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Journal of the Neurological Sciences 261 (2007) 127 – 133 www.elsevier.com/locate/jns Myasthenic crisis: Guidelines

Journal of the Neurological Sciences 261 (2007) 127 133

Journal of the Neurological Sciences 261 (2007) 127 – 133 www.elsevier.com/locate/jns Myasthenic crisis: Guidelines


Myasthenic crisis: Guidelines for prevention and treatment

Agnes Jani-Acsadi, Robert P. Lisak

Department of Neurology, Wayne State University, Detroit, MI 4201 St. Antoine 48201, United States

Available online 4 June 2007


Management of myasthenic crisis (MC) requires admission of the patient into a neurological intensive care unit and timely institution of an efficient and safe treatment. Despite the growing clinical experience with disease modifying immunotherapy there is no clinical consensus regarding the use of plasma exchange or high dose immunoglobulin treatment in an ICU setting. The choice of treatment modalities seem to rely mostly on institutional preferences primarily due to a lack of well-designed clinical trials comparing currently available therapeutic options. In our experience and based on a review of recent literature we advocate the use of plasma exchange (PE) as a primary modality in the acute care setting, supported by other immunomodulatory medications such as corticosteroids. Pharmacological management cannot substitute for adequate intensive care management of the respiratory and bulbar insufficiency associated with MC. Every effort should be done to prevent myasthenic exacerbation/crisis and to develop a maintenance management that leads to effective prevention. © 2007 Elsevier B.V. All rights reserved.

Keywords: Myasthenic crisis; Plasma exchange; Corticosteroids

1. Introduction

Acquired myasthenia gravis is an autoimmune disorder of neuromuscular junction transmission clinically manifesting as variable and fluctuating weakness of certain muscles. Symptoms are due to reduced binding of acetylcholine at the neuromuscular junction (NMJ) due to either the presence of acetylcholine receptor (AChR) antibodies reducing the available postsynaptic acetylcholine receptors found on the end plate of skeletal muscle or by the presence of auto- antibodies directed towards other postsynaptic skeletal muscle components, such as Muscle Specific Kinase (MuSK). Among others systemic illness, surgery, fever, pregnancy, emotional upset and certain drugs may exacerbate myasthenic symptoms. This severe, at times fatal condition may lead to an acute inability to breath and swallow. This status is defined as myasthenic crisis [13]. Prevention and treatment of myas- thenic crisis (MC) often requires admission to an intensive care unit, preferably a neuroscience ICU, close observation and when necessary, intubation of the patient for acute ventilatory and feeding support. Delay in appropriate medical care may

Corresponding author. E-mail address: rlisak@med.wayne.edu (R.P. Lisak).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.

lead to respiratory arrest and ultimately death. Identifying the pathogenic mechanisms as autoimmune has lead to better treatment of these patients that may prevent progression of their condition to a severe worsening such as seen in myasthenic crisis. When crisis occurs, acute care, in addition to supportive therapy, focuses on reducing circulating antibody titers with plasmapheresis (PE) and/or institution or adjustment of immunologic disease modifying therapy with high dose intravenous immunoglobulin and corticosteroids. Despite the growing interest and newer treatment modalities there is a lack of well-designed therapeutic clinical trials comparing currently available treatment modalities including PE and high dose immunoglobulin treatment (IVIg) in the setting of impending or manifest MC.

2. Etiology


autoimmune disorders affecting neuromuscular junction transmission. It usually presents with fluctuating weakness of characteristic voluntary muscles. Most commonly they are related to either isolated ocular dysfunction such as diplopia, ptosis of the upper eye lids or bulbar symptoms such as dysarthria, dysphagia, due to limitation of facial and/or









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muscles of mastication, or in addition, to neck and proximal muscle weakness. If muscles of respiration become markedly

affected, or bulbar function deteriorates to a degree that the airway and pulmonary toilet is precarious, crisis emerges that may lead to an acute inability to maintain adequate air entry and/or aspiration. The patient develops acute respiratory insufficiency and potentially fatal respiratory arrest.

MG is a relatively rare disease with a variable prevalence

of 5 to 15/100,000 [46]. About 15 to 20% of patients with MG experience however a myasthenic crisis at some point in the course of their disease [5,6]. Current statistics still report an about 3 to 8% mortality rate despite newer treatment and intense medical care. Due to an increase in life expectancy and better recognition of the disease the prevalence of MG

has increased representing the well described bimodal clustering of the incidence of MG across the different age and gender groups [5,7,8]. Mortality may approach 4% [5,9] with no documented improvement in fatality rates over the last several decades. Many myasthenic patients are chronically immunocompro- mised and others cannot adequately protect their upper and lower airways. Hence, most cases of crisis are provoked by concurrent infections and fever. Infections, including lower and upper respiratory infections are responsible for at least 70% of the MC cases [9,10]. Surgical interventions and administration of different medications are the other important risk factors. There is a wealth of medications, such as certain antibiotics (aminoglycosids), some cardiac drugs such as lidocaine, pro- cainamid, and quinidine, phenothiazides and magnesium that may provoke the first symptoms or worsen MG [2,11,12]. Differentiating autoimmune acquired MG from other non- immune myasthenic syndromes such as congenital/inherited myasthenic syndromes or drug/toxin induced disease is impor- tant since they do not respond to immunotherapy and require a different therapeutic approach [1315].

3. Symptoms and signs

Myasthenic crisis is traditionally defined as an acute respiratory failure due to worsening MG requiring admission to an intensive care unit (ICU) [16,17]. MC may develop quite suddenly without any warning due to the specific clinical features of the myasthenic state camouflaging the severe respiratory distress: facial weakness, airway collapse and diaphragmatic and accessory muscle failure leading to in- ability to protect the airways with preserved oxygen saturation. In others worsening of primary symptoms related directly to weakness and the presence or worsening secondary features (hypercarbia, hypoxia, symptoms of respiratory or other infections, and weight loss due to dysphagia) of MG may help identify the patient with impending MC [3].

4. Laboratory and other supportive diagnostic tests

MC is characterized by a drop of forced vital capacity

below 1 L, a negative inspiratory force of 20 cm H2O or less

and the need for mechanical respiratory support. Hence close monitoring of respiratory status requires regular bedside pulmonary function testing every 4 to 6 h. Arterial blood gas analysis commonly shows hypercarbia before hypoxia. There should be a low threshold for endotracheal intubation due to the rapid deterioration of the involved bulbar and respiratory muscles. If MC is the first presentation of the disease EMG/NCS is recommended additionally to look for evidence of decrement with slow frequency repetitive nerve stimulation, preferably in the weakest muscles. Increased jitter may be detected by single fiber electromyography in a laboratory experienced to perform these tests and may provide additional support to the diagnosis. If needed serum for anti-acetylcholine receptor or anti- MUSK antibodies should be sent for analysis before the institution of any immunotherapy. Anti-AChR antibodies are elevated in 85 to 90% of patients with generalized MG. Thymoma associated MG may present with crisis or as res- piratory failure with a mediastinal mass with no known history of MG. Chest computerized tomography may help in iden- tifying the cause of respiratory failure and lead to initiating appropriate therapy early in such cases. In some instances thymectomy for thymoma without known MG can result in initial presentation of MG in the postoperative period. MUSK related autoimmune acquired MG presents with slightly different phenotype than that typical of AChR antibody mediated general MG. The predilection of the disease to involve primarily facial, bulbar, respiratory and neck muscles with relative sparing of the limb muscles [18,19] makes close assessment of bulbar function (e.g., swallow, gag) and proper care of excretions (regular suctioning) indispens- able. Attention should be given to the same functions in all other forms of autoimmune MG. We are still learning about other anti-MUSK antibody clinical phenotypes. Historically edrophonium was used to distinguish MC from cholinergic crisis or to support the diagnosis in pre- viously unknown myasthenic patients. Its use in managing MG was of limited efficiency [20]. It is used less due to the known cardiac side effects particularly in older individuals, the subjectivity of testing and the wide spread availability of immunologic and clinical neurophysiological testing. If the patient requires ventilatory support there is no need to distinguish the two crisis entities [3,21].

5. Treatment

Treatment of MG may be aimed either at improving the availability of Ach in the NMJ to improve neuromuscular transmission and and/or to modify the basic immunological cause of acquired MG. Recent articles have repeatedly highlighted the need for evidence-based data on the dif- ferent treatment modalities in both MG and MC [22,23]. The lack of appropriate data is also of concern due to the rising health care costs associated with prolonged ICU care. To date treatment is based on clinical consensus [1,10,13,

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14,17,2427]. Experts agree that early identification, if possible prevention of the impending crisis, elimination of potential triggers such as treatment of infections, maintain- ing appropriate electrolyte balance, appropriate feeding and long-term ventilatory support with tracheostomy if needed, assessing and providing the level of intensity of care necessary to stabilize the patient are mandatory and should be tailored to fit individual patient needs. These goals parallel an increase in our knowledge of the pathogenic mechanism of MG and the ability to recognize and avoid potential precipitating factors of the crisis. It is also supported by an increase in the availability of neurological ICUs and improved management of metabolic and respira- tory insufficiencies. Controversy continues to exist however regarding the benefits of symptomatic therapy (pyridostig- mine) or use of corticosteroids in an acute care setting. There are only few studies available that compare PE and IVIG in MC and most of them do not address important issues satisfactorily such as the speed or onset of the effect or do not include enough patients with crisis [2830].

6. Cholinesterase inhibitors

Symptomatic pharmacologic therapy should always follow stabilization of the patient via standard ICU processes (airway, breathing, cardiovascular support). Cholinesterase inhibitors such as pyridostigmine bromide prolong the presence and activity of ACh in the endplate synaptic cleft and are a mainstay of the management of mild to moderate MG [13]. In the last three to four decades their use has been less in moderate to severe and /or progressive myasthenia or MC, certainly not as a solitary treatment. This is based on the fact that cholinesterase inhibitors may have a variable half- life in severely ill patients and reduced absorption of oral formulations. Over dosage may lead to increased weakness and interference with extubation [31,32]. In the era prior to widespread of ICUs, much was written on the need to distinguish MC from so-called cholinergic crisis. Hence most experts are cautious regarding the use of ChEI in an acute care setting [3,31,32]. In the series of Berroushot [33] (Class IIb evidence) out of 235 MG patents, there were 63 with MC treated in an acute care setting with pyridostigmine ( n = 24), pyridostigmine and prednisolone (( n = 18) and PE alone ( n = 21). They did not find any significant differences in short-term efficacy, comparable long-term outcome and side effect profile between the different regimens. Based on these results they advocated an approach tailored to the individual patient considering the precrisis condition of the patient and the precipitating factors of MC (Class III evidence). In a smaller retrospective review of patients undergoing quite variable treatment regimens, O'Riordan et al. continued pyridostig- mine therapy in the acute stage in 33 out of 35 cases and found no obvious effect of the drug on any patient group [34]. Kawaguchi et al. made no comment regarding AChEI treatment in the 5 MC patients out of the total 470 patients

surveyed [35]. In their current review, Ahmed et al. [21] emphasizes caution with AChEI use especially in a setting of planned thymectomy or extubation based on their experience (Class III). In their retrospective analysis, Panda et al. [36] reported giving a drug holiday from the AChEI throughout the period of ventilation for all of their patients. Another limitation of the AChEI in the setting of MC is the potential for over treatment and the possibility of cholinergic crisis. For this reason some advocated stopping pyridostigmine for a few days until the nature of crisis is clear. In conclusion there are still no randomized, controlled trials looking at the efficacy and/or time course of cho- linesterase inhibitors in MC. Agents that are frequently used to enhance ACh quanta release presynaptically such as guanidine and 3,4-diaminopyrimidine are not used in the treatment of MC.

7. Immunotherapy of MC

Immunotherapy of MG by definition tackles the basis of the disease by suppressing or modifying the autoimmune pathogenic mechanisms of myasthenia gravis. The immu- nosuppressive/modulatory treatments are however associat- ed with a higher degree of potential complications including worsening of myasthenia such as seen with initiation of corticosteroids and numerous well-described side effects [3,13,37]. Their use has been primarily advocated in patients with moderate generalized MG who remain symptomatic after the initiation of AChEI therapy [14,39].

8. Corticosteroid treatment

Use of glucocorticoids (generally prednisone or prednis- olone) in MC has not been evaluated systematically. The principles of use in patients with myasthenia gravis are similar to their application in other immune-mediated sys- temic and neuromuscular diseases such as systemic lupus erythematosus, chronic inflammatory demyelinating poly- neuropathy (CIDP) and acquired inflammatory muscle diseases among others [40]. Historically patients with MG were among the first to be treated with corticosteroid therapy [4143]. However there is still a lack of controlled prospective and randomized trials [39,40]. Corticosteroid formulations may be divided by duration of their action on ACTH suppression as short- (prednisone, prednisolone at an effect of less than 24 to 36 h), intermediate (triamcinolone) and long-acting (dexametha- sone) and also by their relative potency (cortisole has a value of 1, prednisone and prednisolone 4, methylprednisone 5 and dexamethasone 30) [40,44]. Their ease of application with oral forms, although not every detail of their metabolism is quite fully understood, makes them a valuable tool in treating these diseases, although historically only the shorter acting forms were used in MG. The major issue in MC is the acute worsening of weakness with the initiation of the therapy [3,40,45]. Different regimens


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have been proposed to avoid the other well-described corticosteroid side effects [38] and to keep a transient worsening of myasthenia at bay [13,37,40,45]. These regi- mens suggest that in patients in MC who by definition have severe deficits and are already in a controlled setting in an ICU and in need of rapid improvement, a high dose initiation therapy is recommended. Either PE or IVIG therapy to avoid severe exacerbation related to therapy should support this. A starting dose of 60 to 80 mg of prednisone once daily has been recommended with follow up alternating day or high doselower dose regimens and taper to reach the minimum effective dose [13,14]. Different regimens have been published for maintenance of MG and should be used by adjusting it to individual patient needs [13,37,40]. These expert opinions are reflected among others in the published 27 patient case series of O'Riordan [34] and are followed by most critical care neurologists [24]. It also has to be emphasized that an acute steroid induced myopathy may occur in patients who have received non- depolarizing neuromuscular blockade previously and has also been associated with high dose initiation therapy alone as first described by Panegyres et al. in 1993 [46]. The Cochrane Review concluded regarding the use of corticosteroids in MG that there is limited evidence for short - term benefits (at 2 weeks) in generalized MG when compared to placebo and only limited data were available for the 6 months time point. The fluctuating natural course of MG makes the analysis of long-term data difficult but clinical experience is suggestive of long-term benefits. Conversely azathioprine and IVIg showed comparable long-term results in efficacy with corticosteroids [39]. Azathioprine and the other immunosuppressants such as cyclosporine, mycophenolate mofetil and cyclophosphamide or thymectomy are not considered a part of the acute care protocol since their therapeutic action is delayed.

9. Plasma exchange

The basis of the action of plasmapheresis (PE) in MC is that it rapidly eliminates the pathological autoantibodies via mechanical separation or more recently, by immunoadsorp- tion or double filtration techniques [4750]. Traditional plasma exchange entails removal of the pathogenic anti- bodies (antinicotinic ACh receptor, anti-MUSK antibodies and antibodies to as yet to be characterized antigens) and other plasma components such as soluble adhesion mole- cules and cytokines [51], separation from other blood components and then supplementation with 5% human albumin and crystalloids or rarely fresh frozen plasma to maintain homeostasis. The procedure may be carried out by plasma filtration techniques, plasma separation and more recently by antigen-specific immunoadsorption techniques [52,53] that enable the return of non-pathogenic blood components to the patient. A standard course in myasthenia exacerbation entails 5 to 6 exchanges on alternating days utilizing 2 to 4 L per exchange [49,50]. Among the newer

apheretic techniques, double filtration PE and immunoad- sorption [47] showed similar clinical effects for patients with generalized myasthenia with only minor differences noted in post PE serum immunoglobulin levels. Dau [55] emphasized the importance of patient tailored treatment regimens based on the clinical severity of the exacerbation in MC. A series of early, non-randomized studies [5458] quickly established the beneficial, primarily short-term effect of PE and since then it has gained wide application in acute care setting [33,35,59,60]. The 1986 NIH consensus statement supported the use of PE, and no placebo controlled clinical trials have been conducted [61]. PE has shown benefit in MC, management of exacerbations and has become a part in presurgical/prethymectomy pre- paration [62] as well. One of the limitations of PE is the relatively short-lived (2 to 3 weeks) improvement in strength that makes the co- administration of other longer acting immunosuppressive or immunomodulatory agents generally necessary. In addition, significant limitation of PE is its relatively high cost, invasive features (need for venous access and cardiac and hemodynamic instability) and the rare toxic reaction to the anticoagulants such as citrates [13,17,63]. The report of the largest PE database, the French plasma exchange registry reports a decrease in the immediate complications since 1985 due to improved quality of the applied techniques and plasma substitutes [64]. The only randomized early controlled trial by Gajdos was limited by co-administration of prednisone and lack of blinding [65]. Based on their data the Cochrane Review's evidence based evaluation concludes that further trials may need to address long-term effects of PE in MC. The more recent clinical retrospective case series by Mahalati et al. of 36 patients (32 in MC) over a 10 year period reported predictable clinical improvement with successful extubation. They reported no fatalities in the acute phase by using an average of 7.8 exchanges [66]. The retrospective case series of Berroushot did not find however any significant difference between their patients in MC treated with PE, pyridostigmine or pyridostigmine and prednisone regarding effect on ventilation, clinical outcome and fatality rate [33].

10. Intravenous immunoglobulin

The use of high dose intravenous immunoglobulin (IVIg) has gained wide application in the treatment of autoimmune and immunopathologically mediated neuromuscular dis- eases. This was noticeable in the growing number of publications dealing with its application both in acquired adult and juvenile MG and other antibody-mediated neuromuscular diseases such as GuillainBarre syndrome (GBS), CIDP, Multifocal Motor Neuropathy (MMN) and dermatomyositis [17,21,29,30,33,6771,74]. The increased interest can be explained by a number of different factors such as the relative ease of administration compared to PE,

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and a relatively benign long-term side effect profile. There is however a need to perform more adequately designed clinical

response to PE in myasthenic patients refractory to IVIg [83,84]. Since then other studies have compared PE with

trials to establish short- and long-term efficiency as compared


in MC. The retrospective study series of 54 patients by

to the other therapeutic modalities in some of these diseases, including MG and particularly in MC. Nevertheless it has become first line therapy in many immune mediated neuromuscular diseases. Immunoglobulins are part of the body's immune defense system. Their mechanism of action in autoimmune diseases is quite complex and not fully understood [67,72,73]. IVIg seems to affect immune homeostasis by interfering at multi- ple levels [74]. The mode of action most directly related to MG is likely the modulation of the pathogenic autoanti- body response. Other actions include the inhibition of com- plement activation and interference with the membrane attack complex (MAC) formation, modulation of Fc recep- tors, down regulation of the pathogenic cytokine responses, suppression of T cell function and finally interference with antigen recognition [73]. The procedure usually entails the administration of 0.4 g/ kg body weight human pooled IgG over 3 to 5 days, although

Qureshi [29] found better short-term (one month) outcome with PE, despite higher morbidities. Gajdos in an earlier smaller and the first comparative randomized clinical study involving 87 patients did not show a clear difference between the 2 modalities and the alternative treatment regimens of 3 or 5 days (Class III) [27]. They stressed however that IVIg exhibited a very limited risk and a better tolerance profile than PE. Dalakas in a recent review advocated the use of IVIg as a suitable alternative to PE for acute and maintenance therapy of MG [74]. Two of the randomized clinical trials included in The Cochrane Review used IVIg for treatment of myasthenic exacerbation but only the Gajdos study compared PE and IVIg. The study was not blinded. Moreover the mean total volume exchanged seemed to be less than what was used by several other groups in MG/MC. Therefore it was concluded that there is no evidence to support preferentially either PE or IVIg treatment for myasthenic exacerbations

alternative regimens have been proposed earlier for different


autoimmune disorders with what appears to be comparable results [67,74,75]. The side effect profile is considered

12. Conclusion

benign in patients with no significant comorbidities such as renal disease, diabetes, hypercoagulabilty, hypertension,

The introduction of neurological intensive care units has

immobility and advanced age. Adverse reactions include mostly minor reactions, such as headache, chills, myalgias, transient hypertension and are mostly associated with early

put its stamp on the management of myasthenic crisis. Early recognition, better identification of etiological and precip- itating factors and appropriate management of the respira-

or rapid therapy initiation [74­76]. More severe side effects


and bulbar failure make this severe condition more

include allergic reactions, renal failure, thrombotic events and serum sickness [13,68]. A temporary suppression of levels of formed elements of blood may also be seen [77].

accessible to newer treatment modalities. These are aimed at correction or modulation of the underlying immune pathologic mechanisms. In our experience the treatment of

Current preparations should not have the earlier problems of


with plasma exchange has proven to lead to fast and

Hepatitis C contamination [13]. Another limitation is the

predictable recovery. This is supported by a 20 year history

quite significant cost associated with high doses of IVIg that has to be taken into account in addition to the shortage of relevant, evidence based clinical information in an acute care setting. There have also been periodic regional shortages of IVIg. Clinical consensus and data of non-randomized clinical trials and case series (class III) seem to point to a benefit in maintenance therapy of MG [7880]. Jongen [81] in a retrospective, unblinded and uncontrolled analysis of a small number of patients found in 56% (9 out of 16) patients improvement with the peak effect at 7 days. This was less than the 61 % of patient improvement noted by Gajdos [28]. All of the studies had different patient selection criteria and differed in their outcome measures, so it is quite problem- atical to draw a clear causal correlation to IVIg.

of safe and reliable clinical efficiency. Side effects and availability will be less of a factor in a neurological ICU ready to deal with the pertinent issues and with a plasma exchange team, including those responsible for obtaining venous access, when that is an issue. Although widely accepted as a first line therapy in many of the autoimmune neuromuscular diseases, including the treatment of moder- ately severe myasthenia, there is so far no evidence based clinical data to support the use of IVIg as a primary treatment modality for MC. The short-term management of myasthenic crisis should virtually always be followed with appropriate long-term immunosuppressive therapy. New randomized controlled clinical studies will be needed to further clarify the risks and benefits associated with high dose IVIg treatment and the newer techniques in plasma exchange.

11. Comparison of plasma exchange and intravenous immunoglobulin treatment in myasthenic crisis

Lewis et al. [82] advocated the use of PE over IVIg based on early clinical results with PE and a good clinical


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