Unexplained Hypoxemia in a Patient With Transient Ischemic Attack.

CASE PRESENTATION: An 84-year-old woman with a medical history of hypertension, hypothyroidism, and transient ischemic attacks presented with right-sided upper and lower extremity weakness for 1 day. She was a lifetime nonsmoker with no known heart disease or chronic lung disease. She had no occupational exposure or pertinent family history. She denied any fevers, chills, rashes, or shortness of breath. There was no history of recent travel.

Phrenic nerve conduction study to diagnose unilateral diaphragmatic paralysis.

BACKGROUND: Unilateral diaphragmatic paralysis (UDP) has major clinical and etiological implications and, therefore, is important to diagnose. Lung function tests and invasive transdiaphragmatic pressure (Pdi) measurements are widely used to this end but, contrary to phrenic nerve conduction study (NCS), they require volitional maneuvers and/or may be poorly tolerated by patients. The purpose of this study was to compare the diagnostic accuracy of Pdi and phrenic NCS for UDP. METHODS: We retrospectively reviewed 28 patients with suspected UDP. The diagnosis established during a multidisciplinary meeting was the reference standard. RESULTS: Phrenic NCS correlated well with Pdi (r = 0.82, P < .005), and the two tests showed good agreement (κ = 0.82, P < .005). Phrenic NCS and Pdi measurements both had 95% sensitivity, 87.5% specificity, 95% positive predictive, and 87.5% negative predictive values. CONCLUSIONS: Both tests were highly sensitive and specific. Phrenic NCS measurement is a simple, reproducible, noninvasive method whose results correlate well with Pdi and provide insight into the UDP mechanism. In the most difficult cases, combining lung function tests, respiratory muscle assessments, and phrenic NCS can help to establish the diagnosis.

Paradoxical Motion on Sniff Test Predicts Greater Improvement Following Diaphragm Plication.

BACKGROUND: Diaphragm plication (DP) improves pulmonary function and quality of life for those with diaphragm paralysis or dysfunction. It is unknown whether differing degrees of diaphragm dysfunction as measured by sniff testing affect results after plication. METHODS: Patients who underwent minimally invasive DP from 2008 to 2019 were dichotomized based on sniff test results: paradoxical motion (PM) versus no paradoxical motion (NPM); the latter included normal, decreased, and no motion. Preoperative and postoperative pulmonary function testing (PFT) after DP was compared between groups. The impact of the diaphragm height index, a measure of diaphragm elevation, was also assessed. RESULTS: A total of 26 patients underwent preoperative sniff testing, DP, and postoperative PFT. Including all patients, DP resulted in a 17.8% ± 5.5% improvement in forced expiratory volume in 1 second (P < .001), a 14.4% ± 5.3% improvement in forced vital capacity (P < .001), and a 4.7% ± 4.6% improvement in the diffusing capacity of carbon monoxide (P = .539). There were greater improvements in the PM group (n = 16) compared with the NPM group (n = 10) for forced expiratory volume in 1 second (27.2% ± 6.0% versus 3.9% ± 6.2%; P = .017) and forced vital capacity (28.1% ± 5.3% versus -0.5% ± 3.3%; P = .001). There was no difference in the change in the diffusing capacity of carbon monoxide between groups. There were no differences between patients with PM and NPM in the postoperative course or complications. No value for diaphragm height index predicted improvement in PFT after DP. CONCLUSIONS: Patients with PM on sniff test have dramatically greater objective improvements in pulmonary function after plication compared with those without PM. Most patients without PM do not demonstrate improvement in standard PFT. Improvements in dyspnea require additional study.

Cervical foraminal stenosis causing unilateral diaphragmatic paralysis without neurologic manifestation: A case report and review of the literature.

RATIONALE: Unilateral diaphragmatic paralysis due to cervical spondylosis has rarely been reported. We present the first case of unilateral diaphragmatic paralysis without radicular pain or motor weakness due to cervical foraminal stenosis and a review of the related literature. PATIENT CONCERNS: A 59-year-old man presented with dyspnea and fever. His chest radiograph revealed right hemidiaphragmatic paralysis. DIAGNOSES: The differential diagnosis of phrenic nerve palsy excluded mediastinal and neurodegenerative diseases. Imaging studies showed right foraminal stenosis caused by cervical spondylosis at C3-4 and C4-5. INTERVENTIONS: The patient underwent foraminotomy at C3-4 and C4-5 on the right side. The operative findings revealed a severe compression of the C4 root. OUTCOMES: At 3 months postoperatively, the unilateral diaphragmatic paralysis and dyspnea were recovered. LESSONS: Hemidiaphragmatic paralysis deserves careful evaluation for the presence of cervical spondylosis, even without concomitant neurologic manifestations.

Severe neurological crisis in adult patients with Tyrosinemia type 1.

We report six adult patients with Tyrosinaemia type 1 (HT-1) who presented with recurrent porphyria-like neurological crises after discontinuation/interruption of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) treatment. The crises were life-threatening for some of the patients, with respiratory muscle paralysis requiring ventilatory support, hemodynamic disturbance due to autonomic changes requiring resuscitation, acute progressive ascending motor neuropathy causing profound impairment, recurrent seizures, and neuropathic pain. Our patients' porphyria-like presentations were variably misdiagnosed, with delay to diagnosis resulting in more severe recurrent attacks. We report the first series of neurological crises in adult patients with HT-1. These crises, which may be fatal, can be prevented and treated effectively with neurologist/physician awareness and patient education.

Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. RECENT FINDINGS: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. SUMMARY: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

Botox injection into the lower esophageal sphincter induces hiatal paralysis and gastroesophageal reflux.

BACKGROUND: Endoscopic intrasphincteric injection of Botox (ISIB) is used routinely for the treatment of achalasia esophagus and other spastic motor disorders. Studies show that the ISIB reduces the smooth muscle lower esophageal sphincter (LES) pressure. The esophageal hiatus, formed by the right crus of diaphragm, surrounds the cranial half of the LES and works like an external LES. We studied the effects of ISIB on the LES and hiatal contraction and gastroesophageal reflux (GER). Fourteen patients treated with ISIB were studied. Esophageal manometry-impedance recordings were performed before and after the ISIB. Hiatal contraction was assessed during tidal inspiration, forced inspiration, Müller's maneuver, and straight leg raise. In 6 subjects, the manometry were repeated 6-12 mo after the ISIB. The esophagogastric junction (EGJ) pressure was measured at end expiration (LES pressure) and at the peak of maneuvers (hiatal contraction). Transdiaphragmatic pressure (pdi; force of diaphragmatic contraction) was measured at the peak of forced inspiration. GER was measured from the impedance recordings. The EGJ pressure at end expiration (LES pressure) decreased significantly after the Botox injection. The peak EGJ pressure at tidal inspiration, forced inspiration, Müller's maneuver, and straight leg raise was also dramatically reduced by the ISIB. There was no effect of Botox on the pdi during forced inspiration. Seven of 10 subjects demonstrated GER during maneuvers following the ISIB. Six to 12 mo after ISIB, the LES and hiatal contraction pressure returned to the pre-ISIB levels. ISIB, in addition to decreasing LES pressure, paralyzes the esophageal hiatus (crural diaphragm) and induces GER.NEW & NOTEWORTHY The sphincter mechanism at the lower end of the esophagus comprises smooth muscle lower esophageal sphincter (LES) and skeletal muscle crural diaphragm (hiatus). Current thinking is that the endoscopic intrasphincteric injection of Botox (ISIB), used routinely for the treatment of achalasia esophagus, reduces LES pressure. Our study shows that ISIB, even though injected into the LES, diffuses into the hiatus and causes its paralysis. These findings emphasize the importance of esophageal hiatus as an important component of the antireflux barrier and that the ISIB is refluxogenic.

Impact of Phrenic Nerve Palsy on Late Fontan Circulation.

BACKGROUND: Although adverse effects of phrenic nerve palsy (PNP) on early Fontan circulation have been reported, detailed late impact remains unclear. METHODS: Of 218 patients undergoing extracardiac total cavopulmonary connection between 1995 and 2008, 160 who all underwent cardiac catheter examination, spirometry, and exercise capacity testing 10 years after the operation were enrolled. The cohort was divided into 2 groups: with (N = 21) or without PNP (control group, N = 139). The patients with PNP were further divided into the recovered PNP group (n = 10) and the persistent PNP group (n = 11). All but 2 patients who developed PNP (90.9%) underwent diaphragmatic plication. There was no difference in hemodynamic indices at pre-Fontan evaluation among the three groups. RESULTS: Ten years after the Fontan procedure, the averaged forced vital capacity was 81% ± 18% of predicted in the control group, 86% ± 17% in the recovered PNP group, and 56% ± 12% in the persistent PNP group (P < .001). Peak oxygen consumption was linearly correlated to the forced vital capacity (r = 0.222, P = .009). There was no significant difference in the peak oxygen consumption between groups. Significant veno-venous collaterals into the diaphragm from lower body to pulmonary vein(s) or atria more frequently developed in patients who underwent diaphragmatic plication compared with those who did not (P < .001). CONCLUSIONS: Persistent PNP resulted in reduced forced vital capacity; however, its influence on exercise intolerance could not be identified. Diaphragmatic plication should be reserved for patients who experience clinically significant respiratory or hemodynamic sequelae of PNP.

Diaphragmatic paralysis: Evaluation in infants with congenital Zika syndrome.

BACKGROUND: Paralysis of the diaphragm in newborn infants can lead to recurrent infections and life-threatening respiratory insufficiency. The clinical diagnosis of unilateral diaphragmatic paralysis has been reported in infants with laboratory evidence of congenital Zika virus infection and/or the congenital Zika syndrome (CZS) phenotype but no evaluation of phrenic nerve function has been described. All reported infants have had accompanying arthrogryposis. High infant mortality is reported. METHODS: The causal mechanism of congenital diaphragmatic paralysis was evaluated in three infants with arthrogryposis as a manifestation of CZS (two of the three infants had laboratory evidence of ZIKV infection shortly after birth; the remaining infant had negative serology for ZIKV when first tested at 7 months of age). Electromyography and phrenic nerve compound muscle action potential (CMAP) were performed in all infants with diaphragmatic paralysis demonstrated on imaging studies. RESULTS: All infants had evidence of moderate chronic involvement of peripheral motor neurons. Phrenic nerve CMAP was reduced on the side of the diaphragmatic paralysis in two infants and reduced bilaterally in the remaining infant who had primarily anterior involvement of the diaphragm. All three infants had multiple medical complications and one infant died at 18 months of age. CONCLUSION: Evaluation of three infants with CZS and diaphragmatic paralysis demonstrated phrenic nerve dysfunction. In these and other affected infants, arthrogryposis appears to be a constant co-occurring condition and health problems are significant; both conditions are likely due to involvement of the peripheral nervous system in some infants with CZS.

Association Between Diaphragmatic Paralysis and Ipsilateral Cervical Spondylosis on MRI.

PURPOSE: Diaphragmatic paralysis (DP) is an important cause of dyspnea with many underlying etiologies; however, frequently no cause is identified despite extensive investigation. We hypothesized that cervical spondylosis (CS), as manifest by cervical neuroforaminal stenosis on magnetic resonance imaging (MRI), is an underrecognized cause of unilateral DP. METHODS: A retrospective study was performed assessing cervical spine imaging utilization in the investigation of unilateral DP, and the contribution of CS to its pathogenesis. To assess the relationship between CS and DP, comparison was made between severity of ipsilateral and contralateral foraminal stenosis on cervical spine MRI in individuals with idiopathic DP, and to controls with DP of known etiology. RESULTS: Record searches identified 334 individuals with DP who were classified as idiopathic (n = 101) or DP of known etiology (n = 233). Of those with idiopathic DP, only 37% had undergone cervical spine imaging. Cervical spine MRIs, available for 32 individuals from the total cohort identified (n = 15 idiopathic DP, n = 17 DP of known etiology), were reviewed and severity of CS graded (0-2). In idiopathic DP, CS was significantly more severe (grade 2 stenosis) on the side of DP at C3-C4 (73% affected vs 13% unaffected side; p = 0.031) and C4-C5 (60% affected vs 20% unaffected side; p = 0.0039), while no difference was observed in DP of known etiology. Overall severity of CS across all cervical spine levels was significantly worse in idiopathic DP versus those with DP of known etiology. CONCLUSIONS: In unilateral idiopathic DP, severity of CS is associated with DP laterality and is an underrecognized cause of diaphragmatic dysfunction. We propose that evaluation of 'idiopathic' DP should routinely include cervical spine imaging, preferably by MRI.

Exercise Capacity in Unilateral Diaphragm Paralysis: The Effect of Obesity.

PURPOSE: Healthy patients with unilateral diaphragm paralysis (UDP) are often asymptomatic; those with UDP and comorbidities that increase work of breathing are often dyspneic. We report the effect of obesity on exercise capacity in UDP patients. METHODS: All obese and nonobese patients with UDP undergoing cardiopulmonary exercise testing (CPET) during a 32-month period in the exercise laboratory of an academic hospital were compared to a retrospectively identified cohort of obese and nonobese controls without UDP, matched for key features. CPET used a modified Bruce treadmill protocol with breath-to-breath expired gas analysis. O2 uptake, minute ventilation, exercise time, and work rate were recorded at peak exercise. Static pulmonary functions were measured. Kruskal-Wallis, Wilcoxon rank sum, and Fisher's exact tests were used to compare continuous and categorical variables, respectively. Stratified linear regression was used to quantify the effect of UDP and obesity on CPET variables. RESULTS: Twenty-two UDP patients and 46 controls were studied. The BMI of obese and nonobese patients was 33.0±4.2 and 25.8±2.4 kg/m2, respectively. UDP subjects with obesity, compared to controls with neither condition, showed significantly reduced peak O2 uptake normalized to actual body weight (1.57±0.64 versus 2.01±0.88 L/min), shorter exercise time (5.7±2.0 versus 8.5±2.9 minutes), and lower peak ventilation. This was not observed in UDP alone or obesity alone. Peak work rate trended lower in the combined UDP-obesity group. CONCLUSION: Neither UDP nor obesity alone significantly reduced exercise capacity. Superimposed UDP and obesity interact to create a ventilatory limitation to exercise, with reduced peak-VO2, exercise time, and work rate.

Characteristics of the paralysed diaphragm studied by M-mode ultrasonography.

BACKGROUND: M-mode ultrasonography might be useful for detecting hemidiaphragm paralysis. The objective of the present study was to describe the motion recorded by M-mode ultrasonography of both diaphragmatic leaves in patients with a pre-established diagnosis of hemidiaphragm paralysis. METHODS: A study was conducted in 26 patients (18 men, 8 women) with unilateral diaphragmatic paralysis. They were referred to two different rehabilitation centres after thoracic surgery in 23 cases and cardiac interventional procedures in three cases. The pulmonary function tests and the study of the diaphragmatic motion using M-mode ultrasonography were recorded. RESULTS: The pulmonary function tests showed a restrictive pattern. The M-mode ultrasonography reported either the absence of motion or a weak paradoxical (cranial) displacement (less than 0·5 cm) of the paralysed hemidiaphragm during quiet breathing. A paradoxical motion was recorded in all patients during voluntary sniffing, reaching around -1 cm. During deep breathing, a paradoxical motion at the beginning of the inspiration was observed. Thereafter, a re-establishment of the motion in the craniocaudal direction was recorded. The excursions measured on the healthy side, during quiet breathing and voluntary sniffing, were increased in patients suffering from contralateral hemidiaphragm paralysis, when compared with 170 healthy volunteers. CONCLUSIONS: To detect diaphragmatic dysfunction in patients at risk, it would be useful to study diaphragmatic motion by M-mode ultrasonography during quiet breathing, voluntary sniffing and deep breathing.

Phrenic motoneuron structural plasticity across models of diaphragm muscle paralysis.

Structural plasticity in motoneurons may be influenced by activation history and motoneuron-muscle fiber interactions. The goal of this study was to examine the morphological adaptations of phrenic motoneurons following imposed motoneuron inactivity while controlling for diaphragm muscle inactivity. Well-characterized rat models were used including unilateral C2 spinal hemisection (SH; ipsilateral phrenic motoneurons and diaphragm muscle are inactive) and tetrodotoxin phrenic nerve blockade (TTX; ipsilateral diaphragm muscle is paralyzed while phrenic motoneuron activity is preserved). We hypothesized that inactivity of phrenic motoneurons would result in a decrease in motoneuron size, consistent with a homeostatic increase in excitability. Phrenic motoneurons were retrogradely labeled by ipsilateral diaphragm muscle injection of fluorescent dextrans or cholera toxin subunit B. Following 2 weeks of diaphragm muscle paralysis, morphological parameters of labeled ipsilateral phrenic motoneurons were assessed quantitatively using fluorescence confocal microscopy. Compared to controls, phrenic motoneuron somal volumes and surface areas decreased with SH, but increased with TTX. Total phrenic motoneuron surface area was unchanged by SH, but increased with TTX. Dendritic surface area was estimated from primary dendrite diameter using a power equation obtained from three-dimensional reconstructed phrenic motoneurons. Estimated dendritic surface area was not significantly different between control and SH, but increased with TTX. Similarly, TTX significantly increased total phrenic motoneuron surface area. These results suggest that ipsilateral phrenic motoneuron morphological adaptations are consistent with a normalization of motoneuron excitability following prolonged alterations in motoneuron activity. Phrenic motoneuron structural plasticity is likely more dependent on motoneuron activity (or descending input) than muscle fiber activity.

Diaphragm Weakness in the Critically Ill: Basic Mechanisms Reveal Therapeutic Opportunities.

The diaphragm is the primary muscle of inspiration. Its capacity to respond to the load imposed by pulmonary disease is a major determining factor both in the onset of ventilatory failure and in the ability to successfully separate patients from ventilator support. It has recently been established that a very large proportion of critically ill patients exhibit major weakness of the diaphragm, which is associated with poor clinical outcomes. The two greatest risk factors for the development of diaphragm weakness in critical illness are the use of mechanical ventilation and the presence of sepsis. Loss of force production by the diaphragm under these conditions is caused by a combination of defective contractility and reduced diaphragm muscle mass. Importantly, many of the same molecular mechanisms are implicated in the diaphragm dysfunction associated with both mechanical ventilation and sepsis. This review outlines the primary cellular mechanisms identified thus far at the nexus of diaphragm dysfunction associated with mechanical ventilation and/or sepsis, and explores the potential for treatment or prevention of diaphragm weakness in critically ill patients through therapeutic manipulation of these final common pathway targets.

Unilateral diaphragm paralysis: a dysfunction restricted not just to one hemidiaphragm.

BACKGROUND: Most patients with unilateral diaphragm paralysis (UDP) have unexplained dyspnea, exercise limitations, and reduction in inspiratory muscle capacity. We aimed to evaluate the generation of pressure in each hemidiaphragm separately and its contribution to overall inspiratory strength. METHODS: Twenty-seven patients, 9 in right paralysis group (RP) and 18 in left paralysis group (LP), with forced vital capacity (FVC) < 80% pred, and 20 healthy controls (CG), with forced expiratory volume in 1 s (FEV1) > 80% pred and FVC > 80% pred, were evaluated for lung function, maximal inspiratory (MIP) and expiratory (MEP) pressure measurements, diaphragm ultrasound, and transdiaphragmatic pressure during magnetic phrenic nerve stimulation (PdiTw). RESULTS: RP and LP had significant inspiratory muscle weakness compared to controls, detected by MIP (- 57.4 ± 16.9 for RP; - 67.1 ± 28.5 for LP and - 103.1 ± 30.4 cmH2O for CG) and also by PdiTW (5.7 ± 4 for RP; 4.8 ± 2.3 for LP and 15.3 ± 5.7 cmH2O for CG). The PdiTw was reduced even when the non-paralyzed hemidiaphragm was stimulated, mainly due to the low contribution of gastric pressure (around 30%), regardless of whether the paralysis was in the right or left hemidiaphragm. On the other hand, in CG, esophagic and gastric pressures had similar contribution to the overall Pdi (around 50%). Comparing both paralyzed and non-paralyzed hemidiaphragms, the mobility during quiet and deep breathing, and thickness at functional residual capacity (FRC) and total lung capacity (TLC), were significantly reduced in paralyzed hemidiaphragm. In addition, thickness fraction was extremely diminished when contrasted with the non-paralyzed hemidiaphragm. CONCLUSIONS: In symptomatic patients with UDP, global inspiratory strength is reduced not only due to weakness in the paralyzed hemidiaphragm but also to impairment in the pressure generated by the non-paralyzed hemidiaphragm.