Carol L. Armstrong

Correlation of volumetric magnetization transfer imaging with clinical data in MS

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearmans correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

Late cognitive and radiographic changes related to radiotherapy Initial prospective findings

BackgroundAssumptions about the damaging effects of radiotherapy (XRT) are based on studies in which total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension) were excluded. MethodsThe effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade, supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6 years were examined. Radiographic findings were examined regionally. ResultsSelective cognitive declines (in visual memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures, and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-related hyperintensities. ConclusionsThere was no evidence of a general cognitive decline or progression of white matter changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors.

Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation : neuropsychologic outcome and proposed mechanisms

PURPOSE To identify the longitudinal neurobehavioral characteristics of the early-delayed and late-delayed effects of partial-brain radiotherapy for patients with supratentorial brain tumors with favorable histology. This study improves on previous attempts to identify radiation effects, because of the inclusion of baseline measures and the use of subjects as their own controls. PATIENTS AND METHODS Ten neuropsychologic domains were measured in 12 patients at baseline (post-surgery and immediately before initiation of radiotherapy), and followed trimonthly for 1 year. Four to six patients were examined at 2 and 3 years postbaseline. RESULTS Patients were impaired at baseline compared with controls only in visual memory and sentence recall, but demonstrated significant improvement in visual memory by 2 years postbaseline. Speed of processing information also showed a slope of improvement over 2 years. Retrieval from verbal long-term memory was impaired at 1.5 months postcompletion of radiotherapy, but recovered to baseline levels by 1 year. At 2 years postbaseline, long-term memory retrieval demonstrated a decline, but remained unchanged at 3 years. CONCLUSION Long-term memory appears to be sensitive to the effects of radiotherapy. We confirmed our previous findings of a decrement with rebound during the early-delayed period, and propose that these findings are consistent with demyelination/remyelination. Decrement was observed again at 2 years postbaseline, which suggests that memory retrieval may be the earliest marker of late-delayed effects. These neurocognitive patterns are consistent with leukoencephalopathy. Confirmation of these observations will be possible if neuropsychologic testing with the same sensitivity can be incorporated into national collaborative trials.

A Critical Review of the Clinical Effects of Therapeutic Irradiation Damage to the Brain: The Roots of Controversy

We critically examined the damaging affects of therapeutic irradiation by comparing results from cross-disciplinary studies of early- and late-delayed radiotherapy effects. Focus is attained by concentrating on clinical treatment issues (volume of brain, dose, timing of effects, age, modality types, and stereotactic treatment techniques), rather than on methodological means or problems, which is necessary to understand the mechanisms and characteristics of radiotherapy-induced behavioral dysfunction including cognition. We make observations and hypotheses about the actual risks from radiotherapy that could be informative in the treatment decision process, and which may lessen the concerns of some patients and their families about the risks they take when receiving radiation. Conditions that predispose to radiation injury are reviewed: (1) higher doses even to part of the brain versus lower doses to the whole brain, (2) combined treatment modalities, (3) malignancy itself, (4) radiation early during postnatal brain development, and (5) late-delayed effects (more than 3 years posttreatment). Current neurocognitive frameworks for understanding cognitive change over time in children and adults are summarized, along with the literature on effects of brain tumors and treatment on depression. No studies have as yet identified candidate brain regions that are more sensitive to radiotherapy. Two studies have provided early, preliminary evidence for a specific vulnerability of visual attention/memory to the early stage of late radiation damage. Furthermore, radiation effects appear severe only in a minority of patients. Risk is related to direct and indirect effects of cancer type, concurrent clinical factors, and premorbid risk factors.

Processing Speed, Attention, and Working Memory After Treatment for Medulloblastoma: An International, Prospective, and Longitudinal Study

PURPOSE The current study prospectively examined processing speed (PS), broad attention (BA), and working memory (WM) ability of patients diagnosed with medulloblastoma over a 5-year period. PATIENTS AND METHODS The study included 126 patients, ages 3 to 21 years at diagnosis, enrolled onto a collaborative protocol for medulloblastoma. Patients were treated with postsurgical risk-adapted craniospinal irradiation (n = 36 high risk [HR]; n = 90 average risk) followed by four cycles of high-dose chemotherapy with stem-cell support. Patients completed 509 neuropsychological evaluations using the Woodcock-Johnson Tests of Cognitive Abilities Third Edition (median of three observations per patient). RESULTS Linear mixed effects models revealed that younger age at diagnosis, HR classification, and higher baseline scores were significantly associated with poorer outcomes in PS. Patients treated as HR and those with higher baseline scores are estimated to have less favorable outcomes in WM and BA over time. Parent education and marital status were significantly associated with BA and WM baseline scores but not change over time. CONCLUSION Of the three key domains, PS was estimated to have the lowest scores at 5 years after diagnosis. Identifying cognitive domains most vulnerable to decline should guide researchers who are aiming to develop efficacious cognitive intervention and rehabilitation programs, thereby improving the quality of survivorship for the pediatric medulloblastoma population.

Working Memory Impairments in Multiple Sclerosis: Evidence From a Dual-Task Paradigm

The aim of this study was to investigate working memory in multiple sclerosis (MS) patients. To test the hypothesis that the central executive system (CES) of working memory is impaired, 36 MS patients were administered a dual-task paradigm in which a judgment of line orientation measure was performed concurrently with finger tapping, humming a melody, or reciting the alphabet. MS patients exhibited a significantly greater decrement in performance than controls during the more demanding dual-task conditions (concurrent humming or alphabet recitation) as compared with the single-task condition. Dual-task performance in MS patients correlated with performance on the Paced Auditory Serial Addition Test but not with other cognitive or clinical measures. The authors conclude that MS patients have a working memory deficit reflecting an impaired central executive system. Moreover, impairments in speed of information processing in MS patients are associated with this CES deficit. Memory dysfunction is the most common cognitive impairment observed in patients with multiple sclerosis (MS). A long-term memory deficit in these patients is well documented (Grafman, Rao, & Litvan, 1990), but most early studies of MS patients have concluded that short-term memory (STM) is intact. Support for this claim was derived from the observation of a normal digit span, as well as an intact recency effect on supraspan list learning, measures commonly used to assess STM (Caine, Bamford, Schiffer, Shoulson, & Levy, 1986; Rao, Hammeke, McQuillen, Khatri, & Lloyd, 1984). Although most studies continue to focus on the long-term memory impairments in MS patients (Rao, Leo, & Aubin-Faubert, 1989), evidence is accumulating that STM deficits may also exist (Grigsby, Ayarbe, Kravcism, & Busenbark, 1994; Rao et al., 1993). However, the nature of these deficits remain unclear. The purpose of this study was to further investigate STM processing in MS patients. Several experimental tasks have been useful for identifying impairment in various aspects of STM in MS patients. One experimental measure, the Brown-Peterson task (Peterson & Peterson, 1959), measures consolidation of information in STM and the effect of interference on temporarily stored information. With this task, two groups of investigators (Beatty, Goodkin, Monson, Beatty, & Hertsgaard, 1988; Grant,

The impact of frontal and non-frontal brain tumor lesions on Wisconsin Card Sorting Test performance

Several lesion and imaging studies have suggested that the Wisconsin Card Sorting Test (WCST) is a measure of executive dysfunction. However, some studies have reported that this measure has poor anatomical specificity because patients with either frontal or non-frontal focal lesions exhibit similar performance. This study examined 25 frontal, 20 non-frontal low-grade brain tumor patients, and 63 normal controls (NC) on the WCST. The frontal patients were also assigned to either a left frontal (n=10) group or a right frontal group (n=15) and compared with the non-frontal group and NC. It was hypothesized that the frontal brain tumor patients would display greater deficits on categories achieved and a higher number of perseverative errors than non-frontal brain tumor patients on the WCST. Finally, it was predicted that right frontal brain tumors would result in greater executive functioning deficits than left frontal or non-frontal brain tumors. Results indicated that the left frontal group achieved the fewest categories and committed the most perseverative errors compared to the other patient and normal control groups. In addition, the left frontal group committed significantly more perseverative errors than the right frontal group. These results suggest that the WCST is sensitive to the effects of low-grade brain tumors on executive functioning.

The predictive value of longitudinal neuropsychologic assessment in the early detection of brain tumor recurrence

Neuropsychologic tests are widely used to predict the course of progressive neurologic diseases, and recent research has demonstrated the specificity of cognitive measures, even in relatively diffuse diseases. However, the cognitive effects of brain tumors of similar histology and location are known to be highly variable. The authors used the specificity of cognitive function principle to compare two models for the early detection of low‐grade brain tumor recurrence prior to detection with clinically scheduled neuroimaging.

Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma

BACKGROUND The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. METHODS Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis. RESULTS Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes. CONCLUSIONS Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions.

Effects of radiation therapy on adult brain behavior Evidence for a rebound phenomenon in a phase 1 trial

Although radiotherapy (XRT) is a necessary course of treatment to prolong life expectancy in patients with many types of brain neoplasms, it has damaging effects that are little understood. We used a comprehensive neuropsychological battery to evaluate five patients with low-grade brain tumors prior to XRT and then at 3-month intervals up to 9 months postcompletion of XRT. We matched patients by age and education with six normal control subjects to assess baseline impairment. In intrasubject comparisons, we examined change over time postcompletion of XRT. In spite of varying locations of tumors, all patients showed deterioration in long-term memory at a mean of 1.5 months postcompletion of XRT. Patients also consistently demonstrated a rebound effect between means of 4.7 and 7.6 months post-XRT. We found no changes over time in working memory, attention, visuospatial processes, or on any other neuropsychological test with the exception of information-processing speed, which quickened over time. Functional measures of fatigue and mood did not correlate significantly with the long-term memory scores. Long-term memory appears sensitive to the proposed white matter changes thought to be the mechanism for the early-delayed effects of XRT. Our findings suggest a neurobehavioral model for studying the effects of XRT on brain functioning.