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Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System
Over the past 25 years, intraoperative neurophysiology (ION) has established itself as a clinical discipline that uses neurophysiologic methods—especially developed or modified from existing methods of clinical neurophysiology—to detect and prevent intraoperatively induced neurologic injuries. Recent developments have solidified its role in neurosurgery and other surgical disciplines. Ideally, ION not only predicts but also serves to prevent intraoperatively induced injury to the nervous system. Furthermore, ION can be used to document the exact moment when the injury occurred. As a result, it can be used for both educational and medicolegal purposes.
Generally, ION techniques can be divided in two groups: mapping and monitoring. Neurophysiologic mapping is a technique that, when applied intraoperatively, enables us to identify anatomically indistinct neural structures by their neurophysiologic function. This allows the surgeon to avoid lesioning critical structures in the course of the surgical procedure. In essence, the information gained from neurophysiologic mapping allows the surgeon to operate more safely.
The following procedures use a neurophysiologic mapping technique: identification of the primary motor cortex with direct cortical stimulation, identification of the cranial nerve motor nuclei on the surgically exposed floor of the fourth ventricle, mapping of the corticospinal tract (CT) subcortically (i.e., at the level of the cerebral peduncle or at the spinal cord), mapping of the pudendal afferents in the sacral roots, before selective dorsal rhizotomy, and so on.
Neurophysiologic monitoring is a technique that continuously evaluates the functional integrity of nervous tissue and gives feedback to the (neuro)surgeon. This feedback can be instantaneous, as in a recently developed technique of monitoring motor-evoked potentials (MEPs) from the epidural space of the spinal cord or limb muscles. If the surgical procedure allows us to combine monitoring with mapping techniques, then optimal protection of nervous tissue can be achieved during neurosurgery.
Furthermore, ION uses provocative tests to examine their influence on neurophysiologic signals before the surgical procedure. A temporary clamping of the carotid artery during endarterectomy with monitoring of somatosensory-evoked potentials (SEPs) or electroencephalography is a typical example of a provocative test that measures the ability of the collateral cerebral circulation to supply a potentially ischemic hemisphere. Endovascular injection of a short-acting barbiturate or lidocaine into a vascular malformation of the spinal cord, before embolization, and observation of its influence on the neurophysiologic signals is another example of a provocative test.
Supratentorial Surgery
Surgery for brain gliomas has become more and more aggressive. This is based on clinical data that support better patient survival and quality of life after gross total removal of both low- and high-grade lesions; , however, the resection of tumors located in eloquent brain areas, such as the rolandic region and frontotemporal speech areas, requires the identification of functional cortical and subcortical areas that must be respected during surgery. Moreover, the dogmatic assumption that tumoral tissue could not retain function has been repeatedly questioned by neurophysiologic and functional magnetic resonance imaging studies. In response to the need for a safe surgery in eloquent brain areas, the past decade has seen the development of a number of techniques to map brain functions, including, but not limited to, functional magnetic resonance imaging, magnetoencephalography, and positron emission tomography.
The neurophysiologic contribution to brain mapping has been evident since the late 19th century with the pioneering work of Fritsch and Hitzig and Bartholow. In the 20th century, Penfield and colleagues , made invaluable contributions through intraoperative mapping of the sensorimotor cortex, whose findings have been substantiated by a number of recent studies.
Somatosensory-Evoked Potential Phase-Reversal Technique
To indirectly identify the central sulcus, SEPs can be recorded from the exposed cerebral cortex by using the phase-reversal technique. SEPs are elicited by stimulation of the median nerve at the wrist and the posterior tibial nerve at the ankle (40 mA intensity, 0.2 ms duration, 4.3 Hz repetition rate). Recordings are performed from the scalp at CZ′-FZ (for legs) and C3′/C4′-CZ′ (for arms) according to the 10 to 20 International Electroencephalography System. After craniotomy, a strip electrode is placed across the exposed motor cortex and primary somatosensory cortex, transversing the central sulcus. This technique is based on the principle that an SEP, elicited by median nerve stimulation at the wrist, can be recorded from the primary sensory cortex. Its mirror-image waveform can be identified if some of the contacts of the strip electrode are placed on the opposite side of the central sulcus, over the motor cortex ( Fig. 4.1 ). For phase reversal, a strip electrode with four to eight stainless steel contacts with an intercontact distance of 1 cm is used. In the literature, the success rate of the phase reversal technique to indirectly localize the primary motor cortex ranges between 91% , and 97%. Interestingly, identification of the central sulcus by magnetic resonance imaging provided contradictory results when compared with intraoperative phase reversal. Although it is expected that ongoing progress in the field of functional magnetic resonance imaging will eventually replace the need for neurophysiologic tests, ION still retains the highest reliability in mapping of the motor cortex and language areas when compared with functional neuroimaging.
Direct Cortical Stimulation (60-Hz Penfield Technique)
Once the motor strip has indirectly been identified by the phase reversal technique, direct cortical stimulation is required to confirm the localization of the motor cortex. Most current methods are based on the original Penfield technique. This calls for continuous direct cortical stimulation over a period of a few seconds with a frequency of stimulation of 50 to 60 Hz and observation of muscle movements. , , An initial current intensity of 4 mA is used and, if no movements are elicited in contralateral muscles of the limbs and face, stimulation is increased in steps of 2 mA to the point at which movements are elicited. Muscle responses can either be observed visually or documented by multichannel electromyography, which appears to be more sensitive. If no response is elicited with an intensity as high as approximately 16 mA, that area of cortex is considered not functional and can therefore be removed. It should be emphasized that a negative mapping does not always ensure safety. To increase the chances of obtaining a positive mapping result, technical and anesthesiologic drawbacks have to be carefully ruled out and cortical exposure should be generous.
More in general, a limitation to the reliability of cortical mapping is the large variability of threshold for a positive mapping response across and within individuals. A motor response from the same muscular group can be elicited from more than one cortical site, using different stimulation intensities.
Therefore, function localization may vary in different studies as a result of stimulation parameters and mapping strategies. Mapping strategies appear as one of the main variables that may affect the results of stimulation. Two different theories underline the choice of one or the other strategy:
- 1.
Some authors apply the concept that thresholds (the minimum stimulation current required to induce functional changes) vary across the exposed cortex depending on the task being assessed and the location being mapped. This is in keeping with the observation that even afterdischarge (AD) thresholds can vary significantly, not only across the population but also in the same subject at different cortical sites. , Accordingly, they attempt to maximize stimulation currents at each cortical site to ensure the absence of eloquent function. Doing so, it is more common to exceed AD thresholds in adjacent cortices, and there is a higher risk of distal activation owing to current spreading to adjacent sites.
- 2.
Other authors , , keep stimulation intensity constant while mapping the entire cortex and set threshold just below the lowest current observed to induce AD. This strategy is aimed to minimize the risk of inducing ADs (which may invalidate the results) and clinical seizures but may miss the identification of eloquent cortical sites.
Spreading of the current using the 60 Hz stimulation technique is limited to 2 to 3 mm as detected by optical imaging in monkeys. Accordingly, one can assume that using this technique is safe for removal of tumors very close to the motor and sensory pathways as long as stimulation is repeated whenever a 2 to 3 mm section of tumoral tissue is removed. Similarly, this technique allows us to map motor pathways subcortically while removing tumors that arise or extend to the insular, subinsular, or thalamic areas. , At the subcortical level, the stimulation intensity required to elicit a motor response is usually lower than that required for cortical mapping. When performing subcortical mapping, however, we have to keep in mind that a distal muscle response after stimulation of subcortical motor pathways can be misleading. Although this stimulation activates axons distal to the stimulation point, the possibility of damage to the pathways proximal to that point cannot be ruled out. This is a concern, especially when dealing with an insular tumor where there is a risk of cortical or subcortical ischemia induction secondary to manipulation of perforating vessels ( Fig. 4.2 ).
Despite its popularity in the past, this 60 Hz Penfield technique has some disadvantages. With the exception of speech mapping, it is our opinion that these disadvantages should prevent its use as a motor cortex/pathways mapping technique. First, this technique can induce seizures in as many as 20% of patients, despite therapeutic levels of anticonvulsants and regardless of whether there is a preoperative history of intractable epilepsy. , Second, in children younger than 5 years old, direct stimulation of the motor cortex for mapping purposes may not yield localizing information because of the relative unexcitability of the motor cortex. , Third, because this is a mapping and not a monitoring technique, no matter how often cortical or subcortical stimulation is repeated, the functional integrity of the motor pathways cannot be assessed continuously during surgery.
Direct Cortical Stimulation and Motor-Evoked Potential Monitoring (Short Train Of Stimuli Technique)
Recently, mapping techniques have integrated monitoring techniques to continuously assess the functional integrity of the motor pathways and therefore increase the safety of these procedures. , The following is a description of the technique that we use at our institutions and have found suitable for both mapping and monitoring.
Muscle MEPs are initially elicited by multipulse transcranial electrical stimulation (TES). Short trains of five to seven square-wave stimuli of 500 μs duration with an interstimulus interval of 4 ms are applied at a repetition rate of as high as 2 Hz through electrodes placed at C1 and C2 scalp sites, according to the 10 to 20 International Electroencephalography System. The maximum stimulation intensity should be as high as 200 mA, which is strong enough for most cases. Muscle responses are recorded via needle electrodes inserted into the contralateral upper and lower extremity muscles. We usually monitored the abductor pollicis brevis and the extensor digitorum communis for the upper extremities and the tibialis anterior and the abductor hallucis for the lower extremities. For the face area, the orbicularis oculi and orbicularis oris muscles are typically used.
After exposure of the cortex and once phase reversal has been performed, direct cortical stimulation of the motor cortex can be achieved by using a monopolar-stimulating probe to identify the cortical representation of contralateral facial and limb muscles. The same parameters of stimulation used for TES, except for a much lower intensity (≤20 mA), can be used. Sometimes, the short train of stimuli technique requires slightly higher current intensities than those required by the Penfield technique; however, by using a very short train, the charge applied to the brain is significantly reduced and, consequently, the risk of inducing seizures. The number of pulses in the short-train technique is five to seven pulses per second, whereas in the Penfield technique there are 60 pulses per second. The effect of stimulation on the cerebral cortex, from a neurophysiologic point of view, differs between the Penfield technique and the short train of stimuli technique. The Penfield technique delivers one stimulus every 15 to 20 ms continuously for a couple of seconds. The short train of stimuli technique delivers five to seven stimuli in a period of approximately 30 ms with a long pause between trains (470 to 970 ms, which depends on train repetition rate—1 or 2 Hz). Therefore, the Penfield technique is more prone to produce seizures, activating the cortical circuitry more easily than short-train stimuli do. Furthermore, compared with the Penfield technique, the short-train technique does not induce strong muscle twitches that may interfere with the surgical procedure. Responses are usually recorded from needle electrodes used to record muscle MEPs elicited by TES; however, any combination of recording muscles can be used, according to the tumor location. The larger the number of monitored muscles, the lower the chance of a false-negative mapping result. We suggest that stimulation of the tumoral area should always be performed to rule out the presence of some functional cortex. As already described, this is especially true in the case of low-grade gliomas.
In the illustrative case presented in Fig. 4.2 , an impairment of muscle MEPs occurred at the end of tumor removal when opening and closing mapping procedures had already been done and confirmed the integrity of motor pathways distal to the stimulation point at the level of the internal capsule. However, ischemia of the pyramidal tracts secondary to severe vasospasm of the main perforating branches of the middle cerebral artery occurred during hemostasis and was detected by muscle MEP monitoring. If not detected in time, this event would have likely resulted in an irreversible loss of muscle MEPs and, consequently, a permanent motor deficit. Mapping techniques are unlikely to detect these events because they do not allow a continuous “online” assessment of the functional integrity of neural pathways.
In our experience with using the short-train technique, a threshold lower than 5 mA for eliciting muscle MEPs usually indicated proximity to the motor cortex. When muscle responses are elicited through higher stimulation intensities, activation of the CT is of less localizing value because of the possibility of spreading of the current to adjacent areas.
Once mapping of the cortex has clarified the relationship between eloquent motor areas and the lesion, continuous MEP monitoring of the contralateral muscles can be sustained throughout the procedure to assist during the surgical manipulation. To do so, one of the same contacts of the strip electrode can be used as an anode for stimulation while the cathode is at Fz. The stimulation point on the motor cortex with the lowest threshold used to elicit muscle MEPs from contralateral limbs or face usually corresponds with the contact from which the largest amplitude of the mirror-image SEPs was obtained. The same stimulation parameters as those used for the short-train mapping technique can be used.
When removing a tumor that extends subcortically, preservation of muscle MEPs during monitoring from the strip electrode will guarantee the functional integrity of motor pathways and avoid the need for periodic remapping of the cortex at known functional sites.
For insular tumors where the motor cortex is not exposed by the craniotomy, a strip electrode can still be gently inserted into the subdural space to overlap the motor cortex. Phase reversal and/or direct cortical stimulation can be used to identify the electrode with the lowest threshold to elicit muscle MEPs. The use of MEPs during surgery for insular tumors has proved very useful to identify impending vascular derangements to subcortical motor pathways in time for corrective measures to be taken. In spite of the observation that intraoperative MEP changes occurred in nearly half of the procedures, these were reversible in two thirds of the cases.
Warning Criteria and Correlation With Postoperative Outcome
Still debated are the warning criteria for changes in muscle MEPs that are used to inform the surgeon about an impending injury to the motor system. It should be stressed that although for spinal cord surgery, a “presence/absence” of muscle MEPs criterion has proved to be reliable and strictly correlates with postoperative results, , there are not definite MEP parameters indicative of significant impairment during supratentorial surgery. We believe that the predictive value of muscle MEPs is different for supratentorial and spinal cord surgeries. As such, different warning criteria must be employed. This judgment is based on the difference in types of CT fibers in supratentorial portion of the CT as compared with the spinal cord. Different groups with established experience in this field have proposed similar criteria, , suggesting that a shift in latency between 10% and 15% and a decrease in amplitude of more than 50% to 80% correlate with some degree of postoperative motor deficit. However, a permanent new motor deficit has consistently correlated only with irreversible complete loss of muscle MEPs.
A persistent increase in the threshold to elicit muscle MEPs or a persistent drop in muscle MEP amplitude, despite stable systemic blood pressure, anesthesia, and body temperature, represents a warning sign. However, it should be noted that muscle MEPs are easily affected by muscle relaxants, bolus of intravenous anesthetics and high concentrations of volatile (and other) anesthetics such that wide variation in muscle MEP amplitude and latency can be observed. Due to this variability, the multisynaptic nature of the pathways involved in the generation of muscle MEPs, and the nonlinear relationship between stimulus intensity and the amplitude of muscle MEPs, the correlation between intraoperative changes in muscle MEPs (amplitude and/or latency) and the motor outcome are not linear. Further clinical investigation is required to clarify sensitive and specific neurophysiologic warning criteria for brain surgery.
Subcortical Stimulation
Traditionally, in neurosurgery, most of the interest and research with regards to brain tumor surgery in so-called eloquent areas was focused on cortical—rather than subcortical—mapping. This was due to the classical concept of eloquent cortex, in which location of function was reputed to be mostly located in specific cortical regions. Yet the large inter-individual variability of brain functional organization—for example in language —and the lack of consistency in the clinical presentation of damage to the same cortical region, challenged the concept of rigid cortical functional organization. Therefore, while cortical mapping has been, for many decades, the focus of ION during brain tumor surgery, subcortical mapping has emerged over the past decade as an invaluable technique to preserve white matter functional boundaries and, ultimately, to decide when to stop tumor resection.
As the brain is composed of localized but connected specialized areas, an injury to white matter tracts may induce irreversible neurological deficits, since damage to these tracts may cause as much deficit as damage to cortical areas. Subcortical mapping, therefore, is essential because it enables investigation into the functional role of specific subcortical networks.
The concept of brain connectome and hodotopy , and the advent of tractography have contributed further to the increasing popularity of subcortical mapping.
Over the past decade, a few technical aspects related to subcortical mapping have been addressed and clarified, especially with regards to motor pathways.
First, it is now well accepted that the CT can be localized at a subcortical level using the same techniques as for direct cortical stimulation, although cathodal rather than anodal stimulation should be used. A short train of stimuli delivered through a monopolar probe proved to be the most successful technique for subcortical mapping.
Second, several studies attempted to understand the relationship between the threshold current necessary to elicit a subcortical motor response (subcortical threshold) and the distance between the stimulation site and the CT itself. With minor inconsistencies, current evidence suggests that a subcortical threshold current of 1 mA roughly corresponds to a 1 mm distance between the stimulation site and the CT. , Yet, this correlation is based on the assumption that cathodal stimulation and a stimulus duration of 0.5 to 0.7 ms is used. If either anodal stimulation and/or shorter (0.3 ms) duration are used, then the correlation varies substantially.
A third matter of discussion is what should be considered a safe subcortical threshold to avoid post-operative motor deficits. Obviously, the lower the threshold capable of eliciting a response, the higher the risk of postoperative deficit because low threshold means proximity to the CT. A cut-off value of 3 mA has been consistently reported in the literature suggesting that the risk increases when the CT is only 3 to 4 mm away from the dissection. , ,
Nowadays new tools such us suction devices or ultrasonic aspirators combined with a stimulating probe are available, and increase the temporo-spatial resolution of subcortical mapping. Using these technical advances, subcortical threshold as low as 1 to 2 mA might be tolerated. However, this challenge should be based on very robust experience combining expertise in both ION and brain tumor surgery. In general, any subcortical thresholds below 5 mA should be considered at risk of some motor derangements and should prompt careful attention by the surgeon in order to not injure the CT.
Overall, with regards to the preservation of the CT, the best neurophysiological approach should combine both continuous MEP monitoring and subcortical mapping. The first is aimed to monitor the functional integrity of motor pathways from the motor cortex to the muscles, and is the only technique that can detect, and possibly revert or minimize, an impending vascular injury to subcortical motor pathways. Subcortical mapping cannot detect vascular injuries but is essential to determine the distance from the CT and avoid a mechanical injury to this pathway.
Brain Stem Surgery
The human brain stem is a small and highly complex structure containing a variety of critical neural structures. These include sensory and motor pathways; sensory and motor cranial nerve nuclei; cardiovascular and respiratory centers; neural networks supporting swallowing, coughing, articulation, and oculomotor reflexes; and the reticular activating system. In such a complex neural structure, even small lesions can produce severe and life-threatening neurologic deficits.
The neurosurgeon faces two major problems when attempting to remove brain stem tumors. First, if the tumor is intrinsic and does not protrude on the brain stem surface, approaching the tumor implies a violation of the anatomic integrity of the brain stem. Knowledge of the location of critical neural pathways and nuclei is mandatory when considering a safe entry into the brain stem, , but may not suffice when anatomy is distorted. Morota and colleagues reported that visual identification of the facial colliculus based on anatomic landmarks was possible in only three of seven medullary tumors and was not possible in five pontine tumors. The striae medullares were visible in four of five patients with pontine tumors and in five of nine patients with medullary tumors.
Therefore, functional rather than anatomic localization of brain stem nuclei and pathways should be used to identify safe entry zones.
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