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Postgraduate Education Corner: PULMONARY AND CRITICAL CARE PEARLS |

A 46-Year-Old Man With Dyspnea and Left Diaphragm Paralysis FREE TO VIEW

Khalil Diab, MD; Riley J. Snook, MD; Mark Farber, MD, FCCP
Author and Funding Information

Affiliations: From the Department of Medicine (Drs. Diab and Farber), Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, and the Department of Neurology (Dr. Snook), Indiana University School of Medicine, Indianapolis, IN.

Correspondence to: Khalil Diab, MD, 340 West 10th St, Suite 6200, Indianapolis, IN 46202-3082; e-mail: kdiab1977@gmail.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(6):1690-1693. doi:10.1378/chest.09-1072
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A 46-year-old man was referred because of increasing shortness of breath. His symptoms started 1 year prior after he fell while working in Iraq as a contractor. Progressively increasing shortness of breath developed on exertion with a nonproductive cough, and he could walk only 50 ft on presentation. Additional symptoms were occasional dysphagia, diplopia, mild short-term memory problems, morning headaches, hypersomnolence, and severe fatigue toward the end of the day. His medical history included coronary artery disease, obesity, obstructive sleep apnea, hypertension, dyslipidemia, and chronic low back pain, and he was an ex-smoker of 50 pack-years. The patient was on leave from work secondary to his shortness of breath and back pain. He was receiving the following medications: morphine sulfate, sustained release; cyclobenzaprine; tramadol; atorvastatin; clopidogrel; metoprolol; furosemide; and lansoprazole.

Physical Examination

The patient's vital signs on presentation were as follows: temperature, 36.5° C; heart rate, 83 beats/min; BP, 125/64 mm Hg; respiratory rate, 22 breaths/min; oxygen saturation, 95% while breathing room air; and BMI, 33 kg/m2. General examination revealed a man who was overweight and slightly tachypneic. Head and neck examination showed Mallampati stage 3; chest examination revealed decreased air entry at the left base posteriorly. The cardiac, abdominal, and extremity examination findings were normal. A neurologic examination revealed a muscle power of 4+/5 in the bilateral upper and lower extremities proximally and distally. He had difficulty squatting but had a normal gait. Cranial nerves, sensory examination findings, and reflexes were normal.

Laboratory and Radiologic Findings

The patient's cell count and differential cell count were normal. His electrolyte levels were as follows: sodium, 135 mEq/L; potassium, 3.7 mEq/L; chloride, 97 mEq/L; and bicarbonate, 30 mmol/L. Other laboratory findings were as follows: BUN, 10 mg/dL; creatinine, 0.9 mg/dL; and calcium, 9.1 mg/dL. Posteroanterior and lateral plain films of the chest are shown in Figure 1. A CT scan of the chest showed a left-lower-lobe infiltrate with occasional air bronchograms that were suggestive of left-lower-lobe atelectasis and possible pneumonia. No pulmonary emboli were noted. No mediastinal lymph nodes or masses were noted. Arterial blood gas measurements were as follows: pH, 7.35; Pco2, 63 mm Hg; and Po2, 80 mm Hg. Pulmonary function test results are shown in Table 1. There was a 27% decrease in FVC (measured in upright vs supine positions). Fluoroscopy showed markedly limited movement of the right hemidiaphragm and a paralyzed (paradoxical motion) left hemidiaphragm. An electromyogram (EMG) demonstrated increased amplitude and duration of the motor unit potential of the thoracic paraspinal muscles. EMG manifestations as well as serology test results for Lambert-Eaton syndrome and myasthenia gravis were negative. MRIs of the brain, thoracic spine, and lumbar spine, and a CT scan of the cervical spine were unremarkable. Creatinine kinase levels, thyroid function test results, erythrocyte sedimentation rates, and serum protein electrophoresis findings were normal. The antinuclear antibody profile and the test results for anti-Jo antibodies were negative. The aldolase concentration was slightly elevated at 8.4 U/L (normal, 2 to 7 U/L).

Figure Jump LinkFigure 1 Plain film of the chest (posteroanterior and lateral) showing elevation of the left hemidiaphragm. Atelectasis at the left lung base is noted.Grahic Jump Location
Table Graphic Jump Location
Table 1 Pulmonary Function Tests (Neuromuscular Protocol)

Dlco = diffusing capacity for carbon monoxide; Kco = carbon monoxide transfer coefficient; MVV = maximal voluntary ventilation; Pemax = maximal expiratory pressure; Pimax = maximal inspiratory pressure; RV = residual volume; TLC = total lung capacity; VA = alveolar volume measured by methane during diffusing capacity measurement.

What is the diagnosis?
Diagnosis: Adult-onset acid maltase deficiency

The next diagnostic step was to measure acid maltase enzyme levels in a muscle biopsy specimen and in peripheral blood lymphocytes. Unilateral diaphragmatic paralysis is seen fairly commonly. It leads to wide differential diagnoses, including neuromuscular junction disorders, muscular disorders, spinal cord myelopathies, and peripheral neuropathies. These diagnoses are detailed in Table 2.

Table Graphic Jump Location
Table 2 Differential Diagnosis of Diaphragmatic Paralysis in Adults

Acid maltase deficiency, or Pompe disease, is a glycogen storage disease myopathic disorder that was first described in 1932 in a 7-month-old infant. It is a familial disorder, with autosomal-recessive inheritance resulting in a deficiency of the enzyme α-1,4 glucosidase, which releases glucose from glycogen. Glycogen accumulates in skeletal muscle and other organs, causing measurable dysfunction.

Three subtypes of acid maltase deficiency exist, which are infantile, juvenile, and adult. The infantile form usually is severe, involving multiple organs, including the heart, and has a high mortality rate. The juvenile and adult forms present primarily as myopathic disorders, with cardiac involvement being a rare manifestation.

Adult-onset acid maltase deficiency has a highly variable presentation. The age of onset is between 25 and 68 years, with a male/female predominance of 1.7:1. The pelvic, limb girdle, and proximal lower- and upper-extremity muscles are commonly involved.

Respiratory muscle involvement also occurs in about 58% of the patients and can be the initial manifestation of the disease, with diaphragmatic involvement being the most prevalent. Diaphragmatic manifestations include both unilateral diaphragmatic paralysis and bilateral diaphragmatic weakness. The severity of respiratory muscle weakness does not correlate with the severity of other skeletal muscle involvement. Early manifestations in adults include nocturnal symptoms related to rapid eye movement sleep respiratory muscle dysfunction, such as morning headaches and daytime hypersomnolence. These symptoms could be confused with obstructive sleep apnea. Dyspnea on exertion and chronic respiratory acidosis are later manifestations. Pulmonary function tests usually reveal a decreased vital capacity of 13% to 69% predicted, with a significant decrease when measured with the patient in the supine position. The disease is progressive, with decreases in vital capacity of 20% to 30% over several years.

Diagnosis is difficult, requiring a high level of suspicion. Creatinine kinase usually is elevated at 2 to 10 times normal; however, normal levels can be seen. There are no specific EMG findings. Muscle fibrillations, myopathic and neurogenic patterns, and normal EMGs are described. Findings that are specific for the diagnosis include decreased α-1,4 glucosidase activity and the accumulation of cytoplasmic glycogen in peripheral blood lymphocytes. Muscle biopsy of the weakest muscles also is diagnostic, and decreased α-1,4 glucosidase activity is seen in most of the sections. Pathologic findings are variable and nonspecific; a common finding is the presence of vacuolated fibers.

Treatment of respiratory muscle involvement usually is supportive. Nighttime noninvasive ventilation in select patients can lead to improved quality of life and a decreased hospitalization rate, but it does not halt the progression of the disease. Early improvement in vital capacity occurs after initiation, but this improvement does not last. As with other neuromuscular diseases, tracheostomy and nighttime ventilation are beneficial at later stages. Diaphragmatic plication with unilateral diaphragmatic paralysis and diaphragm pacing with bilateral diaphragm weakness can be helpful.

Enzyme replacement with recombinant rabbit α-1,4 glucosidase leads to improved muscle function, reversal of cardiac hypertrophy, and improved survival in infants. It has not been extensively tested in juveniles and adults. Three patients 11, 17, and 33 years of age who were wheelchair bound secondary to acid maltase deficiency received weekly enzyme infusions for >3 years. By the end of the infusion period, the patient who completely depended on a ventilator could tolerate 45 min off the ventilator; the ventilator dependency of the second patient decreased from 18 h to 10 h/d, and the third patient who was not ventilator dependent could walk independently.

Our patient's radiologic studies were consistent with right diaphragmatic weakness and left diaphragmatic paralysis. A cause of these findings could not be discerned from the extensive diagnostic workup. An acid α-1,4 glucosidase assay in the blood was low at 5.6 pmol per punch per hour (normal, 10.0 to 49.0 pmol per punch per hour). A right quadriceps biopsy showed marked type II fiber predominance with no evidence of inflammatory myopathy. A significant and partial reduction in acid maltase activity was found. The level was 1.78 mmol/min/g tissue (reference range, 1.74 to 9.98 mmol/min/g). A diagnosis of adult-onset acid maltase deficiency was made. Replacement therapy is being pursued.

  1. Adult-onset acid maltase deficiency has a highly variable presentation but should be part of the differential diagnosis of unilateral diaphragmatic paralysis without obvious cause.

  2. Respiratory muscle involvement, especially diaphragm involvement, may occur in >50% of these patients.

  3. The disease usually is progressive, with a 20% to 30% decrease in vital capacity over time, and can result in ventilator dependence.

  4. Measurement of enzyme levels in peripheral blood lymphocytes and muscle biopsy specimens of the weakest muscles is diagnostic. Muscle biopsy pathologic findings are highly variable.

  5. Treatment with rabbit α-1,4 glucosidase replacement is beneficial in infants and may lead to significant improvement in muscle function in adults.

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Sivak ED, Salanga VD, Wilbourn AJ, et al. Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann Neurol. 1981;9:613-615. [PubMed] [CrossRef]
 
Trend PSJ, Wiles CM, Spencer GT, et al. Acid maltase deficiency in adults: diagnosis and management in five cases. Brain. 1985;108:845-860. [PubMed]
 
Sivak ED, Ahmad M, Hanson MR, et al. Respiratory insufficiency in adult-onset acid maltase deficiency. South Med J. 1987;80:205-208. [PubMed]
 
Felice KJ, Alessi AG, Grunnet ML. Clinical variability in adult-onset acid maltase deficiency: report of affected sibs and review of the literature. Medicine (Baltimore). 1995;74:131-135. [PubMed]
 
Barbe F, Quera-Salva MA, de Lattre J, et al. Long-term effects of nasal intermittent positive-pressure ventilation on pulmonary function and sleep architecture in patients with neuromuscular diseases. Chest. 1996;110:1179-1183. [PubMed]
 
Van den Hout H, Reuser AJ, Vulto AG, et al. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet. 2000;356:397-398. [PubMed]
 
DiMarco AF, Onders RP, Kowalski KF, et al. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med. 2002;166:1604-1606. [PubMed]
 
Winkel LPF, Van den Hout JMP, Kamphoven JHJ, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up. Ann Neurol. 2004;55:495-502. [PubMed]
 
Pellegrini N, Laforet P, Orlikowsky D, et al. Respiratory insufficiency and limb muscle weakness in adults with Pompe's disease. Eur Respir J. 2005;26:1024-1031. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Plain film of the chest (posteroanterior and lateral) showing elevation of the left hemidiaphragm. Atelectasis at the left lung base is noted.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Pulmonary Function Tests (Neuromuscular Protocol)

Dlco = diffusing capacity for carbon monoxide; Kco = carbon monoxide transfer coefficient; MVV = maximal voluntary ventilation; Pemax = maximal expiratory pressure; Pimax = maximal inspiratory pressure; RV = residual volume; TLC = total lung capacity; VA = alveolar volume measured by methane during diffusing capacity measurement.

Table Graphic Jump Location
Table 2 Differential Diagnosis of Diaphragmatic Paralysis in Adults

Suggested Readings

Sivak ED, Salanga VD, Wilbourn AJ, et al. Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann Neurol. 1981;9:613-615. [PubMed] [CrossRef]
 
Trend PSJ, Wiles CM, Spencer GT, et al. Acid maltase deficiency in adults: diagnosis and management in five cases. Brain. 1985;108:845-860. [PubMed]
 
Sivak ED, Ahmad M, Hanson MR, et al. Respiratory insufficiency in adult-onset acid maltase deficiency. South Med J. 1987;80:205-208. [PubMed]
 
Felice KJ, Alessi AG, Grunnet ML. Clinical variability in adult-onset acid maltase deficiency: report of affected sibs and review of the literature. Medicine (Baltimore). 1995;74:131-135. [PubMed]
 
Barbe F, Quera-Salva MA, de Lattre J, et al. Long-term effects of nasal intermittent positive-pressure ventilation on pulmonary function and sleep architecture in patients with neuromuscular diseases. Chest. 1996;110:1179-1183. [PubMed]
 
Van den Hout H, Reuser AJ, Vulto AG, et al. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet. 2000;356:397-398. [PubMed]
 
DiMarco AF, Onders RP, Kowalski KF, et al. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med. 2002;166:1604-1606. [PubMed]
 
Winkel LPF, Van den Hout JMP, Kamphoven JHJ, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up. Ann Neurol. 2004;55:495-502. [PubMed]
 
Pellegrini N, Laforet P, Orlikowsky D, et al. Respiratory insufficiency and limb muscle weakness in adults with Pompe's disease. Eur Respir J. 2005;26:1024-1031. [PubMed]
 
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