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Cryoneurolysis, also referred to as cryoanalgesia, cryoneuromodulation, or cryoneuroablation, is a procedure used to temporarily block nerve conduction along peripheral nerve pathways. It is performed by inserting a small probe to locate and freeze the target nerve. Other treatments for nerve conditions, such as medications, alcohol injections, or surgery, often fail or lead to more serious side effects. Cryoneurolysis is minimally invasive and has significantly reduced pain in patients with many different conditions. The procedure allows for complete regeneration of the structure and function of the damaged nerve. Cryoneurolysis has been used to treat disorders such as phantom limb pain, pain associated with intercostal nerves, foot neuromas, ilioinguinal nerves, occipital neuralgia, and many others. The procedure can be used on almost any peripheral nerve in the body, and is able to provide targeted nerve degeneration.

History
The use of cold for pain relief and as an anti-inflammatory has been known since Hippocrates' (460-377 B.C) first written records. Since Hippocrates, there have been numerous accounts of ice used as pain relief by Ancient Egyptians, Avicenna of Persia (A.D.982–1070) and many others. In 1812, half-frozen soldiers from the Moscow battle were noted to have been able to tolerate amputations with reduced pain. In 1851, ice and salt mixtures were promoted by Arnott for treatment of nerve pain. In 1899, Campbell White was the first to employ refrigerants, and in 1950, Allington was the first to use liquid nitrogen, both for medical use. In 1961, Cooper et al. created an early cryoprobe, which reached a temperature of -190° C using liquid nitrogen. Following this, in 1967 an ophthalmic surgeon named Amoils further refined the cryoprobe technology using carbon dioxide and nitrous oxide. His device reached a temperature of -70° C. The term "cryoanalgesia" was coined by Lloyd and his coworkers in 1976. Maiwand further developed the technique of cryoneurolysis by performing clinical trials to prove its effectiveness.

Nerve Anatomy
See Nerve

Each nerve is covered by a dense layer of connective tissue called the epineurium. Under the epineurium is a layer of connective tissue called the perineurium, which forms a complete sheath around the axon bundle. Perineurial septae extend into the nerve and separate it into bundles of fibers. The endoneurium surrounds each fiber. Within the endoneurium is the nerve axon, surrounded by a low-protein liquid, called endoneurial fluid. Some axons have a myelin sheath made up of Schwann cells that coat the axon.

Nerve Injury Classification
See Peripheral nerve injury classification



Seddon's Classification
Sir Herbert Seddon published his classification of nerve damage in 1943 based on his observation of trauma cases, and this classification is still being used today.

Neurapraxia

Neurapraxia is the mildest form of nerve injury and results in complete recovery. The endoneurium, perineurium, and epineurium remain intact; the loss of conduction is caused by myelin damage, which interrupts the conduction of impulses down the nerve fiber. This temporary loss of function is completely reversible within hours to days following injury. Wallerian degeneration does not occur. The most common injuries that result in neurapraxia are compression of the nerve or disruption of the blood supply.

Axonotmesis

Axonotmesis is the disruption of the axon of the neuron, with Wallerian degeneration occurring distal to the site of injury. The axon and myelin sheath are affected, but the endoneurium, perineurium, and epineurium remain intact. The most common injuries that result in axonotmesis are severe crush and contusion injuries. The nerve is repaired by degeneration of the nerve distal to the injury, and regrowth of the nerve into the endoneurial tube, which occurs at a rate of approximately 1-2 mm per day.

Neurotmesis

Neurotmesis is an injury that results in the disruption of both the axon and the nerve sheath. Full, functional recovery is not possible; however except in the case of full transection of the nerve, some function may be restored. In neurotmesis, the epineurium and perineurium lose continuity, and the endoneurium becomes disrupted. Due to the disruption of the endoneurium, the nerve path is not continuous which can lead to neuroma formation.

Sunderland’s Classification
In 1951, Sunderland refined Seddon’s classification into 5 degrees based on histopathology instead of on injury classification.

First Degree

Sunderland’s first degree injury and Seddon’s neurapraxia are the same.

Second Degree

Sunderland’s second degree injury and Seddon’s axonotmesis are the same. This degree of injury is classically marked by the presence of Wallerian degeneration of the axon.

Third Degree

Third degree injury involves a lesion of the endoneurium in addition to Wallerian degeneration of the axon, but the perineurium and epineurium remain intact. Surgery to repair the nerve is considered in this degree of injury. Partial functional re-innervation can occur within months to years without surgical intervention.

Fourth Degree

Fourth degree injury includes damage to the endoneurium, perineurium, and epineurium. Surgery is recommended for this degree of injury, but re-innervation will be incomplete.

Fifth Degree

Fifth degree injury is a total transection of the nerve. Without surgical repair, a complete lack of functional recovery with neuroma formation occurs.

Wallerian degeneration
Wallerian degeneration is the degeneration of the axon of a nerve fiber and is typically caused by a crush injury. Degeneration of the axon and myelin sheath occurs distal to the site of injury, and this degeneration results in a longer loss of function than neuropraxia. The rate of axon regeneration is approximately 1-2 mm per day. Full functional recovery is reliable, as the surrounding scaffold structures (endoneurium, perineurium, and epineurium) remain intact to guide the axon to the target site.

Safety
The safety of cryoneurolysis depends on the temperature of the treatment. If the temperature is between -20 and -100°C, then the nerve damage is temporary and will heal completely. If the treatment temperature is lower than -140°C, the effects of the treatment can be permanent and recovery is limited or impossible. In some cases, a complete loss of function of the nerve is desired, but in most cases, the former treatment temperature range is preferred.

Nerve
A -65°C treatment results in a 2nd degree injury (axonotmesis), which would induce Wallerian degeneration of the nerve distal to the site of treatment. Recovery time depends on the length of the nerve distal to the site of treatment, with axonal growth occurring at a rate of 1-2 mm per day. A recent animal study demonstrated that for the temporal nerve, full functional and structural recovery occurs within 16 weeks. Results from a related animal study demonstrate that repeated treatments to the nerve do not diminish the capacity of the nerve to regenerate. In addition, nerves treated multiple times regenerate completely each time they are treated, but they do so on the same time scale as nerves treated only once. As cryoneurolysis damages nerves without forming neuromas or causing neuritis, it can be performed repeatedly without introducing additional safety concerns.

Surrounding Structures
When treating with a needle-based device, puncture of organs or blood vessels can be a concern. Visualization techniques, such as ultrasound or fluoroscopy, can alleviate these concerns. However, the freezing of blood vessels is not a concern, as it would require application of temperatures in excess of -180°C for around 10 minutes; even at these temperatures, the blood vessel would not lyse nor would the blood clot.

Effectiveness
While it has been shown that cryoneurolysis is effective in treating nerve pain, the ideal combination of temperature and duration of freezing is still debated. Cryoneurolysis performed at -20°C or warmer has not shown any significant results, while treatment at -60°C or colder has. Colder temperatures are associated with higher degrees of injury and a longer recovery time for the nerve, resulting in a longer treatment effect for the patient. Since loss of nerve function is temporary, repeated treatments may be required to achieve continuous relief of chronic pain symptoms. Repeated cryoneurolysis has not been shown to further decrease pain beyond the level provided by a single cryoneurolysis treatment. The effects of cryoneurolysis are the same when performed on sensory and motor nerves, with no difference in effect, recovery, or length of relief from symptoms.

Equipment
Cryoneurolysis can be performed by using a probe, called a cryoprobe, which is a hollow tube with a smaller inner tube, or with a narrower needle-like version called a cannula. Pressurized carbon dioxide or nitrous oxide is released into the tube and expands into the tip. According to the Joule-Thomson effect, the phase change of the liquid to gas causes heat to be extracted from the tissue surrounding the probe and the temperature reaches as low as -88.6°C. An ice ball forms at the tip of the cannula and the temperatures in the ice ball range from -50° to -70°C.

Cryoprobe
A common cryoprobe device is the Endocare Percryo device, which has a cryoprobe either 1.7 or 2.4 mm in diameter (~16 gauge and ~13 gauge needles, respectively) (HealthTronics, Inc., Austin, TX, USA). The device has a larger cryoprobe to be able to cryoablate tumors as well as nerves. In order for the procedure to be effective, it is necessary for the target tissue to be precisely located. The first step in locating the correct nerve is palpation. Then, when necessary, fluoroscopic localization is used. The cryoprobe also has a nerve-stimulator in order to precisely locate the nerve. Once the nerve is located, a local anesthetic is injected into the skin. It is important for the patient to not be sedated, unless necessary, so that they may respond to stimulation. To begin the cryoneurolysis, a needle is inserted into the skin and the area is flushed with saline. A catheter is then inserted, through which the cryoprobe may pass. The cryoprobe is inserted into the catheter and the catheter is withdrawn to expose the tip of the probe. Once the nerve is correctly located with the probe, sensory stimulation begins. Once it is confirmed that the nerve is not too close to motor nerves, the gas flow is turned on. Upon initiation of gas flow, the patient will experience a burning sensation lasting for only about 30 seconds. After the first initial 30 seconds, the patient should not feel any pain.

Cannula
A common cannula style device is the iovera° device (myoscience, Redwood City, CA, USA). This device has two configurations: a trident (three-needle) configuration, and a blunt tip cannula configuration. One unique aspect of this device is the ability to treat nerves using only anatomical landmarks, which eliminates the need to use other visualization techniques, such as ultrasound and fluoroscopy. Once the treatment lines are drawn to find the nerve using anatomical landmarks, a local anesthetic is applied and the needles are inserted into the skin. The device uses liquid nitrous oxide that changes phases to gas to cool the surrounding tissue to -65°C. This temperature results in a second degree injury and induces Wallerian degeneration.

Treatment Applications
Cryoneurolysis has been shown to effectiveness treat a variety of conditions, including both pain symptoms and unwanted motor movements.

Forehead Wrinkles
To reduce the appearance of dynamic forehead wrinkles, cryoneurolysis can be applied to the temporal branch of the facial nerve, a motor nerve of the face. This nerve can be located using only anatomical landmarks. Treatment of the nerve results in a lack of movement of the frontalis and corrugator supercilli muscle groups. Results typically last for approximately 3 months.

Knee Pain Secondary to Osteoarthritis
Osteoarthritis is a degenerative disease of joints, including the articular cartilage and subchrondral bone. Symptoms include joint pain, tenderness, stiffness, locking, and sometimes effusion. These symptoms can be treated by performing cryoneurolysis on two of the sensory nerves innervating the knee: the infrapatellar branch of the saphenous nerve and the anterior femoral cutaneous nerve. These two branches can be targeted using anatomical landmarks only. By treating these nerves and reducing or eliminating the pain associated with osteoarthritis, the patient can then start exercising the knee to restore functionality or to prepare for a knee replacement surgery. Quality of life can be much improved by reducing the amount of pain in the knees.

Phantom Limb Pain
Phantom limb pain, sensations of pain perceived in a missing amputated limb, is understood to be caused by interactions between the central nervous system and the peripheral nervous system. The associated pain can range anywhere from mild to severe. The pain sensations have been described as sharp, burning, cramping, shocking, shooting, or like pins and needles. Patients who have pain prior to amputation are more likely to have pain in their phantom limb. Upper extremity phantom limbs have been more likely to cause pain than lower extremity. In an attempt to cure phantom limb pain, Ramachandran created a mirror box in order to trick the brain into seeing the limb. While this helped some patients relieve pain by unclenching a fist or scratching a hand, it did not provide lasting relief. Cryoneurolysis has been used to treat phantom limb pain with moderate success.

Post-Thoracotomy Pain
Post-thoracotomy pain is caused by the intercostal nerves after an incision into the pleural space of the chest. A thoracotomy is a very painful procedure because of the incision, the interruption of muscle and ligamentous structures, and pleural irritation from the chest tube. Respiratory function is often altered, but could be improved by effective analgesia. The current treatments for post-thoracotomy pain are opiates, epidural analgesia, and intercostal nerve blocks. An intercostal nerve block can be a short-term anesthetic block, a longer lasting neurolytic block, or a permanent neurectomy. These treatments are easily available, but have unwanted side effects. There are studies that showed cryoneurolysis on intercostal nerves help reduce pain associated with those nerves.

Zygapophyseal Joint Pain
An estimated 80% of people will have lower back pain at some point in their lifetime. Most of the time, the pain is resolved in six to twelve weeks and does not return. However, many people develop chronic lower-back pain with recurring episodes. A specific characteristic of lumbar facet joint syndrome (a primary cause of lower back pain) is that the pain is difficult to localize, and the pain often radiates into the leg. Walking or carrying heavy things is known to worsen the pain, thus limiting a patient’s ability to perform these and other tasks. Current treatments include physiotherapeutic exercise, behavioral therapy, and medical treatments. Another form of treatment is denervation of the joint using radiofrequency or cryoneurolysis.

Additional Information
Additional clinical trials are ongoing. Visit clinicaltrials.gov for more information. Search using the keyword “cryo” for cryoneurolysis-specific trials targeting both motor and sensory nerves.