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.

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.

Diaphragmatic thickness ratio (inspiratory/expiratory) as a diagnostic method of diaphragmatic palsy associated with interescalene block. / La ratio de grosor diafragmático (inspiratorio/espiratorio) como método diagnóstico de parálisis diafragmática asociada al bloqueo interescálenico.

INTRODUCTION: Diaphragmatic paralysis is a side-effect associated with interscalene block. Thickness index of the diaphragm muscle (inspiratory thickness/expiratory thickness) obtained by ultrasound has recently been introduced in clinical practice for diagnosis of diaphragm muscle atrophy. Our objective was to evaluate this index for the diagnosis of acute phrenic paresis associated with interscalene block. PATIENTS AND METHODS: We designed an observational study in 22 patients scheduled for shoulder arthroscopy. Spirometry was performed (criteria of phrenic paresis was a decrease in FVC and FEV1 ≥20%). Ultrasound apposition zone was assessed in anterior axillary line and diaphragmatic displacement was evaluated on inspiration and expiration (number of intercostal spaces; phrenic paresis considered a reduction ≥25%) and thickness of the diaphragm muscle (a phrenic paresis was considered an index <1.2). These determinations were performed before and at 20min after interscalene block at C5-C6 with 20ml of 0.5% ropivacaine. RESULTS: Twenty-one patients (95%) presented phrenic nerve block according to one or more of the methods used. One patient did not show any symptoms or signs suggestive of phrenic paralysis and was excluded. All the patients presented phrenic paresis based on the diaphragmatic thickness index, with the pre-block index being 1.8±0.5 and post-block of 1.05±0.06 (P<0.001). Ninety percent of the patients (19) presented phrenic paresis according to spirometry and all the patients had a reduction in diaphragmatic movement after the block (from 1.9±0.5 intercostal spaces to 0.5±0.3; P<0.001). CONCLUSION: The index of inspiratory / expiratory diaphragmatic thickness at cut-off <1.2 seems to be useful in the diagnosis of phrenic paresis associated with interscalene block. This index does not require a baseline pre-assessment.

Compensatory effects following unilateral diaphragm paralysis.

Injury to nerves innervating respiratory muscles such as the diaphragm muscle results in significant respiratory compromise. Electromyography (EMG) and transdiaphragmatic pressure (Pdi) measurements reflect diaphragm activation and force generation. Immediately after unilateral diaphragm denervation (DNV), ventilatory behaviors can be accomplished without impairment, but Pdi generated during higher force non-ventilatory behaviors is significantly decreased. We hypothesized that 1) the initial reduction in Pdi during higher force behaviors after DNV is ameliorated after 14 days, and 2) changes in Pdi over time after DNV are associated with concordant changes in contralateral diaphragm EMG activity and ventilatory parameters. In adult male rats, the reduced Pdi during occlusion (∼40% immediately after DNV) was ameliorated to ∼20% reduction after 14 days. Contralateral diaphragm EMG activity did not significantly change immediately or 14days after DNV compared to the pre-injury baseline for any motor behavior. Taken together, these results suggest that over time after DNV compensatory changes in inspiratory related muscle activation may partially restore the ability to generate Pdi during higher force behaviors.

Crus Atrophy: Accuracy of Computed Tomography in Diagnosis of Diaphragmatic Paralysis.

PURPOSE: The aim of this study was to measure the association between crus atrophy as depicted by computed tomography (CT) and fluoroscopic diagnosis of hemidiaphragmatic paralysis in patients with suspected diaphragmatic dysfunction. MATERIALS AND METHODS: A retrospective review of patient data was approved by our institutional review board and was HIPPA-compliant. We reviewed 90 patients who had undergone diaphragmatic fluoroscopy; 72 had CT scans available for measurement of crus thickness at the levels of the celiac and superior mesenteric arteries and the L1 vertebral body. Receiver operating characteristic analysis was used to determine the threshold of crus thinning that best distinguished a paralyzed hemidiaphragm from a nonparalyzed one. RESULTS: Hemidiaphragmatic paralysis caused significant crus thinning at the celiac artery level (mean±SD, 1.7±0.6 vs. 3.6±1.3 mm, P=0.017, on the right; 1.1±0.4 vs. 3.0±1.4 mm, P=0.001, on the left) and the L1 vertebral level (mean±SD, 1.5±0.7 vs. 4.4±1.6 mm, P=0.018, on the right; 1.5±0.6 vs. 3.6+1.7 mm, P=0.017, on the left). On axial CT, thinning to ≤2.5 mm at the celiac artery level identified paralysis of the hemidiaphragm with a sensitivity of 100% and a specificity of 86% on the right and with a sensitivity of 100% and a specificity of 64% on the left. On coronal CT, thinning to ≤2.5 mm at the L1 vertebral level identified paralysis of the hemidiaphragm with a sensitivity of 100% and a specificity of 88% on the right and with a sensitivity of 100% and a specificity of 77% on the left. CONCLUSIONS: Atrophy of the crus assessed by CT is a good discriminator of paralyzed versus nonparalyzed hemidiaphragm in patients with suspected diaphragmatic dysfunction.

Patient with spinal muscular atrophy with respiratory distress type 1 presenting initially with hypertonia.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene and characterized by life-threatening respiratory distress due to irreversible diaphragmatic paralysis between 6weeks and 6months of age. In this study, we describe a two-month-old boy who presented with hypertonia at first and developed to hypotonia progressively, which was in contrast to the manifestations reported previously. Bone tissue compromise was also observed as one of the unique symptoms. Muscle biopsy indicated mild myogenic changes. He was misdiagnosed until genetic screening to be confirmed as SMARD1. SMARD1 is a clinical heterogeneous disease and this case broadens our perception of its phenotypes.

[Bilateral diaphragmatic paralysis due to Parsonage-Turner syndrome]. / Une paralysie diaphragmatique révélatrice d'un syndrome de Parsonage-Turner.

We report the case of a 49-years-old patient who presented to the accident and emergency department with sudden onset dyspnea associated with acute shoulder pain. He was breathless at rest with supine hypoxemia. He had an amyotrophic left shoulder with localized paresis of the shoulder. Both hemi-diaphragms were elevated on chest X-rays. Pulmonary function tests showed a restrictive pattern and both phrenic nerve conduction velocities were decreased. At night, alveolar hypoventilation was evidenced by elevated mean capnography (PtcCO2: 57mmHg). Neuralgic amyotrophy, Parsonage-Turner syndrome was the final diagnosis. This syndrome is a brachial plexus neuritis with a predilection for the suprascapular and axillary nerves. Phrenic nerve involvement is rare but where present can be the most prominent clinical feature as in our case report.

Acute respiratory distress in an alpaca.

An alpaca was presented with a history of respiratory difficulty and death. Histology of the phrenic nerves and diaphragm revealed degenerative changes consistent with denervation atrophy, and a diagnosis of diaphragmatic paralysis was established. No gross or histological abnormalities were observed in the spinal cord or other organs. The etiology of the phrenic nerve neuropathy could not be determined. The need to examine phrenic nerves and diaphragm in camelids with respiratory distress is emphasized, as failure to examine these samples will preclude a diagnosis of diaphragmatic paralysis.

Phrenic motor neuron degeneration compromises phrenic axonal circuitry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury.

Respiratory dysfunction is the leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). Injuries targeting mid-cervical spinal cord regions affect the phrenic motor neuron pool that innervates the diaphragm, the primary respiratory muscle of inspiration. Contusion-type injury in the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. In an attempt to target the phrenic motor neuron pool, two unilateral contusion injury paradigms were tested, a single injury at level C4 and a double injury both at levels C3 and C4, and animals were followed for up to 6 weeks post-injury. Both unilateral cervical injury paradigms are reproducible with no mortality or need for breathing assistance, and are accompanied by phrenic motor neuron loss, phrenic nerve axon degeneration, diaphragm atrophy, denervation and subsequent partial reinnervation at the diaphragm neuromuscular junction, changes in spontaneous diaphragm EMG recordings, and reduction in phrenic nerve compound muscle action potential amplitude. These findings demonstrate significant and chronically persistent respiratory compromise following mid-cervical SCI due to phrenic motor neuron degeneration. These injury paradigms and accompanying analyses provide important tools both for understanding mechanisms of phrenic motor neuron and diaphragm pathology following SCI and for evaluating therapeutic strategies in clinically relevant cervical SCI models.

Imaging of the diaphragm: anatomy and function.

The diaphragm is the primary muscle of ventilation. Dysfunction of the diaphragm is an underappreciated cause of respiratory difficulties and may be due to a wide variety of entities, including surgery, trauma, tumor, and infection. Diaphragmatic disease usually manifests as elevation at chest radiography. Functional imaging with fluoroscopy (or ultrasonography or magnetic resonance imaging) is a simple and effective method of diagnosing diaphragmatic dysfunction, which can be classified as paralysis, weakness, or eventration. Diaphragmatic paralysis is indicated by absence of orthograde excursion on quiet and deep breathing, with paradoxical motion on sniffing. Diaphragmatic weakness is indicated by reduced or delayed orthograde excursion on deep breathing, with or without paradoxical motion on sniffing. Eventration is congenital thinning of a segment of diaphragmatic muscle and manifests as focal weakness. Treatment of diaphragmatic paralysis depends on the cause of the dysfunction and the severity of the symptoms. Treatment options include plication and phrenic nerve stimulation. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.322115127/-/DC1.

Diaphragm paralysis caused by transverse cervical artery compression of the phrenic nerve: the Red Cross syndrome.

BACKGROUND: The etiology of diaphragm paralysis is often elusive unless an iatrogenic or traumatic injury to the phrenic nerve can be clearly implicated. Until recently, there has been little interest in the pathophysiology of diaphragm paralysis since few treatment options existed. METHODS: We present three cases of symptomatic diaphragm paralysis in which a clear clinico-pathologic diagnosis could be identified, specifically a vascular compression of the phrenic nerve in the neck caused by a tortuous or adherent transverse cervical artery. RESULTS: In two patients the vascular compression followed a preceding traction injury, whereas in one patient an inter-scalene nerve block had been performed. Following vascular decompression, all three patients regained diaphragmatic motion on fluoroscopic chest radiographs, and experienced a resolution of respiratory symptoms. CONCLUSION: We suggest that vascular compression of the phrenic nerve in the neck may occur following traumatic or iatrogenic injuries, and result in symptomatic diaphragm paralysis.

Diaphragmatic paralysis: a rare consequence of dengue fever.

BACKGROUND: Dengue is considered one of the most common mosquito borne illnesses in the world. Although its clinical course is usually uneventful, complications have rarely been known to arise. These include neurological manifestations such as neuropathies. CASE PRESENTATION: We report a middle aged patient from urban Sri Lanka who developed diaphragmatic paralysis secondary to phrenic neuropathy a month after recovering from dengue fever. He was managed conservatively and made a full recovery subsequently. CONCLUSION: Isolated phrenic nerve palsy causing diaphragmatic paralysis should be considered a recognized complication of Dengue fever. A patient usually gains full recovery with conservative management.

Neurological causes of diaphragmatic paralysis in 11 alpacas (Vicugna pacos).

BACKGROUND: Diaphragmatic paralysis is a relatively uncommon medical condition in animals not reported in alpacas. OBJECTIVES: Describe the signalment, physical examination, diagnostic testing, clinical, and histopathologic findings related to diaphragmatic paralysis in alpacas. ANIMALS: Eleven alpacas with spontaneous diaphragmatic paralysis. METHODS: A retrospective study examined medical records from a 10-year period and identified 11 alpacas with confirmed diaphragmatic paralysis admitted to Washington State University and Colorado State University Veterinary Teaching Hospitals between September 2003 and October 2009. RESULTS: The 11 alpacas ranged in age from 2 to 12 months. Fluoroscopic imaging confirmed the presence of bilateral diaphragmatic paralysis in the 7 alpacas that were imaged. Arterial blood gas analyses showed hypercapnea, hypoxemia, and low oxygen saturation. Seven alpacas died or were euthanized between 2 and 60 days after onset of respiratory signs. Histopathologic examination of tissues found phrenic nerve degeneration in the 6 alpacas that were necropsied and additional long nerves examined demonstrated degeneration in 2 of these animals. Two animals had spinal cord lesions and 2 had diaphragm muscle abnormalities. No etiologic agent was identified in the alpacas. CONCLUSIONS AND CLINICAL IMPORTANCE: The etiology for diaphragmatic paralysis in these alpacas is unknown. A variety of medical treatments did not appear to alter the outcome.

Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy.

Doxorubicin is a chemotherapeutic agent prescribed for a variety of tumors. While undergoing treatment, patients exhibit frequent symptoms that suggest respiratory muscle weakness. Cancer patients can receive doxorubicin chemotherapy through either intravenous (IV) or intraperitoneal (IP) injections. We hypothesized that respiratory muscle function would be depressed in a murine model of chemotherapy. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via IV or IP injection. Three days later we measured contractile properties of muscle fiber bundles isolated from the diaphragm. Doxorubicin consistently depressed diaphragm force with both methods of administration (P < 0.01). Doxorubicin IP exaggerated the depression in diaphragm force and stimulated tissue inflammation and muscle fiber injury. These results suggest that clinically relevant doses of doxorubicin cause respiratory muscle weakness and that the loss of function depends, in part, on the route of administration.

Interactive effects of corticosteroid and mechanical ventilation on diaphragm muscle function.

Information on the interactive effects of methylprednisolone, controlled mechanical ventilation (CMV), and assisted mechanical ventilation (AMV) on diaphragm function is sparse. Sedated rabbits received 2 days of CMV, AMV, and spontaneous breathing (SB), with either methylprednisolone (MP; 60 mg/kg/day intravenously) or saline. There was also a control group. In vitro diaphragm force, myofibril ultrastructure, αII-spectrin proteins, insulin-like growth factor-1 (IGF-1), and muscle atrophy F-box (MAF-box) mRNA were measured. Maximal tetanic tension (P(o)) decreased significantly with CMV. Combined MP plus CMV did not decrease P(o) further. With AMV, P(o) was similar to SB and controls. Combined MP plus AMV or MP plus SB decreased P(o) substantially. Combined MP plus CMV, MP plus AMV, or MP plus SB induced myofibrillar disruption that correlated with the reduced P(o). αII-spectrin increased, IGF-1 decreased, and MAF-box mRNA increased in both the CMV group and MP plus CMV group. Short-term, high-dose MP had no additive effects on CMV-induced diaphragm dysfunction. Combined MP plus AMV impaired diaphragm function, but AMV alone did not. We found that acute, high-dose MP produces diaphragm dysfunction depending on the mode of mechanical ventilation.

Adult-onset acid maltase deficiency with isolated axial muscle involvement.

INTRODUCTION: We report a patient with acid maltase deficiency who presented with subacute respiratory failure as the first symptom without significant extremity weakness. METHODS AND RESULTS: Electromyography of extremities was normal but showed myopathic changes and myotonic discharges limited to axial muscles only. Muscle biopsy confirmed the diagnosis. CONCLUSION: It is essential to examine axial muscles during electromyography if a patient presents with respiratory failure of unclear etiology even if the clinical examination does not show significant weakness in the extremities and electromyographic findings in the extremities are unremarkable.

Neuronal progenitor transplantation and respiratory outcomes following upper cervical spinal cord injury in adult rats.

Despite extensive gray matter loss following spinal cord injury (SCI), little attention has been given to neuronal replacement strategies and their effects on specific functional circuits in the injured spinal cord. In the present study, we assessed breathing behavior and phrenic nerve electrophysiological activity following transplantation of microdissected dorsal or ventral pieces of rat fetal spinal cord tissue (FSC(D) or FSC(V), respectively) into acute, cervical (C2) spinal hemisections. Transneuronal tracing demonstrated connectivity between donor neurons from both sources and the host phrenic circuitry. Phrenic nerve recordings revealed differential effects of dorsally vs. ventrally derived neural progenitors on ipsilateral phrenic nerve recovery and activity. These initial results suggest that local gray matter repair can influence motoneuron function in targeted circuits following spinal cord injury and that outcomes will be dependent on the properties and phenotypic fates of the donor cells employed.