Bence-Jones proteinuria ≤1 g/24 h c. No lytic or sclerotic lesions in bone d. No anemia, hypercalcemia, or chronic renal insufficiency e. Bone marrow plasma cell infiltration <10% MGUS, monoclonal gammopathy of undetermined significance. 187 www.medlive.cn EFNS/PNS PDN Guideline Journal of the Peripheral Nervous System 15:185–195 (2010) Table 4. Electrophysiological features associated with IgM PDN. 1. Uniform symmetrical reduction of conduction velocities; more severe sensory than motor involvement 2. Disproportionately prolonged DML. This may be quantified as terminal latency index (defined as distal distance/[motor conduction velocity × DML]; i.e., ‘distal velocity’/‘intermediate segment velocity’) ≤0.25 3. Absent sural potential (i.e., less likely to have the ‘abnormal median, normal sural’ sensory action potential pattern) 4. Partial motor conduction block (i.e., proximal/distal CMAP amplitude ratio <0.5) and marked distal CMAP dispersion are very rare CMAP, compound muscle action potential; DML, distal motor latency; PDN, paraproteinemic demyelinating neuropathy. from Kaku et al., 1994; Notermans et al., 2000; Capasso et al., 2002). Antibodies to MAG and other neural antigens Almost 50% of patients with IgM PDN have high titers of anti-MAG IgM antibodies (Nobile-Orazio et al., 1994), more commonly associated with kappa than lambda light chains, and this is the best defined syn- drome of PDN (Van den Berg et al., 1996). Weakly positive anti-MAG antibodies are less specific and may occur in the absence of neuropathy. Testing for antibodies to MAG should be consid- ered in all patients with IgM PDN (Nobile-Orazio et al., 2008). If negative, then testing for IgM antibodies against other neural antigens, including gangliosides GQ1b, GM1, GD1a and GD1b, and SGPG, may be con- sidered. The presence of these antibodies increases the probability of, but does not prove, a pathogenetic link between the paraprotein and the neuropathy. Their diagnostic relevance is not defined. IgG or IgA paraproteinemic demyelinating neuropathy Patients with IgG or IgA PDN usually have both proximal and distal weakness, with motor and sensory impairment, indistinguishable clinically and electro- physiologically from typical CIDP (Joint Task Force of the EFNS and the PNS, 2010). They usually have more rapid progression than IgM PDN (Simovic et al., 1998; Di Troia et al., 1999; Magy et al., 2003). How- ever, a minority of patients with IgG or IgA PDN has the clinical and electrophysiological phenotype typical of IgM PDN. In patients with IgG or IgA paraprotein, no spe- cific antibody has been consistently associated with demyelinating neuropathy, and therefore there is no need to test for serum antibodies to known neural epitopes in routine practice. Other Neuropathy Syndromes Associated with Paraproteinemia This section briefly discusses other types of neu- ropathy associated with a paraprotein, including those with hematological malignancy, systemic symptoms, or axonal electrophysiology, although these are not part of the main guidelines and not discussed in detail. POEMS syndrome POEMS (Polyneuropathy, Organomegaly, Endo- crinopathy, Monoclonal gammopathy and Skin chan- ges) syndrome usually has an underlying osteosclerotic myeloma, with IgA or IgG lambda paraprotein, or is sometimes associated with Castleman disease. POEMS neuropathy has clinical features similar to severe CIDP. Many patients are initially thought to have CIDP or ordinary PDN, until POEMS is suggested by the presence of systemic features. Major diagnostic criteria are polyneuropathy, monoclonal plasma cell proliferative disorder (almost always lambda), and sclerotic bone lesions or Castleman disease or raised vascular endothelial growth factor (VEGF) levels (Dispenzieri, 2007). Minor diagnostic criteria are organomegaly (hepatosplenomegaly or lymphadenopathy); extravascular volume overload (edema, pleural effusion, or ascites); endocrinopathy; skin changes (hypertrichosis, hyperpigmentation, plethora, acrocyanosis, flushing, dermal glomeruloid hemangiomata, and white nails); papilledema; or thrombocytosis/polycythemia (Dispenzieri, 2007). There is no specific diagnostic test for POEMS, so if it is suspected then the diagnostic criteria should be sought by detailed clinical examination and appropriate investigations (Table 2). Serum or plasma VEGF levels are usually markedly raised in POEMS, and are normal or only slightly raised in CIDP or PDN (Watanabe et al., 1998), so are a useful supportive diagnostic test. Nerve biopsy may show uncompacted myelin lamellae (Vital et al., 2003). Electrophysiology often shows a mixed demyeli- nating and axonal picture (Kelly, 1983). Features that may help to distinguish POEMS from CIDP include reduced motor nerve conduction velocities more marked in intermediate than distal nerve segments (increased terminal latency index 0.35–0.6, the oppo- site of IgM PDN); rarity of conduction block; and severe length-dependent axonal loss (Sung et al., 2002; Min et al., 2005). Waldenstro¨m’s macroglobulinemia Waldenstro¨m’s macroglobulinemia is defined by the presence of an IgM (usually kappa) paraprotein (irrespective of concentration) and a bone marrow 188 www.medlive.cn EFNS/PNS PDN Guideline Journal of the Peripheral Nervous System 15:185–195 (2010) biopsy showing infiltration by lymphoplasmacytic lymphoma with a predominantly intertrabecular pattern, supported by appropriate immunophenotypic studies (Owen, 2003). The associated neuropathy is clinically heterogeneous, but patients with indolent or asymptomatic Waldenstro¨m’s macroglobulinemia may have anti-MAG reactivity and clinical features of IgM anti-MAG neuropathy (Baldini et al., 1994). CANOMAD syndrome The syndrome of Chronic Ataxic Neuropathy with Ophthalmoplegia, IgM Monoclonal gammopathy, cold Agglutinins, and Disialoganglioside (IgM anti- ganglioside GD1b/GQ1b) antibodies (CANOMAD) is a rare neuropathy similar to chronic Fisher syndrome, with mixed demyelinating and axonal electrophysiology (Willison et al., 2001). Other neuropathies with a paraprotein Axonal neuropathy is often present in patients with MGUS, but the pathogenesis and causal relationships vary, and this will not be considered further in these guidelines. A few patients with cryoglobulinemia (Vital et al., 2000) or primary (AL) amyloidosis (Vital et al., 2004) have demyelinating neuropathy, although far more have axonal neuropathy. AL-amyloidosis should be suspected in the presence of prominent neuropathic pain or dysautonomia, and may be demonstrated by biopsy of nerve or other tissues. Chronic axonal polyneuropathy with IgG MGUS, without symptoms or signs of amyloidosis, is usually indistinguishable from chronic idiopathic axonal polyneuropathy. In patients with lytic multiple myeloma (usually associated with IgA or IgG kappa or lambda parapro- tein) neuropathy may be caused by heterogeneous mechanisms, including amyloidosis, metabolic- and drug-induced insults, and cord or root compression due to vertebral collapse from lytic lesions (Kelly et al., 1981). Subacute weakness similar to Guillain-Barre´ syndrome may be caused by extensive infiltration of nerves or roots by lymphoma or leukemia (Diaz-Arrastia et al., 1992). Multi focal motor neuropathy is occasionally associated with an IgM MGUS, which does not seem to affect the behavior of the disease (Nobile-Orazio et al., 2005). Is the Paraprotein Causing the Neuropathy? A causal relationship of the paraprotein to the neuropathy is more likely with an IgM than an IgG or IgA MGUS. There is still no expert consensus as Table 5. Causal relat