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Corticosteroids in neurological disorders: The dark side
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
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Review article
Corticosteroids in neurological disorders: The dark side Dimitrios Parissis, Styliani-Aggeliki Syntila ⇑, Panos Ioannidis B’Department of Neurology, Aristotle University of Thessaloniki, AHEPA Hospital, Greece
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Article history: Received 20 September 2016 Accepted 29 May 2017 Available online xxxx
a b s t r a c t Corticosteroids are among the most commonly prescribed drugs by physicians of nearly all medical specialties. Their widespread use in clinical neurology is based either on randomized studies or, most often, on clinical experience and experts’ opinion. Besides the well-known adverse effects of corticosteroids, they may also induce or worsen certain neurological disorders. The purpose of this review is to highlight the negative impact of these drugs on these disorders with emphasis on putative pathophysiological mechanisms of this association. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Corticosteroids belong to the therapeutic armamentarium of clinical neurologists. Vast clinical experience has led to the extensive use of these drugs in the treatment of various neurological diseases. Common examples include, but are not limited to, inflammatory demyelinating disorders of the central nervous system (CNS), primary or secondary cerebral angiitis, infections and neoplasms of the CNS, acute spinal cord injury, myasthenia gravis, inflammatory myopathies and chronic demyelinating polyradiculoneuropathy. On the other hand, literature data have unveiled that corticosteroids are indeed harmful, instead of beneficial, in a subset of patients suffering from certain neurological disorders. In this review, we aim to make a brief report on this interesting relation, whereas, at the same time, we will attempt to indicate the underlying physiological links between steroids and worsening of neurological disease (Table 1). 1.1. Chronic inflammatory demyelinating polyradiculoneuropathy Current treatment guidelines consider corticosteroids as a firstline treatment (level C recommendation) for patients with sensory and motor chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [1]. However, deterioration after corticosteroids has been described in a proportion of patients with CIDP variants, such as motor dominant CIDP and Lewis-Sumner syndrome [2,3]. In the PREDICT trial, which compared dexamethasone with prednisolone in the treatment of CIDP, almost a quarter of the participants showed early deterioration, defined as any increase of the ⇑ Corresponding author at: B’ Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Stilponos Kyriakidi Street, 1, 54636 Thessaloniki, Greece. E-mail address: [email protected] (S.-A. Syntila).
Inflammatory Neuropathy Cause and Treatment (INCAT) scale within 8 weeks from drug onset [4]. Furthermore, a recent trial comparing intravenous (i.v.) immunoglobulin (IVIG) with i.v. methylprednisolone in CIDP disclosed a similar percentage of deteriorating patients in the steroids treatment arm [5]. Notably, a post hoc analysis of the PREDICT trial showed that the majority of worsening patients demonstrated a focal motor pattern of demyelination with prominent conduction blocks and reduced sensory abnormalities on nerve conduction studies [6]. Accordingly, it has been proposed that the above electrophysiological profile might be a risk factor for deterioration during steroids treatment, although this association needs to be confirmed [6]. In any case, The European Federation of Neurological Societies/ Peripheral Nerve Society (EFNS/PNS) treatment guidelines postulate that for pure motor CIDP, IVIG treatment should be the first choice and if corticosteroids are used, patients should be monitored closely for deterioration [1]. A possible explanation of this detrimental effect of corticosteroids might be axonal hyperpolarization by up-regulation of Na+/K+ pump activity [7]. Motor axons demonstrate reduced accommodation to hyperpolarizing membrane potential change and are more susceptible to conduction failure than sensory axons [7]. Corticosteroids have been demonstrated to modulate excitability in motor neurons resulting in hyperpolarization of resting membrane potential [8,9]. Steroids administration also enhances Na+/K+ pump expression in human skeletal muscle fibers [10]. These changes might predispose the already compromised and critically conducting motor axons of patients with CIDP to further conduction failure and block [11]. Interestingly, Chroni et al. reported 2 patients with pure sensory CIDP, who showed exacerbation of sensory symptoms and emerging of muscle weakness 2 weeks after initiation of prednisolone treatment [12]. A similar case was also described by Rajabally
http://dx.doi.org/10.1016/j.jocn.2017.05.040 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
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D. Parissis et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Table 1 A brief overview of neurological disorders prone to deteriorate by steroids. Possible mechanisms CIDP GBS
MMN MG Glioblastoma SDAVF CSCR Myopathy CIM SEL
Clinical trials +
+
Axonal hyperpolarization by up-regulation of Na /K pump activity Inhibition of macrophage function Negative effect on denervated muscle Minor effect on antiganglioside antibodies Similar to CIDP Post-synaptic inhibition Facilitation of Ach release Interference with cell-cycle related genes Decrease of radiological sensitivity Hypervolemia leading to venous hypertension, cord edema and infarction Retinal edema and choroid vessel dilatation Anti-anabolic capability Activation of proteolytic systems Sarcolemmal membrane inexcitability Necrosis of denervated muscle fibers Spinal cord compression
Case reports/series
+ +
+ +
+ +
Animal models
References
+ +
[4–11] [14–16] [19,20]
+
[2,22,23] [26–34]
+
[36–39]
+
+ + +
+ +
[40,41] [42–47] [48–57]
+
+
+
[58–72]
+
+
[73–75]
CIDP: chronic inflammatory demyelinating polyradiculoneuropathy; GBS: Guillain Barre syndrome; MMN: multifocal motor neuropathy; MG: myasthenia gravis; SDAVF: spinal dural arteriovenous fistula; CSCR: central serous chorioretinopathy; CIM: critical illness myopathy; SEL: spinal epidural lipomatosis.
et al. [13]. The authors assumed that steroids alter the balance of lymphocyte subpopulation in favor of B cells, thus increasing the circulating autoantibodies [2,12]. We think that it is still premature to conclude that steroids may be harmful in cases of pure sensory CIDP. 1.2. Guillain-Barre’ syndrome Oral steroids or intravenous methylprednisolone (500 mg/daily for 5 consecutive days) alone are not beneficial in Guillain Barre’ syndrome (GBS) [14,15]. In the high quality trial of van Koningsveld and colleagues, the combination of IVIG and i.v. methylprednisolone was not more effective than IVIG alone, although there was a minimal short term effect in favor of this combined therapy when prognostic variables were taken into statistical consideration [16]. However, according to recent meta-analysis of individual patients’ data from all existing trials, there is moderate quality evidence that corticosteroids do not significantly hasten recovery from GBS or affect the long-term outcome [17]. In addition, based on low quality evidence, oral corticosteroids may even delay recovery of patients with GBS [17]. The well defined lack of a more obvious effect of corticosteroids remains a puzzling issue in an inflammatory neuropathy such as GBS. Possible explanations include the minor effect of steroids on the toxicity of antiganglioside antibodies and subsequent complement activation, or their inhibitory action of macrophage function [18]. Macrophage stripping of myelin is a requirement for remyelination and its inhibition might delay or prevent the recovery process [16]. Alternatively, the harmful effect of steroids on denervated muscle has been implicated [19]. Not surprisingly, in an animal model of GBS, it has been difficult to show a positive effect of corticosteroids [20]. 1.3. Multifocal motor neuropathy Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterized by slowly progressive, asymmetrical weakness of limb muscles without sensory loss [21]. The electrophysiological hallmark of MMN is persistent conduction block (CB) limited to motor nerves. This selective vulnerability has been attributed to either distinct antigenic specificities between motor and sensory fibers or to a greater susceptibility of motor axons to conduction failure [22,23]. MMN patients respond remarkably well to immunotherapy with IVIG. Early deterioration after corticosteroids is a well-
recognized and enigmatic phenomenon reported in MMN [22,24]. It has been hypothesized that motor axons with focal demyelination or conduction block may be more vulnerable to the additional stress on normal membrane excitability produced by corticosteroid treatment [6,11]. Accordingly, the proposed mechanism is identical to the one previously reported in the section for CIDP. Not surprisingly, motor dominant CIDP and Lewis-Sumner patients display frequent and persistent conduction blocks similarly to MMN patients [23]. 1.4. Myasthenia gravis Oral prednisolone, usually started at a low dose on an alternateday regimen, and gradually increased, is the recommended firstchoice short-term immunosuppressant in the treatment of myasthenia gravis (MG) [25]. However, ‘‘paradoxical” exacerbation of myasthenic symptoms during the initiation of prednisolone is a well-known phenomenon [26]. Previous literature data showed inconsistent results concerning incidence and predictors of exacerbation due to methodological differences among these trials [27,28]. The reported frequency varies significantly between 25% and 80%; in about 10% of patients this phenomenon is severe, requiring mechanical ventilation or placement of a feeding tube. According to Bae et al., who used a strict definition of steroidinduced exacerbation, 42% of their patients experienced definite worsening, whereas older age, predominant bulbar symptoms and low Myasthenia Gravis Severity Scale (MGSS) score were independent clinical predictors [26]. Other potential associations, such as high steroid dose, presence of thymoma or high titer of acetylcholine receptor antibody were not identified as contributing factors in this trial. On the contrary, some authors claim this deterioration of symptoms rather represents a transient fluctuation of MG [26]. The pathophysiological substrate of this phenomenon is uncertain given the complex and miscellaneous actions of corticosteroids at the neuromuscular junction. It should be also noticed that most of the relevant literature data originate from studies published in the decades of 70 s and 80 s. Using a rat model of experimental autoimmune MG, Kim et al. showed that prednisolone has a depressive effect on neuromuscular transmission via inhibition at the post- synaptic level. Notably, this only occurred at high concentrations of the drug which are not achieved during treatment of this disease [29]. Similar findings suggesting a possible post-synaptic inhibitory action of steroids were found by other researchers too [30,31].
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
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On the other hand, these drugs attenuate neuromuscular block produced by anti-nicotinic muscle relaxants in both slow and fast skeletal muscle fibers [32]. Evidence for a direct, non-genomic presynaptic action of corticosteroids at motor endplates was corroborated by steroid-induced increases in the frequency and amplitude of miniature endplate potentials [33]. Interestingly, a recent pharmacological study provided strong evidence that methylprednisolone facilitates neuromuscular transmission by increasing the amount of acetylcholine release during high-frequency nerve activity [34]. Preliminary data from the same study suggest that the beneficial effects of corticosteroids depend on the activation of presynaptic muscarinic and adenosine receptors. Accordingly, corticosteroids exert both inhibitory and facilitatory actions on neuromuscular transmission. 1.5. Glioblastoma The administration of steroids to control neurological morbidity associated with brain tumors has been established as a standard of care decades ago. Except for primary central nervous system lymphoma, where steroids exert direct cytotoxic actions, amelioration of brain tumor-associated edema has been proposed to underlie their symptomatic effects in this group of patients [35]. Recently, Pitter et al. performed an interesting retrospective analysis of glioblastoma patients’ cohorts in order to determine the prognostic value of steroid administration in this population [36]. Rather surprisingly, their remarkable findings identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in human glioblastoma patients from three unrelated cohorts [36-38]. In addition, Shields et al. reported a similar negative influence of dexamethasone on survival parameters in a recent correlative analysis of 73 patients with glioblastoma [39]. In favor of their findings, Pitter et al. demonstrated also that dexamethasone compromises radiological efficacy in a murine glioblastoma model in vivo [36]. In these tumors, dexamethasone down regulated several cell cycle-related genes, offering a plausible explanation for a direct detrimental effect of steroids on radiological tissue sensitivity [36]. Alternatively, one cannot exclude that this negative effect of steroids results from the direct toxicity of these drugs, including steroid myopathy, impaired immune function and glucose control, adrenal insufficiency, and bowel perforation. 1.6. Spinal dural arteriovenous fistula Spinal dural arteriovenous fistulas (SDAWFs) are abnormal direct communications between a radicular artery and a radiculomedullary vein, which, in turn, retrogradely fills the coronal plexus around the spinal cord. Shunting of arterial blood flow causes venous congestion, venous hypertension and permanent cord damage in advanced cases [40,41]. To date, episodes of neurological deterioration triggered by steroid treatment has been reported in 7 patients with SDAVF. Presumably, corticosteroids induce transient hypervolemia, especially when given with a saline infusion. This may exaggerate venous hypertension, which further impairs to a critical point the already compromised anterograde venous drainage of the SDAVF, leading to aggravation of cord edema and eventual infarction [40]. Briefly, corticosteroid-induced paraplegia in a patient with a progressive and obscure myelopathy should lead to a thorough search for a SDAVF. 1.7. Central serous chorioretinopathy Central serous chorioretinopathy (CSCR) is a major cause of visual impairment among middle-aged males. We decided to
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include this strictly-speaking non-neurological disorder in the present review, because it may closely mimic idiopathic demyelinating optic neuritis and deteriorate by corticosteroids. CSCR is characterized by the development of a well-circumscribed serous detachment of the neurosensory retina resulting from altered external retinal blood barrier and retinal pigment epithelium. When the detachment involves the macula, the patients become symptomatic [42]. It is well established that corticosteroids can set off or worsen the pathology [43]. This knowledge is important, since a misdiagnosis of demyelinating optic neuritis results to inappropriate use of these drugs leading to visual deterioration. Glucocorticoid, as well as mineralocorticoid (MR) receptors, are expressed in the retina ganglion cells, inner retinal neurons and in endothelial cells of choroid and retinal vessels [44]. Experimental activation of the MR pathway by its ligand aldosterone has been shown to induce retinal edema and choroid vessel dilatation in vivo in the rat eye, making this model analogous to CSCR in humans [45]. The acknowledged link between corticoids and CSCR, has prompted the evaluation of MR antagonists (spironolactone, eplerenone) in the treatment of nonresolving CSCR. Indeed, several studies indicate that MR antagonists positively influence the reduction of subretinal fluid, facilitating the restoration of a healthy retinal anatomy [46,47]. 1.8. Myopathy Iatrogenic steroid myopathy is the most common endocrine associated myopathy to be encountered by clinicians. Cushing’s disease as well as ectopic adrenocorticotrophic hormone (ACTH) production may similarly affect skeletal muscle fibers [48]. Many pathological conditions characterized by muscle atrophy (sepsis, cachexia, starvation, metabolic acidosis, insulinopenia etc.) are associated with increase in circulating glucocorticoid levels [49]. These drugs do not appear to be required for disuse atrophy, but they may clearly exacerbate the deleterious effects of disuse on skeletal muscle mass [50]. Chronic corticosteroid myopathy is characterized by the gradual onset of symmetrical, painless muscle weakness, involving primarily the hip muscles and, to a lesser extent, the shoulder and proximal limb muscles. Plasma CK levels are typically normal, whereas electromyographic studies show either non-specific myopathic changes or normal findings [48]. Glucocorticoids have been shown to cause atrophy of type II fibers illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content, with less or no impact observed in type I fibers. On electron microscopy, enlarging, proliferation and degeneration of mitochondria have been described [51]. The mechanisms underlying the development of chronic corticosteroid myopathy, and in particular muscle atrophy, are complex and the pathophysiology is likely to be multifactorial. Glucocorticoids act primarily at the nuclear level interfering with protein metabolism. They exert an anti-anabolic action by blunting muscle protein synthesis. In particular, they inhibit the stimulatory action of insulin-growth factor-1 (IGF-1) on the phosphorylation of Eif4E-1 binding protein, which plays a key role in the protein synthesis machinery controlling the initial steps of m-RNA translation [52,53]. On the other hand, these drugs lead to muscle protein breakdown by activating several proteolytic systems, namely the ubiquitin-proteasome system, the lysosomal system and the calcium dependent system via upregulation of certain transcriptional factors [48]. Glucocorticoids also stimulate the production of the muscle of myostatin, a local growth factor that possesses strong
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
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muscle anti-anabolic capability [54]. A detailed description of the signalling pathways mediating steroid-induced muscle atrophy is beyond the scope of this review. Lastly, other mechanisms that have been suggested to underlie the development of steroid myopathy are mitochondrial dysfunction and oxidative damage to DNA in skeletal muscles [55]; hypokalemia and hypophosphatemia [56]; and direct alteration of the excitability of the sarcolemma [19,57]. 1.9. Critical illness myopathy Critical illness polyneuropathy (CIP) and myopathy (CIM) are major complications of severe critical illness and its management. Among many risk factors implicated, systemic inflammation response syndrome, sepsis and multiple organ failure appear to play a crucial role in CIP/CIM [58]. The impact of corticosteroids on neuromuscular function in the ICU has been the subject of debate. Early reports have found CIM to occur in patients treated with a combination of high doses of steroids and neuromuscular blocking agents [59,60]. In these patients the most commonly encountered abnormality consists of a selective loss of myosin thick filaments on ultrastructural studies [61]. Prospective studies in unselected intensive care unit (ICU) populations could not identify corticosteroids as an independent risk factor for CIP/CIM [62,63], although three other trials on weakness did [64-66]. Interestingly, the latter studies did not report or treat hyperglycemia, which is an independent risk factor for ICUacquired weakness [61]. These apparently contradicting findings suggest that the relationship between these drugs and neuromuscular complications in ICU patients is more complex and probably depends on other factors such as age, dose, timing and concomitant glycemic control [58]. Indeed, it has been suggested that corticosteroids may have a time-dependent effect on the neuromuscular system in critically ill patients characterized by a short-term protective effect and a longterm deleterious effect [61]. Functional denervation resulting from nerve injury in CIP may provide the link between CIP and CIM. Experimental corticosteroids-induced muscle alterations are significantly enhanced by limb denervation prior to steroids exposure, suggesting that in ICU patients the axonal component of CIP or a chemical denervation such as induced by neuromuscular blockers could increase muscle susceptibility to corticosteroids [61,67]. On the other hand, in an animal model, treatment of denervated muscle with corticosteroids causes more severe necrosis of muscle fibers than denervation alone [19]. It is also well established that muscle membrane dysfunction represents one of the principal physiological abnormalities in CIM [68]. It has been hypothesized that sepsis triggers muscle and, potentially, axonal electrical inexcitability [69]. This functional disturbance may be related to the inactivation of sodium channels at the resting potential and a shift in the voltage dependence of channel inactivation [70,71]. In this respect, the synergistic, negative action of corticosteroids on normal muscle excitability and resting membrane potentials could, in part, contribute to this phenomenon [70,72]. Theoretically, the well-known adverse effects of corticosteroids on muscle structure and functional integrity could act in concert with myo-toxic processes that characterize ICU stay, such as inflammation, immobilization, endocrine stress response, nutritional deficit and impaired microcirculation [58]. 1.10. Spinal epidural lipomatosis Spinal epidural lipomatosis (SEL) is a rare condition defined as a pathological overgrowth of normal fat tissue in the extradural
space. This accumulation causes potentially radiculopathy or compression of the spinal cord resulting in myelopathic neurological deficits [73]. SEL may be idiopathic or secondary to other factors. Among them, steroid excess, either iatrogenic or in the context of Cushing syndrome, is by far the most common etiological factor. SEL can be a complication of long-term corticosteroid treatment but rarely presents in an acute or subacute manner [74]. Approximately 25% of cases are attributed to obesity alone and it has been hypothesized that the increase of background epidural fat in obese people may render obese patients more vulnerable to rapid onset of corticosteroid-induced SEL [75]. Since steroids represent the cornerstone of treatment in many neurological conditions, SEL is an important complication to remember.
2. Conclusion Steroids should be handled with caution in the above mentioned neurological disorders. We cannot but emphasize that a diagnosis of steroid-induced deterioration may be given, only when other factors (e.g. disease or treatment related) have been excluded. At present, the precise pathophysiological mechanisms mediating this phenomenon are only indicative remaining to be clarified in future studies. Apart from theoretical interest, the ‘dark side’ of steroids in neurology has practical importance too. Namely, physicians should be familiar with it, in order to prevent, early recognise and properly treat steroid-associated worsening of neurological disease. References [1] Van den Bergh PY, Hadden RD, Bouche P, et al. European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological and the peripheral nerve society - first revision. Eur J Neurol 2010;17(3):356–63. http://dx.doi.org/ 10.1111/j.1468-1331.2009.02930.x. [2] Donaghy M, Mills KR, Boniface SJ, et al. Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778–83. [3] Viala K, Renié L, Maisonobe T, et al. Follow-up study and response to treatment in 23 patients with Lewis-Sumner syndrome. Brain 2004;127:2010–7. [4] van Schaik IN, Eftimov F, van Doorn PA, et al. Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial. Lancet Neurol 2010;9:245–53. [5] Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012;11:493–502. [6] Eftimov F, Liesdek MH, Verhamme C, van Schaik IN, PREDICT study group. Deterioration after corticosteroids in CIDP may be associated with pure focal demyelination pattern. BMC Neurol 2014;14(1):72. http://dx.doi.org/10.1186/ 1471-2377-14-72. [7] Kiernan MC, Lin CS, Burke D. Differences in activity-dependent hyperpolarization in human sensory and motor axons. J Physiol. 2004;558:341–9. [8] Hall ED. Glucocorticoid effects on the electrical properties of spinal motor neurons. Brain Res 1982;240:109–16. [9] Braughler JM, Hall ED. Acute enhancement of spinal cord synaptosomal (Na+ + K+)-ATPase activity in cats following intravenous methylprednisolone. Brain Res 1981;219:464–9. [10] Nordsborg N, Goodmann C, McKenna MJ, et al. Dexamethasone up-regulates skeletal muscle maximal Na+,K+ pump activity by muscle group specific mechanisms in humans. J Physiol 2005;567(Pt. 2):583–9. [11] Mathey EK, Park SB, Hughes RA, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry 2015;86(9):973–85. http://dx.doi.org/10.1136/jnnp-2014-309697. [12] Chroni E, Veltsista D, Gavanozi E, et al. Pure sensory chronic inflammatory polyneuropathy: rapid deterioration after steroid treatment. BMC Neurol 2015;15(27):27. http://dx.doi.org/10.1186/s12883-015-0291-7. [13] Rajabally YA, Wong SL. Chronic inflammatory pure sensory polyradiculoneuropathy: a rare CIDP variant with unusual electrophysiology. J Clin Neuromuscul Dis 2012;13(3):149–52. 10.1097.
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
D. Parissis et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx [14] Guillain-Barré Syndrome Steroid Trial Group. Double-blind trial of intravenous methylprednisolone in Guillain-Barré syndrome. Lancet 1993;341 (8845):586–90. [15] Hughes RA, Newsom-Davis JM, Perkin GD, et al. Controlled trial of prednisolone in acute polyneuropathy. Lancet 1978;2(8093):750–3. [16] van Koningsveld R, Schmitz PI, Meché FG, et al. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial. Lancet 2004;363(9404):192–6. [17] Hughes RA, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev 2012;8:. http://dx.doi.org/10.1002/14651858. CD001446.pub4. ReviewCD001446. [18] van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol 2008;7(10):939–50. http://dx.doi. org/10.1016/S1474-4422(08)70215-1. [19] Rich MM, Pinter MJ, Kraner SD, et al. Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol 1998;43(2):171–9. [20] King RH, Craggs RI, Gross ML, et al. Effects of glucocorticoids on experimental allergic neuritis. Exp Neurol 1985;87(1):9–19. [21] Dalakas MC. Pathogenesis of immune-mediated neuropathies. Biochim Biophys Acta 2015;1852(4):658–66. Epub 2014 Jun 17. [22] Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: the diagnostic spectrum and response to treatment. Neurology 2007;23(69):1680–7. [23] Lewis RA. Neuropathies associated with conduction block. Curr Opin Neurol 2007;20:525–30. [24] Nobile-Orazio E, Cappellari A, Priori A. Multifocal motor neuropathy: current concepts and controversies. Muscle Nerve 2005;6:663–80. [25] Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, et al. European Federation of Neurological Societies. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010;17(7):893–902. http://dx.doi.org/10.1111/j.1468-1331.2010.03019.x. [26] Bae JS, Go SM, Kim BJ. Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci 2006;13:1006–10. [27] Miller RG, Milner-Brown HS, Mirka A. Prednisone-induced worsening of neuromuscular function in myasthenia gravis. Neurology 1986;36:729–32. [28] Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984;15(3):291–8. [29] Kim YI, Goldner MM, Sanders DB. Short-term effects of prednisolone on neuromuscular transmission in normal rats and those with experimental autoimmune myasthenia gravis. J Neurol Sci 1979;41:223–34. [30] Barone DA, Lambert DH, Poser CM. Steroid treatment for experimental autoimmune myasthenia gravis. Arch Neurol 1980;37:663–6. [31] Wilson RW, Ward MD, Johns TR. Corticosteroids: a direct effect at the neuromuscular junction. Neurology 1974;24(11):1091–5. [32] Dal Belo CA, Leite GB, Fontana MD, et al. New evidence for a presynaptic action of prednisolone at neuromuscular junctions. Muscle Nerve 2002;26:37–43. [33] Makara GB, Haller J. Non-genomic effects of glucocorticoids in the neural system. Evidence, mechanisms and implications. Prog Neurobiol. 2001;65 (4):367–90. [34] Oliveira L, Costa AC, Noronha-Matos JB, et al. Amplification of neuromuscular transmission by methylprednisolone involves activation of presynaptic facilitatory adenosine A2A receptors and redistribution of synaptic vesicles. Neuropharmacology 2015;89:64–76. [35] Piette C, Munaut C, Foidart JM, Deprez M. Treating gliomas with glucocorticoids: from bedside to bench. Acta Neuropathol 2006;112:651–64. [36] Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain 2016;139(Pt 5):1458–71. http://dx.doi.org/10.1093/brain/aww046. [37] Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. [38] Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 2008;9:29–38. [39] Shields LB, Shelton BJ, Shearer AJ, et al. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol 2015;31(10):222. http://dx.doi.org/10.1186/s13014-015-0527-0. [40] O’Keeffe DT, Mikhail MA, Lanzino G, et al. Corticosteroid-Induced Paraplegia-A diagnostic clue for spinal dural arterial venous fistula. JAMA Neurol 2015;72 (7):833–4. 10.1001. [41] McKeon A, Lindell EP, Atkinson JL, Weinshenker BG, Piepgras DG, Pittock SJ. Pearls & Oy-sters: clues for spinal dural arteriovenous fistulae. Neurology 2011;76(3):e10–2. http://dx.doi.org/10.1212/WNL.0b013e3182074a42. [42] Milazzo S, Drimbea A, Betermiez P, et al. Diffuse multiple sclerosis and chronic central serous chorioretinopathy: pitfall not to ignore. Pract Neurol 2013;13:200–3. [43] Wakakura M, Song E, Ishikawa S. Corticosteroid-induced central serous chorioretinopathy. Jpn J Ophthalmol 1997;41(3):180–5. [44] Gallina D, Zelinka C, Fischer AJ. Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors. Development 2014;141(17):3340–51. http://dx.doi.org/10.1242/dev.109835.
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[45] Zhao M, Celenier I, Bousquet E, et al. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. J Clin Invest 2012;122:2672–9. [46] Bousquet E, Beydoun T, Rothschild PR, et al. Spironolactone for non-resolving central serous chorioretinopathy: a randomized controlled crossover study. Retina 2015;35:2505–15. [47] Ghadiali Q, Jung JJ, Yu S, et al. Central serous chorioretinopathy treated with mineralcorticoid antagonists: a one-year pilot study. Retina 2016;36 (3):611–8. http://dx.doi.org/10.1097/IAE.0000000000000748. [48] Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol 2008;197(1):1–10. http://dx.doi.org/10.1677/JOE-070606. [49] Lecker SH, Solomon V, Mitch WE, et al. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 1999;129(1S Suppl):227S–37S. [50] Fitts RH, Romatowski JG, Peters JR, et al. The deleterious effects of bed rest on human skeletal muscle fibers are exacerbated by hypercortisolemia and ameliorated by dietary supplementation. Am J Physiol Cell Physiol 2007;293 (1):C313–20. [51] Gupta A, Gupta Y. Glucocorticoid-induced myopathy: pathophysiology, diagnosis, and treatment. Indian J Endocrinol Metab 2013;17(5):913–6. http://dx.doi.org/10.4103/2230-8210.117215. [52] Shah OJ, Kimball SR, Jefferson LS. Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle. Am J Phys Endocrinol Metab 2000;278:E76–82. [53] Liu Z, Li G, Kimball SR, Jahn LA, Barrett, et al. Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle. Am J Phys Endocrinol Metab 2004;287:E275–81. [54] Welle S, Bhatt K, Pinkert CA. Myofibrillar protein synthesis in myostatindeficient mice. Am J Phys Endocrinol Metab 2006;290:E409–15. [55] Mitsui T, Azuma H, Nagasawa M, et al. Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle. J Neurol 2002;249 (8):1004–9. [56] Anagnos A, Ruffi RL, Kaminski H. Endocrine myopathies. Neurol Clin 1997;15:673–96. [57] Rich MM, Pinter MJ. Sodium channel inactivation in an animal model of acute quadriplegic myopathy. Ann Neurol 2001 Jul;50(1):26–33. [58] Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness. Crit Care 2015;5(19):274. http://dx.doi.org/10.1186/s13054-0150993-7. Review. [59] MacFarlane IA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet 1977;2(8038):615. [60] Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol 2011;10(10):931–41. http://dx.doi.org/10.1016/S1474-4422(11)70178-8. [61] Hermans G, De Jonghe B, Bruyninckx F, et al. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008;12(6):238. [62] Bednarík J, Vondracek P, Dusek L, et al. Risk factors for critical illness polyneuromyopathy. J Neurol 2005;252(3):343–51. [63] Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005;64(8):1348–53. [64] De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288(22):2859–67. [65] Campellone JV, Lacomis D, Kramer DJ, et al. Acute myopathy after liver transplantation. Neurology 1998;50(1):46–53. [66] Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348(8):683–93. [67] Massa R, Carpenter S, Holland P, et al. Loss and renewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnervation. Muscle Nerve 1992;15(11):1290–8. [68] Allen DC, Arunachalam R, Mills KR. Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy. Muscle Nerve 2008;37(1):14–22. [69] Z’Graggen WJ, Lin CS, Howard RS, et al. Nerve excitability changes in critical illness polyneuropathy. Brain 2006;129(Pt. 9):2461–70. [70] Rich MM, Pinter MJ. Crucial role of sodium channel fast inactivation in muscle fibre inexcitability in a rat model of critical illness myopathy. J Physiol 2003;547(Pt 2):555–66. [71] Filatov GN, Rich MM. Hyperpolarized shifts in the voltage dependence of fast inactivation of Nav1.4 and Nav1.5 in a rat model of critical illness myopathy. J Physiol 2004;559(Pt. 3):813–20. Epub 2004 Jul 14. [72] Rich MM, Kraner SD, Barchi RL. Altered gene expression in steroid-treated denervated muscle. Neurobiol Dis 1999;6(6):515–22. [73] Al-Khawaja D, Seex K, Eslick GD. Spinal epidural lipomatosis–a brief review. J Clin Neurosci 2008;15(12):1323–6. http://dx.doi.org/10.1016/j. jocn.2008.03.001. [74] Fogel GR, Cunningham 3rd PY, Esses SI. Spinal epidural lipomatosis: case reports, literature review and meta-analysis. Spine J 2005;5(2):202–11. [75] Lynch RW, Soane T, Gibson R, Pal S, Lees CW. Bilateral lower limb weakness in acute severe ulcerative colitis. Lancet 2016;388(10039):101–2. http://dx.doi. org/10.1016/S0140-6736(16)30857-1.
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Review article
Corticosteroids in neurological disorders: The dark side Dimitrios Parissis, Styliani-Aggeliki Syntila ⇑, Panos Ioannidis B’Department of Neurology, Aristotle University of Thessaloniki, AHEPA Hospital, Greece
a r t i c l e
i n f o
Article history: Received 20 September 2016 Accepted 29 May 2017 Available online xxxx
a b s t r a c t Corticosteroids are among the most commonly prescribed drugs by physicians of nearly all medical specialties. Their widespread use in clinical neurology is based either on randomized studies or, most often, on clinical experience and experts’ opinion. Besides the well-known adverse effects of corticosteroids, they may also induce or worsen certain neurological disorders. The purpose of this review is to highlight the negative impact of these drugs on these disorders with emphasis on putative pathophysiological mechanisms of this association. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Corticosteroids belong to the therapeutic armamentarium of clinical neurologists. Vast clinical experience has led to the extensive use of these drugs in the treatment of various neurological diseases. Common examples include, but are not limited to, inflammatory demyelinating disorders of the central nervous system (CNS), primary or secondary cerebral angiitis, infections and neoplasms of the CNS, acute spinal cord injury, myasthenia gravis, inflammatory myopathies and chronic demyelinating polyradiculoneuropathy. On the other hand, literature data have unveiled that corticosteroids are indeed harmful, instead of beneficial, in a subset of patients suffering from certain neurological disorders. In this review, we aim to make a brief report on this interesting relation, whereas, at the same time, we will attempt to indicate the underlying physiological links between steroids and worsening of neurological disease (Table 1). 1.1. Chronic inflammatory demyelinating polyradiculoneuropathy Current treatment guidelines consider corticosteroids as a firstline treatment (level C recommendation) for patients with sensory and motor chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [1]. However, deterioration after corticosteroids has been described in a proportion of patients with CIDP variants, such as motor dominant CIDP and Lewis-Sumner syndrome [2,3]. In the PREDICT trial, which compared dexamethasone with prednisolone in the treatment of CIDP, almost a quarter of the participants showed early deterioration, defined as any increase of the ⇑ Corresponding author at: B’ Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Stilponos Kyriakidi Street, 1, 54636 Thessaloniki, Greece. E-mail address: [email protected] (S.-A. Syntila).
Inflammatory Neuropathy Cause and Treatment (INCAT) scale within 8 weeks from drug onset [4]. Furthermore, a recent trial comparing intravenous (i.v.) immunoglobulin (IVIG) with i.v. methylprednisolone in CIDP disclosed a similar percentage of deteriorating patients in the steroids treatment arm [5]. Notably, a post hoc analysis of the PREDICT trial showed that the majority of worsening patients demonstrated a focal motor pattern of demyelination with prominent conduction blocks and reduced sensory abnormalities on nerve conduction studies [6]. Accordingly, it has been proposed that the above electrophysiological profile might be a risk factor for deterioration during steroids treatment, although this association needs to be confirmed [6]. In any case, The European Federation of Neurological Societies/ Peripheral Nerve Society (EFNS/PNS) treatment guidelines postulate that for pure motor CIDP, IVIG treatment should be the first choice and if corticosteroids are used, patients should be monitored closely for deterioration [1]. A possible explanation of this detrimental effect of corticosteroids might be axonal hyperpolarization by up-regulation of Na+/K+ pump activity [7]. Motor axons demonstrate reduced accommodation to hyperpolarizing membrane potential change and are more susceptible to conduction failure than sensory axons [7]. Corticosteroids have been demonstrated to modulate excitability in motor neurons resulting in hyperpolarization of resting membrane potential [8,9]. Steroids administration also enhances Na+/K+ pump expression in human skeletal muscle fibers [10]. These changes might predispose the already compromised and critically conducting motor axons of patients with CIDP to further conduction failure and block [11]. Interestingly, Chroni et al. reported 2 patients with pure sensory CIDP, who showed exacerbation of sensory symptoms and emerging of muscle weakness 2 weeks after initiation of prednisolone treatment [12]. A similar case was also described by Rajabally
http://dx.doi.org/10.1016/j.jocn.2017.05.040 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
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Table 1 A brief overview of neurological disorders prone to deteriorate by steroids. Possible mechanisms CIDP GBS
MMN MG Glioblastoma SDAVF CSCR Myopathy CIM SEL
Clinical trials +
+
Axonal hyperpolarization by up-regulation of Na /K pump activity Inhibition of macrophage function Negative effect on denervated muscle Minor effect on antiganglioside antibodies Similar to CIDP Post-synaptic inhibition Facilitation of Ach release Interference with cell-cycle related genes Decrease of radiological sensitivity Hypervolemia leading to venous hypertension, cord edema and infarction Retinal edema and choroid vessel dilatation Anti-anabolic capability Activation of proteolytic systems Sarcolemmal membrane inexcitability Necrosis of denervated muscle fibers Spinal cord compression
Case reports/series
+ +
+ +
+ +
Animal models
References
+ +
[4–11] [14–16] [19,20]
+
[2,22,23] [26–34]
+
[36–39]
+
+ + +
+ +
[40,41] [42–47] [48–57]
+
+
+
[58–72]
+
+
[73–75]
CIDP: chronic inflammatory demyelinating polyradiculoneuropathy; GBS: Guillain Barre syndrome; MMN: multifocal motor neuropathy; MG: myasthenia gravis; SDAVF: spinal dural arteriovenous fistula; CSCR: central serous chorioretinopathy; CIM: critical illness myopathy; SEL: spinal epidural lipomatosis.
et al. [13]. The authors assumed that steroids alter the balance of lymphocyte subpopulation in favor of B cells, thus increasing the circulating autoantibodies [2,12]. We think that it is still premature to conclude that steroids may be harmful in cases of pure sensory CIDP. 1.2. Guillain-Barre’ syndrome Oral steroids or intravenous methylprednisolone (500 mg/daily for 5 consecutive days) alone are not beneficial in Guillain Barre’ syndrome (GBS) [14,15]. In the high quality trial of van Koningsveld and colleagues, the combination of IVIG and i.v. methylprednisolone was not more effective than IVIG alone, although there was a minimal short term effect in favor of this combined therapy when prognostic variables were taken into statistical consideration [16]. However, according to recent meta-analysis of individual patients’ data from all existing trials, there is moderate quality evidence that corticosteroids do not significantly hasten recovery from GBS or affect the long-term outcome [17]. In addition, based on low quality evidence, oral corticosteroids may even delay recovery of patients with GBS [17]. The well defined lack of a more obvious effect of corticosteroids remains a puzzling issue in an inflammatory neuropathy such as GBS. Possible explanations include the minor effect of steroids on the toxicity of antiganglioside antibodies and subsequent complement activation, or their inhibitory action of macrophage function [18]. Macrophage stripping of myelin is a requirement for remyelination and its inhibition might delay or prevent the recovery process [16]. Alternatively, the harmful effect of steroids on denervated muscle has been implicated [19]. Not surprisingly, in an animal model of GBS, it has been difficult to show a positive effect of corticosteroids [20]. 1.3. Multifocal motor neuropathy Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterized by slowly progressive, asymmetrical weakness of limb muscles without sensory loss [21]. The electrophysiological hallmark of MMN is persistent conduction block (CB) limited to motor nerves. This selective vulnerability has been attributed to either distinct antigenic specificities between motor and sensory fibers or to a greater susceptibility of motor axons to conduction failure [22,23]. MMN patients respond remarkably well to immunotherapy with IVIG. Early deterioration after corticosteroids is a well-
recognized and enigmatic phenomenon reported in MMN [22,24]. It has been hypothesized that motor axons with focal demyelination or conduction block may be more vulnerable to the additional stress on normal membrane excitability produced by corticosteroid treatment [6,11]. Accordingly, the proposed mechanism is identical to the one previously reported in the section for CIDP. Not surprisingly, motor dominant CIDP and Lewis-Sumner patients display frequent and persistent conduction blocks similarly to MMN patients [23]. 1.4. Myasthenia gravis Oral prednisolone, usually started at a low dose on an alternateday regimen, and gradually increased, is the recommended firstchoice short-term immunosuppressant in the treatment of myasthenia gravis (MG) [25]. However, ‘‘paradoxical” exacerbation of myasthenic symptoms during the initiation of prednisolone is a well-known phenomenon [26]. Previous literature data showed inconsistent results concerning incidence and predictors of exacerbation due to methodological differences among these trials [27,28]. The reported frequency varies significantly between 25% and 80%; in about 10% of patients this phenomenon is severe, requiring mechanical ventilation or placement of a feeding tube. According to Bae et al., who used a strict definition of steroidinduced exacerbation, 42% of their patients experienced definite worsening, whereas older age, predominant bulbar symptoms and low Myasthenia Gravis Severity Scale (MGSS) score were independent clinical predictors [26]. Other potential associations, such as high steroid dose, presence of thymoma or high titer of acetylcholine receptor antibody were not identified as contributing factors in this trial. On the contrary, some authors claim this deterioration of symptoms rather represents a transient fluctuation of MG [26]. The pathophysiological substrate of this phenomenon is uncertain given the complex and miscellaneous actions of corticosteroids at the neuromuscular junction. It should be also noticed that most of the relevant literature data originate from studies published in the decades of 70 s and 80 s. Using a rat model of experimental autoimmune MG, Kim et al. showed that prednisolone has a depressive effect on neuromuscular transmission via inhibition at the post- synaptic level. Notably, this only occurred at high concentrations of the drug which are not achieved during treatment of this disease [29]. Similar findings suggesting a possible post-synaptic inhibitory action of steroids were found by other researchers too [30,31].
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On the other hand, these drugs attenuate neuromuscular block produced by anti-nicotinic muscle relaxants in both slow and fast skeletal muscle fibers [32]. Evidence for a direct, non-genomic presynaptic action of corticosteroids at motor endplates was corroborated by steroid-induced increases in the frequency and amplitude of miniature endplate potentials [33]. Interestingly, a recent pharmacological study provided strong evidence that methylprednisolone facilitates neuromuscular transmission by increasing the amount of acetylcholine release during high-frequency nerve activity [34]. Preliminary data from the same study suggest that the beneficial effects of corticosteroids depend on the activation of presynaptic muscarinic and adenosine receptors. Accordingly, corticosteroids exert both inhibitory and facilitatory actions on neuromuscular transmission. 1.5. Glioblastoma The administration of steroids to control neurological morbidity associated with brain tumors has been established as a standard of care decades ago. Except for primary central nervous system lymphoma, where steroids exert direct cytotoxic actions, amelioration of brain tumor-associated edema has been proposed to underlie their symptomatic effects in this group of patients [35]. Recently, Pitter et al. performed an interesting retrospective analysis of glioblastoma patients’ cohorts in order to determine the prognostic value of steroid administration in this population [36]. Rather surprisingly, their remarkable findings identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in human glioblastoma patients from three unrelated cohorts [36-38]. In addition, Shields et al. reported a similar negative influence of dexamethasone on survival parameters in a recent correlative analysis of 73 patients with glioblastoma [39]. In favor of their findings, Pitter et al. demonstrated also that dexamethasone compromises radiological efficacy in a murine glioblastoma model in vivo [36]. In these tumors, dexamethasone down regulated several cell cycle-related genes, offering a plausible explanation for a direct detrimental effect of steroids on radiological tissue sensitivity [36]. Alternatively, one cannot exclude that this negative effect of steroids results from the direct toxicity of these drugs, including steroid myopathy, impaired immune function and glucose control, adrenal insufficiency, and bowel perforation. 1.6. Spinal dural arteriovenous fistula Spinal dural arteriovenous fistulas (SDAWFs) are abnormal direct communications between a radicular artery and a radiculomedullary vein, which, in turn, retrogradely fills the coronal plexus around the spinal cord. Shunting of arterial blood flow causes venous congestion, venous hypertension and permanent cord damage in advanced cases [40,41]. To date, episodes of neurological deterioration triggered by steroid treatment has been reported in 7 patients with SDAVF. Presumably, corticosteroids induce transient hypervolemia, especially when given with a saline infusion. This may exaggerate venous hypertension, which further impairs to a critical point the already compromised anterograde venous drainage of the SDAVF, leading to aggravation of cord edema and eventual infarction [40]. Briefly, corticosteroid-induced paraplegia in a patient with a progressive and obscure myelopathy should lead to a thorough search for a SDAVF. 1.7. Central serous chorioretinopathy Central serous chorioretinopathy (CSCR) is a major cause of visual impairment among middle-aged males. We decided to
3
include this strictly-speaking non-neurological disorder in the present review, because it may closely mimic idiopathic demyelinating optic neuritis and deteriorate by corticosteroids. CSCR is characterized by the development of a well-circumscribed serous detachment of the neurosensory retina resulting from altered external retinal blood barrier and retinal pigment epithelium. When the detachment involves the macula, the patients become symptomatic [42]. It is well established that corticosteroids can set off or worsen the pathology [43]. This knowledge is important, since a misdiagnosis of demyelinating optic neuritis results to inappropriate use of these drugs leading to visual deterioration. Glucocorticoid, as well as mineralocorticoid (MR) receptors, are expressed in the retina ganglion cells, inner retinal neurons and in endothelial cells of choroid and retinal vessels [44]. Experimental activation of the MR pathway by its ligand aldosterone has been shown to induce retinal edema and choroid vessel dilatation in vivo in the rat eye, making this model analogous to CSCR in humans [45]. The acknowledged link between corticoids and CSCR, has prompted the evaluation of MR antagonists (spironolactone, eplerenone) in the treatment of nonresolving CSCR. Indeed, several studies indicate that MR antagonists positively influence the reduction of subretinal fluid, facilitating the restoration of a healthy retinal anatomy [46,47]. 1.8. Myopathy Iatrogenic steroid myopathy is the most common endocrine associated myopathy to be encountered by clinicians. Cushing’s disease as well as ectopic adrenocorticotrophic hormone (ACTH) production may similarly affect skeletal muscle fibers [48]. Many pathological conditions characterized by muscle atrophy (sepsis, cachexia, starvation, metabolic acidosis, insulinopenia etc.) are associated with increase in circulating glucocorticoid levels [49]. These drugs do not appear to be required for disuse atrophy, but they may clearly exacerbate the deleterious effects of disuse on skeletal muscle mass [50]. Chronic corticosteroid myopathy is characterized by the gradual onset of symmetrical, painless muscle weakness, involving primarily the hip muscles and, to a lesser extent, the shoulder and proximal limb muscles. Plasma CK levels are typically normal, whereas electromyographic studies show either non-specific myopathic changes or normal findings [48]. Glucocorticoids have been shown to cause atrophy of type II fibers illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content, with less or no impact observed in type I fibers. On electron microscopy, enlarging, proliferation and degeneration of mitochondria have been described [51]. The mechanisms underlying the development of chronic corticosteroid myopathy, and in particular muscle atrophy, are complex and the pathophysiology is likely to be multifactorial. Glucocorticoids act primarily at the nuclear level interfering with protein metabolism. They exert an anti-anabolic action by blunting muscle protein synthesis. In particular, they inhibit the stimulatory action of insulin-growth factor-1 (IGF-1) on the phosphorylation of Eif4E-1 binding protein, which plays a key role in the protein synthesis machinery controlling the initial steps of m-RNA translation [52,53]. On the other hand, these drugs lead to muscle protein breakdown by activating several proteolytic systems, namely the ubiquitin-proteasome system, the lysosomal system and the calcium dependent system via upregulation of certain transcriptional factors [48]. Glucocorticoids also stimulate the production of the muscle of myostatin, a local growth factor that possesses strong
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muscle anti-anabolic capability [54]. A detailed description of the signalling pathways mediating steroid-induced muscle atrophy is beyond the scope of this review. Lastly, other mechanisms that have been suggested to underlie the development of steroid myopathy are mitochondrial dysfunction and oxidative damage to DNA in skeletal muscles [55]; hypokalemia and hypophosphatemia [56]; and direct alteration of the excitability of the sarcolemma [19,57]. 1.9. Critical illness myopathy Critical illness polyneuropathy (CIP) and myopathy (CIM) are major complications of severe critical illness and its management. Among many risk factors implicated, systemic inflammation response syndrome, sepsis and multiple organ failure appear to play a crucial role in CIP/CIM [58]. The impact of corticosteroids on neuromuscular function in the ICU has been the subject of debate. Early reports have found CIM to occur in patients treated with a combination of high doses of steroids and neuromuscular blocking agents [59,60]. In these patients the most commonly encountered abnormality consists of a selective loss of myosin thick filaments on ultrastructural studies [61]. Prospective studies in unselected intensive care unit (ICU) populations could not identify corticosteroids as an independent risk factor for CIP/CIM [62,63], although three other trials on weakness did [64-66]. Interestingly, the latter studies did not report or treat hyperglycemia, which is an independent risk factor for ICUacquired weakness [61]. These apparently contradicting findings suggest that the relationship between these drugs and neuromuscular complications in ICU patients is more complex and probably depends on other factors such as age, dose, timing and concomitant glycemic control [58]. Indeed, it has been suggested that corticosteroids may have a time-dependent effect on the neuromuscular system in critically ill patients characterized by a short-term protective effect and a longterm deleterious effect [61]. Functional denervation resulting from nerve injury in CIP may provide the link between CIP and CIM. Experimental corticosteroids-induced muscle alterations are significantly enhanced by limb denervation prior to steroids exposure, suggesting that in ICU patients the axonal component of CIP or a chemical denervation such as induced by neuromuscular blockers could increase muscle susceptibility to corticosteroids [61,67]. On the other hand, in an animal model, treatment of denervated muscle with corticosteroids causes more severe necrosis of muscle fibers than denervation alone [19]. It is also well established that muscle membrane dysfunction represents one of the principal physiological abnormalities in CIM [68]. It has been hypothesized that sepsis triggers muscle and, potentially, axonal electrical inexcitability [69]. This functional disturbance may be related to the inactivation of sodium channels at the resting potential and a shift in the voltage dependence of channel inactivation [70,71]. In this respect, the synergistic, negative action of corticosteroids on normal muscle excitability and resting membrane potentials could, in part, contribute to this phenomenon [70,72]. Theoretically, the well-known adverse effects of corticosteroids on muscle structure and functional integrity could act in concert with myo-toxic processes that characterize ICU stay, such as inflammation, immobilization, endocrine stress response, nutritional deficit and impaired microcirculation [58]. 1.10. Spinal epidural lipomatosis Spinal epidural lipomatosis (SEL) is a rare condition defined as a pathological overgrowth of normal fat tissue in the extradural
space. This accumulation causes potentially radiculopathy or compression of the spinal cord resulting in myelopathic neurological deficits [73]. SEL may be idiopathic or secondary to other factors. Among them, steroid excess, either iatrogenic or in the context of Cushing syndrome, is by far the most common etiological factor. SEL can be a complication of long-term corticosteroid treatment but rarely presents in an acute or subacute manner [74]. Approximately 25% of cases are attributed to obesity alone and it has been hypothesized that the increase of background epidural fat in obese people may render obese patients more vulnerable to rapid onset of corticosteroid-induced SEL [75]. Since steroids represent the cornerstone of treatment in many neurological conditions, SEL is an important complication to remember.
2. Conclusion Steroids should be handled with caution in the above mentioned neurological disorders. We cannot but emphasize that a diagnosis of steroid-induced deterioration may be given, only when other factors (e.g. disease or treatment related) have been excluded. At present, the precise pathophysiological mechanisms mediating this phenomenon are only indicative remaining to be clarified in future studies. Apart from theoretical interest, the ‘dark side’ of steroids in neurology has practical importance too. Namely, physicians should be familiar with it, in order to prevent, early recognise and properly treat steroid-associated worsening of neurological disease. References [1] Van den Bergh PY, Hadden RD, Bouche P, et al. European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological and the peripheral nerve society - first revision. Eur J Neurol 2010;17(3):356–63. http://dx.doi.org/ 10.1111/j.1468-1331.2009.02930.x. [2] Donaghy M, Mills KR, Boniface SJ, et al. Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778–83. [3] Viala K, Renié L, Maisonobe T, et al. Follow-up study and response to treatment in 23 patients with Lewis-Sumner syndrome. Brain 2004;127:2010–7. [4] van Schaik IN, Eftimov F, van Doorn PA, et al. Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial. Lancet Neurol 2010;9:245–53. [5] Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012;11:493–502. [6] Eftimov F, Liesdek MH, Verhamme C, van Schaik IN, PREDICT study group. Deterioration after corticosteroids in CIDP may be associated with pure focal demyelination pattern. BMC Neurol 2014;14(1):72. http://dx.doi.org/10.1186/ 1471-2377-14-72. [7] Kiernan MC, Lin CS, Burke D. Differences in activity-dependent hyperpolarization in human sensory and motor axons. J Physiol. 2004;558:341–9. [8] Hall ED. Glucocorticoid effects on the electrical properties of spinal motor neurons. Brain Res 1982;240:109–16. [9] Braughler JM, Hall ED. Acute enhancement of spinal cord synaptosomal (Na+ + K+)-ATPase activity in cats following intravenous methylprednisolone. Brain Res 1981;219:464–9. [10] Nordsborg N, Goodmann C, McKenna MJ, et al. Dexamethasone up-regulates skeletal muscle maximal Na+,K+ pump activity by muscle group specific mechanisms in humans. J Physiol 2005;567(Pt. 2):583–9. [11] Mathey EK, Park SB, Hughes RA, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry 2015;86(9):973–85. http://dx.doi.org/10.1136/jnnp-2014-309697. [12] Chroni E, Veltsista D, Gavanozi E, et al. Pure sensory chronic inflammatory polyneuropathy: rapid deterioration after steroid treatment. BMC Neurol 2015;15(27):27. http://dx.doi.org/10.1186/s12883-015-0291-7. [13] Rajabally YA, Wong SL. Chronic inflammatory pure sensory polyradiculoneuropathy: a rare CIDP variant with unusual electrophysiology. J Clin Neuromuscul Dis 2012;13(3):149–52. 10.1097.
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040
D. Parissis et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx [14] Guillain-Barré Syndrome Steroid Trial Group. Double-blind trial of intravenous methylprednisolone in Guillain-Barré syndrome. Lancet 1993;341 (8845):586–90. [15] Hughes RA, Newsom-Davis JM, Perkin GD, et al. Controlled trial of prednisolone in acute polyneuropathy. Lancet 1978;2(8093):750–3. [16] van Koningsveld R, Schmitz PI, Meché FG, et al. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial. Lancet 2004;363(9404):192–6. [17] Hughes RA, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev 2012;8:. http://dx.doi.org/10.1002/14651858. CD001446.pub4. ReviewCD001446. [18] van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol 2008;7(10):939–50. http://dx.doi. org/10.1016/S1474-4422(08)70215-1. [19] Rich MM, Pinter MJ, Kraner SD, et al. Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol 1998;43(2):171–9. [20] King RH, Craggs RI, Gross ML, et al. Effects of glucocorticoids on experimental allergic neuritis. Exp Neurol 1985;87(1):9–19. [21] Dalakas MC. Pathogenesis of immune-mediated neuropathies. Biochim Biophys Acta 2015;1852(4):658–66. Epub 2014 Jun 17. [22] Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: the diagnostic spectrum and response to treatment. Neurology 2007;23(69):1680–7. [23] Lewis RA. Neuropathies associated with conduction block. Curr Opin Neurol 2007;20:525–30. [24] Nobile-Orazio E, Cappellari A, Priori A. Multifocal motor neuropathy: current concepts and controversies. Muscle Nerve 2005;6:663–80. [25] Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, et al. European Federation of Neurological Societies. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010;17(7):893–902. http://dx.doi.org/10.1111/j.1468-1331.2010.03019.x. [26] Bae JS, Go SM, Kim BJ. Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci 2006;13:1006–10. [27] Miller RG, Milner-Brown HS, Mirka A. Prednisone-induced worsening of neuromuscular function in myasthenia gravis. Neurology 1986;36:729–32. [28] Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984;15(3):291–8. [29] Kim YI, Goldner MM, Sanders DB. Short-term effects of prednisolone on neuromuscular transmission in normal rats and those with experimental autoimmune myasthenia gravis. J Neurol Sci 1979;41:223–34. [30] Barone DA, Lambert DH, Poser CM. Steroid treatment for experimental autoimmune myasthenia gravis. Arch Neurol 1980;37:663–6. [31] Wilson RW, Ward MD, Johns TR. Corticosteroids: a direct effect at the neuromuscular junction. Neurology 1974;24(11):1091–5. [32] Dal Belo CA, Leite GB, Fontana MD, et al. New evidence for a presynaptic action of prednisolone at neuromuscular junctions. Muscle Nerve 2002;26:37–43. [33] Makara GB, Haller J. Non-genomic effects of glucocorticoids in the neural system. Evidence, mechanisms and implications. Prog Neurobiol. 2001;65 (4):367–90. [34] Oliveira L, Costa AC, Noronha-Matos JB, et al. Amplification of neuromuscular transmission by methylprednisolone involves activation of presynaptic facilitatory adenosine A2A receptors and redistribution of synaptic vesicles. Neuropharmacology 2015;89:64–76. [35] Piette C, Munaut C, Foidart JM, Deprez M. Treating gliomas with glucocorticoids: from bedside to bench. Acta Neuropathol 2006;112:651–64. [36] Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain 2016;139(Pt 5):1458–71. http://dx.doi.org/10.1093/brain/aww046. [37] Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. [38] Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 2008;9:29–38. [39] Shields LB, Shelton BJ, Shearer AJ, et al. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol 2015;31(10):222. http://dx.doi.org/10.1186/s13014-015-0527-0. [40] O’Keeffe DT, Mikhail MA, Lanzino G, et al. Corticosteroid-Induced Paraplegia-A diagnostic clue for spinal dural arterial venous fistula. JAMA Neurol 2015;72 (7):833–4. 10.1001. [41] McKeon A, Lindell EP, Atkinson JL, Weinshenker BG, Piepgras DG, Pittock SJ. Pearls & Oy-sters: clues for spinal dural arteriovenous fistulae. Neurology 2011;76(3):e10–2. http://dx.doi.org/10.1212/WNL.0b013e3182074a42. [42] Milazzo S, Drimbea A, Betermiez P, et al. Diffuse multiple sclerosis and chronic central serous chorioretinopathy: pitfall not to ignore. Pract Neurol 2013;13:200–3. [43] Wakakura M, Song E, Ishikawa S. Corticosteroid-induced central serous chorioretinopathy. Jpn J Ophthalmol 1997;41(3):180–5. [44] Gallina D, Zelinka C, Fischer AJ. Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors. Development 2014;141(17):3340–51. http://dx.doi.org/10.1242/dev.109835.
5
[45] Zhao M, Celenier I, Bousquet E, et al. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. J Clin Invest 2012;122:2672–9. [46] Bousquet E, Beydoun T, Rothschild PR, et al. Spironolactone for non-resolving central serous chorioretinopathy: a randomized controlled crossover study. Retina 2015;35:2505–15. [47] Ghadiali Q, Jung JJ, Yu S, et al. Central serous chorioretinopathy treated with mineralcorticoid antagonists: a one-year pilot study. Retina 2016;36 (3):611–8. http://dx.doi.org/10.1097/IAE.0000000000000748. [48] Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol 2008;197(1):1–10. http://dx.doi.org/10.1677/JOE-070606. [49] Lecker SH, Solomon V, Mitch WE, et al. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 1999;129(1S Suppl):227S–37S. [50] Fitts RH, Romatowski JG, Peters JR, et al. The deleterious effects of bed rest on human skeletal muscle fibers are exacerbated by hypercortisolemia and ameliorated by dietary supplementation. Am J Physiol Cell Physiol 2007;293 (1):C313–20. [51] Gupta A, Gupta Y. Glucocorticoid-induced myopathy: pathophysiology, diagnosis, and treatment. Indian J Endocrinol Metab 2013;17(5):913–6. http://dx.doi.org/10.4103/2230-8210.117215. [52] Shah OJ, Kimball SR, Jefferson LS. Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle. Am J Phys Endocrinol Metab 2000;278:E76–82. [53] Liu Z, Li G, Kimball SR, Jahn LA, Barrett, et al. Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle. Am J Phys Endocrinol Metab 2004;287:E275–81. [54] Welle S, Bhatt K, Pinkert CA. Myofibrillar protein synthesis in myostatindeficient mice. Am J Phys Endocrinol Metab 2006;290:E409–15. [55] Mitsui T, Azuma H, Nagasawa M, et al. Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle. J Neurol 2002;249 (8):1004–9. [56] Anagnos A, Ruffi RL, Kaminski H. Endocrine myopathies. Neurol Clin 1997;15:673–96. [57] Rich MM, Pinter MJ. Sodium channel inactivation in an animal model of acute quadriplegic myopathy. Ann Neurol 2001 Jul;50(1):26–33. [58] Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness. Crit Care 2015;5(19):274. http://dx.doi.org/10.1186/s13054-0150993-7. Review. [59] MacFarlane IA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet 1977;2(8038):615. [60] Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol 2011;10(10):931–41. http://dx.doi.org/10.1016/S1474-4422(11)70178-8. [61] Hermans G, De Jonghe B, Bruyninckx F, et al. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008;12(6):238. [62] Bednarík J, Vondracek P, Dusek L, et al. Risk factors for critical illness polyneuromyopathy. J Neurol 2005;252(3):343–51. [63] Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005;64(8):1348–53. [64] De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288(22):2859–67. [65] Campellone JV, Lacomis D, Kramer DJ, et al. Acute myopathy after liver transplantation. Neurology 1998;50(1):46–53. [66] Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348(8):683–93. [67] Massa R, Carpenter S, Holland P, et al. Loss and renewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnervation. Muscle Nerve 1992;15(11):1290–8. [68] Allen DC, Arunachalam R, Mills KR. Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy. Muscle Nerve 2008;37(1):14–22. [69] Z’Graggen WJ, Lin CS, Howard RS, et al. Nerve excitability changes in critical illness polyneuropathy. Brain 2006;129(Pt. 9):2461–70. [70] Rich MM, Pinter MJ. Crucial role of sodium channel fast inactivation in muscle fibre inexcitability in a rat model of critical illness myopathy. J Physiol 2003;547(Pt 2):555–66. [71] Filatov GN, Rich MM. Hyperpolarized shifts in the voltage dependence of fast inactivation of Nav1.4 and Nav1.5 in a rat model of critical illness myopathy. J Physiol 2004;559(Pt. 3):813–20. Epub 2004 Jul 14. [72] Rich MM, Kraner SD, Barchi RL. Altered gene expression in steroid-treated denervated muscle. Neurobiol Dis 1999;6(6):515–22. [73] Al-Khawaja D, Seex K, Eslick GD. Spinal epidural lipomatosis–a brief review. J Clin Neurosci 2008;15(12):1323–6. http://dx.doi.org/10.1016/j. jocn.2008.03.001. [74] Fogel GR, Cunningham 3rd PY, Esses SI. Spinal epidural lipomatosis: case reports, literature review and meta-analysis. Spine J 2005;5(2):202–11. [75] Lynch RW, Soane T, Gibson R, Pal S, Lees CW. Bilateral lower limb weakness in acute severe ulcerative colitis. Lancet 2016;388(10039):101–2. http://dx.doi. org/10.1016/S0140-6736(16)30857-1.
Please cite this article in press as: Parissis D et al. Corticosteroids in neurological disorders: The dark side. J Clin Neurosci (2017), http://dx.doi.org/10.1016/ j.jocn.2017.05.040