What is hyperalgesia

Hyperalgesia is increased sensitivity to pain or increased pain from a stimulus that normally provokes pain ¹. Hyperalgesia reflects increased pain on suprathreshold stimulation. This is a clinical term that does not imply a mechanism. For pain evoked by stimuli that usually are not painful, the term allodynia is preferred, while hyperalgesia is more appropriately used for cases with an increased response at a normal threshold, or at an increased threshold, e.g., in patients with neuropathy. It should also be recognized that with allodynia the stimulus and the response are in different modes, whereas with hyperalgesia they are in the same mode. Current evidence suggests that hyperalgesia is a consequence of perturbation of the nociceptive system with peripheral or central sensitization, or both, but it is important to distinguish between the clinical phenomena, which this definition emphasizes, and the interpretation, which may well change as knowledge advances. Hyperalgesia may be seen after different types of somatosensory stimulation applied to different tissues.

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury and to secondary hyperalgesia in normal skin surrounding the injury ². Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic.

Hyperalgesia vs Allodynia

The official International Association for the Study of Pain definition of allodynia is “pain due to a stimulus that does not normally provoke pain” ³. An example would be a light feather touch (that should only produce sensation) causing pain. Allodynia is different from hyperalgesia, which is an exaggerated response from a normally painful stimulus, although both can and often do co-exist. Both are types of neuropathic pain ⁴.

An example of the difference between allodynia and hyperalgesia on the physical exam would be softly rubbing a cotton-tipped swab against a patient’s skin. Lightly brushing a swab against the skin would cause a low-level stimulus, but should not elicit a pain response. A patient who experiences pain with a stimulus that should only cause sensation may have allodynia. If the clinician significantly increases the degree of pressure, some pain would be part of a normal response. A patient who feels an excessive amount of pain would be noted to have hyperalgesia. Thus, on physical exam, allodynia presents as a lowering of the pain threshold, while hyperalgesia presents as a heightening of response ⁴. While this often means that allodynia and hyperalgesia seem to exist along the same continuum of stimuli on physical exam, there is still a clear difference in modalities. With allodynia, the response to the stimulus differs from those who have normal sensation, while in hyperalgesia, the response to the stimulus is the same as those who have normal sensation, but it is an exaggerated response.

Allodynia can be due to an underlying disease such as diabetes-induced neuropathic tactile allodynia or can be the primary disease process itself, such as in postherpetic neuralgia. It is often further classified by the type of stimulus causing the nociception, such as tactile, thermal, dynamic or static allodynia, or by the principal site of nociception, such as cutaneous allodynia ⁵.

Hyperalgesia and allodynia classification

• Allodynia and hyperalgesia are classified according to the sensory modality that elicits pain, i.e. thermal (cold and heat) or mechanical (dynamic touch, punctuate, and pressure).
• Dynamic mechanical allodynia is pain evoked by light brushing or stroking of the skin.
• Pressure (static and deep pressure) allodynia and hyperalgesia are elicited by pressure to skin and deep tissue).
• Punctate allodynia and hyperalgesia are evoked by punctate skin stimulation by a pin or a monofilament.
• Cold and warm allodynia and hyperalgesia are provoked by cold or warm stimuli applied to the skin.

What causes allodynia?

Allodynia is a symptom, not a disease. The exact cause behind allodynia is unknown ⁴. Allodynia is the phenomenon of a non-painful stimulus producing a sharp pain response, which implies an error in neuronal conduction. The mechanism behind this error is unclear. The strongest existing evidence suggests that sensory neuronal fibers may stimulate pain pathways, possibly due to an error in long-term potentiation. However, studies exist that suggest that superficial sensory components may also have involvement, as well as evidence that different mental states can affect the perception of allodynia. If we use the analogy of crisscrossed fibers, the actual location of the crisscrossing can vary and may be located almost anywhere along the peripheral to the central nervous system tract. Allodynia can involve both the peripheral nervous system and central nervous system via sensitization, and the mechanism behind the inappropriate pain sensations can evolve over time; this might partially explain the existing contradictory studies – they may all be measuring allodynia with neuronal confusion at different locations.

A non-painful stimulus such as light skin touch should only activate the low threshold A-beta fibers. In cutaneous allodynia, these A-beta fibers then also communicate with and activate pain pathways, through different sodium channel types than the Nav1.7 sodium channels usually associated with pain, as well as through the modification of dorsal ganglia ⁶. However, allodynic pain is multifactorial, and as people suffering from post-thalamic stroke pain can attest, the crisscrossing of neurons can happen as high as in the cerebellum.

In summary, many types of peripheral nerve fibers communicate with and travel via different central nervous system pathways. Type A nerve fibers are myelinated. They further categorize into alpha fibers, which are mostly responsible for proprioception, beta fibers, which transmit light touch, and delta fibers, which carry both pain and temperature sensations. There are also unmyelinated type C nerve fibers, which carry sensations of aching pain, as well as temperature and pruritus.

Hyperalgesia clinical assessment

• Simple bedside tests include response (pain intensity and character) to cotton swab, finger pressure, pinprick, cold and warm stimuli, e.g., metal thermo rollers at 20 °C and 40 °C, as well as mapping of the area of abnormality.
• Quantitative sensory testing can be used to determine pain thresholds (decreased pain threshold indicates allodynia) and stimulus/response functions (increased pain response indicate hyperalgesia). Dynamic mechanical allodynia can be assessed using a cotton swab or a brush. A pressure algometer and standardized monofilaments or weighted pinprick stimuli are used for assessing pressure and punctate allodynia and hyperalgesia and a thermal tester is used for thermal testing.

Hyperalgesia treatment

Neuropathic pain is difficult to treat. Currently, International Association for the Study of Pain guideline recommendations “first-line treatment in neuropathic pain are tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors (SNRIs), pregabalin, and gabapentin. A weak recommendation for use and proposal as the second-line are lidocaine patches, capsaicin high-concentration patches, and tramadol. Lastly, a weak recommendation for use and proposal as the third-line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only” ⁷.

Visceral hyperalgesia

Visceral hypersensitivity is the most definitive and unifying theory explaining the pathophysiology of all functional gastrointestinal disorders ⁸. This theory is based on the strong association between the enteric nervous system and central nervous system (CNS) and their common embryonic origin ⁹. Patients with functional gastrointestinal disorders have a low threshold for nociceptive stimuli. A variety of ill-defined factors including genetic, environmental, psychosocial (early stressors in life) etc predispose an individual to visceral hyperalgesia. Postulated mechanisms for visceral hyperalgesia include sensitization of primary sensory neurons and central spinal neurons, altered descending inhibitory control, and impaired stress response. This in turn causes alteration of bowel–gut axis and causes abnormal secretion of excitatory neurotransmitters such as serotonin. Serotonin plays a key role in the regulation of gastrointestinal (GI) motility, secretion, and sensation. The bidirectional communication between the brain–gut neurons through various neural and hormonal circuits may lead to changes in the CNS and cause other associated symptoms such as headache. Stimulation of the autonomic nervous system and sympathetic hyperactivity may account for symptoms such as pallor. Novel imaging techniques such as functional magnetic resonance imaging have shown defective visceral pain processing pathways in patients with functional gastrointestinal disorder.

Although, the theory of visceral hyperalgesia has not been specifically proven in patients with abdominal migraine, it is the most evidence-based explanation for all functional gastrointestinal disorders ⁹. A 2017 study found evidence suggesting Y2 receptor antagonism and YY gene deletion may be related to visceral hyperalgesia ¹⁰. The contribution of genetic factors to abdominal migraine is further supported by the presence of family history of migraine or chronic abdominal pain in most of the patients ¹¹. However, more research is needed to identify these factors.

Opioid induced hyperalgesia

Opioid induced hyperalgesia (increased sensitivity to pain) occurs in many different patients, depending on the dose given and the pattern of administration. Most work has reported opioid induced hyperalgesia if you are receiving continuing treatment with opioids or stop taking opioids.

Opioids are a class of drugs commonly used to treat moderate to severe pain. They can be used over prolonged periods to relieve chronic pain. Opioid induced hyperalgesia is a clinical picture which involves increasing pain in patients who are receiving increasing doses of opioids. Opioids are substances such as opium, morphine, heroin, codeine and methadone.

Clinical observation suggests that the degree of opioid-induced hyperalgesia may vary with different opioids ¹². For example, morphine is more likely to produce opioid-induced hyperalgesia than is methadone.

While the exact temporal relationship between the time course of opioid therapy and the development of opioid-induced hyperalgesia is unclear, it is conceivable that opioid-induced hyperalgesia would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course, although it has also arisen in patients receiving a short course of highly potent opioid analgesics ¹³. Patients who are receiving opioid therapy for neuropathic pain may be more susceptible to developing opioid-induced hyperalgesia because of the shared cellular mechanisms involved ¹⁴.

During opioid treatment of pain, a decline in analgesic efficacy has traditionally been thought to result from the development of pharmacological tolerance (or disease progression), best overcome by dose escalation. More recently, it has been recognized that opioids can also activate a pronociceptive mechanism resulting in heightened pain sensitivity or opioid-induced hyperalgesia ¹⁵. Although hyperalgesia had previously been observed during opioid withdrawal, new evidence suggests that increased pain sensitivity can also occur during opioid administration, in the absence of an overt, precipitated withdrawal. This paradoxical opioid-induced pain sensitivity may contribute to reduced opioid analgesic efficacy. Therefore, it is possible that a decrease in opioid analgesic efficacy may be a result of opioid induced hyperalgesia (a pronociceptive mechanism), not simply of pharmacological tolerance. Both a sensitization and a desensitization process are taking place.

Opioid-induced hyperalgesia is mediated through distinct cellular mechanisms, including endogenous dynorphin, the glutamatergic system, and descending
facilitation ¹⁶. Interestingly, the cellular mechanisms of opioid induced hyperalgesia have much in common with those of neuropathic pain and opioid tolerance ¹⁶. For example, both peripheral nerve injury and repeated opioid administration can activate a similar cellular pathway involving activation of the central glutamatergic system ¹⁷. NMDA antagonists such as ketamine have been used clinically to reverse the glutamatergic component of pain sensitivity.

Risk factors for developing opioid induced hyperalgesia

• If you are taking high doses of opioids, you may be more likely to experience increasing pain and sensitivity.
• If you have medical conditions such as kidney failure or liver failure, the effects of opioid medications may be affected. Opioid drugs are broken down by the liver and excreted by the kidney. One of the after products of morphine is much more potent than morphine itself. It is undecided whether a build up of this after product is linked to being more sensitive to pain.
• When you are on opioids and suddenly stop taking the medication, evidence has shown that hyperalgesia has been one of the many symptoms associated with stopping opioid medications.

Opioid induced hyperalgesia signs and symptoms

Opioid induced hyperalgesia symptoms

Doctors may consider this condition in patients who have a history of;

• increasing sensitivity to pain,
• pain that worsens despite high doses of opioids and
• pain that becomes more wide-spread around the body.

Signs of opioid induced hyperalgesia

When the doctor is examining you, some of the following signs may be found. On examination, you may complain of pain from non-painful stimuli, such as soft touching of the skin with cotton wool.

There may be increased activity in your nervous system. These signs include;

• myoclonus (uncontrollable twitching and jerking of muscles or muscle groups),
• seizures (due to abnormal electrical activity in the brain causing things such as abnormal movements, spasms, or changes in behavior).

1. Opioid-induced hyperalgesia may differ from preexisting pain in its quality, location, and distribution pattern. The clinical hallmark of pathological pain is hyperalgesia in a dermatomal or generalized distribution. Quantitative sensory testing may reveal abnormalities in the threshold, tolerability, and distribution patterns of pain. A difference between neuropathic pain and opioid-induced hyperalgesia might be that for many neuropathic pain conditions,
   hyperalgesia arises in a distinct anatomical distribution, whereas opioid-induced hyperalgesia could be generalized in its distribution. This type of testing is in its infancy, but it may eventually reveal whether opioid-induced hyperalgesia is a completely separate phenomenon or can worsen existing neuropathic pain.
2. Opioid-induced hyperalgesia may intensify with opioid dose escalation but improve after supervised opioid tapering. In contrast, undertreatment of preexisting pain and pharmacological opioid tolerance may be overcome by a trial of opioid dose escalation.

Opioid induced hyperalgesia treatment

Research has shown that opioid induced hyperalgesia is a significant consequence of taking opioid medications. If you are taking such medications and are experiencing increasing pain, the use of alternative pain killers and stopping opioids may need to be considered.

In most cases, the first step is to look at reducing or discontinuing the current opioid. Alternatively, the doctor can look at changing your opioid to one with less risk of toxic effects to your nervous system: e.g., – fentanyl or methadone.

Low doses of drugs which have an opposing mechanism of action to opioids (called opioid antagonists), or specific NMDA (N-methyl-D-aspartate; a special amino acid implicated in opioid sensitivity) antagonists (such as ketamine) may be appropriate in some cases. Your doctor will be able to provide you with more information about this.

High levels of water intake is also recommended for your well-being.

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What is pannus

Pannus is an inflammatory soft tissue mass most frequently associated with rheumatoid arthritis and its associated chronic atlanto-axial subluxation ¹. Pannus can also be seen in other conditions in which a chronic atlanto-axial instability exists, such as degenerative arthropathies, os odontoideum or posttraumatic pseudoarthrosis of the odontoid process ². Therefore, many authors have concluded that chronic craniovertebral junction instability plays a very important role in the development of pannus ³.

Pannus is an edematous thickened hyperplastic synovium infiltrated by T lymphocytes and B lymphocytes, plasmocytes, macrophages and osteoclasts. Pannus will gradually erode bare areas initially, followed by the articular cartilage. Pannus causes a fibrous ankylosis which eventually ossifies ⁴. However, there is some controversy in the nature of this pannus. For some authors, this is an inflammatory granulation tissue, which grows from the sinovial between the dens and the posterior articular facet of the posterior arch of C1, or between the dens and the transversal ligament ⁵. For other authors, this tissue is a reactive fibrous tissue secondary to the mechanical stress more than secondary to an inflammatory process ⁶. This would be supported by the fact that pannus is found in patients with no systemic inflammatory process and with only chronic atlanto-axial instability, as happens in cases of traumatic pseudoarthrosis, os odontoideum or degenerative arthropathy ⁷.

Figure 1. Pannus (MRI scan of cervical spine)

Footnote: 75 year old male patient with known rheumatoid arthritis. Now worsening of neck pain. Large soft tissue mass encircling the marked erosion of the dens consistent with “pannus”, is typical of advanced rheumatoid arthritis. Minor extrinsic compression to the upper cervical cord.

Pannus formation

Recent theories on the pathogenesis of rheumatoid arthritis suggest that the synovial cells of these patients chronically express an antigen that triggers the production of rheumatoid factor (RF), an immunoglobulin molecule directed against other autologous immunoglobulins. An inflammatory response is initiated, involving immune complex formation, activation of the complement cascade, and infiltration of polymorphonuclear leukocytes. The proliferating fibroblasts and inflammatory cells produce granulation tissue, known as rheumatoid pannus, within the synovium. The pannus produces proteolytic enzymes capable of destroying adjacent cartilage, ligaments, tendons, and bone. The destructive synovitis results in ligamentous laxity and bony erosion with resultant cervical instability and subluxation ⁹.

Atlantoaxial subluxation results from erosive synovitis in the atlantoaxial, atlanto-odontoid, and atlanto-occipital joints and the bursa between the odontoid and the transverse ligament (see Figure 1 below).

Involvement of the cervical spine typically begins early in the rheumatoid arthritis disease process and often parallels the extent of peripheral disease. Of the 3 types of involvement, atlantoaxial instability is the most common, occurring in up to 49% of patients ¹⁰. Whereas most of these subluxations are anterior, approximately 20% are lateral and approximately 7% are posterior. Superior migration of the odontoid is seen in up to 38% of patients with rheumatoid arthritis. Subaxial subluxation is seen as a discrete pathologic entity in 10-20% of patients.

Subaxial subluxation also develops after previous upper cervical fusions ¹¹. In one series of 79 patients, 36% developed subaxial subluxation at an average of 2.6 years following occipitocervical fusion, and 5.5% experienced subaxial subluxation an average of 9 years following atlantoaxial fusion ¹².

Pannus is located ventrally to the bulbomedullary junction, and can produce a severe myelopathy and even sudden death. Transoral approach has been proposed as the best way to directly manage the ventral compression caused by pannus ¹³. However, several case reports have been reported in the last years in which pannus resolution has been documented after posterior stabilization in different pathologies, such as rheumatoid arthritis, degenerative arthropathies, os odontoideum and traumatic pseudoarthrosis ¹.

Rheumatoid pannus symptoms

Rheumatoid involvement of the cervical spine (rheumatoid spondylitis, ankylosing spondylitis) is just one element in a systemic disease process. Cervical involvement often correlates with the degree of hand and wrist erosion. Cervical involvement also has been associated with the presence of rheumatoid nodules and the use of corticosteroids. Classically, craniocervical neck pain often is associated with occipital headaches.

Intractable neck pain radiating superiorly towards the occiput is one of the earliest and most common symptoms of atlantoaxial subluxation (70% of patients) ¹⁴. Neck pain can also be a symptom of active ankylosing spondylitis and thereby difficult to distinguish from atlantoaxial subluxation; the clue is in the intractable nature of atlantoaxial subluxation. Other symptoms that may help in distinguishing between the primary disease and secondary complication includes radicular pain, Lhermitte’s sign (shocklike sensations through the torso or into the extremities), loss of fine motor control or gait changes, though these features are uncommon in the early stages of atlantoaxial subluxation. Clinical examination should be focused on eliciting signs of myelopathy and associated complications caused by localised compression (e.g., cranial nerve palsies, horner’s syndrome); one report of an patient with ankylosing spondylitis with vertical atlantoaxial subluxation had bilateral hypoglossal nerve palsy ¹⁵.

Compression of the C2 sensory fibers supplying the nucleus of the spinal trigeminal tract can cause facial pain. Compression of the C2 sensory fibers supplying the greater auricular nerve may result in ear pain. Occipital neuralgia results from compression of the C2 sensory fibers supplying the greater occipital nerve. A history of myelopathic symptoms should be sought carefully. Patients may experience weakness, decreased endurance, gait difficulty, paresthesias of the hands, and loss of fine dexterity. Patients with involvement may experience and, eventually, incontinence.

Vertebrobasilar insufficiency may be found, particularly in patients with atlantoaxial instability. Complaints may include vertigo, loss of equilibrium, visual disturbances, tinnitus, and dysphagia. Similar symptomatology can also be caused by mechanical compression of the brainstem. In some patients, neck motion can elicit shocklike sensations through the torso or into the extremities (i.e, Lhermitte sign).

Pannus rheumatoid arthritis diagnosis

The physical diagnosis of these patients frequently is confounded by the severity of their peripheral rheumatoid involvement. Weakness in these patients can also be due to tenosynovitis, tendon rupture, muscular atrophy, peripheral nerve entrapment, or articular involvement, making neurologic impairment less obvious. Signs of myelopathy should raise suspicion of cervical involvement. Rarely, cranial nerve dysfunction can occur secondary to compression of the medullary nuclei by the odontoid. Other rare findings in patients with advanced brainstem compression include vertical nystagmus and Cheyne-Stokes respirations.

Classification of neurologic deficits

The Ranawat classification ¹⁶ can be used to categorize patients with rheumatoid myelopathy based on their clinical history and physical findings (see below). This classification has some utility in determining the potential for neurologic recovery following surgery and is categorized as follows ¹⁶:

• Class 1 – No neural deficit
• Class 2 – Subjective weakness, dysesthesias, and hyperreflexia
• Class 3A – Objective weakness and long-tract signs; patient remains ambulatory
• Class 3B – Objective weakness and long-tract signs; patient no longer ambulatory

Diagnostic studies

Rheumatoid factor seropositivity has been correlated with more extensive cervical involvement (rheumatoid spondylitis, ankylosing spondylitis). The use of the rheumatoid factor as a predictor of neurologic involvement has not been established; therefore, it does not have a role in the surveillance of patients with rheumatoid arthritis with cervical involvement.

All patients with rheumatoid arthritis should have radiographic examination of the cervical spine because cervical involvement (rheumatoid spondylitis, ankylosing spondylitis) can remain asymptomatic. Imaging modalities include plain radiography, magnetic resonance imaging (MRI), polytomography, and computed tomography (CT) scanning. Although prediction of the onset of myelopathy in any particular patient is difficult, studies of large populations of patients have sought to establish parameters for predicting neurologic involvement via imaging studies ¹⁷.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has provided an increased ability to visualize the extent of spinal cord compression, particularly when due to pannus ¹⁸. Dvorak and colleagues ¹⁹ showed that two thirds of patients with atlantoaxial subluxation have a pannus of greater than 3 mm in diameter. Therefore, the bony canal diameter measured on plain radiographs may not represent the true space available for the cord. Kawaida et al. ²⁰ demonstrated spinal cord compression in all patients with rheumatoid arthritis when the space available for the cord (as measured on MRI) was 13 mm or less.

Using MRI, the cervicomedullary angle is an effective indicator of cord distortion from superior migration of the odontoid. This angle incorporates lines drawn along the anterior aspects of the cervical cord and along the medulla. The normal range is 135-175°. Angles less than 135° indicate basilar invagination and have been associated with myelopathy.

Polytomography and CT Scanning

Historically, tomograms were useful for quantitating the degree of basilar invagination and to measure the anterior and posterior atlantodental intervals more accurately in patients with abnormal radiographs. However, computed tomography (CT) scanning with sagittal and coronal reformatting has largely supplanted biplanar tomography. A CT scan combined with intrathecal contrast provides excellent bony detail and the ability to detect spinal cord compression from synovial pannus.

Although the noninvasive nature of magnetic resonance imaging (MRI) has made it the preferred modality for this type of evaluation, CT myelography is useful for patients with contraindications to MRI.

Pannus rheumatoid arthritis treatment

Nonsurgical management

Nonoperative treatment of rheumatoid involvement of the cervical spine (rheumatoid spondylitis, ankylosing spondylitis) is supportive. Early aggressive medical management is important in the global sense, as cervical involvement has been correlated with disease activity. Collars can be used for comfort purposes. Rigid cervical collars most likely do not prevent subluxation; however, they may prevent reduction of a deformity by limiting extension ²¹. Skin sensitivity in this population also causes problems with rigid orthoses. Patients being monitored need careful surveillance for long-tract signs or for radiographic findings suggesting impending neurologic compromise

Surgical management

The identification of a subset of patients with impending neurologic deficit has been elusive due to the poor correlation of neurologic symptoms with radiographic indicators of instability. Therefore, universally accepted surgical indications have been slow to develop. However, patients with rheumatoid arthritis or, particularly, rheumatoid spondylitis (ankylosing spondylitis) who have refractory pain, clearly evident neurologic compromise, or intrinsic spinal cord signal changes on magnetic resonance imaging (MRI) are generally candidates for surgical intervention.

Controversy surrounds treatment for patients with little or no pain, no neural deficit, and radiographs suggestive of instability. To facilitate understanding of the operative indications and perioperative details, categorization of these patients by their pathologic lesion is helpful ²².

Contraindications to surgery for rheumatoid spondylitis (ankylosing spondylitis) include medical conditions that suggest the patient would not tolerate the stress of surgery, such as unstable angina or a recent myocardial infarction or stroke ²³. Active infection with likely bacteremia would also be a relative contraindication to surgery, especially in the setting of planned instrumentation. The patient’s medical condition should be optimized before proceeding with any planned surgical intervention.

Postsurgical complications

Rheumatoid arthritis is a systemic disorder, and patients may have varying degrees of generalized debilitation ²⁴. The postoperative course of such patients can be complicated by fragile skin and poor wound healing. Poor preoperative nutritional status and corticosteroid dependence may potentiate wound-healing problems and predispose toward infection ²⁵.

Some airways are difficult to intubate. Excessive trauma during intubation may be responsible for postoperative breathing problems. Wattenmaker et al. ²⁶ reported a 14% incidence of upper airway obstruction after extubation in patients intubated without fiberoptic assistance, compared with a 1% incidence in patients intubated fiberoptically. The perioperative mortality rate has been reported to be as high as 5-10%.

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