Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma

Abstract

Purpose: Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.

Patients and methods: In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.

Results: Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E'; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E']; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DL(co)(corr); P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E', although impaired sustained attention and naming speed were associated with DL(co)(corr). Neurocognitive performance was associated with academic and vocational functioning.

Conclusion: These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.

Trial registration: ClinicalTrials.gov NCT00760656.

Fig 1.

Patient flow diagram. Eighty-eight survivors were randomly selected from a cohort of more than 400 adult survivors of Hodgkin lymphoma, on the basis of original treatment characteristics.

Fig 2.

(A) Axial flair brain image of a 50-year-old white male diagnosed with Hodgkin lymphoma at age 18 years and treated with 45 Gy radiation to the mantle field. Image demonstrates multiple sites of leukoencephalopathy (arrows). At time of imaging, patient demonstrated pulmonary hypertension and left ventricular diastolic dysfunction by echocardiography. (B) Susceptibility-weighted image of 38-year-old white male diagnosed with Hodgkin lymphoma at age 6 years and treated with 35 Gy radiation to the mantle field. Image demonstrates foci of susceptibility (arrows). Phase filtering (not shown) confirms sites to be consistent with hemosiderin deposits. At time of imaging, patient demonstrated pulmonary hypertension and left ventricular diastolic dysfunction by echocardiography. No history of overt stroke was present in either patient's medical record.

Fig 3.

Neurocognitive performance in age-adjusted z scores (mean, 0; standard deviation, 1.0) as a function of cardiac and pulmonary morbidity. (A) Mean performance (and 95% CIs) for survivors with normal and abnormal cardiac diastolic function. (B) Mean neurocognitive performance (and 95% CIs) for survivors with normal and abnormal diffusing capacity of the lungs for carbon monoxide (DL_CO). Significant group differences are identified for working memory (P = .01), task completion (P = .002), fatigue (P = .007), sustained and variability of attention (P = .001 for each), and processing speed (P = .03).

Fig 4.

Theoretical model of process resulting in neurocognitive impairment and functional limitations in survivors of Hodgkin lymphoma who were treated with thoracic radiation. Although chemotherapy used to treat Hodgkin lymphoma agents may have a direct impact on brain function, the doses of doxorubicin and bleomycin used in our cohort did not increase such risk, likely because higher mantle field radiation intensity was associated with lower doxorubicin and bleomycin exposure. Direct CNS impact of chemotherapy agents should be investigated in survivors treated using modern protocols.

Fig A1.

Cortical thickness in frontal, parietal, and temporal brain regions as a function of neurocognitive performance. (A) Mean thickness values and 95% CIs for survivors with average v below average attention span. (B) Mean thickness values and 95% CIs for survivors with average v below average short-term memory free recall. Significant group differences are identified in attention span for frontal (P = .005), parietal (P = .05), temporal (P = .02), and dorsolateral frontal (P = .005) regions. Significant differences in short-term memory were identified for temporal (P = .001), lateral temporal (P = .009), and medial temporal P = .05) regions.