INTRODUCTION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

Sarcoidosis is characterized as a multisystem granulomatous disease; its etiology and pathogenesis remain poorly understood (1, 2). Neurosarcoidosis is commonly associated with cranial neuropathies, but any portion of the nervous system can be involved. Neuromuscular manifestations are quite variable with an overall incidence of approximately 5-10% (3).

Previous reports have occasionally alluded to involvement of the phrenic nerve in sarcoidosis (5, 6), but to our knowledge there has been no electrodiagnostic documentation of this phenomenon. We report the electrodiagnostic and neuromuscular findings in a patient manifesting severe hypoventilation resulting from diaphragmatic paresis secondary to sarcoid.

	CASE REPORT

A 34-yr-old female presented with the sudden onset of sharp chest pain, cramping abdominal pain, and constipation. At an outlying facility, she underwent surgery for a cecal volvulus. An admission chest radiograph at that time revealed hilar adenopathy and left pleural effusion; evaluation with computed tomography (CT) scan of the chest showed a 2-3-cm solid lesion in the aortopulmonary window. Bronchoscopy and thoracentesis failed to further identify the nature of the lesion. Over the ensuing 2 wk she developed ataxia, difficulty ambulating, exertional dyspnea, and mental status changes. Head CT, magnetic resonance imaging, and electroencephalogram were all normal. Analysis of cerebrospinal fluid (CSF) revealed lymphocytosis with 130 white blood cell count (WBC) (94% lymphs), an elevated CSF protein of 80, and glucose of 47. Her shortness of breath and hypoxemia progressed. An apparent episode of aspiration resulted in cardiopulmonary arrest, necessitating cardiopulmonary resuscitation. She was then given a working diagnosis of Guillain-Barre syndrome and transferred to our intensive care unit for further management.

Past medical history was remarkable for juvenile-onset insulin-dependent diabetes with nephropathy and retinopathy, nephrotic syndrome, hypothyroidism, hypertension, histrionic personality disorder with anxiety attacks, bilateral carpal tunnel syndrome, and left ulnar neuropathy.

On admission the patient was intubated but alert and able to follow commands appropriately. Blood pressure was 160/ 90, temperature 37° C, pulse 130, and she was supported on a ventilator. Chest exam was remarkable for bilateral diffuse rhonchi.

On neurological examination, there was a peripheral cranial nerve VII palsy on the left. Manual muscle testing was in the range of 4/5 in all muscle groups except for 3/5 in the hip flexors bilaterally. Sensory testing demonstrated diminished light touch bilaterally below the hips and absent proprioception and vibration below the knees. Deep tendon reflexes were absent in all four limbs.

Initial management included plasmapheresis and unsuccessful attempts to wean the patient off the ventilator secondary to respiratory muscle weakness (inspiratory efforts < 20 cm H₂O, tachypnea, hypoventilation). A Tensilon test was negative. An enhanced chest CT revealed an aortopulmonic window mass measuring 4 cm in the anterior posterior (AP) and lateral planes by 5 cm in the craniocaudal dimension. There was infiltration into the adjacent mediastinum between the posterior aspect of the ascending aorta and the pulmonary artery. A 1.5-cm right paratracheal node was also identified as well as bilateral pleural effusions. Repeat CSF analysis demonstrated similar lymphocytosis with 118 WBC (94% lymphs) and protein of 69. The T4:T8 lymphocyte subset ratio was five (increased).

Electrodiagnostic studies are shown in Table 1. For phrenic nerve studies, the nerve was stimulated in the neck with surface stimulation just posterior to the sternocleidomastoid muscle. Recording was over the diaphragm with active electrode at the xyphoid process and reference 16 cm laterally (5). Transdiaphragmatic pressures were not measured.

The electrodiagnostic findings were interpreted as consistent with bilateral phrenic neuropathy with marked axonal loss, along with a diffuse peripheral polyneuropathy. These findings were not felt to be indicative of either an acute inflammatory demyelinating polyradiculitis (Guillain-Barre syndrome) or a neuromuscular junction disease. Mononeuritis multiplex and paraneoplastic neuropathy were included in the differential diagnosis.

A biopsy of the chest mass via mediastinoscopy was performed. This revealed noncaseating confluent granulomas with many multinucleated epithelioid histiocytes consistent with the diagnosis of sarcoidosis. There was no pathologic evidence for malignancy or infection. An extensive review for infectious etiologies was eventually negative (stain and cultures for bacteria, typical and atypical mycobacteria, and fungi were all negative in multiple pleural fluid and CSF specimens and from a mediastinal lymph node). The patient was subsequently placed on high-dose corticosteroids.

Since the electrodiagnostic studies suggested marked axon loss in the phrenic nerve and consequently the likelihood of long-term ventilatory support, a tracheostomy was placed. Neurologic improvement was slow. Repeat phrenic nerve studies 3 mo later displayed slight improvement, as shown in Table 2.

Bilateral phrenic nerve stimulation under fluoroscopy failed to produce any discernible diaphragmatic movement. Adjunct therapy with methotrexate was initiated. Approximately 8 mo after initial diagnosis and treatment, the patient was successfully extubated and was ambulatory. Upon tapering her prednisone, however, she became dyspneic and manifested hypoventilation secondary to muscle weakness. She was readmitted and re-evaluated for neuromuscular problems with repeat electrodiagnostic testing. Findings were similar to those of the examination 3 mo after onset of respiratory failure (as in Table 2). Muscle biopsy of the gastrocnemius demonstrated uniformly very atrophic muscle fibers with endoneural fibrosis; there was good fiber type differentiation with type grouping. Sural nerve biopsy revealed marked loss of myelinated axons with endoneural fibrosis; there was no evidence for vasculitis. These biopsy findings were felt to be consistent with the prior diagnoses of sarcoidosis and peripheral neuropathy. Her corticosteroids were increased, although she eventually died of an opportunistic lung infection 2 yr later.

	DISCUSSION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

Neurologic involvement in sarcoidosis is often associated with mononeuritis multiplex, most commonly involving the cranial nerves (5, 7), but it can involve any portion of the nervous system, and peripheral nerves are affected in two-thirds of all neurosarcoid cases (3).

Two previous reviews encompassing a total of 105 histories of neurosarcoidosis refer to two patients with presumptive involvement of the phrenic nerves. Maycock and colleagues (2) reported a patient with right phrenic paralysis that did not improve with time. Zuniga and coworkers (3) described a patient who required ventilatory support because of diaphragmatic weakness, which responded to corticosteroid treatment. A postmortem study revealed diaphragmatic changes indicative of denervation. Dewberry and colleagues (6) have also reported a patient with presumed sarcoid myopathy presenting with diaphragmatic weakness.

In this report, the patient had severe bilateral phrenic neuropathy, which appeared to improve slowly during corticosteroid treatment. The diagnosis of sarcoid was established by histology of lymph nodes as well as by the nature of the lymphocytosis in the CSF. The clinical course in sarcoidosis of the nervous system can be quite variable. It can assume a monophasic course or a progression with waxing and waning symptoms (2, 7). Thus, it is uncertain if steroid treatment impacted significantly in this instance.

The initial electrodiagnostic studies were indicative of almost complete axon loss to the diaphragm. The time course of recovery was consistent with axon growth and reinnervation. An approximate distance from the mass to the diaphragm as measured on the chest CT was 10 to 15 cm. Assuming axonal growth of 1 mm/d, it would require 3 to 5 mo for reinnervation to occur. Our studies demonstrated evidence of reinnervation at 3 mo.

The pathophysiology of sarcoid neuropathy is probably multifaceted. Histologic analysis of nerves has shown both noncaseating granulomas within the endoneurium, with injury primarily affecting large myelinated fibers (8), and granulomas in the epineurium and perineurium associated with periangiitis (9, 10). Muscle and nerve biopsy from our patient was similar. Direct compression and microvascular insult may both be at play, accounting for the variability of electrodiagnostic and clinical findings in neurosarcoidosis (1, 3, 7).

Certainly in this patient, with the paucity of axonal loss peripherally, the possibility of a focal entrapment was considered. The phrenic nerves, as they course through the thorax, differ in their relationships. The right phrenic nerve courses along the lateral aspect of the right brachiocephalic vein, superior vena cava, and the right pericardium in a vertical trajectory. The left phrenic nerve takes a less direct course, lying between the left common carotid and subclavian arteries in the superior mediastinum. It travels beneath the left brachiocephalic vein, then superficially on the aortic arch and the left pulmonary vein to lie between the pericardium over the left ventricle and the mediastinal pleura. Resolution on the chest CT did not allow for direct visualization of the phrenic nerves. But the sarcoid adenopathy was felt to be in a region were it might compress and/or displace them laterally.

Presentations mimicking Guillain-Barre syndrome have been reported in neurosarcoidosis (5, 7, 11, 12). In this patient the precipitous onset of progressive hypoventilation and respiratory failure associated with progressive motor weakness resulted in the tentative diagnosis. Electrodiagnostic evaluation established phrenic neuropathy as the cause for respiratory failure and further aided in the accurate diagnosis of the underlying pathology. We feel phrenic neuropathy should be considered as a source of ventilatory failure in cases of uncertain etiology, particularly when associated with other clinical findings suggestive of sarcoidosis or peripheral neuropathy.

Electrodiagnostic evaluation of the phrenic nerve and diaphragm has been well presented recently (5, 13). This case demonstrates the utility of these techniques in the clinical setting, despite preexisting and environmental factors commonly encountered in an intensive care unit. The diaphragmatic electromyogram was particularly useful in quantifying the severity of the lesion, thus aiding in prognostication as well as clinical decision making.

In summary, this case establishes phrenic neuropathy and peripheral polyneuropathy secondary to neurosarcoidosis as a cause of respiratory failure. It also illustrates the utility of phrenic and diaphragmatic electrodiagnosis in the evaluation as well as prognostication of such lesions.