The Phrenic Nerve

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The Phrenic Nerve Within the Cervical Plexus
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The phrenic nerve arising from cervical levels
C3-C5 within the cervical plexus.

— Image drawn by Jacqueline Marie Gowan

The phrenic nerve exists as a bilateral pair, emerging from cervical levels C3-C5, and descends in the lateral compartments of the neck, over the pericardium, terminating on both the superior and inferior sides of the diaphragm (Nason et al., 2012)[2]. As the chief inspiratory muscle (Qureshi et al., 2009)[3], the diaphragm receives the majority of its innervation from the left and right phrenic nerves (Silverthorn, 2013)[6]. Damage to either of these nerves manifests its symptoms in the diaphragm in the form of muscle weakness or paralysis. Ventilation and metabolic homeostasis are dependent on the ability of the diaphragm to contract, it is paramount therefore that the phrenic nerves remain intact, as damage could lead to respiratory failure and ultimately death.

Anatomy of the Phrenic Nerve

figure 1.
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Course of the Left and Right Phrenic Nerves.  
1. Both the left and right phrenic nerves descend through the posterior
portions of the lateral neck compartments.
2. The phrenic nerves run along the surface of the pericardium, through
the mediastinum with the pericardiophrenic arteries and veins. 
3. Both phrenic nerves terminate on the surface of the diaphragm.
4. Portions of the right arborized phrenic nerve pass through the inferior
vena cava hiatus (located within the central tendon) to reach the inferior
surface of the diaphragm.
5. Portions of the left arborized phrenic nerve pierces the diaphragm
separately through the dome of the left hemidiaphragm.

— Information regarding the course of the Phrenic Nerves was used
from the Nason et al. [2] study.
— Figure drawn by Jacqueline Marie Gowan  

The phrenic nerve exists as a bilateral pair (there is a left and right phrenic nerve). Considered apart of the cervical plexus (Loukas et al., 2006)[1], both phrenic nerves descend from the ventral rami of C3, C4 (the majority), and C5 on either side of the spinal column (Nason et al., 2012)[2]. The phrenic nerves serve as the main source of innervation to the diaphragm (Qureshi et al., 2009)[3], and receive stimulation from both voluntarily (from cortical regions via the corticospinal tracts), and autonomic centres (from dorsal respiratory group nuclei within the medullary centres) (Barret et al., 2010)[4]. The course of the phrenic nerves is illustrated in figure 1.

Anatomy of the Diaphragm

The diaphragm is a musculotendinous dome shaped partition, that forms the roof and floor of the abdominal and thoracic cavities (Qureshi et al., 2009)[3]. The diaphragm is the chief inspiratory muscle (Qureshi et al., 2009)[3], responsible for nearly 80% of the vital capacity during quiet breathing (Wang et al., 2011)[5]. The lions share of innervation supplying the diaphragm comes from both the left and right phrenic nerves (Qureshi et al., 2009)[3]. A small amount of innervation is received along the margins of the diaphragm from the nerves supplying the intercostals (Barret et al., 2010)[4].

The Role of the Diaphragm During Inhalation

During inhalation, the left and right phrenic nerves stimulate the diaphragm and cause it to contact and flatten inferiority (Silverthorn, 2013)[6]. Contraction of the diaphragm enlarges the space within the thoracic cavity (Silverthorn, 2013)[6], and reduces the pressure. Air from the atmosphere is then allowed to travel down its pressure gradient and enter the lungs (inhalation), where it will participate in gas exchange necessary from maintaining metabolic homeostasis (Qureshi et al., 2009)[3]. When the phrenic nerves are not stimulating the diaphragm, elastic recoil dominates, and the diaphragm relaxes to resume its domed shape appearance (Nason et al., 2012)[2]. Relaxation of the diaphragm decreases the space within the thoracic cavity and increases the pressure, which in turn causes air to escape from the lungs and enter the atmosphere (exhalation).

Epidemiology of Phrenic Nerve Damage

Damage to the phrenic nerves can range from mild to severe, with symptoms reflected in the diaphragm from weakness to full paralysis. Because the phrenic nerves are paired, it is possible for an injury to affect one side and not the other. In the worse case scenarios, injuries that bilaterally transect the C3 spinal level are fatal, as they leave ~80% diaphragm completely paralyzed (Wang et al., 2011)[5]. Although surgical / traumatic and compression injuries are briefly explained here, damage to the phrenic nerves can also happen from inflammation, neuropathic, or idiopathic causes (Qureshi et al., 2009)[3].

Surgical / Traumatic

Damage to the phrenic nerve can be the result of a traumatic injury, or as a complication from surgery. Open heart surgeries, lung transplants, esophageal and mediastinal surgeries all pose a significant risk of damaging the phrenic nerves (Qureshi et al., 2009)[3]. Normally, ~2-20% of patients that undergo surgery within the thorax end up with some sort of varying damage to either one or both of their phrenic nerves, resulting in a range of diaphragm symptoms (weakness to paralysis) (Loukas et al., 2006)[1]. Open neck surgeries pose a risk of damaging the C3-C5 rootlets that supply the phrenic nerves. It is critical therefore that surgeons take care in locating the entire course of the phrenic nerves within their patients before proceeding.

Compression

Compression can damage the phrenic nerves and subsequently weaken or paralyze (unilaterally or bilaterally) the diaphragm (Qureshi et al., 2009)[3].

Causes of compression can include (but are not restricted to): 


  1. Cervical Osteoarthritis : which applies pressure on the cervical rootlets that supply the phrenic nerves (either side). 

  2. Bronchogenic Mediastinal Tumours : in ~5% of patients, the phrenic nerves can be tightly compressed, causing damage. 

  3. Substernal thyroids and aortic aneurysms : can squeeze the phrenic nerves up against either the pericardium or the parietal pleura of the lungs. (Qureshi et al., 2009)[3]

Accessory Phrenic Nerves

table 1.
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Percent of Accessory Phrenic Nerves Arising from Various
Locations in 80 Cadavers (Loukas et al., 2006)[1].
 

figure 2.
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1. Joins the phrenic inferior and anterior to the subclavian vein.
2. Joins the phrenic inferior and anterior to the subclavian vein, but
loops around the internal thoracic artery.
3. Joins the phrenic inferior and anterior to the subclavian vein, at the
root of the lung.

— Data Collected from the Loukas et al. study in 2006)[1]
— Figure Drawn by Jacqueline Marie Gowan

Until recently, accessory phrenic nerves that contribute to the left and right phrenic (in addition to the motor neurons from C3-C5) have received little attention. Scientists are starting to realize the importance mapping out the various locations of these accessory nerves, as their damage may contribute to a weakening of the phrenic they contribute to.

The anatomy of accessory phrenic nerves varies greatly between people. In order to make some sense of their course, Loukas et al (2006) collected data from 80 cadavers used in gross anatomy classes from Harvard, The American University of the Caribbean, and St. George Medical School. In their study, they defined an accessory phrenic as any nerve contributing to the main phrenic at levels inferior to the anterior scalene (Loukas et al., 2006)[1]. Only 61.8% of cadavers had at least one accessory phrenic nerve (38.2% of cadavers had no accessory phrenic at all), and bilateral accessory phrenic nerves were found in 38.8%. Of the 80 cadavers studied, only 10 had symmetrical bilateral accessory phrenic nerves. Accessory Phrenic Nerves arising from various locations in the Loukas et al. study are summarized in table 1 (Loukas et al., 2006)[1].

In addition to the various locations accessory phrenic nerves were found, the location at which these nerves united with the main phrenic nerve also differed (Loukas et al., 2006)[1]. Figure 2 illustrates the three most common areas the accessory phrenic nerves joined up with the main phrenic (the left phrenic nerve in the case of figure 2).

Studies that gather data on accessory phrenic nerves in regards to the various areas they arise and anastomose with the main phrenic, illuminate why up to 20% of surgeries (Loukas et al., 2006)[1] within the thoracic cavity carry such a high risk of phrenic nerve damage.

Symptoms of Phrenic Nerve Damage

Unilateral Symptoms

Damage to either the left or right phrenic nerves can range from mild to a full out lesion. The severity of the damage to the phrenic nerves present in diaphragm. In cases where the damage is focused on only one of the phrenic nerves (unilateral), symptoms present on only one side of the diaphragm (hemidiaphragm) (Nason et al., 2012)[2]. Fortunately, unilaterally damaged phrenic nerves is not fatal, and symptoms are mild (Qureshi et al., 2009)[3]. In fact, ~50% of patients with unilateral damage are normally asymptomatic (Nason et al., 2012)[2], and their conditions are found by accident. Those who do present with symptoms may have slight dyspnea, muscle weakness, pain in the chest wall, or a chronic couch (Qureshi et al., 2009)[3]. Aggressive treatment of unilateral damage is not necessary, and most physicians choose to monitor instead (Qureshi et al., 2009)[3]. So long as there are no underlining conditions, the prognosis of an otherwise healthy patient with unilateral damage to their phrenic nerve is good (Qureshi et al., 2009)[3].

Bilateral Symptoms

Bilateral paralysis or weakness in the overall diaphragm is much more serious compared to patients with unilateral damage (Qureshi et al., 2009)[3]. Again, damage to the phrenic nerves can range between mild (death of a few axons) to severe (a full lesion), and the extent of the damage is reflected in the diaphragm (weakness vs paralysis). Patients with severely damaged phrenic nerves may relay solely on the intercostal nerves that innervate the margins of the diaphragm (Barret et al., 2010)[7], as well as accessory muscles of inspiration (external intercostals, sternocleidomastoids, and scalene muscles) to generate a respiratory rhythm (Barret et al., 2010)[7]. At rest, these patients will be able to maintain the minimal requirements of respiration (Barret et al., 2010)[7], however if left untreated, patients with bilateral paralysis are likely to succumb to ventilation failure (Nason et al., 2012)[2], and ultimately death.

Bilateral symptoms are characterized by severe dyspnea, (Qureshi et al., 2009)[3]. Patients often experience hypercapnea and hypoxia when sleeping, which leads to headaches, confusion, memory loss, and eventual motor impairment (Qureshi et al., 2009)[3]. Additionally, patients with bilateral damage to their phrenic nerves are at a high risk of developing pneumonia, or a collapsed lung (Qureshi et al., 2009)[3]. The prognosis of bilateral diaphragm paralysis due to dysfunctional phrenic nerves is poor (Qureshi et al., 2009)[3], and to make matters worse, the majority of these patients have an additional underlining chronic disorder (demyelinating conditions, chronic obstructive pulmonary disease, pulmonary fibrosis, etc) (Qureshi et al., 2009)[3]. Many patients with bilateral paralysis of the diaphragm require a respirator to take over their ventilatory requirements in order to meet the bodes demand for oxygen, as well as maintaining metabolic homeostasis (Qureshi et al., 2009)[3].

Diagnosis

A number of tests are used together in order to diagnose unilateral or bilateral phrenic nerve damage. Two of the more popular tools physicians use are the pulmonary function test, and phrenic nerve stimulation.

Pulmonary Function Tests

table 2.
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Pulmonary Function Test Results from Typical Unilateral
and Bilateral Phrenic Nerve Damaged Patients.
[3]  

Pulmonary function tests are good at diagnosing mild cases of phrenic nerve damage (bilateral or unilateral) that affect the diaphragm, and ultimately respiration (Qureshi et al., 2009)[3]. The results of typical patients with unilateral vs bilateral damage can be seen in figure 2.

FEV1 (forced expiratory volume for one second) : patients with damage to their phrenic nerves, may have difficulty flattening their diaphragm during inhalation, therefore the elastic recoil during exhalation will not be as strong, and a lower FEV1 will be observed.

VC (vital capacity) : as with the FEV1, the VC will also be lowered because patients with unilateral or bilateral damage to their phrenic nerves may not be able to flatten their diaphragms as well as a “healthy” individual. Elastic recoil may not be as strong, and the amount of air exhaled after a deep breath will lower than someone with a fully functional diaphragm.

Phrenic Nerve Stimulation

In order to determine if a weakened or paralyzed diaphragm is a result of neuropathy (damage to the phrenic nerve), or myopathy (intrinsic damage to the diaphragm muscle itself), phrenic nerve stimulation paired with electromyography (EMG) is performed (Qureshi et al., 2009)[3]. The first part of the procedure involves stimulating the phrenic nerves with electrodes while measuring the mechanical response (twitch) of the diaphragm. The second part involves stimulation to the diaphragm directly (bypassing the phrenic nerves) and measuring the mechanical response.

If neuropathy is the cause of weakness in the diaphragm : stimulation to the phrenic nerve will cause a delayed or weakened twitch in the diaphragm. Stimulation of the diaphragm directly will produce a strong and immediate twitch (Qureshi et al., 2009)[3].

If myopathy is the cause of weakness in the diaphragm : stimulation of the phrenic nerve will not cause a delay in the twitch response of the diaphragm, although the force from the twitch will be weaker. Stimulation of the diaphragm directly will produce a weakened twitch as well, and the response will also be immediate (Qureshi et al., 2009)[3].

Treatment

Phrenic Nerve Pacing

In patients having trouble generating a smooth respiratory rhythm form their diaphragms due to unilateral palsy in a phrenic nerve, phrenic nerve pacing is a possible treatment. To be eligible for this procedure, the damaged phrenic nerve must be intact, and the diaphragm must be intrinsically functional (no underlining myopathies) (Nason et al., 2012)[2]. Electrodes are placed adjacent to the damaged phrenic nerve through a thoractomy, and connected to a subcutaneous pocket receiver (Nason et al., 2012)[2]. Phrenic nerve pacing has the potential to liberate patients from the confines of a stationary ventilator, vastly improving their overall quality of life (Wang et al., 2011)[5]. Additionally, DiMarco et al. found that pairing phrenic nerve pacing paired with intercostal nerve pacing on the ipsilateral side of the damage (between T2 and T3 spinal nerves) together helped to improve the strength of the respiratory rhythm needed for sufficient ventilation (DiMarco et al., 1987)[8]. This procedure does not however return physiological control of the respiratory rhythm (Wang et al., 2011)[5], and has been known to potentially cause further nerve injury, and over stimulation from the electrodes can damage the diaphragm (Wang et al., 2011)[5].

Analogous Nerve Transplantation

In a number of other cases, analogous nerve transplantation (grafting nerves from one area of the host to another area of the host) has been shown to improve muscle strength, joint movement, and prevent deformity (Wang et al., 2011)[5]. Material form the spinal accessory nerve (cranial nerve XI — not to be confused with the accessory phrenic nerve) is used for a number of brachial plexus reconstruction surgeries, and it has been proposed that this nerve may act as an ideal candidate for grafting onto damaged phrenics thanks in part to the diameter and length (Wang et al., 2011)[5]. Autologous nerve transplantation may help patients recover their autonomic control over their diaphragms, and ultimately regain respiratory independence (Wang et al., 2011)[5].

Bibliography
1. Loukas, M., Kinsella, C.R., Louis, R.G., Gandhi, S., Curry, B. (2006). Surgical Anatomy of the Accessory Phrenic Nerve. The Society of Thoracic Surgeons, 82, 1870-1875.
2. Nason, L.K. , Walker, C.M., McNeeley, M. F., Burivong, W., Fligner, C.L., Godwin, J.D. (2012). Imaging of the Diaphragm, Anatomy and Function. Radio Graphics, 32, 51-70.
3. Qureshi, A. (2009). Diaphragm Paralysis. Seminars in Respiratory and Critical Care Medicine, 30, 315-320.
4. Barrett, K., Brooks, H., Boitano, S., Barman, S. (2010) Pulmonary Function. Ganong’s Review of Medical Physiology, (587-607). New York City N.Y. McGraw Hill.
5. Wang, C., Yuan, W., Zhou, X.H., Shi, S., Wang, X. (2011). Neurotinization of the Phrenic Nerve with the Accessory Nerve : A new strategy for high cervical spinal cord injury with respiratory distress. Medical Hypotheses, 76, 564-566.
6. Silverthorn, D.U. (2013). Mechanisms of Breathing. Human Physiology. An Integrated Approach, 6E, (568-598).
7. Barrett, K., Brooks, H., Boitano, S., Barman, S. (2010) Regulation of Respiration. Ganong’s Review of Medical Physiology, (625-638). New York City N.Y. McGraw Hill.
8. DiMarco, A.F., Altose, M.D., Cropp, A., Durand, D. (1987). Activation of Intercostal Muscles by Electrical Stimulation of the Spinal Cord. American Review of Respiratory Disorders, 136, (1385-1390).

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