Neurofibroma: Genetic Traits and Impact

Neurofibroma: Genetic Traits and Impact

Neurofibroma is an inheritable genetic condition whereby benign neural tumors (neurofibromas) form on the dermis, subcutaneous skin levels, in the brain and on the spinal cord.1 Neurofibroma possesses a high prevalence rate in terms of genetic transmission from parent to offspring. Generally, if one parent is a carrier for this condition, each offspring has better than a 50% probability of developing the disease.2 Aside from being inherited, Neurofibroma can be demonstrated in families with no genetic predisposition to the disease 3 This is the result of a genetic mutation is either gamete (sperm or egg). Specifically, this genetic anomaly is caused by the gene that regulates the expression and regulation of the protein nuerofibrin4. Like any genetic abnormality the results of the condition vary across individuals 5. Some of the common symptoms include large tumors under the skin, mild cognitive impairment, colored spots on the skin and possible long bone fractures, however this is more pronounced in young children 6

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Neurofibroma is a disease that can impact individuals across a wide range of backgrounds. It is a disorder that can complicate pregnancy, adversely affect Cardiovascular and respiratory functions as well as cause thoracic deformities. The purpose of this analysis is to discuss in detail the background of Neurofibroma, from its genetic roots to its clinical manifestations. Additionally this analysis will focus on the impact Neurofibroma has on various bodily systems such as Respiratory, Cardiovascular and Thoracic. Furthermore, a review of the current pharmacology utilized in treating this disorder will be evaluated on the basis of efficacy and impact. Finally, this analysis will conclude with an overall assessment of the condition, a review of the effective treatments and an examination and the need for future research.

Analysis of Neurofibroma

Genetics of Neurofibroma and the protein Neurofibromin

The Neurofibroma Type 1 gene has been assigned the dubious distinction of having the highest number of mutations and irregularities of any gene within the Human Genome7 the NF-1 gene regulates the expression or deregulation of the protein Neurofibromin, which possesses certain tumor suppression qualities8 the incidence of NF-1 at birth is approximately 1 in 3500, displaying 100% penetrance. Although there is high penetrance, the phenotypic expression of NF-1 is quite variable10

NF-1 mutations lie along the NF gene, however there are 8 different exons and introns in which the mutations are expressed at a significantly higher frequency11 in these 8 regions of the NF-1 gene upwards of 41% of all the mutations are present. Recent studies11 have demonstrated there are other areas were mutations may develop. Accounting for the remaining mutations, 31% are predicated on frame-shift mutations, 9% are nonsense mutations; 8% are missense mutations and 2% are due to amino acid deletions12.

Mutations within the NF-1 gene can ultimately lead to negative consequences in terms of messenger-RNA processing and the protein Neurofibromin. Since the m-RNA is directly responsible for the correct coding and expression of the protein Neurofibromin-any mutations will negative impact protein expression. According to research13, 31% of mutations can lead to recurring mutations being expressed through Neurofibromin. There are over 1,000 variant mutations associated with NF-1 gene and its production of Neurofibromin. The two most common are mutations R304X which causes a frame-shift and allows exon 7 to be skipped whereas the second most common NF-1 mutation is Y2264X, that causes a nonsense mutation allowing exon 37 to be spliced from the genome14. These mutations provide the nexus for the various symptoms associated with Neurofibroma. Having the knowledge of the two most common mutations can drive researchers to examine these mutations, locate the regions within the chromosome where they are most likely to be found and derive treatments to suppress or reverse these mutations.

Clinical Presentation and Pathology

The phenotypic presentations of NF-1 can be divided into two categories: Tumor and non-tumor. The neurofibroma is the most prevalent tumor associated with neurofibromatosis. It is a mass consisting of Schwann cells, fibroblasts, perineurial cells and mast cells arising from peripheral nerves or nerve roots, either growing focally, or spreading length of the nerve15. If the growth includes nerve branches it is term a plexiform neurofibroma. Dermal or Cutaneous neurofibromas are skin tumor growths, which commence prepubertally or during pregnancy, can be found both either above or within the skin surface16. The prevalence of dermal neurofibromas is approximately 95% although the severity of this type of neurofibroma varies from patient to patient and cannot be predicted due to the varying genetic manifestation of the disease. Nodular neurofibromas originate in peripheral nerve but do not invade nearby tissue. Spinal neurofibromas, on the other hand cause spinal root compression can also invade the spinal canal to compress the spinal cord.

Plexiform neurofibromas are the classic sign of neurofibromatosis. Found in approximately 30% of NF1 patients, cause nerve compression as well as the attrition of surrounding structures such as bone. Although neurofibromas are typically benign, also there is a 10% chance of conversion to malignant peripheral nerve sheath tumors (MPNSTs). Conversion to MPNSTs usually originate from deep locations rather than superficial plexiform neurofibromas. Prognosis of NF1 derived MPNSTs is poor with a 5-year survival rate of approximately 21%. The best treatment of MPNSTs is surgery while radiation and chemotherapy have unclear success rates17.

Transformation of neurofibromas can affect the Central Nervous System. The most common CNS manifestation is the optic glioma. Optic gliomas symptomatically present themselves with visual field defects,, vision loss, or neuroendocrine abnormalities. It is unusual for optic gliomas to progress pass seven or eight-year of age. NF1 patients have an increased risk for malignant tumors such as leukemia, for example, acute myelomonocytic leukemia, as well as rhabdomyosarcoma, and pheochromocytoma. Forty six percent of patients develop Lisch nodules.

Non-tumor manifestations of the neurofibromatosis include skin pigmentation abnormalities, learning disabilities, skeletal and vascular dysplasias. Cafe-au-lait spots are hyperpigmented, flat and round areas of the skin that arise during infancy and increase throughout adulthood. Approximately 95% of NF1 patients have cafe-au-lait spots as adults18. Learning disabilities include difficulties with visuospatial construction, memory, and other cognitive skills. Vascular manifestation of the disease are rare, (approximately 1-3% incidence). Possible manifestations can include occlusions, stenosis, arteriovenous malformations, and fistulae.

Diagnosis

The standards for diagnosis of Neurofibroma have stood and withstood academic rigor. The broad standards for diagnosing Neurofibroma involve Cafe-au-lait spots, axillary freckling, Lisch nodes, distinct bony lesions and optic nerve gliomas. The manifestations of NF-1 are widespread and impact many bodily systems20. The skin spots and freckling do not normally cause implications; however some patients become distressed with these spots being present.

The main diagnostic indicator is the presence of Cutaneous Neurofibromas. These fibromas are found in the majority of NF-1 patients. These fibromas often exhibit a purplish tint at the outset. Furthermore the number of these fibromas vary among individuals and families. To date there have been no diagnostic evidence that indicates cutaneous fibromas undergo a malignant evolution.

One of the more potent and threatening conditions associated with NF-1 has an 8% to 13% probability over the lifespan of any NF-1 patient. Malignant Peripheral Nerve Sheath Tumors (MPNST) are difficult to detect and diagnose, metastasize quickly and offer a poor prognosis. Generally the diagnostic conditions associated with a MPNST include persistent pain in the fibromas that last for longer than thirty days, new or unexplained nerve deficits, hardening of the neurofibromas and an increase in the fibroma size. Individuals that develop these tumors more often than not possesses a high degree of cancer in their pedigree. Furthermore, these individuals may suffer from Optic pathway glioma, whole gene deletion, multiple subcutaneous neurofibromas or neurofibroma neuropathy.

Anesthetic Considerations

Dealing with Neurofibroma during surgery is a delicate balance. Various fibromas may present a variety of challenges for the medical team. Recently, a patient in the Taipei Veterans Hospital underwent a segmental resection of the trachea22. The patient was diagnosed as having Endotracheal Neurofibroma which caused significant airway blockage. Using a combination of mild anesthesia, fiberoptic bronchoscopy, intubation and extensive preoperative evaluations the patient’s trachea was re-sectioned without incident.

The balance between surgery, anesthesia and neurofibromas becomes even more tenuous when considering if the patient is female and pregnant. In 2002, Dr. Amir 23 presented a case where a pregnant woman possesses an Inflammatory Myofibroblastic Tumor (IMT) that was blocking the upper trachea. The surgical path taken was to utilize a mild, local anesthetic so as to protect the unborn child. Once the patient was under anesthesia the IMT was excised without incident.

Another tumor-orientated offspring of Neurofibroma is referred to as Pheochromocytoma. A Phaechromocytoma arises in the neural cells most likely around the basal ganglia, vagus nerve and carotid arteries24. Hypertension is the most common symptom of patients with this type of tumor. Treatment involves tumor extraction. These tumors present a challenge for surgeons and anesthesiologists.

These tumors require preoperative, inter-operative and postoperative monitoring by physicians. The anesthesiologist must take a detailed history of the patient in order to determine the correct surgical path. During the surgery the anesthesiologist can employ several different techniques. General anesthesia can be used in connection with regional anesthesia and a neurolept. However, recently, anesthesiologists have suggest a low to mid thoracic epidural combined with adequate general anesthesia. This anesthetic technique will allow for adequate inter-operative monitoring. After the operation, the anesthesiologist must continue to monitor the patient for either hypertension, hypotension and hypoglycemia. The presence of either of these conditions may alter the course of the medication given to the patient once the patient is removed from the anesthesia.

Respiratory System

Neurofibroma can cause systemic problems within the various components of the Respiratory System. As has already been presented, Neurofibromas can cause partial blockages within upper parts of the trachea. However, Neurofibromas can also pose challenges or the anesthesiologist when dealing with nasal, sinus or maxilofacial cavities with Neurofibromas present within. One example of how devastatingly complex the Neurofibroma can become is seen when a benign neurofibroma can cause a superior vena cava compression. Such was the case of a 21-year-old female patient as reported by Oakley25. The patient was experiencing shortness of breath while at rest. Additionally, the patient had a family history of Neurofibroma in her family. After several chest x-rays a biopsy determined the mass was indeed caused by a neurofibroma. The tumor was excised and post-operative examination revealed the tumor was hyper-cellular suggesting a neurofibroma in growth stage without any malignant indications.

These types of tumors are difficult to treat under any conditions. The anesthetic considerations for these types of tumors are involved and complex. According to Dodge26 some patients may experience difficulty during an awake intubation, as a result these patients may undergo rapid induction and muscle paralysis after preoxygenation. This allows for several minutes of apnea without hypoxia during this time extracorporeal oxygenation could be introduced into the patient.

Another form of tumor present in the respiratory system in relation to NF-1 are Intrapulmonary Neurofibromas- these tumors are rare and carry a good prognosis 27. Recent surveys have indicated that this defect may result in pulmonary hypertension and right Ventricular failure. These conditions render an anesthesiologist’s job increasingly difficult when monitoring a patient’s blood pressure and pre-operative oxygen levels.

Chest Wall Deformities

Chest Wall deformities are often the result of severe aberrations of the spinal column usually as a result of severe scolosis. This condition is common in NF-1 patients and impacts approximately 10% of NF-1 patients. Typically this affliction occurs in young children with corrective surgery being the mode of treatment 28. A significant form of scoliosis- kypho-scoliosis, is uncommon, however it has been found to be associated with tumors and a higher than normal neurological deficit- two hallmarks of Neurofibroma 29. Kypho-scoliosis may lead to rotation and as a result could cause a reduction in lung volume and breathing capacity. This scoliosis may ultimately lead to respiratory failure 30. Neurofibroma may lead to a gradual degradation of the rib cage and produce a condition known as “flial chest”; however research has shown this cause to be more uncommon than not.

Hypertension

Hypertension is normally associated with the Cardiovascular system as it relates to diet and cholesterol levels. However Neurofibroma may impact hypertension. Approximately 6% of patients with Neurofibroma are hypertensive. However, in 30% of patients, the symptom is the result of a secondary condition much like a renovascular disorder. Those younger patients who have been diagnosed with Neurofibroma are most likely suffering from a disease called Renal Artery Stenosis. Surgery from this disease has been shown to offer mixed results; however a form of angioplasty, precutaneuos angioplasty has been found to alleviate hypertension.

A more common disorder associated with Hypertension and Neurofibroma is Phaeochromocytoma. These tumors affect 0.1% to 7.5% of patients with NF-1, however 25% of patients diagnosed with Phaeochromocytoma have NF-1-31. Patients exhibiting these tumors tend to be older-mean age 45 and the tumors tend to be non-malignant. There are several common symptoms. They include sudden and sharp frontal or occipital lobe headaches, weight loss and palpitations- these symptoms occur in approximately 60% of all Neurofibroma patients 32.

The anesthetic considerations for this disorder are numerous and complex. The preoperative considerations include evaluating the patients blood pressure and heart rate change. These two factors could be evidence of myocardial schemia. Also, the anesthesiologist must account for an adrenergic blockade. The most critical anesthetic considerations occur in the operating room. During the procedure the anesthesiologist must evaluate the arterial line, monitor urinary output, intubate deep and monitor any inter-operative hypertension. If such hypertension occurs during surgery it can be treated with phentolamine, nitroprussside or nicardipine. Post-operative considerations involve continued monitoring of hypertension which could indicate additional tumors.

Vasculopathy

Neurofibroma may lead to the formation of aortic and cerebral aneurysms 33. It has been proposed that these structures are the result of Schwan cell proliferation with a secondary fibrosis forming on the vessel wall. Although some studies show congenital heart failure as the leading cause34, a secondary review showed no clear evidentiary support 35. The presence of these aneurysms may represent a vascular manifestation of a Neurofibroma. Related to the advent of aortic aneurysms is the onset of hypertrophic cardiomyopathy in relation to Neurofibroma36.

The appearance of such myopathy in conjunction with Neurofibroma has been questioned. Recent studies have demonstrated that Neurofibroma is possibly a secondary cause of this myopathy in that both Neurofibroma and hypertrophic cardiomyopathy involve an abnormal metabolic rate and both represent defects in the development of neural tissue. Furthermore, Neurofiborma may cause the heart to develop hypertrophy and outflow obstruction.

Vascular inflammation results from deficiencies in Neurofibronin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow — derived cells (BMDCs), and neurofibromin regulates the function of each cell type. analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease37

Central Nervous System

Tumors within the Central Nervous System contribute to the overwhelming percentage of the mortality rates among patients with Neurofibroma. Therefore it is logical to conclude these patients needing cranial or spinal neurosurgery. The anesthetic considerations for this type of surgery are along the lines as normal neural surgery.

Prior to surgery the Anesthesiologist must consider the enhance probability of epilepsy, cognitive impairment and the likelihood of undiagnosed Central Nervous System tumors. Cerebrovascular Disease has been reported and presents the similar pathology as Vascular Neurofibromas. However this manifestation is relatively uncommon.

Neurofibroma also plays a significant role in impacting cognitive functions38. Neurofibroma controls the expression of ERK signaling in GABA release 39. The disruptions caused by the mutations resulting Neurofibroma-1, lead to a disruption in the mechanisms that govern learning. Therefore, Neurofibrin regulates, ERK and Synapsis I which in turn affects GABA release and impacts long-term potentiation.

Neurofibromatosis-1 can be used to ascertain the cause of low-grade gliomas in children. Through using NF-1 mice models, researchers have been able to develop models that allow researchers to locate critical growth pathways, define the contribution of the tumor micro-environment to glioma growth and assisted in developing and understanding of the basis for glioma growth. Furthermore such mice models have been used to develop the therapeutic studies to evaluate the efficacy and safety of pharmacological treatments for juvenile gliomas40. It is important to use small-animal models to determine why certain therapies might fail. In addition to the reasons outlined above, defining tumor escape mechanisms (eg, feedback loops, activation of other signaling pathways) are critical to the design of future anticancer drugs.

Gastrointestinal System

Gastrointestinal tumours in NF1 may present with disordered gut motility, abdominal pain, haematemesis or melaena; although neurofibromas, usually affecting the jejenum or stomach, are the most common lesions, leiomyoma, ganglioneuroma and sarcoma have been described. All may result in intestinal perforation. Gastrointestinal symptoms may be the first manifestation of neurofibromatosis.

Gastrointestinal abnormalities in patients with NF-1 are reported to occur in up to 10~25% of patients and consist of four groups of lesions: mesenchymal neoplasms; hyperplasias of intestinal neural tissue; neuroendocrine tumors of the duodenum; and rarely, other gastrointestinal neoplasms such as adenocarcinomas41. Although neurofibromas are the most commonly encountered mesenchymal neoplasm of the gastrointestinal tract in patients with NF-1, Gastrointestinal stromal tumors (GISTs), leiomyomas, and leiomyosarcomas also occur

Clinical symptoms are related to the size and location of the GISTs. Most pathologists use a combination of tumor size and mitotic rate to assess the malignant potential of these tumors. In general, malignant GISTs are larger, more cellular, and more mitotically active. GISTs that are smaller than 5 cm with five mitoses per 50 consecutive high-power fields or less are considered to be benign with a low risk for metastasis. Tumors larger than 10 cm with more than five mitoses per 50 high-power fields are considered to be malignant. All tumors falling between these two extremes are considered to be of uncertain malignant potential with intermediate risk for metastasis. Tumors with more than 50 mitoses per 50 high-power fields are considered to be highly malignant with an aggressive clinical behavior. The liver and the peritoneum are the most common sites of spread in malignant GISTs

An unusual feature of the carcinoid tumor occurring in NF1 is the predilection for the duodenum and especially the ampulla of vater — an uncommon site in the non-NF1 population.42 Patients may present with jaundice or upper gastrointestinal haemorrhage or obstruction; often, by the time a diagnosis is reached, metastases are present in the liver. The subsequent release of vasoactive peptides may result in patients presenting with the carcinoid syndrome of flushing, diarrhea, bronchoconstriction and right heart lesions. Anaesthesia and surgery may be hazardous in this situation. Perioperative management of patients with carcinoid syndrome has been comprehensively reported by Veall.43 it is important to note that carcinoid tumours and phaeochromocytoma may co-exist and, therefore, patients with phaeochromocytoma require imaging of the duodenum to exclude pathology in this region

Pregnancy

Pregnant women with neuropathy may experience numbness or tingling in their hands and feet, muscle weakness, spasms or cramping, lessening or absence of the sense of touch, loss of balance, abnormal blood pressure, constipation, bladder dysfunction or diarrhea. Postpartum neurological complications occur in up to 1% of deliveries. Often prior anesthetic procedures are blamed, with medicolegal implications. A young woman who presented with postpartum foot drop diagnosed as an iatrogenic L5 root lesion after uncomplicated epidural anesthesia. After neurological assessment some 5 mo later she tested positive for the common hereditary neuropathy with liability to pressure palsies mutation that was a likely contributing factor in the development of her postpartum neuropathy. Anesthesiologists should consider hereditary neuropathies in the differential diagnosis of postpartum or postsurgical neurological deficits if there is a suggestive clinical history 42.

Anesthesiologists are often blamed for neurological complications after anesthetic procedures during childbirth, with medicolegal implications. A genetically determined predisposition to compression-induced neuropathies is not rare and is probably under-diagnosed, but a clinical history can provide clues. The incidence of neurological complications arising in the peripartum period may be as frequent as 0.92% 43. Epidural or spinal analgesia/anesthesia is commonly performed during delivery and can cause inadvertent spinal cord or nerve root injury as a result of direct trauma, hematoma, or infection 44. Early 45 and more recent reports have concluded that postpartum foot drop can also be a result of compression of the lumbosacral trunk by the fetal head at the pelvic brim in short women or result from proximal sciatic or peroneal nerve injuries. Postpartum neurological injuries often resolve spontaneously, and neurological assessment may not be necessary. The available literature seems to have overlooked an obvious contributory factor present in a recent case seen at our unit, and it seems likely that anesthetic procedures may be unnecessarily blamed for a proportion of neurological deficits with potential medicolegal implications.

Pharmacology

Spinal cord stimulation (SCS) has proven to be an effective treatment of nerve injury-induced pain, and up to 60% — 70% of well selected patients experience satisfactory pain relief 46. Although the mechanism of action of SCS is only partially understood, experimental data have suggested that a combination of SCS and drugs may be useful to improve pain relief. Previous studies in our laboratory have demonstrated that the effect of SCS on neuropathy-related behavior in nerve-lesioned rats can be enhanced by simultaneous spinal administration of small doses of the gamma-aminobutyric acid (GABA)B receptor antagonist baclofen 47, the adenosine A1 receptor antagonist R-PIA and the two anticonvulsants gabapentin and pregabalin. Furthermore, subsequent clinical trials have indicated that both intrathecal (it) baclofen and adenosine may be effective adjuvants to SCS in patients experiencing pain from nerve injury and in whom stimulation treatment alone is insufficient 48.

Clonidine, an ?2-adrenoceptor antagonist, was originally introduced as an antihypertensive drug. Within pain therapy, it has been used to control nociceptive pain (e.g., postoperative pain) and as an adjunct to both systemic and spinal opioids 49. Moreover, clonidine has been demonstrated to produce analgesia in both human neuropathic pain and in various animal models of neuropathy 50. Some observers even assert that clonidine is more effective in reducing neuropathic than acute pain. Clonidine is one of the most common drugs administered epidurally or it in chronic-pain patients, but its use is limited by cardiovascular and sedative side effects (although less so with the it route of administration).

Pregabalin is a new synthetic molecule and a structural derivative of the inhibitory neurotransmitter ?-aminobutyric acid. It is an ?2-? (?2-?) ligand that has analgesic, anticonvulsant, anxiolytic, and sleep-modulating activities. Pregabalin binds potently to the ?2-? subunit of calcium channels, resulting in a reduction in the release of several neurotransmitters, including glutamate, noradrenaline, serotonin, dopamine, and substance P. The precise mode of action of pregabalin has not been fully elucidated, but it does interact with the same binding site, and has a similar pharmacological profile, as gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the ?2-? subunit of presynaptic, voltage-dependent calcium channels that are widely distributed throughout the peripheral and central nervous system 51. Binding affinity for the ?2-? subunit, and potency, is six times more than that of gabapentin. Up-regulation of the ?2-? subunit may play an important role in hypersensitization processes. Pregabalin appears to produce an inhibitory modulation of neuronal excitability 52, particularly in areas of the central nervous system dense in synaptic connections such as the neocortex, amygdala, and hippocampus. Ectopic activity is reduced while normal nerve function is unchanged 53. As with gabapentin, pregabalin is inactive at GABAA and GABAB receptors, is not converted metabolically into GABA or a GABA antagonist, and it does not alter GABA uptake or degradation.

Absorption of gabapentin is limited by saturable, active, dose-dependent transport in the gastrointestinal tract.54 Therefore, smaller doses, given more frequently, may be required to optimize absorption. Absorption of pregabalin is not saturable, resulting in a linear pharmacokinetic profile. In healthy volunteers, pregabalin is rapidly absorbed with peak blood concentrations within 1 h 55. Average bioavailability exceeds 90% and is independent of dose, which may produce a more predictable patient response. The elimination half-life of pregabalin ranges from 5.5 to 6.7 h, and is independent of dose and repeated dose administration. In contrast to pregabalin, the rate of gabapentin absorption is relatively slow, with peak plasma concentrations occurring around 3 h postdose.

Pregabalin does not undergo hepatic metabolism and is not bound to plasma proteins. It is renally excreted, and 98% of the absorbed dose is excreted unchanged in the urine. Pregabalin elimination is nearly proportional to creatinine clearance. Pregabalin clearance is reduced in subjects with impaired renal function. A 50% reduction in pregabalin daily dose is recommended for patients with creatinine clearance (CLcr) between 30 and 60 mL/min compared with those with CLcr >60 mL/min. After a 4-h hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%.

Pregabalin is well tolerated 56 and associated with dose-dependent adverse effects that are mild-to-moderate and are usually transient. In clinical trials, dizziness and somnolence are the most frequently reported adverse events, with dizziness experienced by 29% of pregabalin-treated patients compared with 9% with placebo and somnolence, experienced by 22% of pregabalin-treated patients compared with 8% with placebo 57. Dose-dependent weight gain has been reported (58). There have been case reports of myoclonus, aterixis, gynecomastia and a single case report has described encephalopathy and edema of the corpus callosum after abrupt discontinuation of pregabalin.

As with all antiepileptic drugs, pregabalin should be withdrawn gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If pregabalin is discontinued, the dose should be gradually tapered over a minimum of 1 wk. There are no head-to-head studies comparing the side effects of pregabalin vs. gabapentin. The trials involving gabapentin have usually used variable doses, whereas the trials with pregabalin used fixed dosing without titration. Differences in study design may influence the reported incidence of side effects. Nonetheless, comparing available studies, side effect profiles appear similar, with the exception perhaps of a more frequent incidence of nausea and diarrhea with gabapentin. Pregabalin is contraindicated in patients with a known hypersensitivity to pregabalin or any of its components.

Conclusion

Neurofibroma has been demonstrated to have multifaceted implications throughout various body systems. Each functional system presents various implications and obstacles for the surgeons and anesthesiologists. Neurofibroma can manifest themselves within a variety of contexts. As explained within this discussion, the most common form of manifestation of Neurofibroma concearns the expression of tumors within the neural system, specifically in the cranial and spinal neural tissues. These tumors are responsible for the overwhelming majority of neural surgeries associated with Neurofibroma.

Anesthesiologists are charged with the responsibility of maintaining patient well being before, during and after the procedures. There are numerous considerations that must be integrated into the decision making process. The anesthesiologist must take into consideration various factors that must be addressed prior to any surgery. For example, the literature made a point to clarify that factors such as blood pressure must be reviewed prior to the procedure in order to ensure that the correct level of anesthetic is employed so the surgical team can effectively remove the neurofibroma.

Numerous diagnostic factors play into determining if an individual has Neurofibroma type 1. This diagnostic step is critical in determining the correct surgical process and therefore will determine the appropriate anesthetic process. There are instances where general anesthesia combined with regional anesthesia is employed. Furthermore, each functional body system presents its own implications for dealing with Neurofibroma. Respiratory, Cardiovascular, Gastrointestinal all present various degrees of considerations for the anesthesiologist. Neurofibroma also has dramatic implications for pregnant women. The degree of pregnancy can determine the course of surgery and the level of anesthesia applied in certain cases. However, with the appropriate pre-operative evaluation and the correct history, the proper level of anesthesia and the appropriate considerations will be evaluated and ultimately the correct actions will be taken.

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2 Id.

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4 Id.

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6 Id.

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12 Id.

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46 Meyerson BA, Linderoth B. Spinal cord stimulation. in: Loeser JD, ed. Bonica’s management of pain. Philadelphia: Lippincott Williams & Wilkins, 2000: 1857 — 76.

47 Cui J-G, O’Connor WT, Ungerstedt U, et al. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain 1997; 73: 87 — 95.

48 Linderoth B, Meyerson B. Spinal cord stimulation: mechanisms of action. in: Burchiel K, ed. Surgical management of pain. New York: Thieme, 2002: 505 — 26.

49 Eisenach JC, DuPen S, Dubois M, et al. Epidural Clonidine Study Group: epidural clonidine analgesia for intractable cancer pain. Pain 1995; 61: 391 — 399

50 Pan H-L, Chen S-R, Eisenach JC. Intrathecal clonidine alleviates allodynia in neuropathic rats. Anesthesiology 1999; 90: 509 — 14

51 Gazulla J, Tintore M. The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: Gabapentin and pregabalin may be of therapeutic benefit. Med Hypotheses 2007;68:131 — 6

52 Hill D, Suman-Chauhan N, Woodruff G. Localization of [3H]gabapentin to a novel site in rat brain: autoradiographic studies. Eur J. Pharmacol 1993;244:303 — 9

53 Chen S, Xu Z, Pan H. Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology 2001;95:1473 — 9

54 Stewart B, Kugler a, Thompson P, Bockbrader H. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993;10:276 — 81

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56 Sabatowski R, Galvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, Versavel M, the 1008 — 045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26 — 35

57 Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L, for the Gabapentin Postherpetic Neuralgia Study Group. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837 — 42

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Neurofibroma: Genetic Traits and Impact

Neurofibroma: Genetic Traits and Impact

Neurofibroma is an inheritable genetic condition whereby benign neural tumors (neurofibromas) form on the dermis, subcutaneous skin levels, in the brain and on the spinal cord.1 Neurofibroma possesses a high prevalence rate in terms of genetic transmission from parent to offspring. Generally, if one parent is a carrier for this condition, each offspring has better than a 50% probability of developing the disease.2 Aside from being inherited, Neurofibroma can be demonstrated in families with no genetic predisposition to the disease 3 This is the result of a genetic mutation is either gamete (sperm or egg). Specifically, this genetic anomaly is caused by the gene that regulates the expression and regulation of the protein nuerofibrin4. Like any genetic abnormality the results of the condition vary across individuals 5. Some of the common symptoms include large tumors under the skin, mild cognitive impairment, colored spots on the skin and possible long bone fractures, however this is more pronounced in young children 6

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Neurofibroma is a disease that can impact individuals across a wide range of backgrounds. It is a disorder that can complicate pregnancy, adversely affect Cardiovascular and respiratory functions as well as cause thoracic deformities. The purpose of this analysis is to discuss in detail the background of Neurofibroma, from its genetic roots to its clinical manifestations. Additionally this analysis will focus on the impact Neurofibroma has on various bodily systems such as Respiratory, Cardiovascular and Thoracic. Furthermore, a review of the current pharmacology utilized in treating this disorder will be evaluated on the basis of efficacy and impact. Finally, this analysis will conclude with an overall assessment of the condition, a review of the effective treatments and an examination and the need for future research.

Analysis of Neurofibroma

Genetics of Neurofibroma and the protein Neurofibromin

The Neurofibroma Type 1 gene has been assigned the dubious distinction of having the highest number of mutations and irregularities of any gene within the Human Genome7 the NF-1 gene regulates the expression or deregulation of the protein Neurofibromin, which possesses certain tumor suppression qualities8 the incidence of NF-1 at birth is approximately 1 in 3500, displaying 100% penetrance. Although there is high penetrance, the phenotypic expression of NF-1 is quite variable10

NF-1 mutations lie along the NF gene, however there are 8 different exons and introns in which the mutations are expressed at a significantly higher frequency11 in these 8 regions of the NF-1 gene upwards of 41% of all the mutations are present. Recent studies11 have demonstrated there are other areas were mutations may develop. Accounting for the remaining mutations, 31% are predicated on frame-shift mutations, 9% are nonsense mutations; 8% are missense mutations and 2% are due to amino acid deletions12.

Mutations within the NF-1 gene can ultimately lead to negative consequences in terms of messenger-RNA processing and the protein Neurofibromin. Since the m-RNA is directly responsible for the correct coding and expression of the protein Neurofibromin-any mutations will negative impact protein expression. According to research13, 31% of mutations can lead to recurring mutations being expressed through Neurofibromin. There are over 1,000 variant mutations associated with NF-1 gene and its production of Neurofibromin. The two most common are mutations R304X which causes a frame-shift and allows exon 7 to be skipped whereas the second most common NF-1 mutation is Y2264X, that causes a nonsense mutation allowing exon 37 to be spliced from the genome14. These mutations provide the nexus for the various symptoms associated with Neurofibroma. Having the knowledge of the two most common mutations can drive researchers to examine these mutations, locate the regions within the chromosome where they are most likely to be found and derive treatments to suppress or reverse these mutations.

Clinical Presentation and Pathology

The phenotypic presentations of NF-1 can be divided into two categories: Tumor and non-tumor. The neurofibroma is the most prevalent tumor associated with neurofibromatosis. It is a mass consisting of Schwann cells, fibroblasts, perineurial cells and mast cells arising from peripheral nerves or nerve roots, either growing focally, or spreading length of the nerve15. If the growth includes nerve branches it is term a plexiform neurofibroma. Dermal or Cutaneous neurofibromas are skin tumor growths, which commence prepubertally or during pregnancy, can be found both either above or within the skin surface16. The prevalence of dermal neurofibromas is approximately 95% although the severity of this type of neurofibroma varies from patient to patient and cannot be predicted due to the varying genetic manifestation of the disease. Nodular neurofibromas originate in peripheral nerve but do not invade nearby tissue. Spinal neurofibromas, on the other hand cause spinal root compression can also invade the spinal canal to compress the spinal cord.

Plexiform neurofibromas are the classic sign of neurofibromatosis. Found in approximately 30% of NF1 patients, cause nerve compression as well as the attrition of surrounding structures such as bone. Although neurofibromas are typically benign, also there is a 10% chance of conversion to malignant peripheral nerve sheath tumors (MPNSTs). Conversion to MPNSTs usually originate from deep locations rather than superficial plexiform neurofibromas. Prognosis of NF1 derived MPNSTs is poor with a 5-year survival rate of approximately 21%. The best treatment of MPNSTs is surgery while radiation and chemotherapy have unclear success rates17.

Transformation of neurofibromas can affect the Central Nervous System. The most common CNS manifestation is the optic glioma. Optic gliomas symptomatically present themselves with visual field defects,, vision loss, or neuroendocrine abnormalities. It is unusual for optic gliomas to progress pass seven or eight-year of age. NF1 patients have an increased risk for malignant tumors such as leukemia, for example, acute myelomonocytic leukemia, as well as rhabdomyosarcoma, and pheochromocytoma. Forty six percent of patients develop Lisch nodules.

Non-tumor manifestations of the neurofibromatosis include skin pigmentation abnormalities, learning disabilities, skeletal and vascular dysplasias. are hyperpigmented, flat and round areas of the skin that arise during infancy and increase throughout adulthood. Approximately 95% of NF1 patients have as adults18. Learning disabilities include difficulties with visuospatial construction, memory, and other cognitive skills. Vascular manifestation of the disease are rare, (approximately 1-3% incidence). Possible manifestations can include occlusions, stenosis, arteriovenous malformations, and fistulae.

Diagnosis

The standards for diagnosis of Neurofibroma have stood and withstood academic rigor. The broad standards for diagnosing Neurofibroma involve Cafe-au-lait spots, axillary freckling, Lisch nodes, distinct bony lesions and optic nerve gliomas. The manifestations of NF-1 are widespread and impact many bodily systems20. The skin spots and freckling do not normally cause implications; however some patients become distressed with these spots being present.

The main diagnostic indicator is the presence of Cutaneous Neurofibromas. These fibromas are found in the majority of NF-1 patients. These fibromas often exhibit a purplish tint at the outset. Furthermore the number of these fibromas vary among individuals and families. To date there have been no diagnostic evidence that indicates cutaneous fibromas undergo a malignant evolution.

One of the more potent and threatening conditions associated with NF-1 has an 8% to 13% probability over the lifespan of any NF-1 patient. Malignant Peripheral Nerve Sheath Tumors (MPNST) are difficult to detect and diagnose, metastasize quickly and offer a poor prognosis. Generally the diagnostic conditions associated with a MPNST include persistent pain in the fibromas that last for longer than thirty days, new or unexplained nerve deficits, hardening of the neurofibromas and an increase in the fibroma size. Individuals that develop these tumors more often than not possesses a high degree of cancer in their pedigree. Furthermore, these individuals may suffer from Optic pathway glioma, whole gene deletion, multiple subcutaneous neurofibromas or neurofibroma neuropathy.

Anesthetic Considerations

Dealing with Neurofibroma during surgery is a delicate balance. Various fibromas may present a variety of challenges for the medical team. Recently, a patient in the Taipei Veterans Hospital underwent a segmental resection of the trachea22. The patient was diagnosed as having Endotracheal Neurofibroma which caused significant airway blockage. Using a combination of mild anesthesia, fiberoptic bronchoscopy, intubation and extensive preoperative evaluations the patient’s trachea was re-sectioned without incident.

The balance between surgery, anesthesia and neurofibromas becomes even more tenuous when considering if the patient is female and pregnant. In 2002, Dr. Amir 23 presented a case where a pregnant woman possesses an Inflammatory Myofibroblastic Tumor (IMT) that was blocking the upper trachea. The surgical path taken was to utilize a mild, local anesthetic so as to protect the unborn child. Once the patient was under anesthesia the IMT was excised without incident.

Another tumor-orientated offspring of Neurofibroma is referred to as Pheochromocytoma. A Phaechromocytoma arises in the neural cells most likely around the basal ganglia, vagus nerve and carotid arteries24. Hypertension is the most common symptom of patients with this type of tumor. Treatment involves tumor extraction. These tumors present a challenge for surgeons and anesthesiologists.

These tumors require preoperative, inter-operative and postoperative monitoring by physicians. The anesthesiologist must take a detailed history of the patient in order to determine the correct surgical path. During the surgery the anesthesiologist can employ several different techniques. General anesthesia can be used in connection with regional anesthesia and a neurolept. However, recently, anesthesiologists have suggest a low to mid thoracic epidural combined with adequate general anesthesia. This anesthetic technique will allow for adequate inter-operative monitoring. After the operation, the anesthesiologist must continue to monitor the patient for either hypertension, hypotension and hypoglycemia. The presence of either of these conditions may alter the course of the medication given to the patient once the patient is removed from the anesthesia.

Respiratory System

Neurofibroma can cause systemic problems within the various components of the Respiratory System. As has already been presented, Neurofibromas can cause partial blockages within upper parts of the trachea. However, Neurofibromas can also pose challenges or the anesthesiologist when dealing with nasal, sinus or maxilofacial cavities with Neurofibromas present within. One example of how devastatingly complex the Neurofibroma can become is seen when a benign neurofibroma can cause a superior vena cava compression. Such was the case of a 21-year-old female patient as reported by Oakley25. The patient was experiencing shortness of breath while at rest. Additionally, the patient had a family history of Neurofibroma in her family. After several chest x-rays a biopsy determined the mass was indeed caused by a neurofibroma. The tumor was excised and post-operative examination revealed the tumor was hyper-cellular suggesting a neurofibroma in growth stage without any malignant indications.

These types of tumors are difficult to treat under any conditions. The anesthetic considerations for these types of tumors are involved and complex. According to Dodge26 some patients may experience difficulty during an awake intubation, as a result these patients may undergo rapid induction and muscle paralysis after preoxygenation. This allows for several minutes of apnea without hypoxia during this time extracorporeal oxygenation could be introduced into the patient.

Another form of tumor present in the respiratory system in relation to NF-1 are Intrapulmonary Neurofibromas- these tumors are rare and carry a good prognosis 27. Recent surveys have indicated that this defect may result in pulmonary hypertension and right Ventricular failure. These conditions render an anesthesiologist’s job increasingly difficult when monitoring a patient’s blood pressure and pre-operative oxygen levels.

Chest Wall Deformities

Chest Wall deformities are often the result of severe aberrations of the spinal column usually as a result of severe scolosis. This condition is common in NF-1 patients and impacts approximately 10% of NF-1 patients. Typically this affliction occurs in young children with corrective surgery being the mode of treatment 28. A significant form of scoliosis- kypho-scoliosis, is uncommon, however it has been found to be associated with tumors and a higher than normal neurological deficit- two hallmarks of Neurofibroma 29. Kypho-scoliosis may lead to rotation and as a result could cause a reduction in lung volume and breathing capacity. This scoliosis may ultimately lead to respiratory failure 30. Neurofibroma may lead to a gradual degradation of the rib cage and produce a condition known as “flial chest”; however research has shown this cause to be more uncommon than not.

Hypertension

Hypertension is normally associated with the Cardiovascular system as it relates to diet and cholesterol levels. However Neurofibroma may impact hypertension. Approximately 6% of patients with Neurofibroma are hypertensive. However, in 30% of patients, the symptom is the result of a secondary condition much like a renovascular disorder. Those younger patients who have been diagnosed with Neurofibroma are most likely suffering from a disease called Renal Artery Stenosis. Surgery from this disease has been shown to offer mixed results; however a form of angioplasty, precutaneuos angioplasty has been found to alleviate hypertension.

A more common disorder associated with Hypertension and Neurofibroma is Phaeochromocytoma. These tumors affect 0.1% to 7.5% of patients with NF-1, however 25% of patients diagnosed with Phaeochromocytoma have NF-1-31. Patients exhibiting these tumors tend to be older-mean age 45 and the tumors tend to be non-malignant. There are several common symptoms. They include sudden and sharp frontal or occipital lobe headaches, weight loss and palpitations- these symptoms occur in approximately 60% of all Neurofibroma patients 32.

The anesthetic considerations for this disorder are numerous and complex. The preoperative considerations include evaluating the patients blood pressure and heart rate change. These two factors could be evidence of myocardial schemia. Also, the anesthesiologist must account for an adrenergic blockade. The most critical anesthetic considerations occur in the operating room. During the procedure the anesthesiologist must evaluate the arterial line, monitor urinary output, intubate deep and monitor any inter-operative hypertension. If such hypertension occurs during surgery it can be treated with phentolamine, nitroprussside or nicardipine. Post-operative considerations involve continued monitoring of hypertension which could indicate additional tumors.

Vasculopathy

Neurofibroma may lead to the formation of aortic and cerebral aneurysms 33. It has been proposed that these structures are the result of Schwan cell proliferation with a secondary fibrosis forming on the vessel wall. Although some studies show congenital heart failure as the leading cause34, a secondary review showed no clear evidentiary support 35. The presence of these aneurysms may represent a vascular manifestation of a Neurofibroma. Related to the advent of aortic aneurysms is the onset of hypertrophic cardiomyopathy in relation to Neurofibroma36.

The appearance of such myopathy in conjunction with Neurofibroma has been questioned. Recent studies have demonstrated that Neurofibroma is possibly a secondary cause of this myopathy in that both Neurofibroma and hypertrophic cardiomyopathy involve an abnormal metabolic rate and both represent defects in the development of neural tissue. Furthermore, Neurofiborma may cause the heart to develop hypertrophy and outflow obstruction.

Vascular inflammation results from deficiencies in Neurofibronin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow — derived cells (BMDCs), and neurofibromin regulates the function of each cell type. analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease37

Central Nervous System

Tumors within the Central Nervous System contribute to the overwhelming percentage of the mortality rates among patients with Neurofibroma. Therefore it is logical to conclude these patients needing cranial or spinal neurosurgery. The anesthetic considerations for this type of surgery are along the lines as normal neural surgery.

Prior to surgery the Anesthesiologist must consider the enhance probability of epilepsy, cognitive impairment and the likelihood of undiagnosed Central Nervous System tumors. Cerebrovascular Disease has been reported and presents the similar pathology as Vascular Neurofibromas. However this manifestation is relatively uncommon.

Neurofibroma also plays a significant role in impacting cognitive functions38. Neurofibroma controls the expression of ERK signaling in GABA release 39. The disruptions caused by the mutations resulting Neurofibroma-1, lead to a disruption in the mechanisms that govern learning. Therefore, Neurofibrin regulates, ERK and Synapsis I which in turn affects GABA release and impacts long-term potentiation.

Neurofibromatosis-1 can be used to ascertain the cause of low-grade gliomas in children. Through using NF-1 mice models, researchers have been able to develop models that allow researchers to locate critical growth pathways, define the contribution of the tumor micro-environment to glioma growth and assisted in developing and understanding of the basis for glioma growth. Furthermore such mice models have been used to develop the therapeutic studies to evaluate the efficacy and safety of pharmacological treatments for juvenile gliomas40. It is important to use small-animal models to determine why certain therapies might fail. In addition to the reasons outlined above, defining tumor escape mechanisms (eg, feedback loops, activation of other signaling pathways) are critical to the design of future anticancer drugs.

Gastrointestinal System

Gastrointestinal tumours in NF1 may present with disordered gut motility, abdominal pain, haematemesis or melaena; although neurofibromas, usually affecting the jejenum or stomach, are the most common lesions, leiomyoma, ganglioneuroma and sarcoma have been described. All may result in intestinal perforation. Gastrointestinal symptoms may be the first manifestation of neurofibromatosis.

Gastrointestinal abnormalities in patients with NF-1 are reported to occur in up to 10~25% of patients and consist of four groups of lesions: mesenchymal neoplasms; hyperplasias of intestinal neural tissue; neuroendocrine tumors of the duodenum; and rarely, other gastrointestinal neoplasms such as adenocarcinomas41. Although neurofibromas are the most commonly encountered mesenchymal neoplasm of the gastrointestinal tract in patients with NF-1, Gastrointestinal stromal tumors (GISTs), leiomyomas, and leiomyosarcomas also occur

Clinical symptoms are related to the size and location of the GISTs. Most pathologists use a combination of tumor size and mitotic rate to assess the malignant potential of these tumors. In general, malignant GISTs are larger, more cellular, and more mitotically active. GISTs that are smaller than 5 cm with five mitoses per 50 consecutive high-power fields or less are considered to be benign with a low risk for metastasis. Tumors larger than 10 cm with more than five mitoses per 50 high-power fields are considered to be malignant. All tumors falling between these two extremes are considered to be of uncertain malignant potential with intermediate risk for metastasis. Tumors with more than 50 mitoses per 50 high-power fields are considered to be highly malignant with an aggressive clinical behavior. The liver and the peritoneum are the most common sites of spread in malignant GISTs

An unusual feature of the carcinoid tumor occurring in NF1 is the predilection for the duodenum and especially the ampulla of vater — an uncommon site in the non-NF1 population.42 Patients may present with jaundice or upper gastrointestinal haemorrhage or obstruction; often, by the time a diagnosis is reached, metastases are present in the liver. The subsequent release of vasoactive peptides may result in patients presenting with the carcinoid syndrome of flushing, diarrhea, bronchoconstriction and right heart lesions. Anaesthesia and surgery may be hazardous in this situation. Perioperative management of patients with carcinoid syndrome has been comprehensively reported by Veall.43 it is important to note that carcinoid tumours and phaeochromocytoma may co-exist and, therefore, patients with phaeochromocytoma require imaging of the duodenum to exclude pathology in this region

Pregnancy

Pregnant women with neuropathy may experience numbness or tingling in their hands and feet, muscle weakness, spasms or cramping, lessening or absence of the sense of touch, loss of balance, abnormal blood pressure, constipation, bladder dysfunction or diarrhea. Postpartum neurological complications occur in up to 1% of deliveries. Often prior anesthetic procedures are blamed, with medicolegal implications. A young woman who presented with postpartum foot drop diagnosed as an iatrogenic L5 root lesion after uncomplicated epidural anesthesia. After neurological assessment some 5 mo later she tested positive for the common hereditary neuropathy with liability to pressure palsies mutation that was a likely contributing factor in the development of her postpartum neuropathy. Anesthesiologists should consider hereditary neuropathies in the differential diagnosis of postpartum or postsurgical neurological deficits if there is a suggestive clinical history 42.

Anesthesiologists are often blamed for neurological complications after anesthetic procedures during childbirth, with medicolegal implications. A genetically determined predisposition to compression-induced neuropathies is not rare and is probably under-diagnosed, but a clinical history can provide clues. The incidence of neurological complications arising in the peripartum period may be as frequent as 0.92% 43. Epidural or spinal analgesia/anesthesia is commonly performed during delivery and can cause inadvertent spinal cord or nerve root injury as a result of direct trauma, hematoma, or infection 44. Early 45 and more recent reports have concluded that postpartum foot drop can also be a result of compression of the lumbosacral trunk by the fetal head at the pelvic brim in short women or result from proximal sciatic or peroneal nerve injuries. Postpartum neurological injuries often resolve spontaneously, and neurological assessment may not be necessary. The available literature seems to have overlooked an obvious contributory factor present in a recent case seen at our unit, and it seems likely that anesthetic procedures may be unnecessarily blamed for a proportion of neurological deficits with potential medicolegal implications.

Pharmacology

Spinal cord stimulation (SCS) has proven to be an effective treatment of nerve injury-induced pain, and up to 60% — 70% of well selected patients experience satisfactory pain relief 46. Although the mechanism of action of SCS is only partially understood, experimental data have suggested that a combination of SCS and drugs may be useful to improve pain relief. Previous studies in our laboratory have demonstrated that the effect of SCS on neuropathy-related behavior in nerve-lesioned rats can be enhanced by simultaneous spinal administration of small doses of the gamma-aminobutyric acid (GABA)B receptor antagonist baclofen 47, the adenosine A1 receptor antagonist R-PIA and the two anticonvulsants gabapentin and pregabalin. Furthermore, subsequent clinical trials have indicated that both intrathecal (it) baclofen and adenosine may be effective adjuvants to SCS in patients experiencing pain from nerve injury and in whom stimulation treatment alone is insufficient 48.

Clonidine, an ?2-adrenoceptor antagonist, was originally introduced as an antihypertensive drug. Within pain therapy, it has been used to control nociceptive pain (e.g., postoperative pain) and as an adjunct to both systemic and spinal opioids 49. Moreover, clonidine has been demonstrated to produce analgesia in both human neuropathic pain and in various animal models of neuropathy 50. Some observers even assert that clonidine is more effective in reducing neuropathic than acute pain. Clonidine is one of the most common drugs administered epidurally or it in chronic-pain patients, but its use is limited by cardiovascular and sedative side effects (although less so with the it route of administration).

Pregabalin is a new synthetic molecule and a structural derivative of the inhibitory neurotransmitter ?-aminobutyric acid. It is an ?2-? (?2-?) ligand that has analgesic, anticonvulsant, anxiolytic, and sleep-modulating activities. Pregabalin binds potently to the ?2-? subunit of calcium channels, resulting in a reduction in the release of several neurotransmitters, including glutamate, noradrenaline, serotonin, dopamine, and substance P. The precise mode of action of pregabalin has not been fully elucidated, but it does interact with the same binding site, and has a similar pharmacological profile, as gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the ?2-? subunit of presynaptic, that are widely distributed throughout the peripheral and central nervous system 51. Binding affinity for the ?2-? subunit, and potency, is six times more than that of gabapentin. Up-regulation of the ?2-? subunit may play an important role in hypersensitization processes. Pregabalin appears to produce an inhibitory modulation of neuronal excitability 52, particularly in areas of the central nervous system dense in synaptic connections such as the neocortex, amygdala, and hippocampus. Ectopic activity is reduced while normal nerve function is unchanged 53. As with gabapentin, pregabalin is inactive at GABAA and GABAB receptors, is not converted metabolically into GABA or a GABA antagonist, and it does not alter GABA uptake or degradation.

Absorption of gabapentin is limited by saturable, active, dose-dependent transport in the gastrointestinal tract.54 Therefore, smaller doses, given more frequently, may be required to optimize absorption. Absorption of pregabalin is not saturable, resulting in a linear pharmacokinetic profile. In healthy volunteers, pregabalin is rapidly absorbed with peak blood concentrations within 1 h 55. Average bioavailability exceeds 90% and is independent of dose, which may produce a more predictable patient response. The elimination half-life of pregabalin ranges from 5.5 to 6.7 h, and is independent of dose and repeated dose administration. In contrast to pregabalin, the rate of gabapentin absorption is relatively slow, with peak plasma concentrations occurring around 3 h postdose.

Pregabalin does not undergo hepatic metabolism and is not bound to plasma proteins. It is renally excreted, and 98% of the absorbed dose is excreted unchanged in the urine. Pregabalin elimination is nearly proportional to creatinine clearance. Pregabalin clearance is reduced in subjects with impaired renal function. A 50% reduction in pregabalin daily dose is recommended for patients with creatinine clearance (CLcr) between 30 and 60 mL/min compared with those with CLcr >60 mL/min. After a 4-h hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%.

Pregabalin is well tolerated 56 and associated with dose-dependent adverse effects that are mild-to-moderate and are usually transient. In clinical trials, dizziness and somnolence are the most frequently reported adverse events, with dizziness experienced by 29% of pregabalin-treated patients compared with 9% with placebo and somnolence, experienced by 22% of pregabalin-treated patients compared with 8% with placebo 57. has been reported (58). There have been case reports of myoclonus, aterixis, gynecomastia and a single case report has described encephalopathy and edema of the corpus callosum after abrupt discontinuation of pregabalin.

As with all antiepileptic drugs, pregabalin should be withdrawn gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If pregabalin is discontinued, the dose should be gradually tapered over a minimum of 1 wk. There are no the side effects of pregabalin vs. gabapentin. The trials involving gabapentin have usually used variable doses, whereas the trials with pregabalin used fixed dosing without titration. Differences in study design may influence the reported incidence of side effects. Nonetheless, comparing available studies, side effect profiles appear similar, with the exception perhaps of a more frequent incidence of nausea and diarrhea with gabapentin. Pregabalin is contraindicated in patients with a known hypersensitivity to pregabalin or any of its components.

Conclusion

Neurofibroma has been demonstrated to have multifaceted implications throughout various body systems. Each functional system presents various implications and obstacles for the surgeons and anesthesiologists. Neurofibroma can manifest themselves within a variety of contexts. As explained within this discussion, the most common form of manifestation of Neurofibroma concearns the expression of tumors within the neural system, specifically in the cranial and spinal neural tissues. These tumors are responsible for the overwhelming majority of neural surgeries associated with Neurofibroma.

Anesthesiologists are charged with the responsibility of maintaining patient well being before, during and after the procedures. There are numerous considerations that must be integrated into the decision making process. The anesthesiologist must take into consideration various factors that must be addressed prior to any surgery. For example, the literature made a point to clarify that factors such as blood pressure must be reviewed prior to the procedure in order to ensure that the correct level of anesthetic is employed so the surgical team can effectively remove the neurofibroma.

Numerous diagnostic factors play into determining if an individual has Neurofibroma type 1. This diagnostic step is critical in determining the correct surgical process and therefore will determine the appropriate anesthetic process. There are instances where general anesthesia combined with regional anesthesia is employed. Furthermore, each functional body system presents its own implications for dealing with Neurofibroma. Respiratory, Cardiovascular, Gastrointestinal all present various degrees of considerations for the anesthesiologist. Neurofibroma also has dramatic implications for pregnant women. The degree of pregnancy can determine the course of surgery and the level of anesthesia applied in certain cases. However, with the appropriate pre-operative evaluation and the correct history, the proper level of anesthesia and the appropriate considerations will be evaluated and ultimately the correct actions will be taken.

1 Ferner RE. Neurofibromatosis 1 and Nuerofibromatosis 2: A Twenty First Century Perspective. Lancet Neurol 2007;6:340-351

2 Id.

3 Haslam RE. Neurocutaneious Syndromes. Nelson Textbook of Pediatrics. 18th Ed. Philadelphia, PA: Saunders Elsiver, 2007: Chapter 596

4 Id.

5 Feldkamp, MM. Neurofibromatosis Type 1: Peripheral Nerve Tumors. Surgical Neurol. 1999;51:211-218

6 Id.

7 Kruyer, H. Recrurrent Mutations in the NF1 Gene are common among Neurofibromatosis Type 1 patients. J. Med. Gen. 2003;40:82-86

8 Mulvihill, J. Neurofibromatosis Type 1 and Neurofibromatosis Type 2. Ann. Intern. Med. 1990;133:39-52

10 Hirsch, J. Neurofibromatosis: Clinical Presentations and Anesthetic Implications. Br. J. Anaesth. 2001;86:555-564

11 Kruyer, H. Recrurrent Mutations in the NF1 Gene are common among Neurofibromatosis Type 1 patients. J. Med. Gen. 2003;40:82-86

11 Id.

12 Id.

13 Id.

14 Mulvihill, J. Neurofibromatosis Type 1 and Neurofibromatosis Type 2. Ann. Intern. Med. 1990;133:39-52

15 Ling, B. Role of the Epidermal Growth Factor Receptor in Neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell. 2005; 7(1):65-75

16 Carroll, S. How Does the Schwann Cell Lineage form Tumors in NF-1. Glia. 2008; 56(14):1590-1605

17 Le, L Cell of Origin and Macroenvironment Contribution for NF-1 associated dermal Neurofibromas. Cell Stem Cell. 2009; 4(5):453-463

18 Riddle, N. CD44 and P53 Immunoexpression patterns in NF-1 Neoplasms-Indicators of Malignancy and Infiltration. Int. J. Clin. Exp. Pathol. 2010; 3(5):515-521

20 Ferner RE. Neurofibromatosis 1 and Nuerofibromatosis 2: A Twenty First Century Perspective. Lancet Neurol 2007;6:340-351

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