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 inflam- matory 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 September 2016· Volume 157· Number 9 www.painjournalonline.com 1887 Copyright Ó 2016 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. 1888 S. Thakur et al.·157 (2016) 1887–1894 PAIN® 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