Pain in Acquired Inflammatory Demyelinating Polyneuropathies Siddarth Thakura, Robert H

Topical Review

Pain in acquired inflammatory demyelinating polyneuropathies Siddarth Thakura, Robert H. Dworkinb,c,d,*, Roy Freemane, Kenneth C. Gorsonf, David N. Herrmanng

1. Introduction absent reflexes, and cytoalbuminological dissociation on cere- 24 Acquired inflammatory demyelinating neuropathies are a hetero- brospinal fluid analysis. In approximately two-thirds of cases, geneous group of autoimmune conditions that share common GBS is preceded by an upper respiratory or gastrointestinal tract infection.82 The condition typically reaches a nadir within 4 sensory, motor, autonomic, clinical, laboratory, and electro- 32,82 diagnostic features.16 They exist in both acute and chronic forms, weeks. It can lead to respiratory muscle compromise, with up to one-third of patients requiring mechanical ventilation.64,84 with variable levels of cell-mediated and humoral immune ́ dysfunction.77 Pain is an increasingly recognized problem Guillain–Barre syndrome exists as a clinical spectrum of in many of these conditions.8,26,39,47,69 This topical review syndromes (Table 1e, available online as Supplemental Digital describes the types of pain associated with commonly encoun- Content at http://links.lww.com/PAIN/A250) with acute inflammatory demyelinating polyneuropathy being the most common tered acquired inflammatory demyelinating polyneuropathies 82 (Table 1; additional conditions presented in electronic supple- subtype in Western countries. Intravenous immunoglobulin ment Table 1e, available online as Supplemental Digital Content (IVIg) and plasma exchange hasten recovery and are equally at http://links.lww.com/PAIN/A250). efficacious. Pain occurs throughout the spectrum of GBS from mild to severely affected patients.69 Although Guillain, Barré, and Strohl 2. Methods described the presence of pain in 1 of 2 patients in their seminal We conducted a literature search using PubMed in November paper, it often is overlooked, as attention is directed to the rapid ́ progression of weakness, management of ventilatory failure, and 2015 for the terms “pain” and “Guillain Barre syndrome,” “acute 32,69 inflammatory demyelinating polyneuropathy,” “chronic inflamma- other medical complications that arise in critically ill patients. tory demyelinating polyneuropathy,” “POEMS,” and “paraprotein However, pain is present in up to 92% of patients with GBS,23,47,52,55,57,69 and if not recognized as a presenting associated chronic demyelinating polyneuropathy.” The search 19,52,72 identified 462 articles; 89 were considered relevant for this review. symptom, it can lead to delays in diagnosis and pain management.24,82

3. Results 3.1.1. Acute pain in early Guillain–Barrésyndrome 3.1. Pain in Guillain–Barrésyndrome Acute pain is often the first symptom experienced by patients with 69,71 ́ GBS in the 2 weeks preceding the onset of weakness. At Guillain–Barre syndrome (GBS) is the most common cause of 47,52 acute neuromuscular paralysis in the postpolio era, with an initial evaluation, pain is reported in up to 86% of patients. annual incidence of 1.1 to 1.8 per 100,000 people world- Pain was observed in 22% to 92% of patients during their illness in Table 2 wide.49,83 It is characterized by rapidly progressive symmetric the studies summarized in , with the differences likely due weakness, acral paresthesias and sensory loss, decreased or to variable approaches to the assessment of pain and patient selection. The pain is usually moderate to severe and occurs in more than Sponsorships or competing interests that may be relevant to content are disclosed one location.4,59,69 The 2 most commonly described patterns at the end of this article. involve deep aching pain in the low back with radiation to the buttock a Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, b c d and legs, and bilateral lower extremity pain and paresthesias Houston, TX, USA, Departments of Anesthesiology, Neurology, and, Psychiatry, 23,47,52,66,72,79 Center for Human Experimental Therapeutics, University of Rochester School of described as burning, tingling, and shooting. Pain can Medicine and Dentistry, Rochester, NY, USA, e Department of Neurology, Beth Israel increase at night and is exacerbated by pressure and move- Deaconess Medical Center, Harvard Medical School, Boston, MA, USA, f Department ment.47,79 ApositiveLas`egue sign (straight leg raise) may be present of Neurology, St. Elizabeth’s Medical Center, Tufts University School of Medicine, on neurologic examination,52,66,72 as well as prominent nerve root Boston MA, USA, g Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA enhancement on magnetic resonance imaging, which has been observed in adult and pediatric GBS patients with pain.29,86 *Corresponding author. Address: Department of Anesthesiology, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA. Tel.: 11 585 275 8214; fax: 11 585 244 The pain associated with GBS is likely multifactorial and 7271. E-mail address: [email protected] (R.H. Dworkin). primarily neuropathic given the aberrant immune-mediated Supplemental digital content is available for this article. Direct URL citations appear damage to peripheral nerves. There is associated nerve in the printed text and are provided in the HTML and PDF versions of this article on inflammation, and to a lesser degree, soft tissue inflammation, the journal’s Web site (www.painjournalonline.com). that also contributes.52,71 Involvement of the nervi nervorum of PAIN 157 (2016) 1887–1894 affected nerve roots may explain the low back and radicular leg © 2016 International Association for the Study of Pain pain.29,69 When the dorsal primary rami are affected, a deep 52 http://dx.doi.org/10.1097/j.pain.0000000000000539 muscular pain in paravertebral regions may occur. The role of

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Table 1 Overview of acquired inflammatory demyelinating neuropathies in which pain can be an important component of the clinical presentation. Neuropathy Clinical characteristics and Laboratory characteristics Electrodiagnostic Treatment* details characteristics Guillain–Barrésyndrome10,31,82 Classically weakness occurs in Elevated CSF protein level, Demyelination of sensory and IVIg and PE reduce the severity of a symmetrical, ascending pattern without a cellular response motor nerves in upper and lower illness and hasten recovery. from distal to proximal muscles, (cytoalbuminological limbs, such as prolonged or Corticosteroids are not effective. with facial weakness in half and dissociation). CSF studies may be absent F-wave latencies, Supportive care with oculomotor nerve involvement in normal for few days after prolonged distal motor latencies, multidisciplinary team about 20%. Antecedent respiratory symptom onset, become slowing of conduction velocities or management of pain, autonomic or gastrointestinal illness in two- abnormal with disease focal motor nerve conduction instability, respiratory insufficiency, thirds of patients. Tendon reflexes progression. block; sural sensory potentials DVT prevention, and rehabilitation. are decreased or absent. Pain and Elevated liver enzymes, creatine often spared. paresthesias precede weakness in kinase, and erythrocyte the majority of cases. Ventilatory sedimentation rate also may be failure requiring mechanical seen. ventilation occurs in up to 30% of patients. Nadir of symptoms occurs in ,4 weeks. Residual weakness and fatigue may persist. Up to 20% of patients are unable to ambulate after 6 months, mortality is approximately 5%. Chronic inflammatory demyelinating neuropathy subtypes9,21,68 CIDP Typically slowly progressive, Cytoalbuminological dissociation Demyelination of motor and IVIg, PE, and corticosteroids have symmetric, proximal, and distal in CSF. sensory nerves with prolonged F- all demonstrated efficacy. They weakness, motor .sensory waves, slowed conduction can be used alone or in involvement, with diminished or velocities, prolonged latencies, combination and maintenance absent reflexes. Symptoms temporal dispersion and therapy is needed for most progress for .8 weeks, may be conduction block. patients. stepwise or recurrent. Cranial nerve deficits, respiratory compromise, and dysautonomia are uncommon in contrast to GBS. Multifocal motor neuropathy Slowly progressive, asymmetric, IgM GM1 antibodies are detected Greater than 50% conduction Intermittent IVIg helps to improve pure motor impairment, distal . in 50% to 80% of cases. block in 2 or more motor nerves strength, can consider combined proximal. Commonly affects with spared sensory responses. PE and pulsed cyclophosphamide branches of brachial plexus, in severely affected patients causing focal muscle weakness refractory to IVIg. No benefit from and atrophy in distribution of an corticosteroids. individual motor nerve. Arms are affected earlier and more severely than legs. Reflexes may be decreased in a patchy distribution. Muscle cramping and fasciculations may be seen. Pain is uncommon but can be observed in advanced cases, more nociceptive than neuropathic in character. Paraprotein-associated chronic demyelinating polyneuropathies9,17,56 IgM anti-MAG neuropathy Insidious, slowly progressive, IgM monoclonal gammopathy Sensory and motor nerve Poor response to sensory .motor polyneuropathy detected on serum involvement, diffusely absent or immunosuppressants, rituximab with considerable ataxia, tremor. immunofixation, anti-MAG markedly reduced sensory nerve has been reported to be effective antibodies. action potentials, prolonged distal in selected cases but not motor latencies and conduction supported in randomized block is rare. controlled trials. (continued on next page)

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Table 1 (continued) Neuropathy Clinical characteristics and Laboratory characteristics Electrodiagnostic Treatment* details characteristics Polyneuropathy, Symmetric polyneuropathy Clonal plasma cell disorder, IgG or Sensory and motor nerve Direct therapy at underlying organomegaly, (similar to CIDP), associated with IgA gammopathy, elevated VEGF, involvement, with demyelinating plasma cell disorder; radiation endocrinopathy, M- osteosclerotic myeloma of thrombocytosis. and axonal features, segmental therapy for localized disease, protein, skin changes subacute onset, positive sensory Cytoalbuminological dissociation conduction slowing, rarely systemic chemotherapy and stem syndrome (POEMS) symptoms with slow development in CSF. conduction block and temporal cell transplant for more diffuse of severe distal weakness. Also dispersion. disease. organomegaly, endocrinopathy, skin changes, papilledema, extravascular fluid overload, abnormal pulmonary function tests are detected. * Supportive care for all comorbid symptoms is imperative. CIDP, chronic inflammatory demyelinating polyneuropathy; CSF, cerebrospinal fluid; DVT, deep venous thrombosis; IVIg, intravenous immunoglobulin; MAG, myelin-associated glycoprotein; PE, plasma exchange; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; VEGF, vascular endothelial growth factor.

inflammation is supported by pathological findings on nerve suggesting that novel treatments developed for other conditions biopsy demonstrating lymphocyte and marcrophage infiltration of also may be beneficial for pain in GBS.47 However, there has been peripheral nerves.4,51,59 The acute neuropathic pain may be limited research on the treatment of chronic pain in patients caused by damage to small myelinated and unmyelinated with GBS. nociceptive fibers.47 Ruts et al.70 demonstrated decreased Patients suffering from chronic pain after GBS also may have unmyelinated fiber density in distal leg skin biopsies from patients non-neuropathic pain. Residual weakness may lead to changes with acute neuropathic pain compared with those without. There in muscles, soft tissues, and joints, causing nociceptive are limited data examining the nature of pain related to immobility pain.37,38,50 Long-term studies have shown that many patients in critically ill patients. Other types of pain include myalgic limb recovering from GBS experienced substantial muscle aches, pain, compression neuropathies, stabbing interscapular pain, cramps, and arthralgia.6,23 Similar to many other chronic arthralgia, visceral pain, and dysautonomic headache, suggest- neuropathic pain conditions, pain in GBS can be “mixed,” with ing both neuropathic and nociceptive mechanisms.38,52,59,69 both nociceptive and neuropathic components.5,80 The management of acute pain inGBSisoftensuboptimal.67,71,72 Pain negatively impacts the quality of life of individuals For example, 1 study found that 86% of GBS patients with pain recovering from GBS.15,38 It has been associated with increased continued to suffer moderate-to-severe pain despite the use of symptoms of weakness, fatigue, disability, and psychosocial antiepileptic drugs, paracetamol/acetaminophen, nonsteroidal anti- distress.37,63,69 In 1 study of GBS patients with pain for more than inflammatory drugs, and opioid analgesics.69 Variable success has 1 year, 22% met criteria for clinical depression.38 been reported with opioids,1,25,52,66,67 corticosteroids,66,71,72 nonsteroidal anti-inflammatory drugs,59 and antiepileptic drugs such as 57,58 38,58,79,87 3.2. Pain in chronic inflammatory demyelinating gabapentin and carbamazepine ; there are limited data, polyneuropathy however, regarding response rates, and a Cochrane review concluded that there was insufficient evidence supporting any Chronic inflammatory demyelinating polyneuropathy (CIDP) is an specific pharmacological intervention.46 Opioid analgesics must be acquired disease of the peripheral nervous system occurring in used cautiously in patients with GBS because of the potential for 1.9 to 8.9 per 100,000 individuals worldwide.44,62 CIDP and GBS altered cognition, reduced respiratory drive, and worsening of share many clinical features, including generalized weakness, impaired gastrointestinal motility in those with autonomic dysfunc- acral sensory loss, and generalized hypo- or areflexia. Electro- tion, although these complications can be minimized with epidural diagnostic testing shows features of an acquired demyelinating opioid administration.1,25,67 The importance of environmental polyradiculoneuropathy, and the cerebrospinal fluid protein level modifications, such as proper positioning and turning, splinting, is elevated in most cases. CIDP is distinguished from GBS by pressure relief at sites of potential nerve compression, physical a progressive or relapsing course for 8 or more weeks, and cranial therapy, and other conservative modalities, should not be nerve and respiratory failure are less common.27,68,82 Pain is not overlooked.37,50,59 considered a cardinal symptom of CIDP, but when present it may cause substantial disability in patients.8 Current diagnostic criteria for CIDP81 do not include pain, 3.1.2. Chronic pain in Guillain–Barrésyndrome which has not been emphasized in much of the contemporary Less is known about chronic pain in GBS because most studies literature.12,14,40 However, pain has been arecognizedpartof have only evaluated acute pain in early GBS.69 The reported CIDP, and was reported in 15% to 17% of patients with CIDP in frequency of chronic pain in GBS has ranged between 36% and the landmark paper by Dyck et al.20 The frequency of pain 71% (Table 1) and the reported characteristics of chronic and acute symptoms in patients with CIDP ranges between 7% and 72% pain have been similar.47 Patients with GBS who were severely (Table 2), with the large variability among studies likely affected and had sensory disturbances were more likely to suffer explained by different assessment methods, study designs, chronic pain.47,69,88 Hyperalgesia and allodynia have been and patient selection. In addition, it is possible that some observed and may reflect central sensitization,47,51 and it has been studies included patients with atypical CIDP who do not fulfill suggested that small fiber dysfunction may account for neuropathic diagnostic criteria or included patients who were misdiagnosed pain in a proportion of patients.47,73 Therefore, pain mechanisms in and had another cause of neuropathy.3 Pain is often moderate GBS may be similar to those in other chronic polyneuropathies, to severe and commonly located in the lower limbs, hands, and

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Table 2 Studies of pain in Guillain–Barrésyndrome (GBS), chronic inflammatory demyelinating polyneuropathy, and paraproteinemic neuropathy. Authors Study design Patients Frequency of pain Pain severity* Other clinical details GBS—acute phase pain, including pain at presentation Dubey et al.19 Retrospective 69 15/69 (22%) Presence of pain associated with delay in diagnosis of GBS Martinez et al.47 Prospective 30 21/30 (70%) Moderate 40%, severe 13%† DN4 with NP 5 6.8; DN4 without NP 5 1.1 Ruts et al.69 Prospective 152 100/152 (66%) Mild 9%, moderate 36%, severe Location of pain: extremities .low 50%, unknown 5%‡ back .interscapular 5 neck .trunk Ruts et al.71 Randomized 223 123/223 (55%) Mild 33%, moderate 28%, severe Description of pain: backache . control trial§ 39%‖ interscapular pain .muscle pain/ cramps .painful par/dysesthesias 5 radicular pain .other .joint pain 5 visceral pain Korinthenberg et al.41 Prospective 95 75/95 (79%) Severe 15%, very severe 18%{ Pediatric patients severity of pain correlated with severity of motor involvement Forsberg et al.23 Prospective 42 30/42 (71%) Wilmshurst et al.86 Retrospective 27 19/27 (70%) Severe 46% Pediatric patients Description of pain: lower back pain with or without radiation .muscle pain .neck pain 5 joint pain Nicholas et al.55 Retrospective 24 22/24 (92%) Location of pain: back pain, shoulder and upper limb pain, buttock and lower limb pain Moulin et al.52 Prospective 55 45/55 (89%) Mean VAS 7 5 47% Description/location of pain: back and leg pain .dysesthetic extremity pain .myalgic-rheumatic extremity pain .visceral pain .pressure palsy .dysautonomic headache Gorson et al.29 Prospective 24 14/24 (58%) Mild 36%, moderate or severe 64%# Description/location of pain: low back pain .radicular leg pain GBS—chronic pain Witsch et al.88 Retrospective 110 40/110 (36%) .12 months postdiagnosis Martinez et al.47 Prospective 27 10/27 (37%) Mean: 5.2† 18 months postdiagnosis Ruts et al.69 Prospective 146 55/146 (38%) Mild 29%, moderate 36%, severe 12 months postdiagnosis 35%‡ Rekand et al.63 Retrospective 50 34/50 (69%) Mean time since diagnosis: 11.3 years Kuitwaard et al.42 Cross-sectional 245 174/245 (71%) Severe 8%{ Mean time since diagnosis: 10 years Forsberg et al.23 Prospective 42 16/42 (38%) 12 months postdiagnosis Bernsen et al.6 Cross-sectional 122 59/122 (48%) Between 31 and 77 months since diagnosis CIDP Nasu et al.53 Retrospective 46 3/46 (7%) Location of pain: distal lower limbs Goebel et al.26 Prospective 24 13/24 (54%) Mild 62%, moderate 26%, severe Location of pain: feet and ankles . 13%** calves .hands .knees, thighs, groin, abdomen, back, buttock, chest, arms, shoulder, neck and head Ruts et al.68 Prospective 8†† 5/8 (71%) Kuitwaard et al.42 Cross-sectional 76 55/76 (72%) Severe 17%‡‡ Boukhris et al.8 Retrospective 27 5/27 (19%) Severe 100%§§ Description/location of pain: radicular pain in lower limbs Boukhris et al.7 Retrospective 11 7/11 (64%) Description of pain: distal dysesthesias .radicular pain Gorson et al.30 Retrospective 10‖‖ 6/10 (60%) Description/location of pain: aching in hand, arm, shoulder .burning sensation in forearm, hand, finger . electrical shock-like pain .shooting, radicular pain from shoulder Simmons et al.74 Retrospective 69 11/69 (16%) Pediatric patients Gorson et al.28 Retrospective 67 28/67 (42%) Description of pain: burning dysesthesias .radicular .aching or (continued on next page)

Table 2 (continued) Authors Study design Patients Frequency of pain Pain severity* Other clinical details cramping muscle pain .lancinating pain McCombe et al.48 Retrospective 92 18/92 (20%) Description of pain: burning feet, aching muscles Dyck et al.20 Retrospective 53 8/53 (15% in hands); 9/53 (17% in feet) Paraproteinemic neuropathy—POEMS syndrome Nasu et al.53 Retrospective 51 39/51 (76%) Description of pain: dysesthesia/ paresthesia, distal lower limb Koike et al.39 Prospective 22 12/22 (55%) Mild 25%, moderate 35%, severe Pain increased with pressure, 42% pinching, ambulation * All reported pain severity included. † Brief Pain Inventory numerical pain scale, 0 5 no pain, 10 5 worst possible pain, 4 to 7 5 moderate, .7 5 severe. ‡ Numeric rating scale, 0 to 4 5 mild, 5 to 7 5 moderate, 8 to 10 5 severe. § Randomized control trial of IVIg 1 placebo vs IVIg 1 methylprednisolone. ‖ Mild 5 pain but no real complaints, moderate 5 complaints, but no analgesics necessary, severe 5 analgesics necessary. { Severity of pain scored using Smiley scale (rated 0-5, with 4 5 severe, 5 5 very severe). # Mild 5 relieved with acetaminophen or nonsteroidal anti-inflammatory agents, moderate-to-severe pain 5 required narcotics or epidural anesthesia. ** Brief numeric rating scale, 0 to 3 5 mild, 4 to 6 5 moderate, $7 5 severe. †† Patients with CIDP with acute onset (A-CIDP). ‡‡ Numeric pain rating scale, $7 5 severe. §§ VAS, patients with pain ,6 were excluded, $7 5 severe. ‖‖ Patients with upper limb predominant multifocal CIDP (UL-CIDP). DN4, Douleur Neuropathique 4; GBS, Guillain–Barrésyndrome; NP, neuropathic pain; VAS, visual analog scale.

lower back, in either a radicular distribution or described as specific antibodies directed at components of nerve myelin,65 such burning and dysesthetic sensations.7,8,28,48 One study demon- as IgM anti–myelin-associated glycoprotein (MAG) antibodies.77 strated decreased epidermal nerve fiber density in CIDP patients IgM anti-MAG neuropathy has been described as painless, but with neuropathic pain compared with those without.11 There also progressive pain with paresthesias and pain-related disability are may be contributions of nociceptive pain mechanisms secondary now recognized.45 There is no established treatment for IgM anti- to dynamic muscle imbalance, weakness, and resulting de- MAG neuropathy, and there have been no studies investigating the generative joint disease.26 Pain has also been reported with CIDP pathophysiology or treatment of pain in IgM-MGUS neuropathies. variants, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM or Lewis–Sumner syndrome)61 and distal 3.4. Pain in the POEMS syndrome acquired demyelinating symmetric neuropathy,35,43 although less frequently than with typical CIDP. Up to two-thirds of patients with Pain is common in patients with osteosclerotic myeloma and distal acquired demyelinating symmetric neuropathy have immu- POEMS (polyneuropathy, organomegaly, endocrinopathy, mono- noglobulin M (IgM) kappa monoclonal gammopathies35 (see clonal gammopathy, and skin changes) syndrome,34 with as many section 3.3). The precise pathophysiology and treatment of pain in as 76% of patients reporting pain that substantially decreased CIDP is not well studied, and there have been no published clinical quality of life.53 Pain usually occurs in the distal lower extremities trials of analgesic medications in CIDP. and is described as aching, prickling, and tingling that increases Although pain may be part of the clinical presentation in CIDP, it with ambulation.34,39,53,85 Koike et al.39 found that 64% of patients is important to avoid misdiagnosis as many patients labeled reported hyperalgesia, with nerve biopsy demonstrating reduced “CIDP” due to mild nerve conduction abnormalities actually have myelinated nerve density and preserved unmyelinated fibers; an idiopathic painful neuropathy3 or neuropathy due to another serum analysis showed elevated levels of the proinflammatory cause.54,76 The presence of distal painful symptoms in the cytokines IL-1b, IL-6, and TNF-a. Neuropathic pain in POEMS may absence of proximal weakness should prompt clinicians to be generated by preserved afferent C-fibers and decreased A-fiber consider an alternative diagnosis and/or referral to a center with inhibition in the presence of cytokine sensitization.39 Bone pain is expertise in peripheral neuropathy.3,75 rare18 but has been described,13 and pain associated with ocular,36 cardiac,89 pulmonary,2 and gastrointestinal78 complications of the disease has been reported. A long-term outcome study 3.3. Pain in nonmalignant paraprotein-associated chronic showed that patients with POEMS syndrome and polyneuropathy demyelinating polyneuropathies demonstrated marked and sustained improvements in neuropathy Paraproteins are monoclonal immunoglobulins produced by severity and disability, as measured by the Neuropathy Impairment a single clone of plasma cells in the bone marrow, and there is Scale and modified Rankin Scale, respectively, with autologous an established relationship between monoclonal gammopathy and stem cell transplantation.34 However, no data on pain outcomes various peripheral neuropathies.60 Paraproteinemic demyelinating were reported, and pain management in POEMS remains neuropathies are predominately chronic, progressive, and sym- a neglected area of research. metric, with prominent distal sensory loss and ataxia and relative sparing of motor function.33 The majority of these neuropathies are 4. Conclusions observed in patients with an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS),60 with half of patients Pain is a common and clinically important symptom in patients with experiencing aching discomfort, dysesthesias, or lancinating acquired inflammatory demyelinating neuropathies, but there has pain.65 The IgM monoclonal protein may be associated with been a long-standing lack of awareness of this clinical feature and

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limited research in this area.8,26 The diagnosis of acquired [4] Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic demyelinating polyneuropathies is often challenging and the polyneuritis. Medicine (Baltimore) 1969;48:173–215. [5] Baron R, Binder A. How neuropathic is sciatica? The mixed pain concept. recognition and management of pain in these patients may not 24,82 Orthopade 2004;33:568–75. beapriority. The magnitude of the problem is suggested by [6] Bernsen RA, de Jager AE, Schmitz PI, van der MechéFG. Long-term the high proportion of patients who seem to have suffered from sensory deficit after Guillain-Barre ´ syndrome. J Neurol 2001;248:483–6. inadequately managed pain.57,58,69,71 The development of treat- [7] Boukhris S, Magy L, Gallouedec G, Khalil M, Couratier P, Gil J, Vallat JM. ments that target the etiologies of these conditions may ultimately Fatigue as the main presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy: a study of 11 cases. J Peripher reduce the burden of pain from acquired inflammatory demyelin- Nerv Syst 2005;10:329–37. ating neuropathies. At present, there is no evidence-based pain [8] Boukhris S, Magy L, Khalil M, Sindou P, Vallat JM. Pain as the presenting treatment for patients with inflammatory demyelinating neuropa- symptom of chronic inflammatory demyelinating polyradiculoneuropathy thies. Awareness and recognition, accurate pain classification, and (CIDP). J Neurol Sci 2007;254:33–8. [9] Bourque PR, Chardon JW, Massie R. Autoimmune peripheral further investigation of pathophysiologic mechanisms may provide neuropathies. Clin Chim Acta 2015;449:37–42. the basis for the development of novel clinical trial designs and [10] Bril V, Katzberg HD. Acquired immune axonal neuropathies. Continuum treatment strategies. In the meantime, it is reasonable to approach (Minneap Minn) 2014;20:1261–73. pain management in patients with acquired inflammatory de- [11] Chiang MC, Lin YH, Pan CL, Tseng TJ, Lin WM, Hsieh ST. Cutaneous myelinating neuropathies on the basis of recent evidence-based innervation in inflammatory demyelinating polyneuropathy. Neurology 22 2002;59:1094–8. recommendations for the treatment of neuropathic pain. Given [12] Cornblath DR, Gorson KC, Hughes RA, Merkies IS. Observations on our current limited understanding, the potential contribution of chronic inflammatory demyelinating polyneuropathy: a plea for a rigorous an individualized multimodal analgesic approach should be approach to diagnosis and treatment. J Neurol Sci 2013;330:2–3. considered. [13] D’Souza A, Lacy M, Gertz M, Kumar S, Buadi F, Hayman S, Dingli D, Zeldenrust S, Kyle R, Ansell S, Inwards D, Johnston P, Micallef I, Porrata L, Litzow M, Gastineau D, Hogan W, Dispenzieri A. Long-term outcomes Conflict of interest statement after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood RHD has received research grants from US Food and Drug 2012;120:56–62. Administration and US National Institutes of Health in the past 12 [14] Dalakas MC. Advances in the diagnosis, pathogenesis and treatment of months, and compensation for activities involving clinical trial CIDP. Nat Rev Neurol 2011;7:507–17. [15] Darweesh SK, Polinder S, Mulder MJ, Baenam CP, van Leeuwen N, research methods from Abide, Adynxx, Aptinyx, Astellas, Biogen, Franco OH, Jacobs BC, van Doorn PA. Health-related quality of life in Coronado, Daiichi Sankyo, Glenmark, Hope, Hydra, Immune, Guillain-Barrésyndrome patients: a systematic review. J Peripher Nerv Johnson & Johnson, Lpath, Medavante, Novartis, NsGene, Syst 2014;19:24–35. Olatec, Periphagen, Phosphagenics, Relmada, Semnur, Spini- [16] Dimachkie MM, Saperstein DS. Aquired immune demyelinating fex, Syntrix, Teva, and Vertex. RF has received research support neuropathies. Continuum (Minneap Minn) 2014;20:1241–60. [17] Dispenzieri A. POEMS syndrome: update on diagnosis, risk-stratification, from the US National Institutes of Health, Michael J. Fox and management. Am J Hematol 2015;90:951–62. foundation, Nestle, and Pfizer; compensation for editorial [18] Dispenzieri A, Kyle RA. Neurological aspects of multiple myeloma and activities as editor of Autonomic Neuroscience: Basic and related disorders. Best Pract Res Clin Haematol 2005;18:673–88. Clinical; and compensation for scientific advisory board contri- [19] Dubey D, Kapotic M, Freeman M, Sawhney A, Rojas JC, Warnack W, Vernino S. Factors contributing to delay in diagnosis of Guillain-Barre ´ butions from Astellas, Biogen, Daiichi Sankyo, Hydra, Glenmark, syndrome and impact on clinical outcome. Muscle Nerve 2016;53: Lundbeck, Pfizer, Shire, and Spinifex. KCG has received 384–7. research grants and provided consulting services for Baxalta, [20] Dyck PJ, Lais AC, Ohta M, Bastron JA, Ozaki H, Groover RV. Chronic CSL Behring, Grifols, and UCB Pharma. DNH has received inflammatory polyradiculoneuropathy. Mayo Clin Proc 1975;50:621–37. ́ research support from the US National Institutes of Health and [21] Eldar AH, Chapman J. Guillain Barre syndrome and other immune mediated neuropathies: diagnosis and classification. Autoimmun Rev Muscular Dystrophy Association in the past 12 months and 2014;13:525–30. compensation for clinical trial related activities or consulting from [22] Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Medpace, Voyager, LAM Therapeutics, and Guidepoint Global. Gilron I, Haanpa¨ ¨ a M, Hansson P, Jensen TS, Kamerman PR, Lund K, The other authors have no conflicts of interest to declare. Moore A, Raja SN, Rice ASC, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73. Appendix A. Supplemental Digital Content [23] Forsberg A, Press R, Einarsson U, de Pedro-Cuesta J, Widen Holmqvist L. Impairment in Guillain-Barre ´ syndrome during the first 2 years after Supplemental Digital Content associated with this article can be onset: a prospective study. J Neurol Sci 2004;227:131–8. found online at http://links.lww.com/PAIN/A250. [24] Fujimura H. The Guillain-Barre ´ syndrome. Handb Clin Neurol 2013;115: 383–402. Article history: [25] Genis D, Busquets C, Manubens E, Davalos A, Baro J, Oterino A. Epidural morphine analgesia in Guillain-Barre ´ syndrome. J Neurol Neurosurg Received 22 October 2015 Psychiatry 1989;52:999–1001. Received in revised form 26 January 2016 [26] Goebel A, Lecky B, Smith LJ, Lunn MP. Pain intensity and distribution in Accepted 22 February 2016 chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2012; 46:294–5. Available online 1 March 2016 [27] Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther Adv Neurol Disord 2012;5:359–73. [28] Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating References polyneuropathy: clinical features and response to treatment in 67 [1] Ali MJ, Hutfluss R. Epidural fentanyl-bupivacaine infusion for consecutive patients with and without a monoclonal gammopathy. management of pain in the Guillain-Barrésyndrome. Reg Anesth 1992; Neurology 1997;48:321–8. 17:171–4. [29] Gorson KC, Ropper AH, Muriello MA, Blair R. Prospective evaluation of [2] Allam JS, Kennedy CC, Aksamit TR, Dispenzieri A. Pulmonary MRI lumbosacral nerve root enhancement in acute Guillain-Barre ´ manifestations in patients with POEMS syndrome: a retrospective syndrome. Neurology 1996;47:813–7. review of 137 patients. Chest 2008;133:969–74. [30] Gorson KC, Ropper AH, Weinberg DH. Upper limb predominant, [3] Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment multifocal chronic inflammatory demyelinating polyneuropathy. Muscle benefit. Neurology 2015;85:498–504. Nerve 1999;22:758–65.

[31] Griffin JW, Li CY, Ho TW, Tian M, Gao CY, Xue P, Mishu B, Cornblath DR, physiological profiles in POEMS syndrome and chronic inflammatory Macko C, McKhann GM, Asbury AK. Pathology of the motor-sensory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 2012;83: axonal Guillain Barrésyndrome. Ann Neurol 1996;39:17–28. 476–9. [32] Guillain G, Barre ´ JA, Strohl A. Sur un syndrome de radiculo-nevrite avec [54] Ng Wing Tin S, Plante-Bordeneuve V, Salhi H, Goujon C, Damy T, hyperalbuminose du liquide cephalo-rachidien sans reaction cellulaire. Lefaucheur JP. Characterization of pain in familial amyloid remarques sur les caracteres cliniques et graphiques des reflexes polyneuropathy. J Pain 2015;16:1106–14. tendineux. Bull Soc Med Hop Paris 1916;28:1462–70. [55] Nicholas R, Playford ED, Thompson AJ. A retrospective analysis of [33] Hadden RD, Nobile-Orazio E, Sommer CL, Hahn AF, Illa I, Morra E, outcome in severe Guillain-Barre ´ syndrome following combined Pollard JD, Lunn MP, Bouche P, Cornblath DR, Evers E, Koski CL, Leger ´ neurological and rehabilitation management. Disabil Rehabil 2000;22: JM, van den Bergh P, van Doorn PA, van Schaik IN. European Federation 451–5. of Neurological Societies/Peripheral Nerve Society guideline on [56] Niermeijer JMF, Fischer K, Eurelings M, Franssen H, Wokke JHJ, management of paraproteinemic demyelinating neuropathies. Report of Notermans NC. Prognosis of polyneuropathy due to IgM monoclonal a joint task force of the European Federation of Neurological Societies and gammopathy: a prospective cohort study. Neurology 2010;74:406–12. the Peripheral Nerve Society—first revision. J Peripher Nerv Syst 2010; [57] Pandey CK, Bose N, Garg G, Singh N, Baronia A, Agarwal A, Singh PK, 15:185–95. Singh U. Gabapentin for the treatment of pain in Guillain-Barre ´ syndrome: [34] Karam C, Klein CJ, Dispenzieri A, Dyck PJB, Mandrekar J, D’Souza A, a double-blinded, placebo-controlled, crossover study. Anesth Analg Mauermann ML. Polyneuropathy improvement following autologous 2002;95:1719–23. stem cell transplantation for POEMS syndrome. Neurology 2015;84: [58] Pandey CK, Raza M, Tripathi M, Navkar DV, Kumar A, Singh UK. The 1981–7. comparative evaluation of gabapentin and carbamazepine for pain [35] Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ. Distal management in Guillain-Barre ´ syndrome patients in the intensive care acquired demyelinating symmetric neuropathy. Neurology 2000;54: unit. Anesth Analg 2005;101:220–5. 615–20. [59] Pentland B, Donald SM. Pain in Guillain-Barre ´ syndrome: a clinical review. [36] Kaushik M, Pulido JS, Abreu R, Amselem L, Dispenzieri A. Ocular findings PAIN 1994;59:158–64. in patients with polyneuropathy, organomegaly, endocrinopathy, [60] Rajabally YA. Neuropathy and paraproteins: review of a complex monoclonal gammopathy, and skin changes syndrome. Ophthalmology association. Eur J Neurol 2011;18:1291–8. 2011;118:778–82. [61] Rajabally YA, Chavada G. Lewis-sumner syndrome of pure upper-limb [37] Khan F, Amatya B. Rehabilitation interventions in patients with acute onset: diagnostic, prognostic, and therapeutic features. Muscle Nerve demyelinating inflammatory polyneuropathy: a systemic review. Eur J 2009;39:206–20. Phys Rehabil Med 2012;48:507–22. [62] Rajabally YA, Simpson BS, Beri S, Bankart J, Gosalakkal JA. [38] Kogos SC, Richards JS, Ban˜ os J, Schmitt MM, Brunner RC, Meythaler Epidemiologic variability of chronic inflammatory demyelinating JM, Salisbury DB, Renfroe SG, White AJ. A descriptive study of pain and polyneuropathy with different diagnostic criteria: study of a UK quality of life following Guillain-Barre ´ syndrome: one year later. J Clin population. Muscle Nerve 2009;39:432–8. Psychol Med Settings 2005;12:111–6. [63] Rekand T, Gramstad A, Vedeler CA. Fatigue, pain and muscle weakness [39] Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, Tanaka are frequent after Guillain-Barre ´ syndrome and poliomyelitis. J Neurol F, Doyu M, Sobue G. Neuropathic pain correlates with myelinated fibre 2009;256:349–54. loss and cytokine profile in POEMS syndrome. J Neurol Neurosurg [64] Ropper AH. The Guillain-Barre ´ syndrome. N Engl J Med 1992;326: Psychiatry 2008;79:1171–9. 1130–6. [40] Koller ¨ H, Kieseier BC, Jander S, Hartung HP. Chronic inflammatory [65] Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. demyelinating polyneuropathy. N Engl J Med 2005;352:1343–56. N Engl J Med 1998;338:1601–7. [41] Korinthenberg R, Schessl J, Kirschner J. Clinical presentation and course [66] Ropper AH, Shahani BT. Pain in Guillain-Barre ´ syndrome. Arch Neurol of childhood Guillain-Barre ´ syndrome: a prospective multicentre study. 1984;41:511–4. Neuropediatrics 2007;38:10–7. [67] Rosenfeld B, Borel C, Hanley D. Epidural morphine treatment of pain in [42] Kuitwaard K, Bos-Eyssen ME, Blomkwist-Markens PH, van Doorn PA. Guillain-Barrésyndrome. Arch Neurol 1986;43:1194–6. Recurrences, vaccinations and long-term symptoms in GBS and CIDP. [68] Ruts L, Drenthen J, Jacobs BC, van Doorn PA. Distinguishing acute- J Peripher Nerv Syst 2009;14:310–5. onset CIDP from fluctuating Guillain-Barre ´ syndrome. Neurology 2010; [43] Larue S, Bombelli F, Viala K, Neil J, Maisonobe T, Bouche P, Musset L, 74:1680–6. Fournier E, Leger JM. Non-anti-MAG DADS neuropathy as a variant of [69] Ruts L, Drenthen J, Jongen JLM, Hop WCJ, Visser GH, Jacobs BC, van CIDP: clinical, electrophysiological, laboratory features and response to Doorn PA. Pain in Guillain-Barre ´ syndrome. Neurology 2010;75:1439–47. treatment in 10 cases. Eur J Neurol 2011;18:899–905. [70] Ruts L, van Doorn PA, Lombardi R, Haasdijk ED, Penza P, Tulen JH, [44] Laughlin RS, Dyck PJ, Melton LJ III, Leibson C, Ransom J, Dyck PJB. Hempel RJ, van den Meiracker AH, Lauria G. Unmyelinated and Incidence and prevalence of CIDP and the association of diabetes myelinated skin nerve damage in Guillain-Barre ´ syndrome: correlation mellitus. Neurology 2009;73:39–45. with pain and recovery. PAIN 2012;153:399–409. [45] Leger ´ JM, Viala K, Nicolas G, Créange A, Vallat JM, Pouget J, Clavelou P, [71] Ruts L, van Koningsveld R, Jacobs BC, van Doorn PA. Determination of Vial C, Steck A, Musset L, Marin B. Placebo-controlled trial of rituximab in pain and response to methylprednisolone in Guillain-Barre ´ syndrome. IgM anti-myelin—associated glycoprotein neuropathy. Neurology 2013; J Neurol 2007;254:1318–22. 80:2217–25. [72] Sanchez-Guerra M, Infante J, Pascual J, Berciano J. Severe back pain in [46] Liu J, Wang LN, McNicol ED. Pharmacological treatment for pain in Guillain-Barre ´ syndrome. Muscle Nerve 2002;25:468. Guillain-Barre ´ syndrome. Cochrane Database Syst Rev 2013;10: [73] Senevirante U, Gunasekera S. Acute small fibre sensory neuropathy: CD009950. another variant of Guillain-Barre ´ syndrome? J Neurol Neurosurg [47] Martinez V, Fletcher D, Martin F, Orlikowski D, Sharshar T, Chauvin M, Psychiatry 2002;72:540–2. Bouhassira D, Attal N. Small fibre impairment predicts neuropathic pain in [74] Simmons Z, Wald JJ, Albers JW. Chronic inflammatory demyelinating Guillain-Barre ´ syndrome. PAIN 2010;151:53–60. polyradiculoneuropathy in children: I. Presentation, electrodiagnostic [48] McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory studies, and initial clinical course, with comparison to adults. Muscle demyelinating polyradiculoneuropathy. A clinical and electrophysiological Nerve 1997;20:1008–15. study of 92 cases. Brain 1987;110:1617–30. [75] Singer MA, Vernino SA, Wolfe GI. Idiopathic neuropathy: new paradigms, [49] McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of new promise. J Peripher Nerv Syst 2012;17:43–9. Guillain-Barre ´ syndrome worldwide. A systematic literature review. [76] Singleton JR, Smith AG, Bromberg MB. Painful sensory polyneuropathy Neuroepidemiology 2009;32:150–63. associated with impaired glucose tolerance. Muscle Nerve 2001;24: [50] Meythaler JM. Rehabilitation of Guillain-Barre ´ syndrome. Arch Phys Med 1225–8. Rehabil 1997;78:872–9. [77] Steck AJ, Czaplinski A, Renaud S. Inflammatory demyelinating [51] Moalem-Taylor G, Allbutt HN, Iordanova MD, Tracey DJ. Pain neuropathies and neuropathies associated with monoclonal hypersensitivity in rats with experimental autoimmune neuritis, an gammopathies: treatment update. Neurotherapeutics 2008;5:528–34. animal model of human inflammatory demyelinating neuropathy. Brain [78] Swanstrom LL, Kurian A, Dunst CM, Sharata A, Bhayani N, Rieder E. Behav Immun 2007;21:699–710. Long-term outcomes of an endoscopic myotomy for achalasia: the [52] Moulin DE, Hagen N, Feasby TE, Amireh R, Hahn A. Pain in Guillain-Barre ´ POEM procedure. Ann Surg 2012;256:659–67. syndrome. Neurology 1997;48:328–31. [79] Tripathi M, Kaushik S. Carbamezapine for pain management in Guillain- [53] Nasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, Ohmori Barrésyndrome patients in the intensive care unit. Crit Care Med 2000; S, Mitsuma S, Koga S, Kuwabara S. Different neurological and 28:655–8.

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[80] Truini A, Barbanti P, Pozzilli C, Cruccu G. A mechanism-based [85] Wang X, Ye S, Xiong C, Gao J, Xiao C, Xing X. Successful treatment with classification of pain in multiple sclerosis. J Neurol 2013;260:351–67. bortezomib and thalidomide for POEMS syndrome associated with [81] van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, multicentric mixed-type Castleman’s disease. Jpn J Clin Oncol 2011;41: Koski CL, Leger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn 1221–4. PA, van Schaik IN. European Federation of Neurological Societies/ [86] Wilmshurst JM, Thomas NH, Robinson RO, Bingham JB, Pohl KRE. Peripheral Nerve Society guideline on management of chronic Lower limb and back pain in Guillain-Barre ´ syndrome and associated inflammatory demyelinating polyradiculoneuropathy: report of a joint contrast enhancement in MRI of the cauda equina. Acta Paediatr 2001; task force of the European Federation of Neurological Societies and the 90:691–703. Peripheral Nerve Society—first revision. Eur J Neurol 2010;17:356–63. [87] Winspur I. Tegretol for pain in the Guillain-Barre ´ syndrome. Lancet 1970; [82] van Doorn PA. Diagnosis, treatment and prognosis of Guillain-Barre ´ 1:85. syndrome (GBS). Presse Med 2013;42:e193–201. [88] Witsch J, Galldiks N, Bender A, Kollmar R, Bosel J, Hobohm C, Gunther [83] van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and A, Schirotzek I, Fuchs K, Juttler E. Long-term outcome in patients with treatment of Guillain-Barre ´ syndrome. Lancet Neurol 2008;7:939–50. Guillain-Barre ´ syndrome requiring mechanical ventilation. J Neurol 2013; [84] Walgaard C, Lingsma HF, Ruts L, Drenthen J, van Koningsveld R, 260:1367–74. Garssen MJ, van Doorn PA, Steyerberg EW, Jacobs BC. Prediction of [89] Yamada M, Yamawaki M, Michikawa M, Kameda N, Furukawa T, Kaneko respiratory insufficiency in Guillain-Barre ´ syndrome. Ann Neurol 2010;67: E. The Crow-Fukase (POEMS) syndrome with vasospastic angina. Eur 781–7. Neurol 1994;34:110.

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