by MONTSERRAT DIAZ-ABAD, MD; NEVINS TODD, MD; LINDSAY ZILLIOX, MD; ANA SANCHEZ, MD; and CHARLENE HAFER-MACHO, MD

Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland. Drs. Zilliox, Sanchez, and Hafer-Macko are with the Department of Neurology, University of Maryland School of Medicine in Baltimore, Maryland.

Funding: No funding was provided.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Abstract: Background: Stepwise approach to therapy and increasing use of immunosuppressive agents have led to increasingly good prognosis and survival in myasthenia gravis (MG). However, there is a small subset of patients with treatment-refractory disease who experience a higher disease burden and increased rates of myasthenic crises and exacerbations, including respiratory failure. A 54-year-old man with treatment-refractory MG on chronic plasma exchange therapy had rapidly fluctuating weakness, poor sleep quality, and worsening respiratory symptoms in between treatments. He was started on home nocturnal noninvasive ventilation with volume-assured pressure support mode and experienced marked improvement in sleep quality, dyspnea, fatigue, and daytime sleepiness.

Keywords: myasthenia gravis, sleep hypoventilation, treatment-refractory, noninvasive ventilation, volume-assured pressure support, respiratory failure

Innov Clin Neurosci. 2019;16(11–12):11–13

Myasthenia gravis (MG) is an autoimmune disease in which antibodies bind to the postsynaptic acetylcholine receptors or related molecules in the neuromuscular junction, causing fatigable skeletal muscle weakness.1 Stepwise approach to therapy and greater use of immunosuppressive agents has led to increasingly good prognosis and survival.2 However, there is a small subset of patients with treatment-refractory disease3 who experience a higher disease burden and increased rates of myasthenic crises.4

Neuromuscular diseases, including MG, cause respiratory failure due to weakness of the respiratory muscles, which initially leads to microatelectasis in the lung bases. As respiratory muscle fatigue progresses, alveolar hypoventilation ensues (first manifested by tachypnea with normal PCO2), followed by the development of hypercapnia, and eventually, severe hypoxemia. Timely application of noninvasive ventilation (NIV) might reverse this process in time to prevent intubation and invasive mechanical ventilation.5

We present the case of a 54-year-old man with treatment-refractory MG on intravenous immunoglobulin (IVIg) and then plasma exchange therapy (PLEX) with rapidly fluctuating weakness and respiratory symptoms treated with NIV with volume-assured pressure support mode (VAPS). He experienced marked improvement in sleep quality, fatigue, and daytime sleepiness with consistent nocturnal ventilatory support.

Case Presentation

A 54-year-old man presented to pulmonary clinic for management of NIV. He had a history of double antibody negative (negative antibodies toward acetylcholine receptor binding, blocking, and modulating; anti-striated muscle and muscle specific kinase) MG diagnosed with a pyridostigmine challenge seven years prior. The patient was first treated with pyridostigmine 30mg three times daily with good clinical response, which confirmed the diagnosis. He could not tolerate higher doses due to gastrointestinal side effects. Over two years, the patient noted stepwise progression of lower extremity weakness and dyspnea on exertion despite the addition of prednisone. He also had chronic fatigue, dysphagia, blurred vision, and occasional ptosis. The patient was concerned about the side effects of prednisone therapy, which was discontinued at his request, and was started on mycophenolate 1000mg twice daily on year two. He continued on the same pyridostigmine dose.

Computed tomography of the chest revealed no thymoma. Sensory and motor nerve conduction studies and needle electromyography were performed on the left upper extremity and were normal. Polysomnography was negative for obstructive sleep apnea, with normal oxygenation and ventilation, and forced vital capacity (FVC) was 3.69L (71%) and arterial blood gas was pH 7.36, PaCO2 50mmHg, PaO2 127mmHg. Due to hypercapnia, an outside center prescribed nocturnal NIV with bilevel positive airway pressure (BPAP) with BiPAP S (Philips Respironics, Murrysville, PA, USA) 12/6cm H2O.

The patient continued on mycophenolate and pyridostigmine. He was started on monthly IVIg infusions (1mg/kg), but due to progressive symptoms, he was treated with rituximab infusion 500mg twice. He improved clinically and was able to stop IVIg and pyridostgmine, continuing on mycophenolate. However, he experienced an episode of transient global amnesia shortly after completing his treatment with rituximab and had several infectious complications. This was not continued. Approximately six months after his treatment with rituximab, he was admitted with a myasthenic exacerbation with bulbar weakness and treated with IVIg (1mg/kg, 70mg) infusion every four weeks in addition to continuing on mycophenolate. There was an initial good symptomatic response. The patient used BPAP by the fifth day post IVIg infusion due to worsening orthopnea and sleep quality. With BPAP, breathing was temporarily improved, and he slept better with fewer awakenings; although, sometimes there was not enough support in terms of breath size or frequency, particularly as dyspnea worsened leading up to the next infusion. IVIg was increased to every two weeks 10 months prior to presentation after a myasthenic crisis. Six months later, IVIg infusions were reduced in dosage to 0.5mg/kg (35mg) but increased to weekly frequency due to rapid symptomatic worsening. After initial improvement post infusion, there was progressive lower extremity weakness; the patient used a cane to ambulate post infusion and a walker by the end of the week. In addition, he experienced dyspnea with activities of daily living and while talking for long periods, chronic fatigue, persistent double vision with occasional ptosis, and fatigue with chewing and dysphagia. All progressively worsened days after the infusion. There was sometimes difficulty clearing airway secretions.

Due to continued disease progression and declining response to IVIg, the patient was switched from IVIg to PLEX one month before presentation, with reported improvement in overall strength, activity level, and dyspnea on exertion. Each session seemed to last about one and a half weeks before breathing became more labored, legs became weaker, and other symptoms worsened. Spirometry while on IVIg had FVC 1.30L (25% predicted). There was no significant improvement in the FVC on PLEX—FVC was 1.65L (32% predicted) four weeks after initiating PLEX therapy.

At initial evaluation, the patient had not been using BPAP for several months because of face sores, nosebleeds, mask discomfort, and air leaks. There were frequent morning headaches, dry mouth, nightmares, nonrestorative sleep, and excessive daytime sleepiness. Sleep was restless, with frequent awakenings due to difficulty breathing. Later in the week, he slept in a recliner due to increasing orthopnea. Pertinent findings on physical exam: body mass index 20.4kg/m2; lungs clear, diminished breath sounds at the bases; decreased diaphragmatic expansion; mild rapid shallow breathing pattern; weak cough; paradoxical inspiratory abdominal motion when supine and discomfort lying flat for an extended period; diplopia at primary and endgaze with associated ptosis and weakness of orbicularis oculi; atrophy of calves and thighs; strength less than 3/5 hip flexors; unable to stand from a seated position without the use of the arms; decreased leg lift, shortened stride length, and slow gait.

The patient was diagnosed with chronic respiratory failure, sleep maintenance insomnia, and ineffective cough related to MG. Because of the rapid cycling of symptoms, nocturnal NIV was started with BiPAP AVAPS (Philips Respironics, Murrysville, PA, USA): Target tidal volume: 500mL (~ 6.5ml/kg); inspiratory positive airway pressure (IPAP) range: 10-20cm H2O; expiratory positive airway pressure (EPAP): 4cm H2O; respiratory rate: 14. Mechanical insufflator-exsufflator (MI-E) was added for cough augmentation.

NIV with a full-face mask was well tolerated by the patient. Without NIV, he could not sleep due to worsening orthopnea. Sleep maintenance insomnia resolved on NIV with restful sleep and no awakenings due to difficulty breathing, and improved daytime fatigue and sleepiness. The patient felt breathing was well supported consistently with this new NIV mode and was also using MI-E twice daily to clear airway secretions. One month later, NIV average downloaded data showed days used was greater than four hours: 100 percent, daily use: 7.8 hours, exhaled tidal volume: 500mL, respiratory rate: 14, minute ventilation: 6.7L/min. Venous blood gas was pH 7.39, PaCO2 44mmHg. Current settings were continued.

Discussion

We present the case of a 54-year-old man with treatment-refractory double seronegative MG that failed to respond to high dose immunosuppression and frequent, regular IVIg, and later PLEX therapy with rapidly fluctuating respiratory muscle weakness. He was treated with NIV VAPS and experienced marked improvement in sleep quality, fatigue, and daytime sleepiness with consistent ventilatory support while on therapy. To our knowledge, the use NIV VAPS mode has not been reported in treatment-refractory MG.

MG is estimated to affect more than 700,000 people worldwide2 and 55,000 in the United States.4 The development of a stepwise approach to therapy and increasing use of immunosuppressive agents has led to increasingly good prognosis, quality of life, and survival in MG.2 MG has multiple variants, and patients with MG should be grouped based on antibody mechanisms, thymic status, response to therapy, and phenotype, as prognosis varies with all these variables. Patients with MG and muscle-specific kinase antibodies, e.g., have more severe weakness, while patients with LRP4 antibodies tend to have only mild-to-moderate symptoms. Ten to 15 percent of patients with MG are seronegative. Patients with late onset MG or MG associated with thymoma or muscle-specific kinase antibodies tend to have the most severe disease and frequently need immunosuppressive drug treatment, while MG associated with muscle specific kinase antibodies has a favorable response to rituximab.1

For a small subset of patients, the disease becomes difficult to control and requires more aggressive treatment.3,4 Patients are considered treatment-refractory when there are persistent symptoms or side effects that limit functioning after an adequate trial of corticosteroids and at least two other immunosuppressive agents. They represent about 10 percent of generalized patients with MG.2 Patients with treatment-refractory MG have increased rates of myasthenic crises and exacerbations; they are twice as likely to die at one-year follow-up compared to patients with nonrefractory MG. Additionally, they experience a higher burden of disease and increased rates of comorbidities compared to patients with nonrefractory MG and controls, in particular diabetes, cardiac arrhythmias, and severe infections.4 Moreover, there is a rare subset of treatment-refractory patients with high disease severity who have severe morbidity, despite treatment with two immunosuppressive treatments, or one immunosuppressive treatment plus IVIg or plasma exchange.4 While used more commonly as rescue modalities for MG crises, IVIg and PLEX might also be used as maintenance therapy when other treatments are insufficiently effective.2

NIV via mask interface can be used to deliver bilevel positive airway pressure (BPAP), providing support to weakened and fatigued respiratory muscles, with inspiratory and expiratory positive airway pressures adjusted to the individual patient. NIV is most useful in the acute setting in patients with MG in crisis who are experiencing respiratory failure. Since rest makes the weakness better in MG, when the respiratory muscles start to fatigue, ventilatory support with NIV can reverse the worsening weakness and prevent full respiratory failure and the requirement of intubation and invasive mechanical ventilation.5 This patient had poor functional status and chronic respiratory failure at baseline, with rapid cycling of symptoms depending on timing of IVIg infusions or PLEX. He had variable ventilatory support needs that paralleled the almost day-to-day variation in respiratory muscle weakness associated with partial temporary response to therapy, in addition to slower overall disease progression. An NIV mode that could provide variable ventilatory support to compensate for varying ventilatory needs was thought to be particularly advantageous for this specific patient; thus, NIV VAPS mode was started instead of traditional BPAP mode.

VAPS is a hybrid NIV mode that uses BPAP to achieve a consistent tidal volume during each breath. In average VAPS (AVAPS), a target tidal volume, fixed EPAP, and backup respiratory rate are prescribed, along with IPAP levels that adjust within a range to maintain the tidal volume despite changes in respiratory mechanics, ventilatory control and respiratory muscle recruitment that can occur with body position changes and during sleep.6 Ambrogio et al7 showed that VAPS was better able to maintain constant minute ventilation by maintaining tidal volume during sleep, including rapid-eye movement sleep, compared to BPAP. While serial BPAP pressure adjustments might be required in some patients with neuromuscular disease, such as amyotrophic lateral sclerosis, to compensate for increasing respiratory muscle weakness and hypercapnia,8 NIV VAPS can help maintain stable minute ventilation long-term in these patients despite marked disease progression.9

In cases of treatment-refractory MG with respiratory muscle weakness, both serial pulmonary monitoring and starting NIV when sleep hypoventilation and chronic respiratory failure develop are important given the potential benefits of therapy. Studies are needed to determine if different NIV modes offer a distinct benefit in the management of MG, in particular for treatment-refractory MG.

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