Pompe disease, caused by deficient levels of circulating acid alpha-glucosidase, can eventually lead to diaphragmatic muscle weakness, resulting in respiratory insufficiency. 

Current advancements in treatment, including enzyme replacement therapy (ERT), have done a remarkable job in improving muscle strength and walking distance, However, scientists have discovered that ERT apparently works better on skeletal muscles than on respiratory muscles. 

“ERT improves survival by clearing glycogen in cardiac muscle and improving cardiac function,” Fusco and colleagues wrote in the International Journal of Molecular Sciences. “However, because ERT does not effectively clear glycogen in respiratory skeletal muscle, airway smooth muscle, and neural control centers, many patients on ERT still suffer from respiratory dysfunction and require ventilatory support.”


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The latest advice for the commencement of ERT is muscle weakness or respiratory muscle weakness represented by a forced vital capacity (FVC) of below 80% predicted. However, continuous respiratory function inadequacy in many patients with Pompe disease on ERT suggests that diaphragmatic muscle damage may become irreversible before therapy is started. 

Assessing Respiratory Function

There are a few standard tools for assessing respiratory function that are cheap, easy to use, and easy to interpret: spirometry and basic tests of respiratory muscle strength. The most commonly used assessment parameters for respiratory strength are FVC and forced expiratory volume in one second (FEV1).

FVC/FEV1 are among the basic tests used as a rough indicator of the severity of respiratory damage in both restrictive diseases (ie, pulmonary fibrosis), which compromise the ability of patients to inhale, and obstructive diseases (ie, chronic obstructive pulmonary disease), which compromise the ability of patients to exhale. If a patient’s FVC drops by more than 20% when changing from an upright to a supine position, physicians can safely assume the patient has diaphragmatic weakness. 

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Another common tool for assessing diaphragmatic integrity is the use of a diaphragmatic ultrasound. The most commonly chosen site for a diaphragmatic ultrasound is between the eighth and ninth intercostal space, between the antero-ancillary and mid-ancillary lines. 

“The normal diaphragm is composed of a relatively thick layer of hypoechoic (dark) muscle tissue encased between 2 hyperechoic (bright) lines of pleural and peritoneal fascia,” Ruggeri and colleagues wrote in Neurological Sciences. “The hypoechoic muscle will thicken significantly during deep inspiration compared to thickness at end expiration.”

Patients are typically instructed to breathe in and out at varying intensity and at various occasions throughout the ultrasound. Taken together, a diaphragmatic ultrasound can be used to measure diaphragmatic mobility and yield important information regarding functional residual capacity and total lung capacity. 

The Possible Role of Chest MRI 

In the Orphanet Journal of Rare Diseases, Harlaar and colleagues conducted a study to evaluate the possible use of chest MRI to quantify diaphragmatic weakness. 

Why the need for an additional diagnostic tool for diaphragmatic disease in the first place? First of all, as mentioned previously, diaphragmatic disease can be irreversible upon presentation—before the indications for ERT are met. Second, routine primary tests do not differentiate between diaphragmatic and intercostal muscles. 

The solution? “Improved insight into the contribution of the different respiratory muscles to inspiration can be provided using spirometry-controlled MRI, evaluating the entire diaphragm and thoracic wall during respiratory movements,” Harlaar et al wrote. 

The research team hence set out to investigate if chest MRI can pick up early signs of diaphragmatic weakness. They carried out spirometry-controlled MRIs on patients with Pompe disease and with controls. Selected participants with Pompe disease had to be able to lie in a supine position for at least half an hour without the need for mechanical ventilation. Pulmonary function tests were performed, followed by an MRI. 

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“We developed a new MRI scanning protocol including end-expiration and end-inspiration breath-hold acquisitions, followed by dynamic acquisitions during forced expiration, forced inspiration, and the sniff maneuver,” the research team wrote. 

The researchers discovered that diaphragmatic motion is decreased in patients with Pompe disease, while the curvature of the diaphragm is increased during inspiration. These are all early signs of diaphragmatic weakness. 

“We have demonstrated that MRI is a sensitive tool for detecting early stages of diaphragmatic weakness in patients with Pompe disease, even when spirometry results are within the normal range,” they concluded. 

The results of this study are encouraging; the general rule of thumb is that the more quickly early signs of a disease are identified, the sooner treatment can be administered and the better the prognosis. 

Another encouraging development from the studies cited in this article is the synergistic combination of existing diagnostic tools (pulmonary function tests/diaphragmatic ultrasound/chest MRI) to help clinicians get a more accurate picture of a patient’s current clinical condition. The increasing propensity of physicians to use tools already at their disposal to yield better diagnostic information is a step forward in the right direction. 

References

Ruggeri P, Lo Monaco L, Musumeci O, et al. Ultrasound assessment of diaphragm function in patients with late-onset Pompe diseaseNeurol Sci. 2020;41(8):2175-2184. doi:10.1007/s10072-020-04316-6

Harlaar L, Ciet P, van Tulder G, et al. Chest MRI to diagnose early diaphragmatic weakness in Pompe diseaseOrphanet J Rare Dis. 2021;16(1):21. doi:10.1186/s13023-020-01627-x

Fusco AF, McCall AL, Dhindsa JS, et al. The respiratory phenotype of Pompe disease mouse modelsInt J Mol Sci. 2020;21(6):2256. doi:10.3390/ijms21062256