Curr Pain Headache Rep (2015) 19:40 DOI 10.1007/s11916-015-0508-x
SECONDARY HEADACHE (M ROBBINS, SECTION EDITOR)
Headache and Pain in Guillain-Barré Syndrome Constantine Farmakidis 1 & Seniha Inan 1 & Mark Milstein 1 & Steven Herskovitz 1
# Springer Science+Business Media New York 2015
Abstract While moderate and severe back or extremity pain is frequent in Guillain-Barré syndrome (GBS), headache appears to be uncommon. Most of the reports of headache in GBS place it in the context of the posterior reversible encephalopathy syndrome (PRES) which is increasingly recognized as a likely dysautonomia-related GBS complication. There are also a few reports of headache in the setting of increased CSF pressure and papilledema and in association with the Miller Fisher GBS variant. In comparison, back and extremity pain is highly prevalent. Aching muscle pain and neuropathic pain are the two most common of several pain types. Pain may be a heralding feature and has been described in patients as long as 2 years after disease onset. Pain management is a major axis of treatment in GBS. Gabapentin is a reasonable first-line choice, and opioid medications can be added for more severe pain but there are few clinical trials to inform specific recommendations. While the understanding of pain pathophysiology in GBS is incomplete, its prevalence and clinical impact are increasingly recognized and studied. Pain should be considered a cardinal manifestation of GBS along with acute, mostly symmetric weakness and diminished reflexes.
Keywords Guillain-Barré syndrome (GBS) . Pain . Headache . Posterior reversible encephalopathy syndrome . Dysautonomia . Back pain This article is part of the Topical Collection on Secondary Headache * Constantine Farmakidis [email protected] 1
Saul R. Korey Department of Neurology, Montefiore Medical Center, Bronx, NY, USA
Introduction The Guillain-Barré syndrome (GBS) is an eponymic umbrella term for a group of often postinfectious, acute, and monophasic immune-mediated neuropathies. Disease incidence is estimated at 1.11 cases per 100,000 person-years [1]. The cardinal manifestations of GBS are symmetric limb weakness and reduced reflexes although the clinical spectrum is remarkably broad and weakness can involve ocular, bulbar, and respiratory muscles. Respiratory insufficiency that occurs in 25 % and autonomic dysfunction that occurs in up to two thirds of patients [2] are potentially life-threatening complications and make GBS one of the important treatable neurologic emergencies worldwide. Pain is an important clinical feature of GBS and was described in the earliest reports of the disease [3]. It was not, however, emphasized in consensus diagnostic criteria, where Bmild sensory symptoms or signs^ were proffered as a feature supporting the diagnosis, without specific mention of pain [4]. Prospective studies of GBS patients have since demonstrated that extremity and back pain is highly prevalent and often severe throughout the spectrum of GBS [5••]. The geographic distribution of pain is broad, and pain can occur as a sentinel symptom prior to weakness, along with the onset of weakness, and can continue for at least 2 years [6]. Fatigue may persist for decades after the weakness from GBS has resolved, indicating multimodal long-term impact in some patients [7]. GBS is now recognized as a neurologic illness where pain occupies a major clinical dimension. Much less is known about headache in GBS. Available data is mostly from case reports, as even larger prospective natural history studies have captured few GBS patients with headache and provided limited further descriptions of headache [8••]. There have been transformative advances in the acute treatment of weakness in GBS with intravenous immune globulin
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(IVIG) and plasmapheresis. Similar advances in diseasespecific pain management are lagging though as the rarity of the disease, its clinical heterogeneity, and the long duration of pain have constrained larger randomized clinical trials. This review summarizes the current state of knowledge about headache and pain in GBS.
Headache and GBS While non-headache pain occurs at some point in the natural history of nearly two thirds or more of GBS patients [5••] [8••], headache appears to be considerably more uncommon. The largest prospective study of pain in GBS which specifically recorded headache pain syndromes sites a 2 % incidence [8••]. Notably, the largest prospective study of pain to date in GBS did not include headache as a type of pain location, further suggesting its lesser prominence in GBS [5••]. Headache has been reported with typical GBS cases and the Miller Fisher syndrome (MFS) [5••, 9, 10], but no reports exist to our knowledge that describe headache with other GBS variants. Most clinical information about headache distribution and characteristics in GBS comes from case reports (Table 1). Headache can be generalized [11], it can be severe [12–14], it can be aggravated by coughing [9], and in MFS it is reported to have a more specific periorbital localization [15]. Time of headache onset is variable as it can occur prior to, concurrent with, or following the onset of motor dysfunction. Headache in GBS appears to occur in three general clinical settings: the posterior reversible encephalopathy syndrome (PRES), the rare scenario where papilledema and increased CSF pressure occur after GBS, and in the Miller Fisher GBS variant. Dysautonomia and PRES Dysautonomia was recognized early in the history of GBS [16], but in-depth understanding of its implications has been more gradual. In 1979, nearly two decades before the formal description of the posterior reversible encephalopathy syndrome (PRES) [17], Aicardi and Del Giudice [18] described a pediatric patient with GBS and central nervous system signs that they hypothesized were most likely due to uncontrolled hypertension. After the description of PRES in 1996 [17] as a reversible syndrome of hypertension, headache, visual disturbances, encephalopathy, and characteristic imaging abnormalities, case reports appeared of PRES complicating the acute phase of GBS [19]. These also included cases where headache was a salient clinical feature, similar with PRES in its more typical presentation [12, 20–22]. There are currently 15 adult cases of PRES and GBS reported in the literature, the majority (87 %)
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being both female and over the age of 55 [23••, 24, 25]. Most developed symptoms of PRES several days after onset of GBS symptoms. The precise incidence of PRES and GBS cooccurrence is not known, but it is a rare exception rather than the rule. While not all cases of PRES and GBS include headache, it is possible that headache is underreported in the subset of PRES patients with critical illness and significant encephalopathy. A patient with GBS and PRES with head heaviness illustrates how somnolence or encephalopathy may interplay with the reporting of headache [25]. In addition, some reported GBS patients have had neuroimaging evidence of PRES but without other clinical features constituting what is the less severe end of the GBS and PRES spectrum [26]. The precise etiology of PRES in the setting of GBS, similar to PRES in other settings, remains uncertain and may be multifactorial. A leading hypothesis is that hypertension due to autonomic dysfunction can exceed the limits of cerebral blood vessels in regulating blood flow leading to vasogenic edema. However, not all patients with PRES and GBS have excessive hypertension [23••] suggesting additional factors may be involved. Endothelial injury may increase vascular permeability and predispose to vasogenic edema. In GBS, this could be due to hypertensive injury or cytotoxic injury from a systemic inflammatory response to an immune-mediated neuropathy [17]. Studies of the inflammatory response in sural nerve biopsy tissue from patients with GBS suggest candidate mechanisms and molecules involved in systemic inflammation and cytotoxic injury [27]. Also, the apparent predominance of women over the age of 55 among GBS patients with PRES raises the possibility that physiologic variables associated with the female sex and advanced age may predispose GBS patients to develop PRES [23••]. The reversible cerebral vasoconstriction syndrome (RCVS) often occurs in similar clinical settings as PRES [28]. This relation appears to hold in GBS as well where one patient to date had dysautonomia with prominent hypertension and developed clinical and radiologic features that partially overlap with both RCVS and PRES [11]. PRES has developed in patients with GBS shortly after administration of IVIG leading some authors to suggest that IVIG was the cause of PRES [29] [30]. However, as GBS patients also develop PRES before any exposure to IVIG treatment, it seems most likely that the strongest association exists between the acute phase (first 4 weeks) of GBS and PRES as opposed to IVIG and PRES. PRES in most instances is an acute and self-limited syndrome, and management in the setting of GBS consists of blood pressure control with parenteral agents, anticonvulsant therapy for patients with seizures, and close clinical monitoring. Headache spontaneously resolves along with PRES, and there seems to be no default indication for specific headache management in this patient population.
12 days before weakness onset 1 day after onset of weakness 3 days before weakness onset 5 days after onset of weakness 8 days after onset of weakness 5 days after onset of weakness About a week before onset of weakness 6 days before weakness, duration 2-3 weeks 27 4 episodes in first month Concurrent with motor onset of MFS
Headache
Headache
Headache
Head heaviness
Headache, severe
Generalized, not thunderclap in onset
Throbbing headache, nausea and vomiting
Headache, severe
Headache and vomiting
Deep-seated, aggravated by coughing
67
F
M
GBS
MFS
MFS
MFS
MFS
MFS
MFS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
NR
NR
NR
NR
NR
NR
NR
420
NR
NR
NR
MRI: normal
NR
NR
NR
NR
NR
NR
100
165
Ventriculography: normal ventricles 500
CT: normal
MRI: convexity SAH, MRA: NR constriction right MCA, left ACA CT: normal 600
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
NR
NR
NR
90
35
348
480
507
106
149
290
109
189
169
147
96
131
CSF OP CSF mm H2O protein (mg/dl)
None
None
None
None
None
None
IIH
IIH
IIH
PRES, IVIG temporal association RCVS
PRES
PRES
PRES
PRES
PRES
PRES
Headache syndrome assignment when possible
[15]
[15]
[15]
[10]
[9]
[9]
[31]
[14]
[32]
[11]
[13]
[25]
[20]
[24]
[21]
[22]
[12]
Reference
ACA anterior cerebral artery, CSF cerebrospinal fluid, CSF OP cerebrospinal fluid opening pressure, CT computed tomography, GBS Guillain-Barré syndrome, IIH idiopathic intracranial hypertension, IVIG intravenous immune globulin, MCA middle cerebral artery, MFS Miller Fisher syndrome, MRA magnetic resonance angiogram, MRI magnetic resonance imaging, NR not recorded, PRES posterior reversible encephalopathy syndrome, RCVS reversible cerebral vasoconstriction syndrome, SAH subarachnoid hemorrhage
13
NR
Right orbit, pulsing, pounding, flashing
F
F
13 10
Concurrent with neurologic onset of MFS
M
35
Left retro-orbital, pulsing, pounding, flashing
M
M
63
45
Severe, bilateral; in the morning; upon coughing 1 day before motor onset of MFS, lasting at least 6 days Constant, with diurnal pain level variation; Concurrent with onset of MFS, lasting radiating up from the neck 3 months Left supraorbital, pulsing, pounding, flashing 6 days after neurologic onset
M
F
F
F
F
F
F
M
F
F
11
22
51
14
58
63
56
57
62
Concurrent with weakness onset 1 day before weakness onset
Headache
Age Sex GBS Brain imaging variant
Headache, severe
Headache tempo
Spectrum of headache descriptions in GBS
Headache characteristics
Table 1
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Increased Intracranial Pressure Reports of GBS complicated by permutations of papilledema, increased CSF pressure, and hydrocephalus have been accumulating in the medical literature since the mid-twentieth century. Many of these patients had headache as a salient part of their illness suggesting that disturbances in fluid and brain tissue distribution within the cranial vault are a significant mechanism of headache in GBS. These clinical syndromes can be conceived as secondary forms of intracranial hypertension in some instances and communicating hydrocephalus in another. A majority of the patients have been children. A representative pediatric case is that of an 11-year-old boy with GBS who 4 weeks after onset of ascending weakness developed headaches and emesis and was found to have papilledema with an opening cerebrospinal fluid (CSF) pressure of 500 mm of H2O with a CSF protein concentration reaching as high as 480 mg/dl but without evidence of hydrocephalus on ventriculography [31]. The patient had surgical subtemporal decompression and CSF drainage with eventual resolution of headaches, disc edema, and neuromuscular weakness. An adult had a similar presentation of apparent secondary intracranial hypertension [32]. This was a 22-year-old woman who developed GBS with mild distal quadriparesis after a prodrome that included throbbing headache, nausea, and vomiting. On admission, she was found to have papilledema, a raised CSF opening pressure that peaked at 350 mm of H2O, and a CSF protein that peaked at 106 mg/dl while head CT imaging showed no hydrocephalus. Due to the patient’s young age, female sex, enlarged blind spots, and marked peripheral visual field constriction, her case substantively overlapped with pseudotumor cerebri. Headache in GBS may also occur with new communicating hydrocephalus after diagnosis [33]. A 10-year-old boy had acute quadriparesis and respiratory failure due to GBS and 12 weeks after onset developed headache, papilledema, and mild bilateral abducens palsies. Brain magnetic resonance imaging showed interval evolution of communicating hydrocephalus compared to an admission scan. The pathophysiologic basis of headache in such cases remains uncertain. The most frequently cited cause is increased CSF protein concentration slowing reabsorption in the arachnoid granulations. Indeed, the CSF protein can be very high in these patients and often the papilledema occurs later in the course of GBS allowing time for disc edema to develop. However, both of these associations are inconsistent in the literature and cases of disc edema have been reported with normal-range CSF protein concentration as well as early in the course of GBS [31]. An alternative explanation for increased intracranial pressure in GBS is increased fluid content in the cerebral parenchyma; in support, historical brain biopsy specimens have shown marked swelling of nerve cells [31].
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There are no treatment studies for headache management in the setting of disc edema and increased intracranial pressure, likely as these appear to be exceedingly rare presentations. Many reported patients have been observed over time to have spontaneous headache improvement parallel to resolving motor manifestations of GBS and other patients have received ventriculoperitoneal shunts and lumbar drains with reported rapid relief of headache [14]. As several case reports show patients’ symptoms resolving spontaneously [34], observation at first and caution are requisite prior to surgical intervention.
Non-headache Pain in GBS Extremity, back, and truncal pain is a pervasive feature of GBS. Natural history studies [5••, 8••, 35] focusing on pain in GBS have established that it is common, most frequently moderate to severe, and seen from disease prodrome, through the acute phase and throughout the first 2 years after diagnosis [6]. Frequency of pain overall in patients with GBS is very high, up to 89 % over 6 months of observation in one study [8••] and 66 % of patients had pain in the first 3 weeks of observation after diagnosis of GBS in another [5••]. Pain also appears to be a consistent manifestation throughout the spectrum of GBS variants and has been reported in MFS [15] and AMAN [36]. In addition, a rare acute smallfiber sensory neuropathy variant of GBS has been postulated with many features of GBS, including albuminocytologic dissociation, but fiber-type involvement limited to small fibers with painful dysesthesias [37]. Low back pain and extremity pain are the most frequent locations of pain in GBS. The largest prospective study of pain in GBS to date reported extremity pain to affect more than 70 % of those with pain and GBS throughout the first year after the illness [5••]. The same group also reported low back or back pain to be the second most common location, peaking at 50 % in the first 3 weeks and remaining near 35 % throughout the first year [5••]. Interscapular, neck, or truncal pain was also common. Rarely, severe midline thoracic back pain is the first symptom and so acute (Ble coup de poignard^) as to suggest spinal subarachnoid-subdural hemorrhage or a herniated disc [38]. Special mention is to be made regarding GBS in pre-school children, where symptoms such as prominent leg pain, difficulty walking, or refusal to walk are frequent but less specific at presentation (65 %) and often lead to misdiagnosis or a delay in diagnosis compared to older children [39]. The second largest prospective study to date of GBS pain [8••] recorded prevalence of pain syndromes conceptualized by fusing location, pain characteristics, and putative pain etiology. In this study, there was no categorization based exclusively on the geographic distribution of pain. In 6 months of follow-up, 62 % had experienced back and extremity pain,
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49 % dysesthetic extremity pain, and 35 % what was termed as myalgic-rheumatic extremity pain. The Ruts group, beyond pain categories based on geography, interpreted pain symptoms to fall into six nosologic types: radicular, meningitic, neuropathic dysesthetic pain, muscle pain, joint pain, and unknown [5••]. In this schema, muscle pain was the most important, never dropping below 43 % prevalence over the first 6 months for patients with any pain. Neuropathic-type pain was the second most prevalent, ranging from 30 to 43 % in patients with pain over the first 6 months. Radicular pain was found in about one quarter to one third of patients with pain in the prodromal and acute phases of the illness, but much less subsequently. Joint pain and pain that was of unclear etiology were rare at onset and seen in about one quarter of studied patients at 6 months. Other investigators found a higher proportion of elevated serum creatine kinase in patients with pain than in patients without pain [35], hypothesizing muscle injury as a potential cause of pain in GBS [35]. Pain can precede weakness in GBS, can be simultaneous with weakness, and may also persist after resolution of weakness. In the prodromal phase, sentinel pain occurs in 36 % of patients, occurring most frequently in the extremities and in the back and low back [5••]. Pain prevalence is maximal during the first 4 weeks of the illness, occurring in 66 % of patients [5••], and then gradually declines both in prevalence and pain severity during longitudinal follow-up [5••, 8••]. Notably, at 52 weeks of follow-up, 38 % of patients are reported to have persistent pain, with extremity pain affecting the vast majority [5••]. The longest follow-up from diagnosis available in GBS patients is 2 years, with pain starting to plateau at 33 % prevalence. The highest proportion of patients with severe pain, as determined with a score of 8–10 in a 0 to 10 numerical rating scale, was seen in the acute phase (50 %) and then stabilized at about 35 % over a year [5••]. At 52 weeks after GBS diagnosis, among patients with persistent pain, severity was rated as mild, moderate, and severe in about equal-sized groups.
Pathophysiology of Pain Clinical and electrophysiologic data in GBS point towards involvement of large myelinated motor and sensory fibers in the peripheral nervous system. Classic pathological findings in GBS correlate well and consist of segmental demyelination and cellular infiltration of inflammatory cells such as macrophages and T cells with patchy involvement of spinal roots and large and small sensory nerves [40]. The precise mechanisms for pain generation remain uncertain and may be multiple. Inflammatory cell infiltration at the level of the nerve trunk may irritate nociceptive endings within the nerve sheaths, or nervi nervorum [41•]. This has been
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hypothesized to account for deep, aching pain, encountered early in the natural history of GBS, most often as back pain. Inflamed and disrupted primary pain sensing or nociceptive fibers may account for a neuropathic or dysesthetic pain that is also common in GBS [41•]. This may be due to abnormal modulation and hyperexcitability in injured nerve fibers. Epidermal nerve fiber density (ENFD) measurements in skin biopsies of GBS patients have demonstrated consistent, early, and sustained reduction of small-fiber nerves in GBS [42, 43]. Similar ENFD abnormalities are common in painful neuropathies [44] and point to an additional source of neuropathic pain and perhaps dysautonomia in GBS. Studies in rats with experimental autoimmune neuritis (EAN), an animal model of GBS, have shown increased nociception sensitivity associated with T cell and macrophage infiltration of affected peripheral nerves [45]. This finding is parallel to what is known about GBS in humans. Additional studies in EAN have shown microglial cell infiltration also in the dorsal horn of the spinal cord of mice with increased sensitivity to noxious stimuli. These findings suggest that spinal microglia and associated signaling molecules and their receptors play a role in pain generation in GBS [46].
Management of Pain Immunotherapy in GBS with IVIG or plasma exchange within 2 weeks of onset has been shown to be an effective treatment that accelerates recovery [47–49]. IVIG is believed to bind autoantibodies targeting nerve epitopes and block complement activation, thus limiting nerve injury and nerve conduction failure [50]. Plasma exchange removes antibodies and complement involved in nerve injury. Neither treatment, however, is successful in adequately controlling pain in GBS. Historically, a wide selection of medications has been used to treat pain in GBS including non-steroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, anticonvulsants, tricyclic antidepressants, and neuroleptics [35, 51]. Clinicians have further reported a few cases of successful pain management with epidural opioids and capsaicin [51–53]. Prospective and randomized studies of pain management in GBS are few. The largest study recruited patients from a treatment trial investigating standard IVIG treatment in GBS compared to IVIG with added methylprednisolone intravenously for 5 days. There was no significant difference in disability scores at 4 weeks in the two treatment groups [54], and similarly there was no evidence for a significant effect on the presence or intensity of pain in the methylprednisolone group [55•]. Gabapentin has an established role in the treatment of chronic neuropathic pain [56] although its analgesic mechanism is poorly understood. A small double-blinded, placebocontrolled, crossover study in 18 GBS patients in intensive
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care showed lower mean pain scores in the gabapentin phase with no increase in adverse effects compared to the placebo phase [57]. Another small, randomized, double-blinded, placebo-controlled study of gabapentin, carbamazepine, and placebo in GBS patients, also in the intensive care unit, found lower median pain scores on all seven treatment days for gabapentin compared to both other groups, with no reported side effects [58]. These studies are small and provide lowquality evidence. However, as opioids cause sedation and NSAIDs have potentially serious gastrointestinal side effects, gabapentin remains an option with a significant track record in reducing neuropathic pain and limited side effects in this setting.
Conclusion Studies reporting the natural history of pain in GBS included patients that were already receiving pain treatment as needed. The persistent high prevalence of pain despite treatment underscores the primacy of pain in GBS, across different GBS variants and over time. Non-headache extremity and back pain is by far the most frequent and defining pain syndrome in GBS. Headache in GBS is uncommon, quite heterogeneous, and most well described in the context of PRES, which is an increasingly reported complication of GBS. At this time, there is limited data to make specific recommendations for back and extremity pain management. Clinicians may use gabapentin and opioids for breakthrough pain, but a proportion of patients are likely to remain refractory. Headache with PRES typically follows the self-limiting course of the acute neurologic and hemodynamic disturbance, and there appears to be no routine indication for specific headache treatment. The International Guillain-Barré syndrome Outcome Study (IGOS) is an ongoing international multicenter prospective study that is investigating biomarker prevalence and aims to develop models for early disease prognosis. An additional IGOS goal is to collect detailed prospective data on the natural history of pain in GBS and its variants. With enrollment expected to surpass the initial goal of 1000, this will be the largest prospective study of GBS to date and is likely to deepen the understanding of the illness’s natural history. While the mechanisms of pain in GBS are likely multiple, and the optimal approach for pain management is still emerging, more recent prospective longitudinal studies have firmly established the epidemiologic primacy of pain in GBS. In the modern era of GBS, pain should be understood as an additional cardinal disease manifestation along with extremity weakness, diminished reflexes, and various sensory symptoms.
Compliance with Ethics Guidelines Conflict of Interest Constantine Farmakidis reports personal fees from MNOW. Seniha Inan and Mark Milstein each declare no potential conflicts of interest. Steven Herskovitz reports personal fees from Oxford University Press. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Page 7 of 7 40 41.• Asbury AK. Pain due to peripheral nerve damage: an hypothesis. Neurology. 1984;34(12)):1587–90. Enduring hypotheses about the pathophysiologic origin of pain in GBS. 42. Pan CL. Cutaneous innervation in Guillain-Barré syndrome: pathology and clinical correlations. Brain (London, England : 1878). 2003;126:386–97. 43. Ruts L. Unmyelinated and myelinated skin nerve damage in Guillain-Barré syndrome: correlation with pain and recovery. Pain (Amsterdam). 2012;153(2):399–409. 44. Periquet MI. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53(8):1641–7. 45. Moalem-Taylor G. Pain hypersensitivity in rats with experimental autoimmune neuritis, an animal model of human inflammatory demyelinating neuropathy. Brain Behav Immun. 2007;21(5):699– 710. 46. Luongo L. Spinal changes associated with mechanical hypersensitivity in a model of Guillain-Barré syndrome. Neurosci Lett. 2008;437(2):98–102. 47. The Guillain-Barré syndrome Study Group. Plasmapheresis and acute Guillain-Barré syndrome. Neurology. 1985;35(8):1096–104. 48. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet (British edition). 1997;349(9047):225–30. 49. van der Meché FG. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. Dutch Guillain-Barré Study Group. N Engl J Med. 1992;326(17): 1123–9. 50. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015–25. 51. Connelly M. Epidural opioids for the management of pain in a patient with the Guillain-Barré syndrome. Anesthesiology (Philadelphia). 1990;72(2):381–3. 52. Morgenlander JC, Hurwitz BJ, Massey EW. Capsaicin for the treatment of pain in Guillain-Barre syndrome. Ann Neurol. 1990;28(2): 199. 53. Rosenfeld B, Borel C, Hanley D. Epidural morphine treatment of pain in Guillain-Barré syndrome. Arch Neurol. 1986;43(11):1194– 6. 54. van Koningsveld R. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for GuillainBarré syndrome: randomised trial. Lancet (British edition). 2004;363(9404):192–6. 55.• Ruts L. Determination of pain and response to methylprednisolone in Guillain-Barré syndrome. J Neurol. 2007;254(10)):1318–22. Clinical trial showing no benefit with methylprednisolone for pain management in patients with GBS. 56. Moore RA. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;3:CD007938. 57. Pandey CK, Bose N, Garg G, Singh N, Baronia A, Agarwal A, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719–23. table of contents. 58. Pandey CK, Raza M, Tripathi M, Navkar DV, Kumar A, Singh UK. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg. 2005;101(1):220–5. table of contents.
SECONDARY HEADACHE (M ROBBINS, SECTION EDITOR)
Headache and Pain in Guillain-Barré Syndrome Constantine Farmakidis 1 & Seniha Inan 1 & Mark Milstein 1 & Steven Herskovitz 1
# Springer Science+Business Media New York 2015
Abstract While moderate and severe back or extremity pain is frequent in Guillain-Barré syndrome (GBS), headache appears to be uncommon. Most of the reports of headache in GBS place it in the context of the posterior reversible encephalopathy syndrome (PRES) which is increasingly recognized as a likely dysautonomia-related GBS complication. There are also a few reports of headache in the setting of increased CSF pressure and papilledema and in association with the Miller Fisher GBS variant. In comparison, back and extremity pain is highly prevalent. Aching muscle pain and neuropathic pain are the two most common of several pain types. Pain may be a heralding feature and has been described in patients as long as 2 years after disease onset. Pain management is a major axis of treatment in GBS. Gabapentin is a reasonable first-line choice, and opioid medications can be added for more severe pain but there are few clinical trials to inform specific recommendations. While the understanding of pain pathophysiology in GBS is incomplete, its prevalence and clinical impact are increasingly recognized and studied. Pain should be considered a cardinal manifestation of GBS along with acute, mostly symmetric weakness and diminished reflexes.
Keywords Guillain-Barré syndrome (GBS) . Pain . Headache . Posterior reversible encephalopathy syndrome . Dysautonomia . Back pain This article is part of the Topical Collection on Secondary Headache * Constantine Farmakidis [email protected] 1
Saul R. Korey Department of Neurology, Montefiore Medical Center, Bronx, NY, USA
Introduction The Guillain-Barré syndrome (GBS) is an eponymic umbrella term for a group of often postinfectious, acute, and monophasic immune-mediated neuropathies. Disease incidence is estimated at 1.11 cases per 100,000 person-years [1]. The cardinal manifestations of GBS are symmetric limb weakness and reduced reflexes although the clinical spectrum is remarkably broad and weakness can involve ocular, bulbar, and respiratory muscles. Respiratory insufficiency that occurs in 25 % and autonomic dysfunction that occurs in up to two thirds of patients [2] are potentially life-threatening complications and make GBS one of the important treatable neurologic emergencies worldwide. Pain is an important clinical feature of GBS and was described in the earliest reports of the disease [3]. It was not, however, emphasized in consensus diagnostic criteria, where Bmild sensory symptoms or signs^ were proffered as a feature supporting the diagnosis, without specific mention of pain [4]. Prospective studies of GBS patients have since demonstrated that extremity and back pain is highly prevalent and often severe throughout the spectrum of GBS [5••]. The geographic distribution of pain is broad, and pain can occur as a sentinel symptom prior to weakness, along with the onset of weakness, and can continue for at least 2 years [6]. Fatigue may persist for decades after the weakness from GBS has resolved, indicating multimodal long-term impact in some patients [7]. GBS is now recognized as a neurologic illness where pain occupies a major clinical dimension. Much less is known about headache in GBS. Available data is mostly from case reports, as even larger prospective natural history studies have captured few GBS patients with headache and provided limited further descriptions of headache [8••]. There have been transformative advances in the acute treatment of weakness in GBS with intravenous immune globulin
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(IVIG) and plasmapheresis. Similar advances in diseasespecific pain management are lagging though as the rarity of the disease, its clinical heterogeneity, and the long duration of pain have constrained larger randomized clinical trials. This review summarizes the current state of knowledge about headache and pain in GBS.
Headache and GBS While non-headache pain occurs at some point in the natural history of nearly two thirds or more of GBS patients [5••] [8••], headache appears to be considerably more uncommon. The largest prospective study of pain in GBS which specifically recorded headache pain syndromes sites a 2 % incidence [8••]. Notably, the largest prospective study of pain to date in GBS did not include headache as a type of pain location, further suggesting its lesser prominence in GBS [5••]. Headache has been reported with typical GBS cases and the Miller Fisher syndrome (MFS) [5••, 9, 10], but no reports exist to our knowledge that describe headache with other GBS variants. Most clinical information about headache distribution and characteristics in GBS comes from case reports (Table 1). Headache can be generalized [11], it can be severe [12–14], it can be aggravated by coughing [9], and in MFS it is reported to have a more specific periorbital localization [15]. Time of headache onset is variable as it can occur prior to, concurrent with, or following the onset of motor dysfunction. Headache in GBS appears to occur in three general clinical settings: the posterior reversible encephalopathy syndrome (PRES), the rare scenario where papilledema and increased CSF pressure occur after GBS, and in the Miller Fisher GBS variant. Dysautonomia and PRES Dysautonomia was recognized early in the history of GBS [16], but in-depth understanding of its implications has been more gradual. In 1979, nearly two decades before the formal description of the posterior reversible encephalopathy syndrome (PRES) [17], Aicardi and Del Giudice [18] described a pediatric patient with GBS and central nervous system signs that they hypothesized were most likely due to uncontrolled hypertension. After the description of PRES in 1996 [17] as a reversible syndrome of hypertension, headache, visual disturbances, encephalopathy, and characteristic imaging abnormalities, case reports appeared of PRES complicating the acute phase of GBS [19]. These also included cases where headache was a salient clinical feature, similar with PRES in its more typical presentation [12, 20–22]. There are currently 15 adult cases of PRES and GBS reported in the literature, the majority (87 %)
Curr Pain Headache Rep (2015) 19:40
being both female and over the age of 55 [23••, 24, 25]. Most developed symptoms of PRES several days after onset of GBS symptoms. The precise incidence of PRES and GBS cooccurrence is not known, but it is a rare exception rather than the rule. While not all cases of PRES and GBS include headache, it is possible that headache is underreported in the subset of PRES patients with critical illness and significant encephalopathy. A patient with GBS and PRES with head heaviness illustrates how somnolence or encephalopathy may interplay with the reporting of headache [25]. In addition, some reported GBS patients have had neuroimaging evidence of PRES but without other clinical features constituting what is the less severe end of the GBS and PRES spectrum [26]. The precise etiology of PRES in the setting of GBS, similar to PRES in other settings, remains uncertain and may be multifactorial. A leading hypothesis is that hypertension due to autonomic dysfunction can exceed the limits of cerebral blood vessels in regulating blood flow leading to vasogenic edema. However, not all patients with PRES and GBS have excessive hypertension [23••] suggesting additional factors may be involved. Endothelial injury may increase vascular permeability and predispose to vasogenic edema. In GBS, this could be due to hypertensive injury or cytotoxic injury from a systemic inflammatory response to an immune-mediated neuropathy [17]. Studies of the inflammatory response in sural nerve biopsy tissue from patients with GBS suggest candidate mechanisms and molecules involved in systemic inflammation and cytotoxic injury [27]. Also, the apparent predominance of women over the age of 55 among GBS patients with PRES raises the possibility that physiologic variables associated with the female sex and advanced age may predispose GBS patients to develop PRES [23••]. The reversible cerebral vasoconstriction syndrome (RCVS) often occurs in similar clinical settings as PRES [28]. This relation appears to hold in GBS as well where one patient to date had dysautonomia with prominent hypertension and developed clinical and radiologic features that partially overlap with both RCVS and PRES [11]. PRES has developed in patients with GBS shortly after administration of IVIG leading some authors to suggest that IVIG was the cause of PRES [29] [30]. However, as GBS patients also develop PRES before any exposure to IVIG treatment, it seems most likely that the strongest association exists between the acute phase (first 4 weeks) of GBS and PRES as opposed to IVIG and PRES. PRES in most instances is an acute and self-limited syndrome, and management in the setting of GBS consists of blood pressure control with parenteral agents, anticonvulsant therapy for patients with seizures, and close clinical monitoring. Headache spontaneously resolves along with PRES, and there seems to be no default indication for specific headache management in this patient population.
12 days before weakness onset 1 day after onset of weakness 3 days before weakness onset 5 days after onset of weakness 8 days after onset of weakness 5 days after onset of weakness About a week before onset of weakness 6 days before weakness, duration 2-3 weeks 27 4 episodes in first month Concurrent with motor onset of MFS
Headache
Headache
Headache
Head heaviness
Headache, severe
Generalized, not thunderclap in onset
Throbbing headache, nausea and vomiting
Headache, severe
Headache and vomiting
Deep-seated, aggravated by coughing
67
F
M
GBS
MFS
MFS
MFS
MFS
MFS
MFS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
GBS
NR
NR
NR
NR
NR
NR
NR
420
NR
NR
NR
MRI: normal
NR
NR
NR
NR
NR
NR
100
165
Ventriculography: normal ventricles 500
CT: normal
MRI: convexity SAH, MRA: NR constriction right MCA, left ACA CT: normal 600
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
MRI: PRES
NR
NR
NR
90
35
348
480
507
106
149
290
109
189
169
147
96
131
CSF OP CSF mm H2O protein (mg/dl)
None
None
None
None
None
None
IIH
IIH
IIH
PRES, IVIG temporal association RCVS
PRES
PRES
PRES
PRES
PRES
PRES
Headache syndrome assignment when possible
[15]
[15]
[15]
[10]
[9]
[9]
[31]
[14]
[32]
[11]
[13]
[25]
[20]
[24]
[21]
[22]
[12]
Reference
ACA anterior cerebral artery, CSF cerebrospinal fluid, CSF OP cerebrospinal fluid opening pressure, CT computed tomography, GBS Guillain-Barré syndrome, IIH idiopathic intracranial hypertension, IVIG intravenous immune globulin, MCA middle cerebral artery, MFS Miller Fisher syndrome, MRA magnetic resonance angiogram, MRI magnetic resonance imaging, NR not recorded, PRES posterior reversible encephalopathy syndrome, RCVS reversible cerebral vasoconstriction syndrome, SAH subarachnoid hemorrhage
13
NR
Right orbit, pulsing, pounding, flashing
F
F
13 10
Concurrent with neurologic onset of MFS
M
35
Left retro-orbital, pulsing, pounding, flashing
M
M
63
45
Severe, bilateral; in the morning; upon coughing 1 day before motor onset of MFS, lasting at least 6 days Constant, with diurnal pain level variation; Concurrent with onset of MFS, lasting radiating up from the neck 3 months Left supraorbital, pulsing, pounding, flashing 6 days after neurologic onset
M
F
F
F
F
F
F
M
F
F
11
22
51
14
58
63
56
57
62
Concurrent with weakness onset 1 day before weakness onset
Headache
Age Sex GBS Brain imaging variant
Headache, severe
Headache tempo
Spectrum of headache descriptions in GBS
Headache characteristics
Table 1
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Increased Intracranial Pressure Reports of GBS complicated by permutations of papilledema, increased CSF pressure, and hydrocephalus have been accumulating in the medical literature since the mid-twentieth century. Many of these patients had headache as a salient part of their illness suggesting that disturbances in fluid and brain tissue distribution within the cranial vault are a significant mechanism of headache in GBS. These clinical syndromes can be conceived as secondary forms of intracranial hypertension in some instances and communicating hydrocephalus in another. A majority of the patients have been children. A representative pediatric case is that of an 11-year-old boy with GBS who 4 weeks after onset of ascending weakness developed headaches and emesis and was found to have papilledema with an opening cerebrospinal fluid (CSF) pressure of 500 mm of H2O with a CSF protein concentration reaching as high as 480 mg/dl but without evidence of hydrocephalus on ventriculography [31]. The patient had surgical subtemporal decompression and CSF drainage with eventual resolution of headaches, disc edema, and neuromuscular weakness. An adult had a similar presentation of apparent secondary intracranial hypertension [32]. This was a 22-year-old woman who developed GBS with mild distal quadriparesis after a prodrome that included throbbing headache, nausea, and vomiting. On admission, she was found to have papilledema, a raised CSF opening pressure that peaked at 350 mm of H2O, and a CSF protein that peaked at 106 mg/dl while head CT imaging showed no hydrocephalus. Due to the patient’s young age, female sex, enlarged blind spots, and marked peripheral visual field constriction, her case substantively overlapped with pseudotumor cerebri. Headache in GBS may also occur with new communicating hydrocephalus after diagnosis [33]. A 10-year-old boy had acute quadriparesis and respiratory failure due to GBS and 12 weeks after onset developed headache, papilledema, and mild bilateral abducens palsies. Brain magnetic resonance imaging showed interval evolution of communicating hydrocephalus compared to an admission scan. The pathophysiologic basis of headache in such cases remains uncertain. The most frequently cited cause is increased CSF protein concentration slowing reabsorption in the arachnoid granulations. Indeed, the CSF protein can be very high in these patients and often the papilledema occurs later in the course of GBS allowing time for disc edema to develop. However, both of these associations are inconsistent in the literature and cases of disc edema have been reported with normal-range CSF protein concentration as well as early in the course of GBS [31]. An alternative explanation for increased intracranial pressure in GBS is increased fluid content in the cerebral parenchyma; in support, historical brain biopsy specimens have shown marked swelling of nerve cells [31].
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There are no treatment studies for headache management in the setting of disc edema and increased intracranial pressure, likely as these appear to be exceedingly rare presentations. Many reported patients have been observed over time to have spontaneous headache improvement parallel to resolving motor manifestations of GBS and other patients have received ventriculoperitoneal shunts and lumbar drains with reported rapid relief of headache [14]. As several case reports show patients’ symptoms resolving spontaneously [34], observation at first and caution are requisite prior to surgical intervention.
Non-headache Pain in GBS Extremity, back, and truncal pain is a pervasive feature of GBS. Natural history studies [5••, 8••, 35] focusing on pain in GBS have established that it is common, most frequently moderate to severe, and seen from disease prodrome, through the acute phase and throughout the first 2 years after diagnosis [6]. Frequency of pain overall in patients with GBS is very high, up to 89 % over 6 months of observation in one study [8••] and 66 % of patients had pain in the first 3 weeks of observation after diagnosis of GBS in another [5••]. Pain also appears to be a consistent manifestation throughout the spectrum of GBS variants and has been reported in MFS [15] and AMAN [36]. In addition, a rare acute smallfiber sensory neuropathy variant of GBS has been postulated with many features of GBS, including albuminocytologic dissociation, but fiber-type involvement limited to small fibers with painful dysesthesias [37]. Low back pain and extremity pain are the most frequent locations of pain in GBS. The largest prospective study of pain in GBS to date reported extremity pain to affect more than 70 % of those with pain and GBS throughout the first year after the illness [5••]. The same group also reported low back or back pain to be the second most common location, peaking at 50 % in the first 3 weeks and remaining near 35 % throughout the first year [5••]. Interscapular, neck, or truncal pain was also common. Rarely, severe midline thoracic back pain is the first symptom and so acute (Ble coup de poignard^) as to suggest spinal subarachnoid-subdural hemorrhage or a herniated disc [38]. Special mention is to be made regarding GBS in pre-school children, where symptoms such as prominent leg pain, difficulty walking, or refusal to walk are frequent but less specific at presentation (65 %) and often lead to misdiagnosis or a delay in diagnosis compared to older children [39]. The second largest prospective study to date of GBS pain [8••] recorded prevalence of pain syndromes conceptualized by fusing location, pain characteristics, and putative pain etiology. In this study, there was no categorization based exclusively on the geographic distribution of pain. In 6 months of follow-up, 62 % had experienced back and extremity pain,
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49 % dysesthetic extremity pain, and 35 % what was termed as myalgic-rheumatic extremity pain. The Ruts group, beyond pain categories based on geography, interpreted pain symptoms to fall into six nosologic types: radicular, meningitic, neuropathic dysesthetic pain, muscle pain, joint pain, and unknown [5••]. In this schema, muscle pain was the most important, never dropping below 43 % prevalence over the first 6 months for patients with any pain. Neuropathic-type pain was the second most prevalent, ranging from 30 to 43 % in patients with pain over the first 6 months. Radicular pain was found in about one quarter to one third of patients with pain in the prodromal and acute phases of the illness, but much less subsequently. Joint pain and pain that was of unclear etiology were rare at onset and seen in about one quarter of studied patients at 6 months. Other investigators found a higher proportion of elevated serum creatine kinase in patients with pain than in patients without pain [35], hypothesizing muscle injury as a potential cause of pain in GBS [35]. Pain can precede weakness in GBS, can be simultaneous with weakness, and may also persist after resolution of weakness. In the prodromal phase, sentinel pain occurs in 36 % of patients, occurring most frequently in the extremities and in the back and low back [5••]. Pain prevalence is maximal during the first 4 weeks of the illness, occurring in 66 % of patients [5••], and then gradually declines both in prevalence and pain severity during longitudinal follow-up [5••, 8••]. Notably, at 52 weeks of follow-up, 38 % of patients are reported to have persistent pain, with extremity pain affecting the vast majority [5••]. The longest follow-up from diagnosis available in GBS patients is 2 years, with pain starting to plateau at 33 % prevalence. The highest proportion of patients with severe pain, as determined with a score of 8–10 in a 0 to 10 numerical rating scale, was seen in the acute phase (50 %) and then stabilized at about 35 % over a year [5••]. At 52 weeks after GBS diagnosis, among patients with persistent pain, severity was rated as mild, moderate, and severe in about equal-sized groups.
Pathophysiology of Pain Clinical and electrophysiologic data in GBS point towards involvement of large myelinated motor and sensory fibers in the peripheral nervous system. Classic pathological findings in GBS correlate well and consist of segmental demyelination and cellular infiltration of inflammatory cells such as macrophages and T cells with patchy involvement of spinal roots and large and small sensory nerves [40]. The precise mechanisms for pain generation remain uncertain and may be multiple. Inflammatory cell infiltration at the level of the nerve trunk may irritate nociceptive endings within the nerve sheaths, or nervi nervorum [41•]. This has been
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hypothesized to account for deep, aching pain, encountered early in the natural history of GBS, most often as back pain. Inflamed and disrupted primary pain sensing or nociceptive fibers may account for a neuropathic or dysesthetic pain that is also common in GBS [41•]. This may be due to abnormal modulation and hyperexcitability in injured nerve fibers. Epidermal nerve fiber density (ENFD) measurements in skin biopsies of GBS patients have demonstrated consistent, early, and sustained reduction of small-fiber nerves in GBS [42, 43]. Similar ENFD abnormalities are common in painful neuropathies [44] and point to an additional source of neuropathic pain and perhaps dysautonomia in GBS. Studies in rats with experimental autoimmune neuritis (EAN), an animal model of GBS, have shown increased nociception sensitivity associated with T cell and macrophage infiltration of affected peripheral nerves [45]. This finding is parallel to what is known about GBS in humans. Additional studies in EAN have shown microglial cell infiltration also in the dorsal horn of the spinal cord of mice with increased sensitivity to noxious stimuli. These findings suggest that spinal microglia and associated signaling molecules and their receptors play a role in pain generation in GBS [46].
Management of Pain Immunotherapy in GBS with IVIG or plasma exchange within 2 weeks of onset has been shown to be an effective treatment that accelerates recovery [47–49]. IVIG is believed to bind autoantibodies targeting nerve epitopes and block complement activation, thus limiting nerve injury and nerve conduction failure [50]. Plasma exchange removes antibodies and complement involved in nerve injury. Neither treatment, however, is successful in adequately controlling pain in GBS. Historically, a wide selection of medications has been used to treat pain in GBS including non-steroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, anticonvulsants, tricyclic antidepressants, and neuroleptics [35, 51]. Clinicians have further reported a few cases of successful pain management with epidural opioids and capsaicin [51–53]. Prospective and randomized studies of pain management in GBS are few. The largest study recruited patients from a treatment trial investigating standard IVIG treatment in GBS compared to IVIG with added methylprednisolone intravenously for 5 days. There was no significant difference in disability scores at 4 weeks in the two treatment groups [54], and similarly there was no evidence for a significant effect on the presence or intensity of pain in the methylprednisolone group [55•]. Gabapentin has an established role in the treatment of chronic neuropathic pain [56] although its analgesic mechanism is poorly understood. A small double-blinded, placebocontrolled, crossover study in 18 GBS patients in intensive
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care showed lower mean pain scores in the gabapentin phase with no increase in adverse effects compared to the placebo phase [57]. Another small, randomized, double-blinded, placebo-controlled study of gabapentin, carbamazepine, and placebo in GBS patients, also in the intensive care unit, found lower median pain scores on all seven treatment days for gabapentin compared to both other groups, with no reported side effects [58]. These studies are small and provide lowquality evidence. However, as opioids cause sedation and NSAIDs have potentially serious gastrointestinal side effects, gabapentin remains an option with a significant track record in reducing neuropathic pain and limited side effects in this setting.
Conclusion Studies reporting the natural history of pain in GBS included patients that were already receiving pain treatment as needed. The persistent high prevalence of pain despite treatment underscores the primacy of pain in GBS, across different GBS variants and over time. Non-headache extremity and back pain is by far the most frequent and defining pain syndrome in GBS. Headache in GBS is uncommon, quite heterogeneous, and most well described in the context of PRES, which is an increasingly reported complication of GBS. At this time, there is limited data to make specific recommendations for back and extremity pain management. Clinicians may use gabapentin and opioids for breakthrough pain, but a proportion of patients are likely to remain refractory. Headache with PRES typically follows the self-limiting course of the acute neurologic and hemodynamic disturbance, and there appears to be no routine indication for specific headache treatment. The International Guillain-Barré syndrome Outcome Study (IGOS) is an ongoing international multicenter prospective study that is investigating biomarker prevalence and aims to develop models for early disease prognosis. An additional IGOS goal is to collect detailed prospective data on the natural history of pain in GBS and its variants. With enrollment expected to surpass the initial goal of 1000, this will be the largest prospective study of GBS to date and is likely to deepen the understanding of the illness’s natural history. While the mechanisms of pain in GBS are likely multiple, and the optimal approach for pain management is still emerging, more recent prospective longitudinal studies have firmly established the epidemiologic primacy of pain in GBS. In the modern era of GBS, pain should be understood as an additional cardinal disease manifestation along with extremity weakness, diminished reflexes, and various sensory symptoms.
Compliance with Ethics Guidelines Conflict of Interest Constantine Farmakidis reports personal fees from MNOW. Seniha Inan and Mark Milstein each declare no potential conflicts of interest. Steven Herskovitz reports personal fees from Oxford University Press. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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