Radiation therapy-induced phrenic neuropathy mimicking metastasis to the diaphragmatic crus on ¹8F-FDG PET/CT.

Benign unilateral uptake in the diaphragmatic crus is a relatively uncommon finding on (18)F-FDG PET/CT that can mimic the appearance of malignancy in patients with known cancer, as illustrated in this patient with neuroendocrine carcinoma. It is important for the PET interpreter to recognize this finding and attribute it to benign uptake based on the patient's history and symptoms at the time of the scan. Correlation with the findings of other available imaging modalities is also important to characterize focal uptake in unusual locations.

Late onset malnutrition from esophageal and phrenic dysfunction after radiotherapy for Hodgkin's lymphoma: a case report.

Radiotherapy may lead to late-onset, rare, but sometimes life-threatening complications that need to be recognized for timely management. We report the case of a 39-year-old man who presented with a 20-kg weight loss with severe dysphagia and respiratory failure. His medical history was noticeable for Hodgkin's lymphoma that was treated 20 y previously. The physical examination and electroneuromyography indicated vagal and phrenic neuropathies. We concluded that the patient had late-onset esophageal motor disorder and bilateral phrenic paralysis secondary to the radiotherapy received 20 y previously for the lymphoma. The patient's management included long-term nutritional support. Although late-onset vagal and phrenic nerve injuries have been described separately after radiotherapy, we report the first case of paralysis at both sites. Another striking feature of this observation is the subsequent severe malnutrition that accompanied these paralyses.

Bilateral phrenic nerve dysfunction: a late complication of mantle radiation.

Neurologic complications from radiotherapy can be immediate or can occur many years after treatment. A known complication of radiotherapy to the supraclavicular and axillary lymph nodes is brachial plexus neuropathy. Although not a common injury, phrenic nerve dysfunction has been reported in association with radiation-induced brachial neuropathy. We describe a patient who developed asymmetric diaphragmatic weakness secondary to phrenic nerve paralysis 37 years after receiving mantle radiation for Hodgkin lymphoma. The patient did not have an associated brachial plexus neuropathy or a secondary malignancy involving the phrenic nerves. A radiation-induced injury was the most likely cause.

Opioid receptors on bulbospinal respiratory neurons are not activated during neuronal depression by clinically relevant opioid concentrations.

Opioids depress the activity of brain stem respiratory-related neurons, but it is not resolved whether the mechanism at clinical concentrations consists of direct neuronal effects or network effects. We performed extracellular recordings of discharge activity of single respiratory neurons in the caudal ventral respiratory group of decerebrate dogs, which were premotor neurons with a likelihood of 90%. We used multibarrel glass microelectrodes, which allowed concomitant highly localized picoejection of opioid receptor agonists or antagonists onto the neuron. Picoejection of the mu receptor agonist [d-Ala(2), N-Me-phe(4), gly-ol(5)]-enkephalin (DAMGO, 1 mM) decreased the peak discharge frequency (mean +/- SD) of expiratory neurons to 68 +/- 22% (n = 12), the delta(1) agonist d-Pen(2,5)-enkephalin (DPDPE, 1 mM) to 95 +/- 11% (n = 15), and delta(2) receptor agonist [d-Ala(2)] deltorphin-II to 86 +/- 17% (1 mM, n = 15). The corresponding values for inspiratory neurons were: 64 +/- 12% (n = 11), 48 +/- 30% (n = 12), and 75 +/- 15% (n = 11), respectively. Naloxone fully reversed these effects. Picoejection of morphine (0.01-1 mM) depressed most neurons in a concentration dependent fashion to maximally 63% (n = 27). Picoejection of remifentanil (240-480 nM) did not cause any significant depression of inspiratory (n = 11) or expiratory neurons (n = 9). 4. Intravenous remifentanil (0.2-0.6 microg.kg(-1).min(-1)) decreased neuronal peak discharge frequency to 60 +/- 12% (inspiratory, n = 7) and 58 +/- 11% (expiratory, n = 11). However, local picoejection of naloxone did not reverse the neuronal depression. Our data suggest that mu, delta(1), and delta(2) receptors are present on canine respiratory premotor neurons. Clinical concentrations of morphine and remifentanil caused no local depression. This lack of effect and the inability of local naloxone to reverse the neuronal depression by intravenous remifentanil suggest that clinical concentrations of opioids produce their depressive effects on mechanisms upstream from respiratory bulbospinal premotor neurons.

Post-exercise diaphragm shielding: a novel approach to exercise-induced diaphragmatic fatigue.

Based on the "post-exercise diaphragm shielding" hypothesis this study tested whether both diaphragmatic force-generation (DFG) and diaphragmatic fatigue (DF) remain unchanged during consecutive exercise-trials. Twelve subjects (V(O2 max) 58.4+/-6.6 ml kg(-1) min(-1)) performed three consecutive exercise-trials (T(alpha)/T(beta)/T(gamma); workload(max) 85% V(O2 max)) each followed by recovery (6 min). Twitch transdiaphragmatic pressure during supramaximal magnetic phrenic nerve stimulation (TwPdi, every 30s), ratings of perceived exertion (RPE, every 90 s) and ergospirometric data (continuously) were assessed throughout the entire protocol (46.5 min). DFG and DF did not differ among all trials (TwPdi-baseline: 2.2+/-0.7 kPa; TwPdi-peak: T(alpha)/T(beta)/T(gamma) 3.1+/-0.7 kPa vs 3.0+/-0.8 kPa vs 3.2+/-0.8 kPa; TwPdi-bottom: T(alpha)/T(beta)/T(gamma) 1.9+/-0.6 kPa vs 2.0+/-0.7 kPa vs 1.8+/-0.5 kPa, both p>0.4, RM-ANOVA). Furthermore, TwPdi revealed close relationships with RPE (r=0.91, p<0.0001) and oxygen uptake (r=0.94, p<0.0001) during exercise. In conclusion, both DFG (baseline-to-peak) and DF (baseline-to-bottom) achieve similar magnitudes during and after consecutive exercise-trials and are closely linked to RPE and oxygen uptake. This suggests that DF neither reflects impaired diaphragmatic function nor impairs exercise performance; rather it is likely to reflect post-exercise diaphragm shielding.

Superiority of nasal mask pressure over mouth pressure, as a surrogate of diaphragm twitch-related esophageal pressure, in healthy humans.

Assessing diaphragm function is clinically and physiologically pertinent. It can rely on the measurement of pressure responses to phrenic stimulation. Combining mouth pressure (Pm) with cervical magnetic stimulation (CMS) is painless and easy to perform, but Pm-CMS poorly reflects esophageal pressure (Pes-CMS) because of poor pressure transmission across the airway. We reasoned that the mouth opening and neck flexion that are associated with the measurement of Pm-CMS would impair upper airway dynamics and further hinder pressure transmission. Therefore, we assessed the CMS-related pressure measured in a nasal mask (Pmask; mouth closed) without neck flexion as a possible surrogate of Pes-CMS, in 14 men and 3 women, age 24.5+/-2.2. Pes-CMS was 15.7+/-4.3 cmH2O, significantly higher than Pm-CMS (13.5+/-5.6 cmH2O, P<0.0001) but not different from Pmask-CMS (15.2+/-4.9 cmH2O). The concordance correlation coefficient was low (0.6808) between Pes-CMS and Pm-CMS. It was higher between Pes-CMS and Pmask-CMS (0.8730). Pm-CMS wrongly classified five subjects as abnormal (<10 cmH2O), versus 1 for Pmask and 5 for Pm (P=0.025). Passing and Bablok regressions found no difference between Pes-CMS and Pmask-CMS, but identified a systematic difference and a proportional error between Pes-CMS and Pm-CMS. We conclude that Pmask-CMS is a better surrogate of Pes-CMS than Pm-CMS.

Diaphragm pacing with a spinal cord stimulator: current state and future directions.

Diaphragm pacing with electrical stimulation of the phrenic nerve is an established treatment for central hypoventilation syndrome. The device, however, is not readily available. We tested the same spinal cord stimulator we use for pain control in phrenic nerve stimulation. We implanted a spinal cord stimulator (Itrel 3 or X-trel, Medtronic, MN) in 6 patients with chronic hypoventilation because of brainstem or high cervical cord dysfunction. The stimulation electrode was placed along the right phrenic nerve in the neck, and the device was implanted in the anterior chest. We used the cyclic mode, and set the parameters at I second ramp up, 2 seconds on, 3 seconds off. The pulse width and the frequency were set at 150 microseconds and 21 Hz, respectively. The amplitude of the output was adjusted to obtain sufficient tidal volume and to maintain PaCO2 at around 40 mm Hg. During a follow-up period up to four years, stable and sufficient ventilation was observed in all patients without any complications. Although further long follow-up is necessary, diaphragm pacing with the spinal cord stimulator is feasible and effective for the treatment of the central hypoventilation syndrome.

Variability and failure of neurotransmission in the diaphragm of mdx mice.

Loss of specific muscle force and evidence of myopathy are present in the diaphragm of mdx mice by 4 weeks of age. The neuromuscular junction of dystrophic muscle also shows structural abnormalities at this age. Whether these structural alterations result in neural transmission abnormalities is currently unclear, particularly at physiological firing frequencies. Thus, we investigated the extent of neurotransmission variability and failure during 35 and 100 Hz stimulation in the diaphragm of 6 to 8-month-old mdx mice in comparison to age-matched controls. Neurotransmission failure was similar across groups at both stimulation frequencies, despite the presence of disrupted post-synaptic acetylcholine receptors (AChRs). Neural transmission variability, however, measured by comparing variation in force production during direct muscle stimulation compared to variation in force production during phrenic nerve stimulation was significantly greater in dystrophic muscle. Together, these results suggest that neurotransmission is maintained at physiologic firing frequencies in dystrophic muscle, but the precision of neurotransmission is attenuated. A reduced density of functional AChRs likely underlies the increase in neurotransmission variability.

Diaphragmatic function in advanced Duchenne muscular dystrophy.

The aim of this study was to assess diaphragm electrical activation and diaphragm strength in patients with advanced Duchenne muscular dystrophy during resting conditions. Eight patients with advanced Duchenne muscular dystrophy (age of 25 +/- 2 years) were studied during tidal breathing, maximal inspiratory capacity, maximal sniff inhalations, and magnetic stimulation of the phrenic nerves. Six patients were prescribed home mechanical ventilation (five non-invasive and one tracheotomy). Transdiaphragmatic pressure and diaphragm electrical activation were measured using an esophageal catheter. During tidal breathing (tidal volume 198 +/- 83 ml, breathing frequency 25 +/- 7), inspiratory diaphragm electrical activation was clearly detectable in seven out of eight patients and was 12 +/- 7 times above the noise level, and represented 45 +/- 19% of the maximum diaphragm electrical activation. Mean inspiratory transdiaphragmatic pressure during tidal breathing was 1.5 +/- 1.2 cmH2O, and during maximal sniff was 7.6 +/- 3.6 cmH2O. Twitch transdiaphragmatic pressure deflections could not be detected. This study shows that despite near complete loss of diaphragm strength in advanced Duchenne muscular dystrophy, diaphragm electrical activation measured with an esophageal electrode array remains clearly detectable in all but one patient.

[Measurement of diaphragm compound muscle action potential with magnetic stimulation of the phrenic nerve and multipara esophageal electrode in intensive care unit].

OBJECTIVE: To investigate whether magnetic stimulation of the phrenic nerve and multipara esophageal electrode can be used to measure diaphragm compound muscle action potential (CMAP) in intensive care unit (ICU). METHODS: Ten normal subjects and 10 patients in ICU were studied. A newly designed multipara esophageal catheter with 5 pairs of electrodes was used to record the diaphragm CMAP elicited by magnetic stimulation and transcutaneous electrical stimulation of the phrenic nerve. RESULTS: Good quality CMAPs were obtained from normal subjects and patients in ICU. In normal subjects, the phrenic nerve conduction time (PNCT) and amplitude of the diaphragm CMAP measured with electrical stimulation [(7.2 +/- 0.8) ms, (1.52 +/- 0.40) mV] were similar to those measured with magnetic stimulation [(7.1 +/- 0.8) ms, (1.56 +/- 0.38) mV, all P > 0.05, pooled left and right values]. The amplitude of the diaphragm CMAP in patients [(0.73 +/- 0.38) mV] was much smaller than that in normal subjects [(1.58 +/- 0.38) mV, P < 0.01, pooled left and right values]. CONCLUSION: This study suggests that magnetic stimulation combined with a multipara esophageal electrode could be a useful technique in assessing diaphragm function in ICU.

Chronic hypoxia abolishes expiratory prolongation following carotid sinus nerve stimulation in the anesthetized rat.

In anesthetized rats, increases in phrenic nerve (PN) amplitude and frequency during brief periods of hypoxia or electrical stimulation of the carotid sinus nerve (CSN) are followed by an increase in expiratory duration. We investigated the effects of chronic exposure to hypoxia on PN responses to CSN stimulation. In Inactin anesthetized (100 mg/kg) Sprague-Dawley rats PN discharge and arterial pressure responses to 10-120 s of CSN stimulation (20 Hz, 0.2 ms duration pulses) were recorded after 7-10 days exposure to hypoxia (10 +/- .5% O2). In normoxic rats, the degree of CSN-evoked expiratory prolongation was dependent upon the duration of CSN stimulation. CSN-evoked increases in PN burst amplitude were not different comparing chronic hypoxic rats to rats maintained at normoxia while CSN-evoked increases in PN burst frequency were greater in chronic hypoxic rats (p<.05). CSN-evoked expiratory prolongation was abolished in chronic hypoxic rats. Following chronic hypoxia, changes occur within the central processing of arterial chemoreceptor inputs so that CSN stimulation evokes an enhanced PN frequency response and no expiratory prolongation.

D1-dopamine receptor blockade slows respiratory rhythm and enhances opioid-mediated depression.

Previous studies indicate that dopamine modulates the excitability of the respiratory network and its susceptibility to depression by exogenous opioids, but the roles of different subtypes of dopamine receptor in these processes are still uncertain. In this study, D1-dopamine receptor (D1R) involvement in dopaminergic modulation of respiratory rhythm and mu-opioid receptor mediated depression were investigated in pentobarbital-anesthetized cats. Intravenous administration of the D1R blocker SCH-23390 (100-200 microg/kg) slowed phrenic nerve and expiratory neuron respiratory rhythms by prolonging the inspiratory and expiratory phases. Phrenic nerve discharge intensity also increased more gradually during the inspiratory phase. SCH-23390 (150 microg/kg) also enhanced dose-dependent depression of phrenic nerve and expiratory neuron excitability, as well as rhythm disturbances, produced by the mu-opioid receptor agonist fentanyl (2-20 microg/kg, i.v.). The results suggest an important role for the D1-subtype of receptor in respiratory rhythm modulation, and indicate that this type of receptor participates in dopaminergic compensatory mechanisms directed against opioid-mediated network depression.

Role in the inspiratory off-switch of vagal inputs to rostral pontine inspiratory-modulated neurons.

Neurons of the pontine respiratory group (PRG) in the region of the nucleus parabrachialis medialis and the Kolliker-Fuse nucleus are believed to play an important role in promoting the inspiratory (I) off-switch (IOS). In decerebrate gallamine-paralyzed cats ventilated with a cycle-triggered pump system (lung inflation during the neural I phase), we studied the effects of vagal (V) afferent inputs on firing of I-modulated neurons (the most numerous population in PRG) and on I duration. The predominant V effect on unit activity was inhibitory, as shown by two types of test: (a) withholding of inflation during an I phase, which produced increase of unit firing and of its respiratory modulation (58/66 neurons in 14 cats), indicating disinhibition due to removal of phasic V input; (b) delivery of afferent V stimulus trains during a no-inflation I phase, which produced decrease of unit firing and of its respiratory modulation (20 neurons). In addition, application of V input during the neural expiratory (E) phase, which lengthened E phase duration, produced no effect on the neurons' firing, suggesting that the inhibition during I was presynaptic in origin. The results may be interpreted by the hypothesis that the medullary late-I presumptive IOS neurons receive excitatory inputs from the PRG I-modulated neurons as well as from V afferents.. With relatively strong V input, this pontine excitatory output is reduced by inhibition, whereas with relatively weak V input that excitatory output is increased due to reduction of inhibition. Thus the pontine and the V influences on the IOS can operate in a complementary manner dependent on state.

Dopamine1 receptor agonists reverse opioid respiratory network depression, increase CO2 reactivity.

In adult pentobarbital-anesthetized and unanesthetized decerebrate cats, the D(1)R agonists (6-chloro-APB, SKF-38393, dihydrexidine) given intravenously restored phrenic nerve and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons after the discharges were abolished by the micro-opioid receptor agonist fentanyl given intravenously. Reversal of opioid-mediated discharge depression was prevented by the D(1)R antagonist SCH23390. Iontophoresis of the micro-opioid receptor agonist DAMGO depressed firing of medullary bulbospinal inspiratory neurons. Co-iontophoresis of SKF-38393 did not restore firing and had no effect on bulbospinal inspiratory neuron discharges when applied alone. The D(1)R agonists given intravenously prolonged and intensified phrenic nerve and bulbospinal inspiratory neuron discharges. They also increased reactivity to CO(2) by lowering the phrenic nerve apnea threshold and shifting the phrenic nerve-CO(2) response curve to lower et(CO(2)) levels. Intravenous fentanyl on the other hand decreased CO(2) reactivity by shifting the phrenic nerve apnea threshold and the response curve to higher et(CO(2)) levels. Fentanyl effects on reactivity were partially reversed by D(1)R agonists.

Relief of non-metastatic shoulder pain with mediastinal radiotherapy in patients with lung cancer.

Three patients with lung cancer and shoulder pain for which no local cause could be found are described. All three benefited from a course of palliative radiotherapy to ipsilateral mediastinal disease remote from the site of the pain. It is suggested that the pain is referred from intrathoracic involvement of the phrenic nerve by cancer, and that palliative irradiation of the mediastinum should be considered if investigations fail to reveal a local cause for ipsilateral shoulder pain.

Bilateral diaphragmatic weakness: a late complication of radiotherapy.

Brachial plexus neuropathy is an unfortunate complication that sometimes follows radiotherapy to the axillary and supraclavicular regions. A patient is described who, 30 years after radiotherapy for Hodgkin's disease and more than 10 years after the development of radiation-induced bilateral brachial plexus neuropathy, presented with bilateral diaphragmatic weakness secondary to bilateral phrenic nerve weakness. Previous radiotherapy was the most probable cause of the condition.

Response of the mediastinal and thoracic viscera of the dog to intraoperative radiation therapy (IORT).

IORT may be a potentially useful adjunctive treatment combined with surgery and/or external beam irradiation in treating locally advanced lung and esophageal tumors. To begin investigation of this modality, the tolerance of intact mediastinal structures to IORT was studied using adult American Foxhounds (wt. 25-30 kg). Groups of six animals received IORT to doses of 20, 30, or 40 Gy to two separate intrathoracic ports, using 9 MeV electrons to treat a portion of the collapsed right upper lobe, and 12 MeV electrons to treat the mediastinal structures. A group of three dogs received thoracotomy with sham irradiation. Two dogs from each treatment dose group, as well as one sham-irradiated control, were sacrificed electively at 1, 3, and 12 months following IORT. There were no acute nor late IORT related mortalities. Post-operative weight loss was minimal (average 4.5% of pre-operative weight) for all dogs. Serial esophagrams showed no inflammation or ulceration. No cardiac nor pulmonary changes were noted clinically. At autopsy, the irradiated lung showed evidence of acute pneumonitis at 1 month with progressive fibrosis at 3 months and 1 year. Esophageal reactions were minimal, with only two dogs (one 30 Gy and one 40 Gy) demonstrating histologically confirmed esophagitis at 1 month. Tracheal changes were minimal. Cardiac damage was evident in the right atrial tissues. In several dogs, this cardiac damage ranged from myocardial vascular changes to frank ischemic necrosis noted at 1 and 3 months, and dense fibrosis at 1 year. The phrenic nerves showed normal function, but had evidence of perineural fibrosis. The large vessels demonstrated only mild histologic evidence of irradiation. The results of this large animal study suggest that intact mediastinal structures will tolerate small volume IORT to doses of 20 Gy without significant clinical sequellae. Although the histologic changes in the right atrium and contralateral lung are worrisome, no cardiac nor pulmonary problems arose over the 1 year follow-up. Irradiation of the contralateral lung and other sensitive structures can be reduced by careful selection of electron beam energy and use of custom lead shielding.