Myasthenic Crisis Treated in a Neurological Intensive Care Unit: Clinical Features, Mortality, Outcomes, and Predictors of Survival

Methods

Patients

The MG patients at our hospital were followed up since July 2008, including a cohort of 2023 MG patients. Patients had been diagnosed with MG because they showed two or more of the following clinical features: clinical evidence of muscle weakness and easy fatigability, significant decremental response on repetitive nerve stimulation, presence of anti-AChR or anti-MuSK antibodies, or objective clinical response to the neostigmine test [3]. Other diseases that mimic MG must be excluded, including Lambert-Eaton myasthenic syndrome, peripheral neuropathy, myopathies and motor neuron disease. MC was defined as respiratory failure from muscle weakness requiring mechanical ventilation with intubation or noninvasive ventilatory support (continuous or bi-level positive airway pressure) [3]. Patients were intubated if clinical assessment indicated compromised respiratory effort documented by decreased patient comfort with either single breath count less than 10, respiratory rate more than 30 per minute, decreased chest expansion, paradoxical diaphragmatic movements or arterial blood gas showing drop in oxygen saturation. Furthermore, general criteria for intubation also included impaired swallowing mechanism leading to ineffective cough and nasal voice, inability to clear secretions. MG patients intubated for respiratory failure due to acute respiratory distress syndrome, congestive heart failure, and hypoxic-ischemic coma were excluded since in those cases respiratory muscle weakness was not a contributing factor for intubation. Post-thymectomy crises were also excluded. In this retrospective study, patients admitted to the neurological ICU with first MC onset were investigated. MC patients managed only on the general ward were not included in the study. The decision to mechanically ventilate was taken on a case-by-case basis according to the patient’s respiratory condition and with the consent of patients or relatives. Death of MC patients occurring at ICU and as well as at the residence were recorded. The period of evaluation of the patients was until May 2017.

Data collection

The following demographic data were recorded for each patient: gender, age of MG onset, age at first MC onset requiring ICU management, presence of anti-AChR or -MuSK antibodies, and history of thymoma, thymectomy, and other autoimmune diseases. In addition, the following information was also collected: MG duration before MC, score on Myasthenia Gravis–Activities of Daily Living (MG-ADL) scale at disease onset, score on the Myasthenia Gravis Foundation of America (MGFA) scale at ICU admission , length of hospital stay, length of ICU stay, and duration of ventilator use. Primary precipitating factors were identified whenever possible; these included infection, surgery, medication, aspiration, pregnancy, and stressor. Possible secondary precipitating factors were also identified. Data was collected on the last time of arterial blood gas measurements before intubation, including white blood cell count (WBC), Ph, PO2, and PCO2. Functional outcomes were assessed using the MGFA postintervention status every 3 months after discharge from the ICU. All included patients had follow-up duration of 12 months after discharged from ICU. In the present study, patients with different functional outcome were considered to experience good , intermediate, and poor prognosis. Good outcome was defined as achievement of complete stable remission (CSR), pharmacologic remission (PR) or minimal manifestations (MM). A status of improvement (IM) was categorized as intermediate outcome. Unchanged (U), worse (W), exacerbation (E) and died (D) were classified as poor outcome. CSR indicates no fatigable muscle weakness of MG for at least one year and being free of medication for MG. PR shows those MG patients taking some form of drug for MG excluding cholinesterase inhibitors, but with the same clinical criteria as for CSR. MM indicates MG patient who has no symptoms of functional limitations but has some weakness that is only detectable by careful examination. IM indicates a sustained substantial reduction in MG medications or substantial decrease in pretreatment clinical manifestations.

Statistical analysis

Descriptive statistics were used to evaluate clinical features. Data for continuous variables were compared between groups using the independent t test, while data for categorical variables were compared using the chi-squared or Fisher’s exact tests. Correlation analyses were performed using Spearman’s rank correlation test. The following variables were tested for their potential association with outcome: age of first MC onset requiring ICU management, arterial blood gas values, WBC, MG-ADL at MC onset, duration of ventilation and hospitalization, and ICU stay. Predictors of poor outcome were determined using logistic regression, followed by Cox regression to identify significant independent predictors. All analyses were performed using SPSS 18.0 (IBM, Chicago, IL) and a threshold of significance of p<0.05.

Results

Demographic and clinical information

During the study period, 115 patients (39 males, 76 females) suffered first MC onset requiring ICU management were admitted to our neurological ICU (Table 1). The rate of first MC was 5.68%. Mean age at MG onset was 39.52 years (range, 15.23–73.56 years). Mean duration from MG onset to first MC onset requiring ICU management was 24.08 months (range, 1.20 to 110.50). Fifty-eight percent ofpatients experienced their first MC within one year after symptom onset. Mean age at first MC onset requiring ICU management was 40.18 years (range, 17.42–75.80 years), and 79 patients (20 males, 59 females) suffered first MC onset while younger than 50 (mean age at onset, 31.20). The remaining 36 patients (19 males, 18 females) experienced first MC onset when they were older than 50 (mean age at onset, 66.35).

All patients met at least one positive diagnostic test recognized in the inclusion criteria. The neostigmine test showed the highest overall sensitivity (88.18%, 97/110 positive, 5 not tested), followed by the repetitive stimulation test (83.17%, 84/101 positive, 14 not tested), and the anti-AChR autoantibody test (67.02%, 63/94 positive, 21 not tested) (Table 1).

Precipitants of MC Infection was the most frequent precipitant of MC, occurring in 51.30% of cases (59/115). This took the form of lower respiratory tract infection in 48 patients and upper respiratory infection in 11 patients. In addition, 8 of these 59 patients experienced both infection and hypokalemia. Precipitating factors due to medication occurred in 18 patients (15.65%); 11 patients among them developed MC due to failure to comply with treatment, and MC in 7 patients was aggravated by high-dose steroid therapy. These 7 patients received oral steroid before crises, but acute deterioration following initiation of intra-venous methylprednisolone 1000mg/day treatment precipitated the ICU admission, and they showed symptoms of severe weakness of the respiratory and/or bulbar muscles and inability to maintain adequate ventilation. Three patients had MC during pregnancy (2.61%), one patient developed MC with emotional upset after losing his family member (0.87%), and one patient had MC after severe hypokalemia (0.87%). No obvious precipitant was identified in the remaining 33 patients (28.70%) (Table 1).

Respiratory status, mechanical ventilation, and ICU stay

Included patients spent a mean of 12.25 days (range, 1 to 55) in the ICU and a mean of 26.21 days(range, 3 to 81) in the hospital overall. All patients received mechanical ventilation, for a mean duration of 189.50 hours (range, 4 to 925). Respiratory status of all patients was evaluated prior to intubation, the last time of blood gas analysis before intubation indicated mean pH of 7.38 (range, 7.11 to 7.56), mean PO2 of 105.21 mmHg (range, 56 to 185), and mean PCO2 of 48.93 mmHg (range, 18.30 to 93.10). Leukocytosis was seen in 109 patients, and mean white blood cell count before intubation was 16.53×109/L (range, 8.01×109 to 25.83×109) (Table 2).

At the time of MC onset, 38 (33.04%) had mild symptoms (IIB), 64 patients (55.65%) had moderate symptoms (MGFA IIIB), and 11 (9.57%) had severe symptoms (IVB) (Table 2). In addition, 30 patients (26.09%) received tracheostomies (MGFA V) at a mean of 10.2 days after presentation. The MGFA status of most patients progressively improved during follow-up. Mean MG-ADL score at first MC onset was 16.63), and it correlated positively with PCO2 before intubation (p= 0.004). .Several factors were assessed for possible association with duration of mechanical ventilation, hospital stay and ICU stay (Table 3). Both PCO2 before incubation and MG-ADL score at MC onset correlated positively with duration of ventilation and ICU stay. Longer duration of mechanical ventilation correlated positively with longer stay in the ICU and in the hospital.

Treatment

Prior to admission to ICU, most patients received acetylcholinesterase inhibitors; and pyridostigmine bromide was given to 103 MC patients (89.57%) before intubation. Four patients continued on a decreased dose after establishing mechanical ventilator support. Seven-six patients were on oral prednisolone or intravenous methylprednisolone prior to admission to ICU (66.09%). During stay in ICU, 106 patients were given steroids (92.17%). Specifically, intra-venous methylprednisolone 1000mg/day was administered for 3-5 days, followed by oral prednisolone (1 mg/kg/day). During ICU staying, intravenous immunoglobulin (IVIG) therapy was given to 78 patients (67.82%), 68 of whom received steroid pulse IVIG combination therapy. Four patients received the combination of corticosteroids, IVIG, and plasma exchange. The remaining patients were unable to receive steroids or IVIG or plasma exchange because of hemodynamic instability or severe sepsis or the family’s economic hardship. Other oral immunosuppressants such as tacrolimus were given to 12 patients (10.43%).

Functional outcome and mortality

For the prognosis, 89 patients (77.39%) showed good outcome, 5 (4.35%) had intermediate and 21 (18.26%) had poor outcome. Eighteen patients died in the ICU; all these fatalities resulted from severe comorbidities that had kept them bed-ridden for a long time: pneumonia and respiratory failure (n = 7); bacteremia sepsis (n = 4); and uremia (n = 3) and heart failure (n = 3), followed by respiratory arrest (n = 1). Three patients died after discharge from the ICU: 1 succumbed to pneumonia and respiratory arrest, and 2 stopped treatment and requested early discharge because of financial problems. The twenty-one patients who died were significantly older than those who survived (57.93 vs 33.67 years, p = 0.0009). Table 4 summarized the characteristics of all the included MC patients categorized to two outcome groups, those with good outcome and those with intermediate or poor outcome. The mean age of first MC onset requiring ICU management was older in the intermediate or poor outcome group, the difference was statistically significant. Patients with intermediate or poor outcome had significantly lower pH and PO2 as well as significantly higher PCO2 in the last time of blood gas analysis before intubation, compared to patients with good outcomeIn contrast; the two groups did not differ in WBC count or in the duration of ventilation, hospitalization, or ICU stay.

Univariate analysis using the log rank test identified the following four variables as significantly associated with survival: age at first MC onset requiring ICU management, gender, PO2, and PCO2 (Table 5). Older age of first MC requiring ICU management, male gender, lower PO2, and higher PCO2 were associated with higher mortality risk. However, multivariate logistic regression only identified pre-intubation PCO2 as an independent factor associated with survival. Higher pre-intubation PCO2 was associated with higher mortality risk. Cox regression identified that age at first MC onset requiring ICU management was the key factor which significantly influenced the mortality among the variables examined (p=0.031).

Discussion

MC is a potentially life-threatening complication in patients with MG, but the mortality rate has fallen dramatically over the past 60 years. The introduction of the neurological ICU has substantially improved early recognition of MC, identification of its precipitating factors and respiratory management of patients. The present work may help further improve the early recognition and care of patients who suffer MC by providing a picture of clinical characteristics and even suggestions of baseline factors that may help predict survival.

Mean age at first MC onset requiring ICU management was 40.18 years. However, the median age at first MC onset was 55 years in a US study [3]. One possible explanation for this discrepancy is ethnicity; other explanations include the differences in sample size, environmental factors and other population factors. In the present study, we found that first MC affecting people younger than 50 years affected women disproportionately, most of whom were aged 20-50; in contrast, first MC affecting people older than 50 did not show gender bias. These results are consistent with other studies [3, 6, 8, 9]. The average interval from onset of MG to first MC requiring ICU managemsnt was 24.08 months in our cohort, much longer than the 8 months reported in another study [3]. Our results are consistent with recent reports of a median interval from onset to crisis of 3 years [9] and mean duration of MG prior to ICU admission of 3.8 years [10]. A longer interval from MG onset to first MC probably reflects recent improvements in recognition of the disease, management of respiratory and bulbar conditions, and greater access to newer treatment modalities. Just over half our patients experienced their first MC within one year of symptom onset, consistent with a study showing that MC typically occurs within the first 2 years after MG diagnosis [11].

While MG diagnosis in Europe and North America is most often supported using the tensilon test, the neostigmine test is used more often in China. In our study, the neostigmine test showed overall sensitivity of 88.18%, a little bit lower compared to the 96.8% reported by another study in China [12]. These results validate the important role of this test for MG diagnosis in China. The proportion of patients in our cohort who took the repetitive stimulation test and gave a positive result was 83.17%%, higher than the 77.4% reported in a cohort of 1,108 Chinese MG patients [12], and higher than the 75.9% reported in an Italian cohort [13]. The higher rate of positive results on the repetitive stimulation test in our study may reflect the fact that we included all MC patients admitted to the ICU during the study period, none of whom had ocular MG. Sixty-three patients in 94 cases were positive for anti-AChR antibodies. This may underestimate the real prevalence of such antibodies, since this test is not routine in China because of resource limitations.

Infection, especially lower respiratory tract infection, was the most common identifiable precipitant of MC, followed by medication, and inadequate treatment/drug withdrawal. Other studies have also identified respiratory tract infection as the most frequent cause of MC, accounting for about half of crises resulting in ICU admission [9, 10, 14]. Failure to comply with treatment or drug withdrawal was a frequent cause of MC accounting for 11 patients out of 115 in our study. Initial treatment with steroid led to exacerbation of MG in 30-50% of patients and decompensation in patients with MC, whereas 9-18% of them develop MC [15]. In the present study, 7 patients out of 115 develop MC due to high-dose steroid therapy. Therefore, initiation of high-dose steroid should occur in a hospital setting, where the respiratory function can be monitored[15]. Predictors of exacerbation from steroid include older age, bulbar symptoms, and lower score on Myasthenia Severity Scale [15-17]. Our study showed pregnancy as a trigger of MC being responsible for crisis in 3 out of 115 patients, and study reported that pregnancy can aggravate MG in 33% of the MG cases [5, 18, 19].

We suggest a detailed review of systems when the disease is getting worse, with attention to infectious sources, respiratory symptoms, and drug exposures (12). Physicians must pay careful attention to respiratory rate, difficulty with phonation, a quiet voice, weak neck muscles, work of breathing, and oxygenation. If the patient demonstrates vital capacity (VC) <10–20 mL/kg or negative inspiratory force (NIF) < –20 to –30 cm H2O, diagnosis of MC is considered. However, these values are not derived from studies on patients with MG, but rather from studies in patients with GBS (20–22). We recommend that physicians should focus on the respiratory status of the patient, and trends in these symptoms, rather than relying on absolute numbers of VC or NIF. We also identified higher MG-ADL score at MC onset as a potential indicator that ICU care will be needed. Indeed, MG-ADL score >18 points at MC has been reported to predict the need for ICU management with 75% sensitivity and 77.8% specificity [14]. Surprisingly, we detected severe hypercarbia in our cohort before intubation (mean PCO2, 48.93 mmHg). Since MG-ADL score at MC onset correlated positively with PCO2 before intubation, respiratory status may be tightly associated with MC symptoms, and hypercarbia may affect daily activities of patients with MC. Mean duration of ICU stay was 12.25 days in our study, similar to the median of 14 days reported in a US study thirty years ago [6] or the median of 13 days reported in a US study more recently [3]. The mean duration of ventilation of 189.50 hours in our study is similar to the 8 days reported in a US study [20]. We found that pre-intubation PCO2 and MG-ADL score at MC onset were associated with duration of ventilation and ICU stay. Previous work also identified pre-intubation serum bicarbonate > 30mg/dl as an independent risk factor for prolonged intubation [3]. Higher PCO2 prior to mechanical ventilation may indicate more severe condition that will likely require extensive respiratory support and ICU management.

About eighty percent of our patients showed good functional outcome during follow-up. This likely reflects the potentially reversible character of MG and substantial advances in therapeutic and supportive measures [11]. Study has showed that MG is often associated with better functional outcomes at one year than other diseases requiring neurocritical care [21]. However，patients with intermediate and poor outcome had older age of first MC onset, and lower pH and PO2, as well as higher PCO2 before intubation. Previous study retrospectively included 38 MC patients admitted to the Neuro-medical ICU, and found that 4 patients died in hospital, and the remainder of patients with different age of MC onset (older (>50 years) and younger (<50 years) patients) did not show differences in long-term outcome [10]. However, one study found that being older than 50 at first MC independently predicted prolonged intubation [3], while another reported that being younger than 40 at MG onset was associated with higher likelihood of remission [13]. The associations between age of first MC onset and outcomes need to be clarified in larger studies with long follow-up. Astudy showed that pre-ventilation pH below 7.30 and high PCO2 were associated with poor functional outcome and death [22]. A study comparing MC patients in the ward or in the ICU reported that only those in the ICU had abnormal arterial blood gases, and that patients in the ICU had lower pH and higher PCO2 [14]. Low pH and high PCO2 indicate chronic respiratory acidosis, which may be associated with severe disability and death, especially in MG patients who experience MC. Little is known about the outcome of first MC patients suffering from acute severe axacerbations following ICU discharge. In the present study, pre-intubation PCO2 and age of first MC onset were considered to be factors associated with survival. Therefore, in MC patients with extremely high PCO2 level before intubation may obtain poorer prognosis, especially in patients with older age.

By the end of follow-up, 21 of 115 patients in our cohort had died (18.26%).This mortality rate is near the high end of the range of 6-30% reported for MC patients in several studies [3, 9, 23-25]. However, the mortality rate of MC fell from 42% in the early 1960s to contemporary rates of 4 to 10% with the improvement of the advent of IVIg and plasma exchange and ICU management [3, 6]. The relatively high mortality rate in our study may reflect the fact that we included all consecutive patients who presented in the neurological ICU during the study period irrespective of their place of management. For example, some MC patients admitted in our center were managed in the general ward. Study has shown that compared to MC patients who received general ward management, MC patients with ICU management had higher MG-ADL scale scores and higher MGFA classification [14]. There could be selection bias, since more seriously ill patients could be selected in the present study. The other fact needed to consider is the ground clinical reality in developing countries, and poor awareness on this part of patients in addition to drug nonaffordability is the actual reality in China. In resource-challenged settings like China, vigorous and concerted efforts should be made in MC prevention, timely identification, emergency intervention, and aggressive treatment.

Our study has several shortcomings, exacerbated by the small sample size. Our population may have been affected by referral bias because our hospital is a tertiary referral center. As a result of the retrospective design of our study, we may have failed to include certain patients who were not entered properly in the hospital computer system, and we could not control for different treatment strategies chosen by physicians on duty. We did not analyze data related to other parameters that might have affected clinical outcomes, including maximal expiratory pressure and maximal inspiratory pressure on pulmonary function tests.

References

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Tables

Table 1 Baseline demographic and clinical data of patients with first MC onset

*Parameter*	value
*Age at MG onset (yr)*		39.52 ± 16.73
*Age at first MC onset (yr)*		40.18 ± 17.63
*Duration of MG before first MC (mo)*		24.08 ± 25.26
*Neostigmine Test (positive/negative/not tested)*		97/13/5
*RNS (positive/negative/not tested)*		84/17/14
*Anti-AChR auto-antibodies (positive/negative/not tested)*		63/31/21
*Precipitant (Infection/Medication/ Pregnancy/ Stressor/Hypokalemia without precipitant)*		59/18/3/1/1/33

Abbreviations: MC, myasthenic crisis; mo, month(s); yr, year(s); RNS, repetitive nerve stimulation

Table 2 Laboratory tests, disease characteristics and outcomes of patients with first MC onset

*Parameter*	value
*Arterial blood gas before intubation*
pH		7.38 ± 0.10
PO₂ (mmHg)		105.21 ± 43.26
PCO₂ (mmHg)		48.93 ± 16.21
*Blood test*
WBC (10⁹/L)		16.53 ± 6.12
*Clinical severity*
MGFA (IIB/IIIB/IVB)		38/64/11
*MG-ADL scale score*		16.63 ± 4.21
*Duration on ventilation (hours)*		189.50 ± 221.30
*Duration of hospitalization (days)*		26.21±15.68
*ICU stay (days)*		12.25 ± 13.21

Abbreviations: ICU, intensive care unit; MC, myasthenic crisis; MG-ADL, Myasthenia Gravis–Activities of Daily Living scale;

MGFA, Myasthenia Gravis Foundation of America scale; mRS, modified Rankin scale; WBC, white blood cell count;

﹡, MG-ADL scale score At onset vs In ICU p<0.05.

Table 3 Factors associated with duration on ventilation, duration of hospitalization, and ICU stay

	*duration on ventilation*			*ICU stay*
	*r_s*	*P value*		*r_s*	*P value*
*Age at first MC onset* *pH before intubation* *PO2 before intubation* *PCO2 before intubation* *MG-ADL at first MC onset* *duration on ventilation*	0.341 - 0.171 - 0.268 0.316 0.536 /		0.061 0.367 0.149 0.042 0.002 /	0.235 - 0.142 - 0.212 0.411 0.752 0.843	0.167 0.491 0.242 0.025 <0.0001 <0.0001

Abbreviation: ICU, intensive care unit

Table 4 Comparison of patients showing good or poor outcome*

	*Good outcome*	*Intermediate or poor outcome*	*P value*
*Age at first MC onset*	32.43 ± 7.71	54.23 ± 15.96	< 0.0001
pH	7.41 ± 0.62	7.28 ± 0.13	0.0004
*PO2*	116.92 ± 42.75	80.24 ± 32.45	0.0398
*PCO2*	37.97 ± 7.91	58.54 ± 20.82	0.0005
*WBC*	14.51 ± 4.67	16.12 ± 5.36	0.4543
*Duration on ventilation, h*	168.34 ± 234.41	241.76 ± 268.78	0.2876
*Duration of hospitalization, d*	21.43 ± 15.24	28.25 ± 17.73	0.5341
*ICU stay, d*	10.32 ± 16.13	17.23 ± 14.34	0.1709

Abbreviations: ICU, intensive care unit; WBC, white blood cell count

*Defined based on the MGFA postintervention status.

Table 5 Predictors of death

*Univariate*	*Exp (Coef)*	*95% CI*	*P value*
*Age at first MC onset*	1.131	1.021 to 1.243	0.004
*Gender*	7.865	1.652 to 55.864	0.023
*PO2*	0.752	0.625 to 0.012	0.051
*PCO2*	1.031	1.012 to 1.437	0.019
*WBC* *MG-ADL at first MC onset*	1.136 1.093	0.834 to1.369 0.915 to 1.574	0.569 0.152
*Duration of ventilation*	1.682	0.957 to 2.373	0.163
*Duration of hospitalization*	1.006	0.841 to 1.023	0.727
*ICU stay*	1.021	0.915 to 1.147	0.736
*Multivariate*	*Exp (Coef)*	*95% CI*	*P value*
*PCO2*	1.132	1.067 to 1.342	0.021

Abbreviations: ICU, intensive care unit; MG-ADL, Myasthenia Gravis-Activities of Daily Living scale; WBC, white blood cell count

Myasthenic Crisis Treated in a Neurological Intensive Care Unit: Clinical Features, Mortality, Outcomes, and Predictors of Survival

Abstract

Background

Methods

Results

Discussion

Conclusion

Declarations

References

Tables