Myasthenia Crisis Vs Cholinergic Crisis: Challenges in Crisis Management Without Plasmapheresis or Intravenous Immunoglobulin (IVIG)

Introduction: Myasthenia gravis (MG) is an acquired autoimmune disorder clinically characterized by skeletal muscle weakness & fatigability on exertion with prevalence as high as 2–7 in 10,000 and women are affected more frequently than men (~3:2). Over 12-16% of generalized MG patients experience crisis once in their lifetime. A serious complication of myasthenia gravis is respiratory failure. This may be secondary to an exacerbation of myasthenia (myasthenia crisis) or to treatment with excess doses of a cholinesterase inhibitor (cholinergic crisis). Case Report: Thirty-two years old woman refereed from a private hospital to ED for further treatment with myasthenia in crisis, after nine days of treatment in the previous ICU. Patient already in intubation with mechanical ventilation and history of the treatment of a high dose of multiple anticholinesterase drugs and steroids without plasmapheresis or immunoglobulin intravenous. During admission, diarrhea was present, with no sign of GI infection. On the third day of admission, the patient performed a Spontaneous Breathing Trial and was a success then extubated. Then two day after extubation, the patient falls to respiratory failure and need mechanical ventilation. Anticholinesterase test was performed, and it shows no improvement in clinical signs, and diagnose as Cholinergic Crisis. After re-adjustment of anticholinesterase drug with a lower dose, clinically, the respiratory condition improved, and on the 10th day of admission, the patient was succeed extubated. At 12nd days of ICU admission, patient discharge from ICU. Discussion: Myasthenia and Cholinergic Crisis is a severe and life-threatening condition characterized by generalized muscle weakness with a respiratory compromise that requires ventilatory support. Respiratory failure may be present in the cholinergic crisis without cholinergic symptoms (miosis, diarrhea, urinary incontinence, bradycardia, emesis, lacrimation, or salivation). The most important management aspect of Myasthenia patients in crisis is the recognition and treatment of myasthenia vs cholinergic crisis.


INTRODUCTION
Myasthenia crisis is a myasthenia gravis' (MG) complication that characterized by worsening of skeletal muscle weakness which is resulting in respiratory failure that requires intubation and mechanical ventilation. (1) The cholinergic crisis is an emergency that is mainly characterized by flaccid paralysis and respiratory failure, which mainly occurs due to improper administration or intake of anticholinergic agents in MG patients. (2) The worldwide incidents are about 8 to 20 cases per 100,000 people. (3) Crisis periods occur on 15-20% of myasthenia patients, at least once in their lives. First crisis occurs on 8-12 months from onset of MG with 5% mortality rate. (1) (4) In the last three to four decades the use of cholinesterase inhibitors drug has been less in moderate to severe and/or crisis, certainly not as a single treatment. Because cholinesterase inhibitors may have a different half-life in critically ill patients which resulting in absorption decreasing of enteral formulations. Increased weakness and interference with extubation may be lead by overdose of these drugs with the resulting incident of cholinergic crisis with or without other cholinergic symptoms. (5)(6) Plasmapheresis or Intravenous Immunoglobulin (IVIg) is the gold standard of MG therapy in crisis, and most guidelines not recommended continuity of cholinesterase inhibitors during the crisis. (3)-(5)(6)

CASE REPORT
Thirty-two years old woman refereed from a private hospital to ED for further treatment with myasthenia in crisis and suspect pneumonia, after nine days of treatment in the previous ICU. Patient already in intubation with mechanical ventilation (MV) and history of the treatment of high dose of multiple anticholinesterase drug, Pyridostigmine oral 60mg every 4 hours, Neostigmine iv. 0,5mg every 8 hours and steroid, methylprednisolone iv 62,5mg every 8 hours, without plasmapheresis, IVIg, or another immunosuppressant. The patient diagnoses with MG for 3 years with routine daily pyridostigmine oral without dose adjustment by a physician. A week before admission on the previous ICU, the patient got common cold for three days and a general weakness that resulting in dyspnea needed for MV.
During admission at Emergency Department, Dr. Soetomo General Academic Hospital, patient with Glasgow coma scale (GCS) E4 Mx V6 (with endotracheal tube), stable vital sign, assisted respiration with slight rhonchi in a small area in both lung and from muscle strength grading examination, superior and inferior extremity got scale 5 out of 5 and 2-4 out of 5 with mean motoric strength grade were 4 out of 5. Other signs and symptoms are diarrhea without signs of intestinal infection. Form laboratory (Table 1) and radiology examination (figure 1), there are increased white blood count and liver function test with other normal blood laboratory and normal chest x-ray. Diarrhea still present for the first two days of treatment in ICU and muscle weakness getting worse with mean extremity motoric strength grade was below 3 out of 5. Pyridostigmine dose were reduced to 60 mg every 8 hours. The next day evaluation, diarrhea has already stopped but there is no improvement on muscle strength scale, so based on clinical judgment, the dose of pyridostigmine was increased into double dose (60 mg every 4 hours). After increasing dose, muscle strength grade was increased and the spontaneous breathing trial was performed successfully.
Pyridostigmine dose was re-adjusted by reducing a half and the patient was extubated on the third day of ICU treatment. After 24 hours extubating, patient show tachypnea until 30-35 breath per-minute with a stable vital sign and without muscle weakness and any cholinergic sigh (such as hypersalivation, diarrhea, miosis, and hyper-lacrimation).
The anticholinergic test was performed by using neostigmine 0,5 mg iv. and the result was positive by decreased respiration rate until normal, then pyridostigmine dose was increased by 60 mg every 4 hours. Even though the PaO2/FiO2 ratio was 230 before the Anticholinergic test, the clinically respiration condition was getting better after the test, so the patient are not re-intubation for observation. But the next day, another tachypnea episode happened again with the patient unable to cough and fall to respiratory failure. This episode was followed by muscle weakness. The patient was re-intubate and pyridostigmine dose was increased twice as before (120 mg every 4 hours). Chest X-ray after re-intubation shows sputum retention with a decrease of PaO2/FiO2 Ratio (288).
Re-adjustment dose was based on an anticholinergic test that performed the previous day, and no sign of cholinergic activity at all. After two days of re-intubate, muscle weakness was getting worse and still, there was no signs of cholinergic activity. Readjust pyridostigmine dose was doing by reducing it with the assumption it could be caused by the cholinergic crisis. We gradually decrease the dose, on the first day reduce to 60 mg every 4 hours, then every 8 hours. On the eighth to ninth days of ICU treatment or third to fourth days after re-intubate, muscle strength was increase and patient able to be wean from mechanical ventilation.
On the tenth days of ICU treatment, patients were extubate and pyridostigmine dose were adjusted slightly increased (60 mg every 6 hours) to prevent possible another myasthenia crisis (dose too low) with the precaution of cholinergic dose (dose too high). Evaluation after re-adjustment of anticholinesterase drug with a lower dose, clinically, respiratory condition, and muscle strength were improving (detail Figure 2). Corticosteroids (CSs) therapy were given continually with methylprednisolone iv. 125 mg every 6 hours, and tapering down at ward. After the twelfth days of ICU treatment, patient discharge from ICU and move to neurology ward, and chest x-ray on the fifteenth days of hospital admission shows normal result.

DISCUSSION
The pathogenesis of MG is the absent of acetylcholine receptors (AChRs) on the postsynaptic membrane of the neuromuscular junction (NMJ) because of the production of AChR and/or muscle-specific receptor tyrosine kinase (MuSK) antibodies (Abs), which as the result of the loss of postsynaptic AChRs and associated with NMH destruction.  (8)(9) AChEIs work as enzyme Acetylcholinesterase (AchE) competitive blockade in the extracellular matrix of the folded postsynaptic muscle endplate membrane. The result of these actions are the breaks down of Acetylcholine (ACh) into choline and acetate, the inactive metabolites of ACh. Pyridostigmine, that available in 60-mg tablets, is one of the most commonly used drug, which begins to work 30 minutes after oral administration and duration of action about 3-6 hours. (8) AChEIs induce the corresponding adverse cholinergic effects on both muscarinic and nicotinic synapses, such as gastrointestinal tract hypermotility (e.g., abdominal pain, diarrhea, etc.), hyper-salivation and respiratory hyper-secretions, hyperhidrosis, and bradycardia or arrhythmia. Overtreatment of AChEIs may give rise to a serious cholinergic crisis (e.g., respiratory failure), which results from overactivity of neuromuscular transmission by excessive ACh.
The cholinergic crisis is uncommon because most of the guidelines suggest to stop AChEIs when crisis period occurs, but the cholinergic crisis is still an important evaluation of the patient in myasthenic crisis in received AChEIs treatment. (1)(8)(9) Randomized controlled trials in myasthenic crisis have been limited, perhaps because MG is a rare disease and difficult to recruit many suitable patients. Because of these reasons, most physicians have chosen immunotherapies that available within their medical environments and based on their own clinical experiences. (8) Patients cannot be therapeutic with plasmapheresis or IVIg because they are not financially able and do not have insurance. So, even though at the crisis, the only option was AChEIs and corticosteroids (CSs). CSs are commonly used as the first-line drug as Immunosuppressants (IS). The reason using these drugs is for inducing comparatively rapid remission and bridging to long-term maintenance therapy using other ISs or immunomodulators until the onsite of these drugs. CSs are used in conjunction with AChEIs. High-dose methyl prednisolone may be initiated at the same time with AChEIs since the effect of methylprednisolone happens after 2 weeks. (1) The use of Highdose corticosteroids in MG patients should be performed with caution, as this drug can worsening of weakness in non-ventilated patients, around one-third of the cases. In the mechanical ventilated patient, the initiation or the escalation of these drugs should be considered. ( Respiratory failure may be present in the cholinergic crisis without other cholinergic symptoms, such as miosis, diarrhea, urinary incontinence, bradycardia, emesis, lacrimation, or salivation. Therefore, as with all seriously ill patients, priority is given to establishing and maintaining an airway and assuring adequate breathing. The respiratory status of a patient with myasthenia or cholinergic crisis can worsen unpredictably. Close monitoring of the patient's respiratory status and dose adjusting of AChEIs are mandatory. (1)(4)(6)(11)

CONCLUSION
Both myasthenia and cholinergic crisis can be present as respiratory failure. Respiratory failure may be present in the cholinergic crisis without other cholinergic symptoms and signs. Close monitoring of the patient's respiratory status and dose adjusting of AChEIs are mandatory and challenging.