Myasthenic crisis: Guidelines for prevention and treatment

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Abstract

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.

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 autoantibodies 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 [1], [2], [3]. Prevention and treatment of myasthenic 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 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.

Section snippets

Etiology

Acquired MG is a rather heterogeneous group of 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 muscles of mastication, or in addition, to neck and proximal muscle weakness. If muscles of

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 inability to protect the airways with preserved oxygen saturation. In others worsening of

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

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 different 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

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

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 immunosuppressive/modulatory treatments are however associated 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

Corticosteroid treatment

Use of glucocorticoids (generally prednisone or prednisolone) 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 systemic and neuromuscular diseases such as systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy (CIDP) and acquired inflammatory muscle diseases among others [40]. Historically patients with MG were among the first to be treated with corticosteroid

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 immunoadsorption or double filtration techniques [47], [48], [49], [50]. Traditional plasma exchange entails removal of the pathogenic antibodies (antinicotinic ACh receptor, anti-MUSK antibodies and antibodies to as yet to be characterized antigens) and other plasma components such as soluble adhesion molecules and cytokines [51],

Intravenous immunoglobulin

The use of high dose intravenous immunoglobulin (IVIg) has gained wide application in the treatment of autoimmune and immunopathologically mediated neuromuscular diseases. 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 Guillain–Barre syndrome (GBS), CIDP, Multifocal Motor Neuropathy (MMN) and dermatomyositis [17], [21], [29], [30], [33], [67], [68], [69], [70]

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 response to PE in myasthenic patients refractory to IVIg [83], [84]. Since then other studies have compared PE with IVIg in MC. The retrospective study series of 54 patients by 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

Conclusion

The introduction of neurological intensive care units has put its stamp on the management of myasthenic crisis. Early recognition, better identification of etiological and precipitating factors and appropriate management of the respiratory and bulbar failure make this severe condition more accessible to newer treatment modalities. These are aimed at correction or modulation of the underlying immune pathologic mechanisms. In our experience the treatment of MC with plasma exchange has proven to

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