A  leucotome  or  McKenzie leucotome  is a  surgical instrument  used for performing  leucotomies  (also known as  lobotomy ) and other forms of  psychosurgery .


Invented by  Canadian  neurosurgeon Dr. Kenneth G. McKenzie in the 1940s, the leucotome has a narrow shaft which is inserted into the brain through a hole in the skull, and then a plunger on the back of the leucotome is depressed to extend a wire loop or metal strip into the brain. The leucotome is then rotated, cutting a core of brain tissue. [ 1 ]  This type was used by the  Nobel Prize -winning Portuguese neurologist  Egas Moniz . [ 2 ]


Another, different, surgical instrument also called a leucotome was introduced by  Walter Freeman  for use in the transorbital lobotomy. Modeled after an  ice-pick , it consisted simply of a pointed shaft. It was passed through the tear duct under the eyelid and against the top of the eyesocket. A mallet was used to drive the instrument through the thin layer of bone and into the brain along the plane of the bridge of the nose, to a depth of 5 cm. Due to incidents of breakage, a stronger but essentially identical instrument called an  orbitoclast  was later used. [ 4 ]


Lobotomies were commonly performed from the 1930s to the 1960s, with a few as late as the 1980s in France. [ 5 ]


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Microvascular decompression  ( MVD ), also known as the  Jannetta procedure , [ 1 ]  is a  neurosurgical  procedure used to treat  trigeminal neuralgia  (along with other cranial nerve neuralgias), a pain syndrome characterized by severe episodes of intense facial pain, and  hemifacial spasm . The procedure is also used experimentally to treat  tinnitus  and  vertigo  caused by vascular compression on the  vestibulocochlear nerve . [ 2 ]  As the goal of the Jannetta procedure is to relieve (vascular) pressure on the trigeminal nerve, it is a specific type of a  nerve decompression  surgery. [ 3 ]


Nicholas Andre  first described  trigeminal neuralgia  in 1756.  In 1891 Sir  Victor Horsley  proposed the first open surgical procedure for the disorder involving the sectioning of preganglionic rootlets of the  trigeminal nerve .   Walter Dandy  in 1925 was an advocate of partial sectioning of the nerve in the  posterior cranial fossa .  During this procedure he noted  compression of the nerve  by vascular loops, and in 1932 proposed the theory that trigeminal neuralgia was caused by compression of the nerve by blood vessels, typically the  superior cerebellar artery . [ 4 ]   With the advent of the  operative microscope ,  Peter J. Jannetta  was able to further confirm this theory in 1967 and advocated moving the offending vessel and placing a sponge to prevent the vessel from returning to its native position as a treatment for trigeminal neuralgia. [ 5 ]


Patients most likely to benefit from a microvascular decompression have a classic form of trigeminal neuralgia. [ 6 ]  The diagnosis of this disorder is on the basis of the patients' symptoms and from a neurological examination.  No blood test or genetic marker exists to diagnose the disease. An  MRI scan  can help eliminate other diagnoses. Newer MRI techniques may allow for the visualization of vascular compression of the nerve. Patients who improve with an MVD are likely to have pain which is episodic rather than constant. The pain typically has an electrical quality to it and is intense. The pain can usually be triggered.  Common triggers include light touch, eating, talking or putting on make-up. Most patients whose face pain improved with an MVD also improved at least temporarily with medication.


In addition to having the proper type of pain, candidates for an MVD must also be healthy enough to undergo surgery.  The risk of surgery may increase with increasing patient age.


Patients are put to sleep using  general anaesthesia  and are positioned on their back with their head turned or on their side with the symptomatic side facing up. Electrical monitoring of facial function and hearing is used.  A straight incision is made two finger-breadths behind the ear about the length of the ear.  A portion of the skull around 30 mm (1.2 inches) in diameter is removed exposing the underlying brain covering known as the  dura .  The dura is opened to expose the  cerebellum .  The cerebellum is allowed to fall out of the way exposing the side of the  brainstem .  Using a microscope or endoscope and micro-instruments, the  arachnoid membrane  is dissected allowing visualization of the 8th, 7th and finally the trigeminal nerve.  The offending loop of blood vessel is then mobilized.  Frequently a groove or indentation is seen in the nerve where the offending vessel was in contact with the nerve. Less often the nerve is thin and pale.  Once the vessel is mobilized a sponge like material is placed between the nerve and the offending blood vessel to prevent the vessel from returning to its native position.


After the decompression is complete, the wound is flushed clean with saline solution. The dura is closed in a watertight fashion.  The skull is reconstructed and the overlying tissues are closed in multiple layers.  The patient is allowed to wake up and is taken to an intensive care unit or other close observation unit. [ 7 ]


The largest reported series of MVDs was reported by Jannetta and published in  The New England Journal of Medicine  in 1996.  The initial success rate was 82% for complete relief with an additional 16% having partial relief for a combined initial success rate of 98%.  At 10 year follow-up, 68% had excellent or good relief. 32% had recurrent symptoms. [ 8 ]  Other series report similar or better results. [ 9 ]


Serious complications from an MVD include death (0.1%), stroke (1%), hearing loss (3%) and facial weakness (0.5%). Dr. Jannetta has called facial paralysis (as opposed to weakness) a "major and common complication of the MVD." (2 separate depositions under oath: Levy v Jannetta, CCP Allegheny County, GD 81–7689.


Other complications include leakage of spinal fluid and wound infection (1%).  Most patients will have transient neck pain and stiffness from the surgical incision and from seeding of the spinal fluid with small amounts of blood. [ 10 ]


Several other surgical procedures exist for the treatment of trigeminal neuralgia, including percutaneous  rhizotomy , percutaneous  glycerol  injection, percutaneous balloon compression, rhyzotomy and stereotactic  radiosurgery  (SRS).  When compared to the other procedures, MVD carries the highest long-term success rate, but it also carries the highest risk. [ citation needed ] [ 11 ]


Migraine surgery  is a  surgical operation  undertaken with the goal of reducing or preventing  migraines .  Migraine surgery most often refers to surgical  nerve decompression  of one or several nerves in the head and neck which have been shown to trigger migraine symptoms in many migraine sufferers. [ 1 ] [ 2 ] [ 3 ] [ 4 ]   Following the development of nerve decompression techniques for the relief of migraine pain in the year 2000, these procedures have been extensively studied and shown to be effective in appropriate candidates. [ 5 ] [ 6 ] [ 7 ]   The nerves that are most often addressed in migraine surgery are found outside of the skull, in the face and neck, and include the  supra-orbital  and  supra-trochlear nerves  in the forehead, the  zygomaticotemporal nerve  and  auriculotemporal nerves  in the temple region, and the  greater occipital ,  lesser occipital , and  third occipital nerves  in the back of the neck. [ 8 ] [ 1 ] [ 9 ] [ 3 ] [ 2 ] [ 4 ] [ 10 ] [ 11 ] [ 12 ]   Nerve impingement  in the nasal cavity has additionally been shown to be a trigger of migraine symptoms.


Migraine surgery is usually reserved for migraine patients who fail more conservative therapy or who cannot tolerate the side effects of drugs used to treat their migraines.  Appropriate patients are screened using injections of  local anesthesia  to provide a temporary  nerve block . In some cases,  Botox  may be used to provide temporary decompression of the nerve. [ 13 ]   Patients who respond to nerve blocks often see an immediate though temporary reduction in their pain by "shutting off" the nerve that is triggering the migraine, while pain relief following Botox injections is provided by relaxation of nearby muscle tissue that may be compressing the nerve.  Patients who respond well to these screening procedures are felt to be excellent candidates for migraine surgery. [ 14 ] [ 6 ] [ 15 ] [ 16 ]


Migraine surgery is an outpatient procedure which addresses  peripheral nerves  through limited incisions.  Depending on the symptoms of the patient and the screening results following nerve blocks or Botox, different areas of the head and neck may be addressed to treat the nerves found to be the migraine trigger in a given patient.  Migraine surgery is always individualized to each patient's symptoms and anatomy.


Nerves found in the forehead ( supra-orbital  and  supra-trochlear nerves ) are either addressed using  endoscopic surgery  or by using an incision in the crease of the upper eyelid. [ 17 ] [ 18 ]   Structures that are found pressing on the nerves here are released and may include  bone  at the upper orbit,  fascia ,  blood vessels , or muscle tissue.  The  supra-orbital  and  supra-trochlear nerves  travel through the  corrugator supercilii muscle  which enables frowning of the  brow .  These nerves are released from these muscles so they may lie free of pressure from these muscle structures.  Small blood vessels  which travel with these nerves may be divided to prevent pressure as well.  In the  bony notch  where these nerves exit the eye socket, small pieces of bone or connective tissue may be removed so undue pressure is not placed on the nerves in this region. [ 19 ] [ 20 ] [ 21 ]


The  zygomaticotemporal nerve  and  auriculotemporal nerves  are found in areas between the top of the ear and the lateral portion of the eye, in different areas of the temple.  These nerves can also be addressed by endoscopic techniques, or well hidden small incisions.   Blood vessels  next to or crossing these nerves are often found to be the source of compression, and these blood vessels may be divided to prevent irritation of these nerves.  Associated  temporal muscle  release in the region of these nerves may also be indicated. [ 22 ]   Because these nerves are very small and provide feeling to small regions of the scalp, they are often cut or avulsed, allowing the ends to retract into muscle tissue to prevent  neuroma  formation. [ 23 ]


Chronic irritation of the  occipital nerves  is called  occipital neuralgia  and is frequently the cause of migraine symptoms.  The  greater occipital  and  third occipital nerves  are addressed through an incision at the base of the scalp in the upper neck by either a vertical or transverse incision.  Incisions are usually placed within the hairline.  The  greater occipital nerve  travels through several muscle layers (including the  trapezius muscle  and  splenius capitis muscle ) where it is often compressed, and therefore surgery for this nerve involves releasing it from tight muscle and fascia in the upper neck.  Blood vessels found crossing the nerve such as the  occipital artery  may be divided in order to avoid chronic pressure and irritation of the  greater occipital nerve . [ 2 ] [ 24 ]   The  third occipital nerve  is a small nerve that travels near the greater occipital nerve and may treated similarly in order to alleviate chronic irritation. [ 11 ]


The  lesser occipital nerve  is a small nerve that has additionally been found to be associated with migraine pain.  This nerve is found near the  sternocleidomastoid muscle  and may be decompressed or divided here through a small incision.  As this small nerve provides feeling for a small region of the scalp, the minimal numbness resulting from the division of this nerve often goes un-noticed. [ 8 ] [ 11 ] Neurostimulation surgery, in which electrical stimulators are implemented over the occipital and/or superorbital nerves, has also been used to treat migraines, although there is scarce evidence for the effectiveness of this procedure.


The nerves of the nasal lining may be impinged by structures in the nose such as the  nasal septum  and  turbinates .   Nasal surgery  to decompress these regions may include  septoplasty ,  turbinectomy , or other  rhinoplasty  procedures. [ 25 ]


Though initially thought to be experimental surgery, the benefits of migraine surgery have now been well documented.  Followup data has shown that 88% of migraine surgery patients experienced a positive response to the procedure after 5 years.  29% of patients have been shown to achieve complete elimination of their migraine disease, while an additional 59% of patients reported a significant decrease in their pain and symptoms 5 years following their migraine surgery.  12% of patients undergoing migraine surgery reported no change in their symptoms after 5 years. [ 5 ] [ 6 ] [ 7 ] [ 26 ]


Migraine surgery has additionally been studied in a  socioeconomic  context and has been shown to reduce both direct and indirect costs associated with migraine disease. Such costs after migraine surgery have been shown to be reduced by a median of $3,949 per patient per year. [ 27 ]


Chronic daily headache is a major worldwide health problem that affects 3–5% of the population and results in substantial disability. Advances in the medical management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments. However, a significant proportion of these patients are intractable to drug treatment. [ 28 ]  The successful use of surgical procedures for the treatment of migraine is becoming more frequently reported in the medical literature, particularly for those patients who do not respond to medication. There is resistance in some quarters the concept of surgery for migraine, on the grounds that it is unnecessarily invasive. On the contrary, others argue that to undergo a relatively minor and minimally invasive once-off surgical procedure is not as invasive as having to permanently take chronic medication, which in many people has unpleasant or intolerable side effects, or is ineffective. The answer to this conundrum lies however in informed consent - the patient must be advised of all the possibilities, and of all the pros and cons of each option, so that an informed choice can be made. In some instances, patients opt for the drug route, and only take the surgical option when the medication has not had the desired effect. For others, the thought of being on chronic medication is anathema.


In many migraine sufferers, the pain originates in painfully dilated extracranial terminal branches of the external carotid artery. [ 29 ]  That vasodilatation is an important factor in migraine is further confirmed by the fact that the most widely used migraine rescue medications, the ergots, the triptans, and the promising newer drugs, the  gepants , possess one significant common denominator: they all potently constrict abnormally dilated extracranial arteries while simultaneously reducing or eliminating migraine pain. Furthermore, to date all migraine-provoking agents have had vasodilating properties. [ 30 ]


In patients where the pain has been positively diagnosed to originate from the scalp arteries (the terminal branches of the external carotid artery), the preventive treatment of choice is surgical cauterization of the responsible arteries – known as the Shevel Procedure. [ 31 ]


In order to pinpoint the position of the relevant arteries, a three-dimensional CT scan is done, which allows accurate visualization of the course of each artery. This is necessary, as the course of the arteries varies from person to person, and even from side to side in the same individual. During surgery, the position of the artery is further verified by means of a Doppler Flowmeter, with which one can hear the blood flowing through the vessel. Use of the three-dimensional CT scan and the Doppler Flowmeter allows the surgeon to make use of the smallest possible incision, so the procedure is minimally invasive. The most common vessels involved in the pain of migraine are the terminal branches of the  external carotid artery , and in particular, the  superficial temporal artery  and its frontal branch, and the  occipital artery , but the maxillary, posterior auricular, supra-orbital, and supra-trochlear branches may also be involved. These vessels are subcutaneous (just under the skin) and the small incisions required to access them and the minimally invasive nature of the procedure means that the surgery can be done in a day facility. As these vessels have no connection with the arterial supply to the brain, the Shevel Procedure is exceedingly safe with no unpleasant side effects. The cosmetic effect is excellent as most of the incisions are within the hairline. [ 31 ]


Arterial surgery is only indicated once there is positive confirmation that the arteries are indeed the source of pain. Some migraine sufferers have a visibly distended artery on the temple during an attack, which confirms that the arteries are involved. The distention usually subsides as the pain is controlled by vasoconstrictor drugs ( ergots  or  triptans ). [ 32 ]  In some, this artery is always visible, but it is only when it becomes distended during an attack that it becomes important for diagnosis. Patients who take triptans or ergots for relief of migraine pain are also prime candidates for arterial surgery. The reason for this is that the action of these drugs is to constrict the painfully dilated branches of the external carotid artery - the same arteries that are targeted by the surgery. The purpose of the surgery is to provide a permanent 'triptan or ergot effect'. Most of these arteries are in the scalp and are readily accessible to minimally invasive surgery. This treatment modality is of particular value in: 1) patients who have not responded to preventive drug therapy, 2) patients who are unable to use drug therapy because they experience unacceptable side effects, 3) patients who have to make too frequent use of abortive drugs such as the triptans or ergots, and 4) patients who would prefer not to be on permanent medication. Included in this category are those with Chronic Daily Headache (headache on more than 15 days per month) and patients with what is known as "refractory headache" - headache that has not benefited from any other form of treatment. Elliot Shevel, a South African surgeon, showed that patients with chronic migraine experienced a significant reduction in pain levels and significant improvement in their quality of life following the surgery. [ 31 ]


Trigger site release was first described by a plastic surgeon, Dr Bahaman Guyuron. [ 33 ]  The theory is that  trigger sites  (TSs) exist where  sensory nerves  are being compressed by a surrounding  muscle . The nerve becomes inflamed, and a cascade of events is initiated, triggering migraine headaches. Thus far, three muscle trigger areas where the nerve passes through a muscle have been identified as surgical candidates – where the a)  greater occipital nerve  pierces through the  semispinalis capitis muscle , b) the  zygomaticotemporal nerve  passes through the  temporalis muscle , and c) the  supraorbital / supratrochlear  nerves pass through the  glabellar  muscle group (the  corrugator supercilii ,  depressor supercilii , and  procerus muscles ). [ 34 ] [ 35 ] [ 36 ]  Several large series of studies have been conducted to evaluate the efficacy of surgical obliteration of trigger points. Almost all demonstrated more than 90% response in a carefully selected group of patients who have a positive response to  Botox  therapy, with at least 50% improvement to complete resolution of migraine pain.


Patients have to be screened preoperatively with a full  neurological examination , and subsequent  Botox  injection. [ 37 ]  A positive response to Botox has been an accurate predictor of a successful outcome. Single or multiple TSs may be treated. Migraine headaches can start in one area depending on their corresponding trigger site and spread to the rest of the head. It is important to identify the initial trigger sites rather than address all the areas of pain, after the inflammation involves the entire  trigeminal tree .
 Forehead  migraine headaches : In the  glabellar  area the  supra-orbital  and  supra-trochlear  nerves are  skeletonized  by  resecting  the  corrugator  and  depressor supercilii muscle  using an  endoscopic  approach similar that of used for cosmetic  forehead lift .
 Temporal  migraine headaches : The temporal area, where the  zygomaticotemporal  branch of trigeminal nerve passes through the  temporalis  muscle, is addressed using a similar endoscopic approach but involves removing a segment of the nerve rather than transecting the muscle. This results in a slight sensory defect over temporal skin area, but cross- innervation  from other sensory nerves helps to limit the damage.
 Occipital  migraine headaches : The  posterior neck  area where the  greater occipital nerve  passes through the  semispinalis capitis muscle  is addressed with an  open surgical approach  with resection of a small segment of the semispinalis muscle and shielding the nerves with a  subcutaneous adipose  flap. [ 35 ]


A further  trigger point , not involving muscles, has been identified in the  nose  of patients who have significant  nasal septum  deviation with enlargement of the  turbinates . [ 35 ]  The nasal trigger points where enlarged turbinates are in contact with the nasal septum are addressed with a septoplasty and a turbinectomy.


There is evidence that a link exists between migraine with aura and the presence of a patent foramen ovale (PFO), a hole between the upper chambers (the atria) of the heart. [ 38 ]  It is estimated that 20-25% of the general population in the United States has a PFO. [ 39 ] [ 40 ]  Medical research studies have shown that migraineurs are twice as likely as the general population to have a PFO, [ 38 ] [ 39 ]  that over 50% of sufferers of migraine with aura have a PFO, [ 38 ]  that patients with a PFO are 5.1 times more likely to suffer from migraines and 3.2 times more likely to have migraines with aura than the general population, [ 38 ]  and that patients with migraine with aura are much more likely to have a large opening than the general PFO population. [ 38 ] [ 40 ] [ 41 ]  There is however some controversy, as some have shown a link, [ 42 ]  while others have failed to demonstrate a link. [ 43 ]


A catheter is advanced up to the hole in the heart after it is inserted in a vein in the leg. Through the catheter, a device is then placed which blocks the hole between the left and right atria of the heart. There are a number of different devices being used or tested, the Coherex FlatStent PFO Closure System, [ 44 ]  the CardioSEAL, [ 45 ]  and the AMPLATZER PFO Occluder device. [ 46 ]


Migraine frequency and severity has been shown to be reduced if the hole (PFO) is patched surgically. [ 47 ]  It has been suggested that there is an advantage to non-pharmacological migraine relief - "in contrast to drugs, PFO closure appears highly effective against migraines and usually has no side effects". [ 48 ]  Because PFO closure continues to prove successful, new devices are being produced to make the surgery easier to perform and less invasive. Some studies, however, have emphasized caution in relating PFO closure surgeries to migraines, stating that the favorable studies have been poorly designed retrospective studies and that insufficient evidence exists to justify the dangerous procedure. [ 49 ] [ 50 ]  There have however been reports of short-term increases in migraine frequency and intensity following the surgery. [ 46 ] [ 51 ] [ 52 ]


Published reports from open-label studies have demonstrated possible efficacy of ONS in a variety of primary headache disorders, including chronic migraine. [ 28 ] [ 53 ]  ONS for the treatment of medically intractable headaches was introduced by Weiner and Reed  [ 54 ]  ONS is typically performed with the equipment normally used for spinal cord stimulation (SCS), which includes electrodes and their leads, anchors to fasten the leads to connective tissue, and the implantable pulse generator (IPG).


Electrodes are placed subcutaneously (under the skin) superficial to the cervical muscle fascia, transverse to the affected occipital nerve trunk at the level of C1, usually using fluoroscopic guidance. The standard procedure is typically performed in two stages. The first stage, carried out under local anesthesia with sedation, is used to test the stimulation and determine optimal placement of electrodes. The second part, which involves insertion of the rest of the ONS system, is carried out under general anesthesia. However, a recent report of a small case series described successful placement of ONS systems entirely under general anesthesia while still achieving the desired occipital region stimulation. [ 55 ]


A stimulation trial can be performed before the permanent implantation, with the view to improving selection of the candidates for a permanent stimulation. The procedure involves inserting percutaneous (through the skin) leads into the epidural space and externally powering them for 5–7 days. If the trial is successful in terms of significant pain improvement, the patient is offered a permanent implantation. However, in primary headache syndromes, unlike in neuropathic pain, there can be a considerable delay of several weeks to months before the response emerges and therefore the utility of a stimulation trial in selecting patients for permanent implantation remains questionable for now. [ 53 ]


The involvement of the pericranial muscles in migraine has been well documented, [ 56 ] [ 57 ] [ 58 ] [ 59 ]  and muscle relaxation techniques have been used successfully to prevent migraine.


Intra-oral appliance are designed to relax the pericranial muscles, which have been reported to be tender in 100% of migraine sufferers during an attack. [ 56 ]  There are a number of different designs, which have been reported to be effective in many migraine sufferers. [ 60 ] [ 61 ] [ 62 ] [ 63 ]


Biofeedback is the process of gaining greater awareness of many physiological functions primarily using instruments that provide information on the activity of those same systems, with a goal of being able to manipulate them at will. [ 64 ] [ 65 ]  Some of the processes that can be controlled include brainwaves, muscle tone, skin conductance, heart rate and pain perception. [ 66 ]  Biofeedback to induce muscle relaxation is widely used in migraine prevention. [ 67 ] [ 68 ]


OnabotulinumtoxinA (trade name  Botox ) received FDA approval for treatment of chronic migraines (occurring more than 15 days per month) in 2010. The toxin is injected into the muscles of head and neck. Approval followed evidence presented to the agency from two studies funded by Allergan, Inc. showing an improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment. [ 69 ] [ 70 ]  Since then, several randomized control trials have shown Botulinum Toxin Type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine [ 71 ]


Surgical cauterization of the superficial blood vessels of the scalp (the terminal branches of the external carotid artery) is only carried out if it has been established with certainty that these vessels are indeed the source of pain. It is a safe and relatively atraumatic procedure which can be performed in a day facility. [ 72 ]


Migraine surgery  which involves decompression of certain  nerves  around the head and neck may be an option in certain people who do not improve with medications. [ 73 ]  It is only effective in those who respond well to  Botox  injections in specific areas. [ 74 ] [ 75 ]


There also appears to be a  causal  link between the presence of a  patent foramen ovale  (PFO) and migraine. [ 76 ] [ 77 ]  There is evidence that the correction of the  congenital heart defect , PFO, reduces migraine frequency and severity. [ 78 ]  Recent studies have advised caution, though, in relation to  PFO  closure for migraine, as insufficient evidence exists to justify this dangerous procedure. [ 79 ] [ 80 ]


Multiple subpial transections  is a surgical treatment modality for  epilepsy  used in scenarios wherein epileptogenic  brain  regions (from where  partial seizures  originate) cannot be removed safely. The surgeon makes a series of shallow cuts (transections) into the brain's  cerebral cortex . These cuts are thought to interrupt some fibers that connect neighboring parts of the brain, but they do not appear to cause long-lasting impairment in the critical functions that these areas perform.


Multiple subpial transections can help to reduce or eliminate seizures arising from vital functional areas of the cerebral cortex. This procedure has been successful in an unusual type of epilepsy called  Landau-Kleffner syndrome , [ 1 ]  at least for a limited time.


Bleeding at the site of the transection is possible, but the procedure is generally well tolerated. Major complications appear to be rare. Transections in  language  areas of the brain may mildly impair the language function served by that area.


Epilepsy surgery is reserved for people whose seizures are not well controlled by seizure medicines (this situation is sometimes describes as being  medically refractory ). In the past, epilepsy patients were referred for surgery only after they had taken medicine after medicine without success, often for 10 years or more. However, now the definition of medically refractory has changed and surgery is being performed as early as 1 to 2 years after the diagnosis of epilepsy is first made.


In children, the definition of medically refractory is even more individualized to the specific child's situation. Surgery may be considered for some children after only weeks or months of treatment with seizure medicines.


In general, a person is considered to be a potential candidate for surgery if adequate trials of two first-line seizure medicines (ones that are commonly effective in controlling the type of seizures the person is experiencing) and one two-drug combination all have failed to control the seizures. A trial of a medication is considered adequate when it has been increased gradually to the maximum dosage that does not cause serious side effects and then is given for a long enough period. If the person has frequent seizures, any improvement will be obvious after a short time. However, if the seizures generally occur far apart it may take months to determine whether the time between seizures is increasing.


At some epilepsy centers, patients are offered additional conventional or experimental medications before surgery is considered. However, research suggests that each time a trial of medication fails to control a person's seizures, it becomes less likely that a different medicine or combination will be successful. Since uncontrolled seizures present serious physical risks and social and  psychological  consequences, the trend these days is to proceed with surgery much sooner than in the past if it seems appropriate for that person.


Success rates for epilepsy surgery are constantly improving, and advances in preoperative assessments are largely responsible. Proper patient selection and a thorough presurgical workup are the cornerstones of surgical success.


If a review of the person's experiences with seizure medicines shows that adequate tests of at least a few different medications have not succeeded in controlling the seizures, then the person may be referred to a specialist for a preoperative (or presurgical) assessment.


The preoperative assessment has two general objectives:


The number and type of tests that make up the preoperative assessment will depend on the type of surgery being considered. General objectives of the tests include:


The  N-localizer [ 3 ]  is a device that enables guidance of  stereotactic surgery  or  radiosurgery  using tomographic images that are obtained via  computed tomography  (CT), [ 4 ]   magnetic resonance imaging  (MRI), [ 5 ]  or  positron emission tomography  (PET). [ 6 ]  The N-localizer comprises a diagonal rod that spans two vertical rods to form an N-shape (Figure 1) and permits calculation of the point where a tomographic image plane intersects the diagonal rod. Attaching three N-localizers to a stereotactic instrument allows calculation of three points where a tomographic image plane intersects three diagonal rods (Figure 2). These points determine the spatial orientation of the tomographic image plane relative to the stereotactic frame. [ 7 ]


The N-localizer is integrated with the Brown-Roberts-Wells (BRW), [ 8 ]  Kelly-Goerss, [ 9 ]  Leksell, [ 10 ]  Cosman-Roberts-Wells (CRW), [ 11 ]  Micromar-ETM03B, FiMe-BlueFrame, Macom, and Adeor-Zeppelin [ 12 ]  stereotactic frames and with the Gamma Knife  radiosurgery  system. [ 13 ]


An alternative to the N-localizer is the  Sturm-Pastyr localizer  that comprises three rods wherein two diagonal rods form a V-shape and a third, vertical rod is positioned midway between the two diagonal rods (Figure 3). [ 14 ]  The Sturm-Pastyr localizer is integrated with the Riechert-Mundinger and Zamorano-Dujovny stereotactic frames. [ 15 ]


Compared to the N-localizer, the Sturm-Pastyr localizer is less accurate and necessitates more elaborate calculations to determine the spatial orientation of the tomographic image plane relative to the stereotactic frame. [ 16 ]  In contrast to the N-localizer that does not require specification of the pixel size in a tomographic image, [ 17 ]  the Sturm-Pastyr localizer requires precise specification of the pixel size. [ 18 ]


Research conducted four decades after the introduction of the N-localizer [ 19 ]  and Sturm-Pastyr localizer [ 20 ]  has revealed computational techniques that improve the accuracy of both localizers.


Nerve allotransplantation  (allo- means "other" in Greek) is the transplantation of a nerve to a receiver from a donor of the same species. For example, nerve tissue is transplanted from one person to another. Allotransplantation is a commonly used type of transplantation of which nerve repair is one specific aspect.


The transplant is called an  allograft , allogeneic transplant, or homograft. [ 1 ]  Currently the only FDA approved nerve allograft is the Avance graft of  AxoGen .


A nerve allograft is used for the reconstruction of peripheral nerve discontinuities in order to support the axonal regeneration across a nerve gap caused by any injury. It is human nerve tissue, processed to remove cellular and noncellular factors such as  cells ,  fat ,  blood , axonal debris and chondroitin sulfate proteoglycans while preserving the three-dimensional scaffold and basal lamina tubular structure of the nerve. This means the nerve allograft only consists of  extracellular matrix  (ECM), which is sterile and decullularized. [ 1 ]


There are three types of nerves;


In a  trauma  or surgical resection, a nerve can be damaged, which is called a nerve defect. This defect needs to be repaired in order to regain full or partial sensory and motor function.
Peripheral nerve injury is a major clinical problem and can result in  neuropathic pain , which is pain arising as a direct consequence of a lesion or disease affecting the  somatosensory system .
Damaged nerve fibers continuously excite electric pulses, inducing pain or abnormal sensation  dysesthesia . It has been shown that in allograft surgeries, post-operative neuropathic pain was present in some patients, but only if they had this condition pre-operatively. [ 2 ]  Patients without neuropathic pain before their surgery did not complain about neuropathic pain afterwards. [ 2 ]  Hence, allograft treatment does not seem to be a risk factor for this specific problem.


Golden standard therapy for transected nerves is an end-to-end repair of the nerve, also known as primary nerve repair. With a certain amount of tension on the nerve due to the injury, the blood flow to the nerve decreases, which can eventually lead to ischemia and nerve damage. The gap between the nerve ends could then, for example, be bridged by a nerve that is harvested from a less critical area from the same patient. The piece of nerve used in this case is called an autograft  autotransplantation . [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]


A commonly used nerve for autotransplantation is the  sural nerve  in the upper leg. Unfortunately, this treatment does have some disadvantages. First, there is a risk of donor site morbidity and functional loss. Secondly, patients have an increased risk of symptomatic neuroma formation. Thirdly,  a longer  anaesthesia  time is needed because of the additional surgical site for the donor nerve. Lastly, higher costs also due to the extra surgical site. Despite these downsides, reducing the function of the affected area is beyond the risks committed with harvest of the donor nerve. [ 4 ] [ 7 ] [ 8 ]
In case of insufficient amount of autologous nerve tissue or the inability to attach both nerve ends securely and tension free, these two options are not possible.


Another option to bridge the gap is nerve allotransplantation. Nerve allografts are prepared from donated human nerve tissue. An allograft contains many of the beneficial characteristics of nerve autograft, such as three-dimensional microstructural scaffolding and protein components inherent to nerve tissue. [ 3 ]  One of the adverse effects of nerve allotransplantation is the immunogenic response. Tissue from another human being is used to restore the defect, which can induce an immunogenic response. An immune response against an allograft or xenograft is called  transplant rejection . To prevent this rejection, new immunosuppressive techniques are performed on the graft, before it is transplanted into the receiver. The donated nerve tissue is disinfected, by selectively removing cellular components and debris to cleave growth inhibitors and then terminally sterilized. [ 3 ]  These procedures make the immunogenic response insignificant.  Processed nerve allografts have now been used successfully to restore nerve continuity for over two decades.


Rhazes , a Persian doctor, was the first who mentioned nerve repair in 900 AD. Nerve regeneration, is described for the first time in 1795 and in 1885 the first nerve allograft transplantation was reported. [ 9 ]  In 1945, after WWII, Sir Sunderland described the anatomy of the peripheral nerves and developed techniques to improve the outcomes of nerve repair.
A successful regeneration for short allografts (<4 cm) was achieved. However, there was a period of failure to accomplish successful recovery for all the allografts longer than 4 cm.  Therefore, 'The Peripheral Nerve Injury committee' did not support nerve allograft until, in the early 1970s the first successful clinical trials on longer grafts were reported by using a new combination of radiation and freeze-drying techniques. [ 4 ]
Nowadays rejection is still an adverse effect of nerve allotransplantation, but modern immunosuppressive regimens are used to prevent this rejection. This is why these days, rejection has become a very rare complication and nerve allograft has become more relevant. [ 4 ]


An  axon  is the part of a  neuron  which conducts electrical impulses. Axons are surrounded by  myelin , which contain  Schwann cells . Schwann cells improve the electrical conduction. The myelin is surrounded by  endoneurium , which is a protective sheath of connective tissue. This is surrounded by  perineurium  and  epineurium , of which the latter is the outmost layer of dense connective tissue. When it comes to nerve repair, it is crucial that those layers make a good connection.


There are several kinds of  organ transplantation  techniques.


The nervus suralis, a nerve from the lower leg, is most often used. Consequently, the patient will miss the specific nerve used as an autograft; therefore a person's own nerves can not be used for an unlimited number of times.


The  surgery  of an allograft nerve can be explained in a few steps. First the surgeon has to prepare the broken nerve to do the standard operation procedures. This means the surgeon has to examine the local tissue and resecting scar tissue if needed. The proximal and distal segments of the injured nerves should be debrided to healthy tissue by visual and tactile signs. After that, the surgeon measures the distance between both nerve ends as well as the diameter of the damaged nerve. The processed nerve allografts come in different sizes, so that a gap can be closed without unwanted tension. When he has chosen the right allograft nerve, the procedure is no different from when an autograft is used. The same applies to the  microsurgery , that a surgeon may use to repair the nerve. This means the sutures which connect the allograft with the damaged nerve are placed in the epineurium. So all other important anatomical structures of the nerve are kept intact. [ 1 ]


There are several factors that help a  surgeon  decide whether he should choose a nerve-autograft or an allograft. The differences between autografts and allografts are discussed above.
The use of nerve autografts has some disadvantages. One is that the surgeon always creates a defect on the 'donorplace', from where the nerve is taken.
Another disadvantage is that when the defect is large, the amount of available autografts may be insufficient.


Nerve allografts bring a possible solution for these problems.
Because allografts are human nerves, processed in such a way that the immune response against the transplant is not provoked, the procedure differs little from the autograft-procedure except for the fact that there is no need to create a 'donorplace' defect. Therefore, allografts can be used more often in the same patient than autografts.


After the nerve is repaired, whether it is by using an autograft or an allograft,  wallerian degeneration  will be seen distal to the coaptation. This means that the part of the nerve that lies distal to the breaking point starts dissolving. The other end of the nerve will then grow back in this direction. The surgeon's  transplant  then only functions as the shell through which this growth can take place.


Studies suggest that nerve allografts work just as good as nerve autografts and are therefore a good alternative to the classic nerve autograft. [ 5 ] [ 8 ]


Currently nerve reconstruction is limited in length. There is a relationship between the length of the nerve gap and the level of recovery following nerve repair. Two large clinical studies have divided three different gap lengths: 5-14mm, 15-29mm and 30-50mm nerve gaps. After adjustment for technical failures. The nerve grafts of 5-14mm had a 100% meaningful level of functional recovery in both studies. For nerve grafts above 15mm is seen in both studies a meaningful recovery around 80%. It seems likely that a shorter nerve gap has a better recovery, but despite that a significant difference was not found. [ 5 ] [ 8 ]


Since some studies on nerve allotransplantation determined the outcomes of sensory, motor and mixed nerves separately, the meaningful recovery for each nerve type has been assessed. Comparison of these outcomes has found no difference in successful recovery. [ 5 ] [ 8 ] [ 10 ]  In other words, the sensation and movement of the affected body parts, in most studies the forearm, equally improved. Successful recovery of all three nerve types was achieved in approximately 80 to 85% of cases. [ 5 ] [ 8 ]  Mixed nerves had a slightly lower recovery rate than sensory and motor nerves, but the success rate was still within the range just mentioned. [ 5 ] [ 8 ]  Concluding, allograft surgery can be appropriately used for the functional repair of nerve injury in sensory, motor and mixed nerves. [ 2 ] [ 5 ] [ 8 ] [ 10 ]


The use of nerve allografts is a relatively new development and therefore autografts are currently still used more frequently.
Efforts are being made to determine which procedure, i.e. autograft or allograft surgery, is preferred for each nerve type, but more research needs to be done. No comparison of these two procedures has been made in one single clinical study, let alone in a  randomized controlled trial . This specific study type is of crucial value for  evidence-based medicine .


A  neurectomy , or  nerve resection  is a neurosurgical procedure in which a  peripheral nerve  is cut or removed to alleviate  neuropathic pain  or permanently disable some function of a nerve. The nerve is not intended to grow back. For  chronic pain  it may be an alternative to a failed  nerve decompression  when the target nerve has no motor function and  numbness  is acceptable. [ 1 ]  Neurectomies have also been used to permanently block  autonomic function  (e.g.  excessive sweating  in hands [ 2 ]  or involuntary muscle movement causing  cramps [ 3 ] ), and special  sensory function  not related to pain (e.g. vestibular nerve dysfunction causing  vertigo [ 4 ] ).


A temporary  nerve block  with an  anesthetic  is usually performed before surgery to confirm the diagnosis of neuropathic pain. [ 1 ]  Risks include numbness,  neuroma , and complications due to lack of innervation.


A presacral neurectomy is typically conducted to decrease severe pain and  menstrual cramps  in the  lower abdomen . Pain in this region is difficult to treat with noninvasive treatments.  Endometriosis  is the most common cause for this severe pain. One solution that doctors often mistakenly recommend as a cure is a  hysterectomy , or removal of the  uterus .  However, this often does not relieve endometriosis pain because the disease is left behind on other organs such as the bladder, bowels, or pelvic side walls, and  it can thrive on its own hormone supply. Another is to perform a presacral neurectomy. This is a procedure that interrupts the nerves going towards and/or around the uterus. [ 5 ]   Pain located on either side of the lower abdomen (but not mid line) should not be treated with a neurectomy. Only individuals with pain that is not relieved by the use of  NSAIDs  should consider this procedure. Techniques have been developed for this procedure to be performed  laparoscopically . [ 5 ]


The incision is typically directly under the  navel . Normally three small holes are made in the lower abdomen to allow for the instruments and other various surgical tools. Nerve tissue that runs to the uterus is interrupted at the sacral promontory; a point at which  spine  and  sacrum  meet. This is the best area to access and obtain a clear view of the nerves in the uterus. Proper precautions must be taken as to avoid unnecessary complications with the major blood vessels surrounding the uterus. Some of the complications post-operation include  urinary retention , as well as  constipation . Neither has been reported to cause lasting effects. [ 5 ]


Recent technological advances have allowed this same procedure to be done robotically, a minimally invasive technique similar to laparoscopy. The outcome of the procedure is identical to an open approach (laparotomy), but the incisions are much smaller allowing for less post-operation pain. Less pain following this surgery allows for a quicker recovery period too; two weeks as opposed to six weeks, on average. [ 6 ]


A vestibular neurectomy is an operation that severs the vestibular nerve, which contributes to balance, while sparing the cochlear nerve, which contributes to hearing. The procedure has the potential to relieve  vertigo , but may preserve the ability to hear. [ 7 ]   It is important to note that this procedure will not reverse the effects of  deafness .  The risks include:  hearing loss ,  tinnitus , dizziness, facial weakness,  spinal fluid  leak, and various infections. [ 8 ]  There are several different surgical approaches that can be used to complete this procedure: the middle cranial fossa, retrolabrynthine, retrosigmoid, and translabrynthine. [ 9 ]  The  middle cranial fossa  approach is one that most often requires neurosurgical expertise. The advantage of this procedure is that the  vestibular nerve  is clearly visible and can be sectioned without harming the  cochlear nerve  fibers. [ 7 ]


The general procedure begins by positioning the patient supine with the head turned to the side with surgical ear upright. An incision is made at the lower portion of the  zygomatic root  to the area of the  temporal  region for roughly seven centimeters. Precautions are taken by clamping flaps of tissue as to not impede further actions.  To expose the IAC (Inner Auditory Canal) properly, portions of bone from the  metal fundus  and also the  tegmen tympani  must be removed. [ 8 ]  The SVN ( superior vestibular nerve ) is then identified and cut at the point furthest from the vestibular crest. Along with the SVN,  Scarpa's ganglion  is also cut and removed. [ 8 ]


In cases of  Ménière's disease , a neurectomy may be needed when no other medical treatment is sufficient for over six months. In bilateral Ménière's disease, the procedure is done on the worse-off ear. Some procedures are done on both ears, but the risk of hearing loss then becomes significantly greater. [ 8 ]


Some ablations that have been previously performed laparoscopically are also now offered via the pulsed  radiofrequency technique . Pulsed radiofrequency ablation relies on delivering an electrical field specifically to neural tissue in order to damage it while minimizing injury to the surrounding area. For example, this technique has been used in patients with chronic shoulder pain as a way to perform a neurectomy of the suprascapular nerve with less risk of damage to nearby muscles within the rotator cuff. [ 10 ]  There is still a lack of evidence directly comparing the efficacy and safety of this technique compared to the traditional laparoscopic method, but there is evidence that it improves range of motion and pain compared to placebo [ 10 ]  or sham surgery. [ 11 ]


Neurectomy can be an alternative to a  nerve decompression  for  nerve entrapment , such as when the nerves have no motor function and numbness along the  dermatome  is acceptable. A neurectomy is not a mutually exclusive option to a decompression as a neurectomy can also be used after a failed decompression. [ 1 ]


There are many nerves in the human body that are purely sensory such as the  cutaneous nerves , which provide innervation to all parts of the skin. The cutaneous nerves are especially susceptible to compression from wearables or injuries due to their superficial location. Some examples of wearable-induced irritation are supraorbital neuralgia from tight goggles, [ 12 ]  superficial radial neuropathy from handcuffs, [ 13 ]  and meralgia paresthetica from tight pants. [ 14 ]  As cutaneous nerves cover all areas of the skin, and any surgery which requires incisions may inadvertently cause injury or scarring, now entrapping a cutaneous nerve. [ 15 ]


A common tradeoff when electing to a neurectomy is that numbness along the nerve distribution is expected. Studies that have measured how bothersome numbness is to patients have found that most patients are not bothered at all by the numbness, and the ones that are find the numbness minimally bothering. [ 16 ] [ 17 ]


Intercostal  neuralgia  is a neuropathic condition that involves the  intercostal nerves . The primary symptom is pain and it may be localized to the distribution of one or more of the intercostal nerves, manifesting as chest and abdominal pain. [ 18 ]  No treatment modality prior to neurectomy (e.g. systemic medications,  cryoablation , therapeutic  nerve blocks , and radioablation) has given effective pain relief and none have been curative. [ 19 ]


The success outcome is typically measured as a 50% or more decrease in  visual analog scale  (VAS) scores, which are numerical pain scores from 0 - 10 or 0-100. Success rates are often reported as 70%. [ 20 ] [ 21 ] [ 22 ]  Studies reporting on intercostal neurectomy often report cure rates (100% reduction in symptoms), even though it is not the primary success outcome. For example, patients may say they are cured or report pain scores of zero. There is a wide span of the reported cure rates, ranging from 22 - 67%. [ 20 ] [ 21 ] [ 23 ]  A double-blind, randomized, controlled surgery trial found a 22% cure rate for the surgery group and a 4% cure rate for the sham surgery group, suggesting that these cure rates cannot be purely attributable to the  natural history of the disease  or a  placebo effect . [ 21 ]


Lateral femoral cutaneous neuralgia, often known as  Meralgia Paresthetica , involves neuropathic pain on the outer thigh. The use of a nerve decompression or neurectomy to treat nerve pain along the  lateral femoral cutaneous nerve  is a firmly established surgical treatment.  [ 24 ] [ 25 ]  However, the more effective treatment between a decompression and neurectomy is still being researched.


Between a nerve decompression and a neurectomy, the neurectomy is associated with a higher success rate which has been validated by two  Cochrane  reviews. The reviews found decompressions beneficial in 88% of cases and neurectomy beneficial in 94% of cases. [ 26 ] [ 27 ]  A German national cohort study found similar results where complete pain relief from decompression was seen in 63% of cases but complete pain relief from neurectomy was seen in 85%. [ 28 ]


Neurectomy is also used in equine medicine, primarily for cases of persistent  lameness  that is non-responsive to other forms of treatment. It is most commonly used for animals with  navicular syndrome  and suspensory ligament desmitis. [ 29 ]


NeuroArm  is an engineering research  surgical robot  specifically designed for  neurosurgery . It is the first  image-guided ,  MR-compatible  surgical robot that has the capability to perform both  microsurgery  and  stereotaxy . [ 1 ]


IMRIS , Inc. acquired NeuroArm assets in 2010, and the company is working to develop a next generation of the technology for worldwide commercialization.  It will be integrated with the VISIUS(TM) Surgical Theatre under the name SYMBIS(TM) Surgical System. [ 2 ]


NeuroArm was designed to be image-guided and can perform procedures inside an  MRI . NeuroArm includes two remote detachable manipulators on a mobile base, a workstation and a system control cabinet. For biopsy- stereotaxy , either the left or right arm is transferred to a stereotactic platform that attaches to the MR bore. The procedure is performed with image-guidance, as MR images are acquired in near real-time. The  end-effectors  interface with surgical tools which are based on standard neurosurgical instruments.


End-effectors are equipped with three-dimensional force-sensors, providing the sense of touch. The surgeon seated at the workstation controls the robot using force feedback hand controllers. The workstation recreates the sight and sensation of microsurgery by displaying the surgical site and 3D MRI displays, with superimposed tools. NeuroArm enables remote manipulation of the surgical tools from a control room adjacent to the surgical suite. [ 3 ]  It was designed to function within the environment of 1.5 and 3.0  tesla  intraoperative MRI systems. As neuroArm is MR-compatible, stereotaxy can be performed inside the bore of the magnet with near real-time image guidance. NeuroArm possesses the  dexterity  to perform microsurgery, outside of the MRI system.


Telerobotic operations  both inside and outside the magnet are performed using specialized tool sets based on standard neurosurgical instruments, adapted to the end effectors. Using these, NeuroArm is able to cut and manipulate soft tissue, dissect tissue planes, suture, biopsy, electrocauterize, aspirate and irrigate. [ 4 ]


The project began in 2002 when  Daryl , B.J., and Don Seaman provided $2 million to fund the design efforts.  Dr. Sutherland and his group established a collaboration with the Canadian space engineering company   MacDonald Dettwiler and Associates  (MDA). [ 5 ]   Close collaboration between MDA's robotic engineers and University of Calgary physicians, nurses, and scientists contributed to the design and development of NeuroArm. Official launch of the project was on April 17, 2007. [ 6 ]


NeuroArm was designed to take full advantage of the imaging environment provided by intraoperative MRI. The ability to couple near real-time, high resolution images to robotic technologies provides the surgeon with image guidance, precision, accuracy, and dexterity. [ 7 ]  MDA's engineers were immersed in the operating room to study typical tool and surgeon motions in order to use biomimicry for effective design of the computer-assisted surgical device. The OR environment, personnel, surgical rhythm and instrumentation remain unchanged. The surgeon, sitting at the workstation, is provided a virtual environment that recreates the sight, sound, and touch of surgery. Functions like tremor filtering and motion scaling were applied to increase precision and accuracy while functions like no-go zones and linear lock were applied to enhance safety. Surgical tools near the patient's head are incapable of fully independent movement and are slaved to the surgeon’s movement at all times. Pre-planned automatic motions are used to move the robot arms away from the patient's head for manual tool exchange, and then return them to the original position and orientation.


On May 12, 2008, the first image-guided MR-compatible robotic neurosurgical procedure was performed at  University of Calgary  by Dr. Garnette Sutherland using the NeuroArm. [ 8 ]


Neurofibromatosis type II  (also known as  MISME syndrome  – multiple inherited schwannomas, meningiomas, and ependymomas) is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral  benign   brain tumors  in the nerve sheath of the  cranial nerve VIII , which is the "auditory-vestibular nerve" that transmits sensory information from the  inner ear  to the  brain . Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. Neurofibromatosis type II (NF2  or  NF II) is caused by  mutations  of the  "Merlin"   gene , [ 2 ]  which seems to influence the form and movement of  cells . The principal treatments consist of  neurosurgical  removal of the tumors and surgical treatment of the eye lesions. Historically the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.


NF2 is an inheritable disorder with an  autosomal dominant  mode of transmission. [ 3 ]


There are two forms of the NF2: [ 4 ]


Symptoms can occur at any age, typically in adolescence and early adulthood, and rarely seen in children, and the severity depends on the location of the tumours. Symptoms include, but are not limited to: [ citation needed ]


Because hearing loss in those with NF2 almost always occurs after acquisition of verbal language skills, people with NF2 do not always integrate well into  Deaf culture  and are more likely to resort to auditory  assistive technology . [ citation needed ]
One of these devices is the  cochlear implant , which can sometimes restore a high level of auditory function even when natural hearing is totally lost. However, the amount of destruction to the cochlear nerve caused by the typical NF2 schwannoma often precludes the use of such an implant. In these cases, an  auditory brainstem implant  (ABI) can restore some level of hearing, supplemented by  lip reading . [ citation needed ]


NF2 is caused by inactivating mutations in the NF2 gene located at 22q12.2 of  chromosome 22 , type of mutations vary and include protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations and others. Deletions, too, in the  NH 2 -terminal domain  of merlin proteins have been associated with early tumor onset and poor prognosis in people with NF2. [ 5 ]  Protein truncating mutations correlate with more severe phenotype. [ 6 ]   There is a broad clinical spectrum known, but all people with the condition who have been checked have been found to have some mutation of the same gene on  chromosome 22 . Through statistics, it is suspected that one-half of cases are inherited, and one-half are the result of new,   de novo   mutations . [ citation needed ]


The hearing loss caused by NF2 is gradual and results from the presences of bilateral cochleovestibular schwannomas, also known as acoustic neuromas, which damage to cochlear nerve causing hearing loss. [ citation needed ]  Hearing loss may also result from benign tumors that grow on the vestibular and auditory nerves, which lead to the inner ear. [ citation needed ]


NF2 is caused by a defect in the gene that normally gives rise to a product called  Merlin  or  Schwannomin , located on chromosome 22 band q11-13.1. Merlin was first discovered as a structural protein functioning as an actin cytoskeleton regulator. Later merlin's tumour suppressant role was described. Merlin regulates multiple proliferative signalling cascades such as  receptor tyrosine kinase  signalling,  p21-activated kinase  signalling,  Ras  signalling,  MEK - ERK  cascade,  MST-YAP cascade . [ 7 ]  In a normal cell, the concentrations of active (dephosphorylated) merlin are controlled by processes such as  cell adhesion  (which would indicate the need to restrain cell division). It has been shown that Merlin inhibits  Rac1  which is crucial for cell motility and tumour invasion. [ 8 ]  Also, merlin's interaction with  cyclin D  was described. [ 9 ]  It is known that Merlin's deficiency can result in unmediated progression through the  cell cycle  due to the lack of contact-mediated tumour suppression, mainly because of the cell:cell junction disruption, sufficient to result in the tumors characteristic of Neurofibromatosis type II. Recent studies showed that besides its cytoskeletal and cytoplasmic functions Merlin also translocates to the nucleus and suppresses proliferation by inhibiting E3  ubiquitin ligase  CRL4(DCAF1). [ 10 ]  Finally, most recent studies indicated that Merlin also plays important role in energy metabolism regulation. [ 11 ] [ 12 ]  Mutations of NF2 is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. The Schwannomin-peptide consists of 595  amino acids . Comparison of Schwannomin with other  proteins  shows similarities to proteins that connect the  cytoskeleton  to the  cell membrane . Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.
Ependymomas are tumors arising from the  ependyma , an epithelium-like tissue of the  central nervous system . [ 13 ]  In people with NF2 and ependymomas, the tumor suppressant function of Merlin may be compromised. Loss of function mutations occurring in  chromosome 22q , where Merlin proteins are coded, can promote  tumorigenesis , or the creation of new tumorous cells. [ 5 ]  Deletions, too, in the  NH 2 -terminal domain  of merlin proteins have been associated with early tumor onset and poor prognosis in affected people. [ 5 ]


The so-called  acoustic neuroma  of NF2 is in fact a  schwannoma  of the nervus vestibularis, or vestibular schwannoma. The misnomer of acoustic neuroma is still often used. The vestibular schwannomas grow slowly at the inner entrance of the internal auditory meatus (meatus acousticus internus). They derive from the nerve sheaths of the upper part of the nervus vestibularis in the region between the central and peripheral myelin (Obersteiner-Redlich-Zone) within the area of the porus acousticus, 1 cm from the brainstem. [ citation needed ]


Many people with NF2 were included in studies that were designed to compare disease type and progression with exact determination of the associated mutation. The goal of such comparisons of genotype and phenotype is to determine whether specific mutations cause respective combinations of symptoms. This would be extremely valuable for the prediction of disease progression and the planning of therapy starting at a young age. The results of such studies are the following: [ citation needed ]


These results suggest that other factors (environment, other mutations) will probably determine the clinical outcome.


NF2 is a genetically transmitted condition. Diagnosis is most common in early adulthood (20–30 years); however, it can be diagnosed earlier. NF2 can be diagnosed due to the presence of a bilateral vestibular schwannoma, or an acoustic neuroma, which causes a hearing loss that may begin unilaterally. [ 14 ]  If a patient does not meet this criterion of diagnosis, they must have a family history of NF2, and present with a unilateral vestibular schwannoma and other associated tumors (cranial meningioma, cranial nerve schwannoma, spinal meningioma, spinal ependymomas, peripheral nerve tumor, spinal schwannoma, subcutaneous tumor, skin plaque). This being said, more than half of all patients diagnosed with NF2 do not have a family history of the condition. [ 14 ]  Although it has yet to be included into clinical classification, peripheral neuropathy, or damage to the peripheral nerves, which often causes weakness, numbness and pain in the hands and feet, may also lead to a diagnosis of NF2. In children, NF2 can present with similar symptoms, but generally causes "visual disturbances (cataracts, hamartomas), skin tumors, mononeuropathhy (facial paresis, drop foot), symptomatic spinal cord tumors, or non-vestibular intracranial tumors". [ 14 ]


Bilateral vestibular schwannomas are diagnostic of NF2. [ 15 ]


Ferner et al. [ 16 ]   give three sets of diagnostic criteria for NF2:


Another set of diagnostic criteria is the following: [ citation needed ]


The criteria have varied over time. [ 17 ]
The last revision of the NF2 criteria was done by M.J. Smith in 2017. This included the consideration of a LZTR1 mutation (schwannomatosis) instead of NF2 and excluded bilateral vestibular schwannomas that occur after 70 years of age. [ 18 ]


There are several different surgical techniques for the removal of acoustic neuroma. [ 19 ]  The choice of approach is determined by size of the tumour, hearing capability, and general clinical condition of the person.


Larger tumors can be treated by either the translabyrinthine approach or the retrosigmoid approach, depending upon the experience of the surgical team. With large tumors, the chance of hearing preservation is small with any approach. When hearing is already poor, the translabyrinthine approach may be used for even small tumors. Small, lateralized tumours in people with NF2 with good hearing should have the middle fossa approach. When the location of the tumour is more medial a retrosigmoid approach may be better.


Auditory canal decompression is another surgical technique that can prolong usable hearing when a vestibular schwannoma has grown too large to remove without damage to the cochlear nerve. In the IAC (internal auditory canal) decompression, a middle fossa approach is employed to expose the bony roof of the IAC without any attempt to remove the tumor. The bone overlying the acoustic nerve is removed, allowing the tumour to expand upward into the middle cranial fossa. In this way, pressure on the cochlear nerve is relieved, reducing the risk of further hearing loss from direct compression or obstruction of vascular supply to the nerve.


Radiosurgery  is a conservative alternative to cranial base or other intracranial surgery. With conformal radiosurgical techniques, therapeutic radiation focused on the tumour, sparing exposure to surrounding normal tissues. Although radiosurgery can seldom completely destroy a tumor, it can often arrest its growth or reduce its size. While radiation is less immediately damaging than conventional surgery, it incurs a higher risk of subsequent malignant change in the irradiated tissues, and this risk is higher in NF2 than in sporadic (non-NF2) lesions.


There are no prescription medicines currently indicated for reduction in tumor burden for NF2 patients, although in patient studies  Bevacizumab  has resulted in reduction in tumor growth rates and hearing improvements in  some  patients. [ 20 ] [ 21 ]


As hearing loss in individuals with NF2 is generally gradual, eventually profound and sensorineural, the best options for treatment for hearing loss are cochlear implants and auditory brainstem implants (ABIs), as well as supplementing hearing with lip-reading, cued speech or sign language.


A cochlear implant is an electronic device that is surgically implants to stimulate the cochlear nerve. [ 22 ]  Cochlear implants will work only when the cochleovestibular nerve (8th nerve) and the cochlea are still functioning. In a study done with open-set speech perception testing and closed-set speech perception testing by Neff et al., they discovered that the use of cochlear implants with NF2 patients allowed significant improvement of hearing abilities. [ 23 ]  In testing of recognition of sentences of everyday speech, five out of six patients scored within the 90–100% range, and in testing of hearing in noise setting, four of six of the patients scored within the 83–96%. [ 23 ]  Additionally, all testing was done without lip-reading.


Auditory Brainstem Implants, or ABIs, are used when the cochlea or any portion of the cochleovestibular nerve are not functioning due to damage to those areas or anatomic abnormalities. [ 24 ]  The procedure is done by implanting a device that send an electrical signal directly to the cochlear nucleus, allowing sound to bypass the peripheral auditory system and straight into the brain stem. [ citation needed ]


NF2 is a life limiting condition. It is a rare genetic disorder that involves noncancerous tumors of the nerves that transmit balance and sound impulses from the inner ear to the brain. The prognosis is affected by early age onset, a higher number of meningiomas and schwannomas and having a decrease in mutation. [ 25 ]


An early diagnosis is the best way to ensure improvement in management. Although, even with an early diagnosis, some patients still die very young. [ citation needed ]


Meningiomas and schwannomas occur in around half of patients with NF2. Meningiomas are tumors that are both intracranial and intraspinal. Schwannomas are tumors that are often centered on the internal auditory canal. Patients with NF2 who have meningiomas have a higher risk of mortality, and the treatment can be very challenging. Individuals who develop schwannomas frequently develop hearing loss and deafness. [ 25 ]  These individuals may also develop tinnitus after being presented with unilateral hearing loss. The first symptom that individuals may encounter is dizziness or imbalance. [ citation needed ]


Truncating mutations lead to smaller and non-functional protein products. Studies have shown that missense mutations and large deletions can both cause predominantly mild phenotypes. Phenotype is more variable in patients with splice-site mutations, and a milder disease in patients with mutations in exons 9–15. [ 25 ]  Patients with a missense mutation have a greater survival rate than nonsense and frameshift mutations.


Incidence of the condition is about 1 in 60,000. [ 26 ]


Neurolysis  is the application of physical or chemical agents to a  nerve  in order to cause a temporary degeneration of targeted nerve fibers. When the nerve fibers degenerate, it causes an interruption in the transmission of nerve signals. In the medical field, this is most commonly and advantageously used to alleviate pain in  cancer  patients. [ 1 ]


The different types of neurolysis include  celiac plexus  neurolysis,  endoscopic  ultrasound guided neurolysis, and lumbar sympathetic neurolysis. Chemodenervation and  nerve blocks  are also associated with neurolysis.


Additionally, there is  external neurolysis . Peripheral nerves move (glide) across bones and muscles. A peripheral nerve can be trapped by scarring of surrounding tissue which may lead to potential nerve damage or pain. An external neurolysis is when scar tissue is removed from around the nerve without entering the nerve itself. [ 2 ]


Neurolysis is a chemical  ablation  technique that is used to alleviate pain. Neurolysis is only used when the disease has progressed to a point where no other pain treatments are effective. [ 1 ]  A neurolytic agent such as alcohol, phenol, or glycerol is typically injected into the  nervous system . Chemical neurolysis causes deconstructive  fibrosis  which then disrupts the  sympathetic ganglia . This results in a reduction of pain signals being transmitted throughout the nerves. [ 3 ]  The effects generally last for three to six months. [ 1 ]


Certain neurolysis techniques have been reported to be used in the early 1900s for the treatment of pain by the neurologist  Mathieu Jaboulay . Early reported neurolysis helped treat  vasospastic disorders  such as arterial occlusive disease before the introduction of  endovascular  procedures. [ 3 ]


Celiac plexus neurolysis (CPN) is the chemical ablation of the celiac plexus. This type of neurolysis is mainly used to treat pain associated with advanced  pancreatic cancer . Traditional  opioid  medications used to treat pancreatic cancer patients may yield inadequate pain relief in the most advanced stages of pancreatic cancer, so the goal of CPN is to increase the efficiency of the medication. This in turn may lead to a decreased dosage, thereby decreasing the severity of the side effects. [ 3 ]  CPN is also used to decrease the chances of a patient developing an addiction for opioid medications due to the large doses commonly used in treatment. [ 3 ]


CPN can be performed by percutaneous injection either anterior or posterior to the celiac plexus. [ 4 ]  CPN is generally performed complementary to  nerve blocks , due to the severe pain associated with the injection itself. Neurolysis is commonly performed only after a successful celiac plexus block. [ 4 ]  CPN and celiac plexus block (CPB) are different in that CPN is permanent ablation whereas CPB is temporal pain inhibition. [ 4 ]


There are multiple posterior percutaneous approaches, but no clinical evidence suggests that any one technique is more efficient than the rest. The posterior approaches generally utilize two needles, one at each side of the  L1 vertebral body  pointing towards the  T12 vertebral body . [ 3 ]


Increasing the spread of the injection may increase the efficacy of the neurolysis. [ 3 ]


Endoscopic ultrasound (EUS)-guided neurolysis is a technique that performs neurolysis using a linear-array echoendoscope. [ 5 ]  The EUS technique is minimally invasive and is believed to be safer than the traditional percutaneous approaches. EUS-guided neurolysis technique can be used to target the  celiac plexus , the  celiac ganglion , or the broad plexus in the treatment of pancreatic cancer-associated pain. [ 5 ]


EUS-guided celiac plexus neurolysis (EUS-CPN) is performed with either an oblique-viewing or forward-viewing echoendoscope and is passed through the mouth into the  esophagus . From the  gastroesophageal junction , EUS imaging allows the doctor to visualize the  aorta , which can then be traced to the origin of the  celiac artery . The celiac plexus itself cannot be identified, but is located relative to the celiac artery. The neurolysis is then performed with a spray needle that disperses a neurolytic agent, such as alcohol or phenol, into the celiac plexus. [ 5 ]


EUS-CPN can be performed unilaterally (centrally) or bilaterally, however, there is no clinical evidence supporting the superiority of one over the other. [ 5 ]


EUS-guided neurolysis can also be performed on the  celiac ganglion  and the broad plexus in a similar fashion to the EUS-CPN. The celiac ganglion neurolysis (EUS-CGN) is more effective than EUS-CPN and broad plexus neurolysis (EUS-BPN) is more effective than EUS-CGN. [ 5 ]


Lumbar sympathetic neurolysis is typically used on patients with  ischemic  rest pain, generally associated with nonreconstructable  arterial occlusive disease . Although the disease is the basis for this type of neurolysis, other diseases such as peripheral  neuralgia  or vasospastic disorders can receive lumbar sympathetic neurolysis for pain treatment. [ 6 ]


Lumbar sympathetic neurolysis is performed between the  L1-L4 vertebrae  with separate injections at each vertebra junction. The chemicals used for neurolysis of the nerves cause destructive fibrosis and cause a disruption of the  sympathetic ganglia . The vasomotor tone is decreased in the area affected by the neurolysis, which in addition to arteriovenous shunting, create a light pink appearance within the affected area. Lumbar sympathetic neurolysis alters the ischemic rest pain transmission by changing  norepinephrine  and  catecholamine  levels or by disturbing afferent fibers. This procedure is mainly used only when other feasible approaches to pain management are unable to be used. [ 6 ]


Lumbar sympathetic neurolysis is performed by using absolute alcohol, but other chemicals such as phenol, or other techniques such as  radiofrequency  or  laser ablation  have been studied. To aid in the procedure,  fluoroscopy  or  CT  guidance is used. Fluoroscopic guidance is the most frequent, giving better real-time monitoring of the needle. The general technique of administering lumbar sympathetic neurolysis involves using three separate needles rather than one because it allows for better longitudinal spread of the chemicals. [ 6 ]


Complications can arise from this procedure such as  nerve root  injury, bleeding,  paralysis , and more. Complications have been seen to be diminished when using the aforementioned radiofrequency or laser ablation techniques in comparison to the injection of alcohol or phenol. Generally, approximately two-thirds of patients can expect a favorable outcome (pain relief with minimal complications). Overall, the minimally invasive technique of lumbar sympathetic neurolysis is important in the relief of ischemic rest pain. [ 6 ]


Chemodenervation is a process used to manage focal muscle overactivity through the use of either phenol, alcohol, or one of the more recently discovered  botulinum toxins  (BoNTs). [ 1 ]  Chemodenervation is used as a complement to neurolysis. The agent of choice is injected into the muscle fibers as opposed to nerve tissue and the two work together to dull the neuronal signaling within the muscles. [ 1 ]


The effects of alcohol and phenol injections are different from the effects of BoNTs. Neurolysis mediates the effects of alcohol and phenol injections but does not mediate the effects of BoNT injections. Phenol and alcohol are less expensive, faster acting, can treat larger areas, and can be re-administered or boosted in less than three months, however, those injections also require the patient to be sedated, cause muscle scarring, and can lead to muscle fibrosis. [ 1 ]  BoNT injections are easier to inject, better accepted by patients, and have reversible effects on muscles, however, they are more expensive, act very slowly, and the body can develop a resistance to them. [ 1 ]


Neuronavigation  is the set of computer-assisted technologies used by neurosurgeons to guide or "navigate" within the confines of the skull or vertebral column during surgery, and used by psychiatrists to accurately target rTMS ( transcranial magnetic stimulation ).  The set of hardware for these purposes is referred to as a  neuronavigator .


Neuronavigation is recognized as the next evolutionary step of  stereotactic surgery , a set of techniques that dates back to the early 1900s and that gained popularity during the 1940s, particularly in Germany, France and the U.S., with the development of surgery for the treatment of movement disorders such as  Parkinson's disease  and  dystonias . In its infancy the purpose of this technology was to create a mathematical model describing a proposed coordinate system for the space within a closed structure, e.g., the skull. This "fiducial spatial coordinate system” uses  fiducial markers  as a reference to describe with high accuracy the position of specific structures within this arbitrarily defined space. The surgeon then refers to that data to target particular structures within the brain. This technology was boosted by the collection of data on human anatomy in “stereotactic atlases”, expanding the quantitatively defined “targets” that could be readily used in surgery. Finally, the advent of modern neuro-imaging technologies such as  computed tomography  (CT) and  magnetic resonance imaging  (MRI)—along with the ever-increasing capabilities of digitalization, computer-graphic modelling and accelerated manipulation of data through complex mathematical algorithms via robust computer technologies—made possible the real-time quantitative spatial fusion of images of the patient's brain with the created “fiducial coordinate system” for the purpose of guiding the surgeon's instrument or probe to a selected target. In this way the observations done via highly sophisticated neuro-imaging technologies (CT, MRI,  angiography ) are related to the actual patient during surgery.


The ability to relate the position of a real surgical instrument in the surgeon's hand or the microscope's focal point to the location of the imaged pathology, updated in "real time" in an "integrated operating room", highlights the modern version of this set of technologies.  In its current form, neuronavigation began in the 1990s and has adapted to new neuro-imaging technologies, real-time imaging capabilities, new technologies to transfer the information in the operating room for 3-D localization, real-time neuro-monitoring,  robotics , and new and better algorithms to handle data via more sophisticated computer technology.


In its later conceptualization, the term  neuronavigation  has started to overlap fuse with  surgical-virtualization  in which a neurosurgeon is able to visualize the scenario for surgery in a 3-D model of manipulable computer data. In this way the physician can "practice and check" the surgery, try alternative approaches, assess possible difficulties, etc., before the real surgery takes place.


The standard TMS protocol which was FDA approved in 2008 estimates the location of the  DLPFC  by finding the left motor cortex and marking a spot 5 cm anterior to it. Later two more methods were introduced using measurements of the head and calculating the location of the  DLPFC  as 1) the F3 (EEG 10/20 system) or 2) the Beam method.  Both were estimations with some limitations. With the introduction of Neuronavigation, direct visualization of structures can be achieved either with an individual's (specially ordered) MRI or an average brain (MNI) stretched to the dimensions of the individual. There is now greater significance of this increased accuracy due to recent evidence that stimulation of the gyral crown is less effective than stimulation of the sulcal bank. The introduction of robotic controlled TMS also may make Neuronavigation more important. Several manufacturers offer complete systems including Ant Neuro or Axilum Robotics.


Assistive technologies are used during spinal fusion surgery to increase accuracy, especially for the placement of  pedicle  screws. [ 1 ]  A review of navigation techniques for spine surgery published in 2019 listed four currently available options: [ 2 ]


Neuroplastic  or  neuroplastic and reconstructive surgery  is the surgical specialty involved in reconstruction or restoration of patients who undergo surgery of the central or peripheral nervous system. The field includes a wide variety of surgical procedures that seek to restore or replace a patient's skull, face, scalp,  dura  (the protective covering of the brain and spinal cord), the spine and/or its overlying tissues.


Neuroplastic surgery has adapted reconstructive principles from the fields of  craniofacial surgery , and  plastic and reconstructive surgery  and refined them in order to prevent and/or address challenging deformities which result from Neurosurgical Procedures. The evolution of this new specialty and first center for Neuroplastic and Reconstructive Surgery was started at  Johns Hopkins University Hospital  in Baltimore, Maryland by a formal collaboration between the Department of Plastic and Reconstructive Surgery and Department of Neurosurgery, under the vision of Dr. Chad Gordon. [ 1 ]  Upon arrival to Johns Hopkins Hospital, Gordon formed a multi-disciplinary team of physicians, scientists and engineers. [ 2 ]  The team's unified goal was to develop techniques and devices to treat adult neurosurgical patients. These advances led to several "first-in-human" publications and skull implant/craniofacial computer-assisted technology patents, and allowed for the establishment of the first formal fellowship training program in Neuroplastic and Reconstructive Surgery. [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  In March 2018, Dr. Gordon was appointed the Director of Neuroplastic and Reconstructive Surgery at Johns Hopkins. In 2018, the "Society of Neuroplastic Surgery" was officially formed with the mission to "advance the art, science, and technology related to Neuroplastic and Reconstructive Surgery", and at that time, Dr. Gordon was elected to be the society's first President. [ 14 ]


The first peer-reviewed journal to recognize neuroplastic and reconstructive surgery as its own field was the  Journal of Craniofacial Surgery  which dedicated its January 2018 issue to introducing the new field of neuroplastic surgery to its readership. In that issue, the editor-in-chief, Mutaz Habal, published an editorial on neuroplastic surgery where he stated:  "Based on the desire to present the fact that neuroplastic surgery is there, we have a dedicated this issue of the  Journal of Craniofacial Surgery . This presentation mostly involves surgical procedures that will be termed ‘‘neuroplastic’’ in the years to come." [ 15 ]


Training in neuroplastic surgery requires completion of a neuroplastic and reconstructive surgery fellowship which lasts 1–2 years. Such fellowships are available to individuals who have completed a residency in P lastic and Reconstructive Surgery ,  ENT Surgery ,  Neurosurgery  or  Oral and Maxillofacial surgery . As of today, the only formal fellowship training program in neuroplastic and reconstructive surgery is located at the  Johns Hopkins School of Medicine  and Johns Hopkins Hospital. [ 16 ]  The fellowship is co-sponsored by both Departments of Plastic Surgery and Neurosurgery. For each of the clinical fellows in the program, there is an expected volume of participating in over 110 neuro-cranial reconstructions per year with Dr. Gordon and his neurosurgery colleagues, as well as a large spectrum of complex scalp reconstruction and craniofacial cases. The first surgeon formally trained in "Neuroplastic and Reconstructive Surgery" was Dr. Gabriel Santiago [2016-18], who completed  ENT surgery  residency in the  US Navy  prior to starting the fellowship. [ citation needed ]  The first Neuroplastic Surgery Research Fellow was Dr. Amir Wolff [2017-18], an attending oral-maxillofacial surgeon from Rambam Medical Center in Haifa, Israel. [ citation needed ]


The first Annual Neuroplastic and Reconstructive Surgery Symposium was held at  Harvard Medical School / Massachusetts General Hospital  in September 2015, co-chaired by Dr.  Chad Gordon  (Johns Hopkins) and Dr.  Michael Yaremchuk  (Harvard). Its overarching mission was to increase collaboration, awareness and synergy amongst numerous disciplines including  craniofacial plastic surgery , adult-based  cranial neurosurgery ,  biomedical engineering , and  neurology  for improved patient outcomes. Since then, the symposium has grown significantly and rotates annually between Harvard Medical School/Massachusetts General Hospital (Boston, MA) and  Johns Hopkins School of Medicine / Johns Hopkins Hospital  (Baltimore, MD). Its main emphasis relates to  cranioplasty , implants and implantable  neurotechnologies . [ 17 ]


Neurotomy  may refer to the application of heat (as in  radio frequency nerve lesioning ) or freezing to sensory nerve fibers to cause their temporary degeneration, usually to relieve pain. Neurotomy and  neurolysis  (where the degeneration is caused by the application of chemical agents) are forms of  neurolytic block . "Neurotomy" is sometimes used as a synonym for  neurectomy , the surgical cutting or removal of nervous tissue. [ 1 ]


Neutron capture therapy  ( NCT ) is a type of  radiotherapy  for treating locally invasive malignant tumors such as primary  brain tumors , recurrent  cancers of the head and neck region , and cutaneous and extracutaneous melanomas. It is a two-step process:  first , the patient is injected with a tumor-localizing drug containing the  stable isotope  boron-10 ( 10 B), which has a high propensity to  capture  low energy "thermal"  neutrons . The  neutron cross section  of  10 B (3,837  barns ) is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. In the  second  step, the patient is radiated with  epithermal neutrons , the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. After losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the  10 B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough  10 B.


All clinical experience with NCT to date is with boron-10; hence this method is known as  boron neutron capture therapy  ( BNCT ). [ 1 ]  Use of another non-radioactive isotope, such as  gadolinium , has been limited to experimental animal studies and has not been done clinically. BNCT has been evaluated as an alternative to conventional radiation therapy for malignant brain tumors such as  glioblastomas , which presently are incurable, and more recently, locally advanced recurrent  cancers of the head and neck  region and, much less often, superficial melanomas mainly involving the skin and genital region. [ 1 ] [ 2 ] [ 3 ]


James Chadwick  discovered the neutron in 1932. Shortly thereafter, H. J. Taylor reported that boron-10 nuclei had a high propensity to capture low energy "thermal" neutrons. This reaction causes nuclear decay of the boron-10 nuclei into helium-4 nuclei (alpha particles) and lithium-7 ions. [ 4 ]  In 1936, G.L. Locher, a scientist at the Franklin Institute in Philadelphia, Pennsylvania, recognized the therapeutic potential of this discovery and suggested that this specific type of neutron capture reaction could be used to treat cancer. [ 5 ] [ 1 ]  William Sweet, a neurosurgeon at the Massachusetts General Hospital, first suggested the possibility of using BNCT to treat malignant brain tumors to evaluate BNCT for treatment of the most malignant of all brain tumors, glioblastoma multiforme (GBMs), using borax as the boron delivery agent in 1951. [ 6 ]  A clinical trial subsequently was initiated by Lee Farr using a specially constructed nuclear reactor at the Brookhaven National Laboratory [ 7 ]  in Long Island, New York, U.S.A. Another clinical trial was initiated in 1954 by Sweet at the Massachusetts General Hospital using the Research Reactor at the Massachusetts Institute of Technology (MIT) in Boston. [ 6 ]


A number of research groups worldwide have continued the early ground-breaking clinical studies of Sweet and Farr, and subsequently the pioneering clinical studies of Hiroshi Hatanaka (畠中洋) in the 1960s, to treat patients with brain tumors. [ 8 ]  Since then, clinical trials have been done in a number of countries including Japan, the United States, Sweden, Finland, the Czech Republic, Taiwan, and Argentina. After the nuclear accident at Fukushima (2011), the clinical program there transitioned from a reactor neutron source to accelerators that would produce high energy neutrons that become thermalized as they penetrate tissue. [ citation needed ]


Neutron capture therapy is a binary system that consists of two separate components to achieve its therapeutic effect. Each component in itself is non-tumoricidal, but when combined they can be highly lethal to cancer cells.


BNCT is based on the nuclear capture and decay reactions that occur when non-radioactive  boron-10 , which makes up approximately 20% of natural elemental boron, is irradiated with neutrons of the appropriate energy to yield excited boron-11 ( 11 B*). This undergoes radioactive decay to produce high-energy  alpha particles  ( 4 He nuclei) and high-energy  lithium-7  ( 7 Li) nuclei. The nuclear reaction is: [ citation needed ]


Both the alpha particles and the lithium nuclei produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of 5–9  μm . This approximately is the diameter of the target cell, and thus the lethality of the capture reaction is limited to boron-containing cells. BNCT, therefore, can be regarded as both a biologically and a physically targeted type of radiation therapy. The success of BNCT is dependent upon the selective delivery of sufficient amounts of  10 B to the tumor with only small amounts localized in the surrounding normal tissues. [ 8 ]  Thus, normal tissues, if they have not taken up sufficient amounts of boron-10, can be spared from the neutron capture and decay reactions. Normal tissue tolerance, however,  is determined by the nuclear capture reactions that occur with normal tissue hydrogen and nitrogen. [ 8 ]


A wide variety of boron delivery agents have been synthesized. [ 9 ]  The first, which has mainly been used in Japan, is a polyhedral borane anion,  sodium borocaptate  or BSH ( Na 2 B 12 H 11 SH ), and the second is a dihydroxyboryl derivative of  phenylalanine , called  boronophenylalanine  or BPA. The latter has been used in many clinical trials. Following administration of either BPA or BSH by intravenous infusion, the tumor site is irradiated with neutrons, the source of which, until recently, has been specially designed nuclear reactors and now is neutron accelerators. Until 1994, low-energy (< 0.5  eV ) thermal neutron beams were used in Japan [ 10 ]  and the United States, [ 6 ] [ 7 ]  but since they have a limited depth of penetration in tissues, higher energy (> .5eV < 10 keV) epithermal neutron beams, which have a greater depth of penetration, were used in clinical trials in the United States, [ 11 ] [ 12 ]  Europe, [ 13 ] [ 14 ]  Japan, [ 15 ] [ 16 ]  Argentina, Taiwan, and China until recently when accelerators replaced the reactors. In theory BNCT is a highly selective type of  radiation therapy  that can target tumor cells without causing radiation damage to the adjacent normal cells and tissues. Doses up to 60–70  grays (Gy)  can be delivered to the tumor cells in one or two applications compared to 6–7 weeks for conventional fractionated external beam photon irradiation. However, the effectiveness of BNCT is dependent upon a relatively homogeneous cellular distribution of  10 B within the tumor, and more specifically within the constituent tumor cells, and this is still one of the main unsolved problems that have limited its success. [ 1 ]


The radiation doses to tumor and normal tissues in BNCT are due to energy deposition from three types of directly ionizing radiation that differ in their  linear energy transfer  (LET), which is the rate of energy loss along the path of an ionizing particle: [ citation needed ]


1. Low-LET  gamma rays , resulting primarily from the capture of thermal neutrons by normal tissue hydrogen atoms [ 1 H(n,γ) 2 H];


2. High-LET  protons , produced by the scattering of fast neutrons and from the capture of thermal neutrons by nitrogen atoms [ 14 N(n,p) 14 C]; and


3. High-LET, heavier charged  alpha particles  (stripped down helium [ 4 He] nuclei) and  lithium -7 ions, released as products of the thermal neutron capture and decay reactions with  10 B [ 10 B(n,α) 7 Li].


Since both the tumor and surrounding normal tissues are present in the radiation field, even with an ideal epithermal neutron beam, there will be an unavoidable, non-specific background dose, consisting of both high- and low-LET radiation. However, a higher concentration of  10 B in the tumor will result in it getting a higher total dose than that of adjacent normal tissues, which is the basis for the therapeutic gain in BNCT. [ 17 ]  The total radiation dose in Gy delivered to any tissue can be expressed in photon-equivalent units as the sum of each of the high-LET dose components multiplied by weighting factors (Gy w ), which depend on the increased radiobiological effectiveness of each of these components. [ citation needed ]


Biological weighting factors have been used in all of the more recent clinical trials in patients with high-grade gliomas, using boronophenylalanine (BPA) in combination with an epithermal neutron beam. The  10 B(n,α) 7 Li part of the radiation dose to the scalp has been based on the measured boron concentration in the blood at the time of BNCT, assuming a blood: scalp boron concentration ratio of 1.5:1 and a compound biological effectiveness (CBE) factor for BPA in skin of 2.5. A  relative biological effectiveness  (RBE) or CBE factor of 3.2 has been used in all tissues for the high-LET components of the beam, such as alpha particles. The RBE factor is used to compare the biologic effectiveness of different types of ionizing radiation. The high-LET components include protons resulting from the capture reaction with normal tissue nitrogen, and recoil protons resulting from the collision of fast neutrons with hydrogen. [ 17 ]  It must be emphasized that the tissue distribution of the boron delivery agent in humans should be similar to that in the experimental animal model in order to use the experimentally derived values for estimation of the  radiation  doses for clinical radiations. [ 17 ] [ 18 ]  For more detailed information relating to computational dosimetry and  treatment planning , interested readers are referred to a comprehensive review on this subject. [ 19 ]