A comparison of critical structure dose and toxicity risks in patients with low grade gliomas treated with IMRT versus proton radiation therapy.

Proton therapy offers dosimetric advantage of decreased dose to non-target tissues. This study explored the potential benefits of proton radiation therapy versus photon based intensity modulated radiation therapy (IMRT) for patients with low grade gliomas (LGG) through dosimetric comparison and biological modeling of potential radiation-induced toxicities. Eleven patients were treated with fractionated proton radiation therapy on a prospective protocol assessing for feasibility and treatment toxicity of proton radiation therapy in patients with LGG. IMRT treatment plans were created for each patient using the same CT planning data set and defined structures. The prescription dose to clinical target volume (CTV) was 54 Gy(RBE). The toxicity risk of IMRT and protons was estimated based upon equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) modeling. The risk of secondary tumors for each modality was estimated. Proton EUD for most immediate normal tissue structures was between 10-20 Gy lower than the EUD delivered by IMRT. However, the difference in NTCP was negligible for both modalities. The mean excess risk of proton radiation-induced second tumor in the brain per 10,000 cases per year is 47 (range 11-83), while the mean risk for IMRT is 106 (range 70-134). The mean ratio of excess risk IMRT/protons is 2.2 (range 1.6-6.5), demonstrating that the risk of secondary tumors is consistently higher for IMRT. Proton therapy effectively reduces the dose to surrounding normal tissues in LGG patients. IMRT has a twofold higher risk of secondary intracranial tumors as compared to proton therapy. In most cases, NTCP is negligible for both modalities. The benefit of proton therapy over IMRT may be more substantial in patients with tumors in proximity to critical structures.

Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma.

PURPOSE: To compare treatment plans from standard photon therapy to intensity modulated X-rays (IMRT) and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. METHODS: Proton planning was accomplished using an in-house 3D planning system. IMRT plans were developed using the KonRad treatment planning system with 6-MV photons. RESULTS: Substantial normal-tissue dose sparing was realized with IMRT and proton treatment of the posterior fossa and spinal column. For example, the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from IMRT and protons, respectively. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons. Long-term toxicity with emphasis on hearing and endocrine and cardiac function should be substantially improved secondary to nontarget tissue sparing achieved with protons. CONCLUSION: The present study clearly demonstrates the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared to conventional X-rays. Of the two conformal treatment methods evaluated, protons were found to be superior to IMRT.

Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis.

PURPOSE: To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. METHODS AND MATERIALS: Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. RESULTS: The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. CONCLUSION: Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

Objective detection and localization of multiple sclerosis lesions on magnetic resonance brainstem images: validation with auditory evoked potentials.

To develop an objective method for detecting multiple sclerosis (MS) brainstem lesions, magnetic resonance (MR) images (multiple planar, spin-echo, acquired in three planes of section) of sixteen MS patients and fourteen normal subjects were analyzed with an algorithm that detected regions with a relatively increased intensity on both a spin-echo image and a T2 image. To be considered a lesion, such regions had to overlap in at least two orthogonal planes. Using a digitized atlas of the human brainstem, the lesion locations were mapped with respect to the brainstem anatomy. This method was evaluated by comparing the location of MS lesions with the brainstem auditory evoked potentials obtained from these subjects. Brainstem lesions were detected in five MS patients; four had lesions impinging upon the auditory system and one did not. All four had abnormal evoked potentials. The fourteen normal subjects, the one MS patient with brainstem lesions outside the auditory pathway, and the eleven other MS patients with no brainstem lesions all had normal evoked potentials. The requirement that lesions be detected in at least two planes of section greatly improved the specificity of the algorithm. The consistency between the MR and brainstem auditory evoked potentials results supports the validity of this imaging analysis algorithm for objectively localizing brainstem lesions.

Sound lateralization and interaural discrimination. Effects of brainstem infarcts and multiple sclerosis lesions.

Subjects with brainstem lesions due to either an infarct or multiple sclerosis (MS) underwent two types of binaural testing (lateralization testing and interaural discrimination) for three types of sounds (clicks and high and low frequency narrow-band noise) with two kinds of interaural differences (level and time). Two major types of abnormalities were revealed in the lateralization performances: perception of all stimuli, regardless of interaural differences (time and/or level) in the center of the head (center-oriented), or lateralization of all stimuli to one side or the other of the head (side-oriented). Similar patterns of abnormal lateralization (center-oriented and side-oriented) occurred for MS and stroke patients. A subject's pattern of abnormal lateralization testing was the same regardless of the type of stimulus or type of interaural disparity. Lateralization testing was a more sensitive test than interaural discrimination testing for both types of subjects. Magnetic resonance image (MRI) scanning in three orthogonal planes of the brainstem was used to detect lesions. A semi-automated algorithm superimposed the auditory pathway onto each MRI section. Whenever a lesion overlapped the auditory pathway, some binaural performance was abnormal and vice versa. Given a lateralization test abnormality, whether the pattern was center-oriented or side-oriented was mainly determined by lesion site. Center-oriented performance was principally associated with caudal pontine lesions and side-oriented performance with lesions rostral to the superior olivary complex. For lesions restricted to the lateral lemniscus and/or inferior colliculus, whether unilateral or bilateral, just noticeable differences (JNDs) were nearly always abnormal, but for caudal pontine lesions JNDs could be normal or abnormal. MS subjects were more sensitive to interaural time delays than interaural level differences particularly for caudal pontine lesions, while stroke patients showed no differential sensitivity to the two kinds of interaural differences. These results suggest that neural processing of binaural stimuli is multilevel and begins with independent interaural time and level analyzers in the caudal pons.

Effects of localized pontine lesions on auditory brain-stem evoked potentials and binaural processing in humans.

OBJECTIVES AND METHODS: Four sets of measurements were obtained from 11 patients (44-80 years old) with small, localized pontine lesions due to vascular disease: (1) Monaural auditory brain-stem evoked potentials (ABEPs; peaks I to VI); (2) Binaural ABEPs processed for their binaural interaction components (BICs) in the latency range of peaks IV to VI; (3) magnetic resonance imaging (MRI) of the brain-stem; and (4) psychoacoustics of interaural time disparity measures of binaural localization. ABEPs and BICs were analyzed for peak latencies and interpeak latency differences. Three-channel Lissajous' trajectories (3-CLTs) were derived for ABEPs and BICs and the latencies and orientations of the equivalent dipoles of ABEP and BICs were inferred from them. RESULTS: Intercomponent latency measures of monaurally evoked ABEPs were abnormal in only 3 of the 11 patients. Consistent correlations between sites of lesion and neurophysiological abnormality were obtained in 9 of the 11 patients using 3-CLT measures of BICs. Six of the 11 patients had absence of one or more BIC components. Seven of the 11 had BICs orientation abnormality and 3 had latency abnormalities. Trapezoid body (TB) lesions (6 patients) were associated with an absent (two patients with ventral-caudal lesions) or abnormal (one patient with ventral-rostral lesions) dipole orientation of the first component (at the time of ABEPs IV), and sparing of this component with midline ventral TB lesions (two patients). A deviant orientation of the second BICs component (at the time of ABEPs V) was observed with ventral TB lesions. Psychoacoustic lateralization in these patients was biased toward the center. Rostral lateral lemniscus (LL) lesions (3 patients) were associated with absent (one patient) or abnormal (two patients) orientation of the third BICs component (at the time of ABEPs VI); and a side-biased lateralization with behavioral testing. CONCLUSIONS: These results indicate that: (1) the BICs component occurring at the time of ABEPs peak IV is dependent on ventral-caudal TB integrity; (2) the ventral TB contributes to the BICs component at the time of ABEPs peak V; and (3) the rostral LL is a contributing generator of the BICs component occurring at the time of ABEP peak VI.

Imaging subcortical auditory activity in humans.

There is a lack of physiological data pertaining to how listening humans process auditory information. Functional magnetic resonance imaging (fMRI) has provided some data for the auditory cortex in awake humans, but there is still a paucity of comparable data for subcortical auditory areas where the early stages of processing take place, as amply demonstrated by single-unit studies in animals. It is unclear why fMRI has been unsuccessful in imaging auditory brain-stem activity, but one problem may be cardiac-related, pulsatile brain-stem motion. To examine this, a method eliminating such motion (using cardiac gating) was applied to map sound-related activity in the auditory cortices and inferior colliculi in the brain stem. Activation in both the colliculi and cortex became more discernible when gating was used. In contrast with the cortex, the improvement in the colliculi resulted from a reduction in signal variability, rather than from an increase in percent signal change. This reduction is consistent with the hypothesis that motion or pulsatile flow is a major factor in brain-stem imaging. The way now seems clear to studying activity throughout the human auditory pathway in listening humans.

Generators of the brainstem auditory evoked potential in cat. I. An experimental approach to their identification.

This paper is the first in a series aimed at identifying the cellular generators of the brainstem auditory evoked potential (BAEP) in cats. The approach involves (1) developing experimental procedures for making small selective lesions and determining the corresponding changes in BAEP waveforms, (2) identifying brainstem regions involved in BAEP generation by examining the effects of lesions on the BAEP and (3) identifying specific cell populations involved by combining the lesion results with electrophysiological and anatomical information from other kinds of studies. We created lesions in the lower brainstem by injecting kainic acid which is generally toxic for neuronal cell bodies but not for axons and terminals. This first paper describes the justifications for using kainic acid, explains the associated problems, and develops a methodology that addresses the main difficulties. The issues and aspects of the specific methods are generally applicable to physiological and anatomical studies using any neurotoxin, as well as to the present BAEP study. The methods chosen involved (1) measuring the BAEP at regular intervals until it reached a post-injection steady state and perfusing the animals with fixative shortly after the last BAEP recordings were made, (2) using objective criteria to distinguish injection-related BAEP changes from unrelated ones, (3) making control injections to identify effects not due to kainic acid toxicity, (4) verifying the anatomical and functional integrity of axons in lesioned regions, and (5) examining injected brainstems microscopically for cell loss and cellular abnormalities indicating dysfunction. This combination of methods enabled us to identify BAEP changes which are clearly correlated with lesion locations.

Brainstem lesions and click lateralization in patients with multiple sclerosis.

The ability to lateralize dichotic clicks with either interaural time delays (ITD) or interaural level differences (ILD) was tested in seven multiple sclerosis (MS) subjects who had normal audiograms. Along with the psychoacoustical tests, magnetic resonance images (MRI) of the subjects' brainstem were obtained. After matching each MRI section with the corresponding section of a computerized atlas of the brainstem, the parts of the auditory pathway affected by each MS lesion were determined. Of the seven subjects two performed normally with both types of interaural asymmetry and had no brainstem lesions involving the auditory pathway. Two subjects performed normally only with level differences, but perceived all the dichotic clicks with different ITDs in the center of the head; both had lesions involving the trapezoid body. Three subjects could not perform normally with either task, perceiving the clicks to the sides and never in the center for both ITDs and ILDs; all three had unilateral lesions of the lateral lemniscus. A multi-level decision making model is proposed to account for these results.

Multiple sclerosis lesions of the auditory pons are not silent.

To understand the relationship between brainstem lesions and auditory neurology in patients with multiple sclerosis, we compared behavioural, electrophysiological and imaging data in 38 patients with probable or definite multiple sclerosis and normal or near normal hearing. Behavioural measures included (i) general hearing tests (audiogram, speech discrimination) and (ii) hearing tests likely to be critically dependent upon brainstem processing (masking level difference, interaural time and level discrimination). Brainstem auditory evoked potentials provided the electrophysiological data. Multiplanar high-resolution MRI of the brainstem provided the anatomical data. Interaural time discrimination for high-frequency sounds was by far the most sensitive of all tests with abnormalities in 71% of all subjects. Whenever any other test was abnormal this test was always abnormal. Interaural time discrimination for low-frequency sounds and evoked potentials were closely related and next most sensitive with abnormalities in approximately 40% of all subjects. Interaural level discrimination and masking level difference were least sensitive with abnormalities in < 10% of subjects. Speech discrimination scores correlated significantly with the masking level differences, as well as with interaural time discrimination for high-frequency sounds. Pontine lesions were found in five of the 16 patients, in whom an objective method for detecting magnetic resonance lesions could be applied. All four with lesions involving the pontine auditory pathway had marked abnormalities in interaural time discrimination and evoked potentials. None of the other 12 had evoked potentials abnormalities. We conclude that neurological tests requiring precise neural timing can reveal behavioural deficits for multiple sclerosis lesions of the auditory pons that are otherwise 'silent'. Of all neurological systems the auditory system at the level of the pons is probably the most sensitive to multiple sclerosis lesions, because of its exceptional dependence upon neural timing in the microsecond range and the lack of redundancy in the encoding of high-frequency sounds. Precise neural timing may be critical for some aspects of speech processing.

Binaural auditory processing in multiple sclerosis subjects.

In order to relate human auditory processing to physiological and anatomical experimental animal data, we have examined the interrelationships between behavioral, electrophysiological and anatomical data obtained from human subjects with focal brainstem lesions. Thirty-eight subjects with multiple sclerosis were studied with tests of interaural time and level discrimination (just noticeable differences or jnds), brainstem auditory evoked potentials and magnetic resonance (MR) imaging. Interaural testing used two types of stimuli, high-pass (> 4000 Hz) and low-pass (< 1000 Hz) noise bursts. Abnormal time jnds (Tjnd) were far more common than abnormal level jnds (70% vs 11%); especially for the high-pass (Hp) noise (70% abnormal vs 40% abnormal for low-pass (Lp) noise). The HpTjnd could be abnormal with no other abnormalities; however, whenever the BAEPs, LpTjnd and/or level jnds were abnormal HpTjnd was always abnormal. Abnormal wave III amplitude was associated with abnormalities in both time jnds, but abnormal wave III latency with only abnormal HpTjnds. Abnormal wave V amplitude, when unilateral, was associated with a major HpTjnd abnormality, and, when bilateral, with both HpTjnd and LpTjnd major abnormalities. Sixteen of the subjects had their MR scans obtained with a uniform protocol and could be analyzed with objective criteria. In all four subjects with lesions involving the pontine auditory pathway, the BAEPs and both time jnds were abnormal. Of the twelve subjects with no lesions involving the pontine auditory pathway, all had normal BAEPs and level jnds, ten had normal LpTjnds, but only five had normal HpTjnds. We conclude that interaural time discrimination is closely related to the BAEPs and is dependent upon the stimulus spectrum. Redundant encoding of low-frequency sounds in the discharge patterns of auditory neurons, may explain why the HpTjnd is a better indicator of neural desynchrony than the LpTjnd. Encroachment of MS lesions upon the pontine auditory pathway always is associated with abnormal BAEPs and abnormal interaural time discrimination but may have normal interaural level discrimination. Our data provide one of the most direct demonstrations in humans of relationships among auditory performance, evoked potentials and anatomy. We present a model showing that many of these interrelationships can be readily interpreted using ideas developed from work on animals, even though these relationships could not have been predicted with confidence beforehand. This work provides a clear advance in our understanding of human auditory processing and should serve as a basis for future studies.

Effects of multiple sclerosis brainstem lesions on sound lateralization and brainstem auditory evoked potentials.

Magnetic resonance (MR) imaging, brainstem auditory evoked potentials (BAEPs), and tests of interaural time and level discrimination were performed on sixteen subjects with multiple sclerosis (MS). Objective criteria were used to define MR lesions. Of the eleven subjects in whom no pontine lesions were detected and the one subject who had pontine lesions that did not encroach upon the auditory pathways, all had normal BAEPs and interaural level discrimination, although a few had abnormal interaural time discrimination. Of four subjects with lesions involving the pontine auditory pathway, all had both abnormal BAEPs and abnormal interaural time discrimination; one also had abnormal interaural level discrimination. Analysis of the data suggest the following: waves I and II are generated peripheral to the middle of the ventral acoustic stria (VAS); wave III is generated ipsilaterally in the region of the rostral VAS, caudal superior olivary complex (SOC) and trapezoid body (TB); and waves V and L are generated contralaterally, rostral to the SOC-TB. The region of the ipsilateral rostral SOC-TB is implicated as part of the pathway involved in the generation of waves V and L. Interaural time discrimination of both high and low frequency stimuli were affected by all brainstem lesions that encroached on auditory pathways. A unilateral lesion in the region of the LL affected interaural time discrimination for low-frequency stimuli less severely than bilateral lesions of the LL or a unilateral lesion of the VAS. The only interaural level discrimination abnormality occurred for a subject with a unilateral lesion involving the entire rostral VAS. It appears that detailed analysis of lesion locations coupled with electrophysiological and psychophysical data holds promise for testing hypotheses concerning the function of various human auditory brainstem structures.

The effect of brainstem lesions on brainstem auditory evoked potentials in the cat.

Brainstem auditory evoked potentials (BAEPs) were recorded before and after cuts were made in either the midline trapezoid body (TB), the lateral lemniscus (LL), or the combined dorsal and intermediate acoustic striae (DAS/IAS) in 23 anesthetized cats. Monaural and binaural rarefaction clicks were presented at a rate of 10 per s, and the potentials recorded from a vertex electrode referenced to either earbar or to the neck. The potentials were filtered so that fast and slow components could be examined separately and special efforts were exerted to obtain stable conditions so that small changes in waveforms could be significant. Lesions of the DAS/IAS produced negligible changes in either the fast or slow waves. Lesions of the midline TB reduced the amplitudes of peaks P3 through P5, while greatly reducing the amplitude of the slow wave. Complete lesions of the LL always reduced the amplitude of the slow wave. Lesions of the ventral part of the LL were more likely to reduce the amplitude of P4-P5. Our interpretations of these lesion experiments are based on the idea that individual fast peaks of the BAEP represent compound action potentials of fiber pathways. According to this view, only synchronized activity generated in populations of neurons that are both favorably oriented in space and significant in number, will contribute to the fast peak.

Comparison of cat and human brain-stem auditory evoked potentials.

Brain-stem auditory evoked potentials (BAEPs) elicited by clicks were recorded from both humans and cats. The responses of the two species were compared as functions of click level, click rate, ear stimulated, and electrode position. Since the BAEPs appear to have both high- and low-frequency components, the responses were filtered to analyze these components separately. The similarities and differences in the behavior of the peaks of the two species support the view that the first three (positive and negative) high-frequency peaks which are comparably numbered have similar generators, but the later comparably numbered peaks do not. The presence of binaural interaction beginning with P4 and PV suggests a correspondence between peaks P4 through P5 in cat with PV through PVI, respectively, in human. The similarity in behavior of these peaks also support this correspondence. Furthermore, when conduction times are estimated from interpeak latencies, this correspondence of peaks agrees more closely with the relative pathway lengths in the two species, than does the correspondence based on comparable numbering.

Number and distribution of stapedius motoneurons in cats.

Cell bodies of stapedius motoneurons were identified by retrograde transport of horseradish peroxidase (HRP) following injections into the stapedius muscle. Large injections were made in an attempt to label all stapedius motoneurons. To control for labeling of non-stapedial neurons resulting from spread of HRP, we determined the locations of brainstem neurons labeled by HRP applied to the facial nerve, the chorda tympani nerve, the auricular branch of the vagus nerve, the tensor tympani muscle, and the cochlea. In three cats analyzed in detail, 1,133-1,178 neurons projecting to the stapedius muscle were identified. Arguments are given which suggest that in these three cats all stapedius motoneurons were labeled. The labeled stapedius neurons may all be motoneurons because they all stain positively for acetylcholinesterase and have medium-coarse Nissl bodies. Most stapedius motoneurons were located around the motor nucleus of the facial nerve. Staphedius motoneurons were also found near the descending limb of the facial-nerve root, in the peri-olivary neuropil, and in the reticular formation with the ascending fibers of the facial-nerve root.

Is there a medial nucleus of the trapezoid body in humans?

The medial nucleus of the trapezoid body (MNTB) appears to be a prominent auditory structure in many mammals. However, the presence of an MNTB in the human brain has not been clearly established. One of the most characteristic features of the cat MNTB is the presence of large somatic endings with multiple synaptic sites, the calyces of Held. We examined adult human brains at both light and electron microscopic levels and found neurons with unusually large endings in a location that is similar to that for the MNTB in other animals. Moreover, the sizes and shapes of some cells in this area are similar to the principal cells of the cat MNTB. These observations support the idea that humans have cells that resemble MNTB neurons in other species. It has been suggested that the cat MNTB may be involved in the generation of wave 3 of its brainstem auditory evoked potentials, so the presence of an MNTB in the human brain may have implications in interpreting brainstem potentials in man.

Auditory evoked potentials and auditory behavior following prenatal and perinatal asphyxia in rhesus monkeys.

Two types of asphyxia were studied in monkeys, total asphyxia during mid-pregnancy (94--98 days gestation) and combined partial and total axphyxia at term (165 days gestation). Auditory evoked potentials and the acquisition of 2 auditory discrimination tasks were studied in asphyxiated animals as well as in group of controls. The brains of all asphyxiates were examined histologically. No auditory discrimination deficit was found in the asphyxiated animals; however, the auditory evoked potentials differentiated between control and asphyxiated animals, especially those with verified inferior colliculus damage.