Cognitive and neuropsychiatric impairment in cerebral radionecrosis patients after radiotherapy of nasopharyngeal carcinoma
© Wu et al.; licensee BioMed Central Ltd. 2014
Received: 25 March 2013
Accepted: 9 January 2014
Published: 13 January 2014
We sought to characterize the cognitive function and neuropsychiatric symptoms in cerebral radionecrosis (CRN) patients who have received conformal radiation for nasopharyngeal carcinoma.
A total of 40 patients treated with radiotherapy (RT) that developed CRN (RT + CRN), 40 patients treated with radiotherapy that did not have CRN (RT-No-CRN), and 36 newly diagnosed untreated nasopharyngeal carcinoma patients (No-RT) were recruited. The cognitive function and neuropsychiatric symptoms were evaluated with Montreal cognitive assessment (MoCA), the mini-mental state examination (MMSE), activity of daily living scale (ADL), neuropsychiatric inventory (NPI), Hamilton depression scale (HAMD) and Hamilton anxiety scale (HAMA).
The RT + CRN group had the lowest mean MMSE, MoCA and ADL scores, while highest mean NPI, HAMD and HAMA scores among the three patient groups (P < 0.05). Thirty (75%) of the RT + CRN patients were deemed cognitively impaired by the MoCA compared with 9 (22.5%) by the MMSE (χ 2 = 22.064; P < 0.001). Eighty-two percents of subject in RT + CRN group experienced neuropsychiatric symptoms within the past 4 weeks. Irritability, anxiety, depression and agitation in the RT + CRN group were of the most significantly frequent among the 3 groups.
The CRN patients generally have manifestations in cognitive and psychological impairment, which have their typical characteristics, and should be considered in CRN treatment and rehabilitation. The MoCA classifies more CRN patients as cognitively impaired than the MMSE, justifying further studies of the MoCA as an appropriate screen for CRN.
KeywordsCerebral radionecrosis Nasopharyngeal carcinoma Cognitive impairment Neuropsychiatric symptom
Radiotherapy (RT) is the main treatment modality for nasopharyngeal carcinoma (NPC) and has produced excellent outcomes in terms of survival rate . To reach satisfactory local control, the radiation field extends from the skull base to the lower neck and a total dose of about 70 Gy is generally required. In these cases, some important normal structures, including the brain, are exposed to the high dose radiation, and side effects are inevitable. One possible severe consequence is the occurrence of cerebral radionecrosis (CRN), which has an incidence rate of 3.6% ~ 8.3% in different reports [2, 3]. CRN is usually irreversible and may progress over time . The risk is highest in the first 6 months to 3 years after irradiation, but can persist for decades [5, 6]. CRN is neuropathologically defined as necrosis with severe vascular lesions (stenosis, thrombosis, haemorrhage, fibrinoid vascular necrosis) . Among patients after RT of NPC, the temporal lobes are most frequently involved . The outcome varies from focal neurologic deficits to death. By using MRI, the lesion can be manifested as the early finger-like T2-hyperintensity area representative of reactive white matter edema and the late cyst-like changes corroborating with liquefactive necrosis and surrounding gliosis [8, 9].
A major manifestation of CRN is the development of cognitive and neuropsychiatric impairment. Patients usually exhibit cognitive dysfunction ranges from inattention, impaired short term memory, bradyphrenia, to frank dementia, and are often accompanied with neuropsychiatric symptoms. Cognitive and neuropsychiatric impairment have been recognized as a significant problem in CRN patients. There is, however, a paucity of research in this population. The objective of this study was to characterize cognitive impairment and neuropsychiatric symptoms in CRN patients who have received conformal radiation for NPC, and also to develop a sensitive instrument for routine screening. In addition, it is known that cognitive and neuropsychiatric deficits are correlated significantly with the development of CRN. Therefore, it might be of clinical significance to determine the cognitive and neuropsychiatric function on the early diagnosis of CRN.
RT + CRN
(n = 36)
(n = 40)
(n = 40)
45.5 ± 8.6
47.3 ± 9.4
48.3 ± 9.7
Gender (No. M/F)
9.4 ± 2.8
10.4 ± 2.9
10.3 ± 3.0
Age at the completion of RT (y)
43.5 ± 10.0
43.9 ± 9.2
Post-RT interval (y)
3.8 ± 2.6
4.3 ± 2.9
Total RT dosage (Gy)
70.5 ± 2.0
70.7 ± 1.6
CTCAE grade (1/2/3/4/5) (No.)
The Mini Mental State Examination (MMSE) , Montreal Cognitive Assessment (MoCA) (Beijing version) and Activity of Daily Living Scale (ADL)  were used to evaluate the general cognitive function. Both MMSE and MoCA were widely used cognitive screens, and MoCA has previous been documented to have superior sensitivity in brain tumor patients [13, 14]. The time to administer each test was recorded. Impairment on the MMSE was defined as a score below 17 to illiterate patients, 20 to primary school culture patients, and 24 to individuals with more than 6 years of education. Cutoff scores for the MoCA was determined at 26 (scores of 25 or below will indicate impairment), as defined by the MoCA’s author . A bonus point was given to individuals with <12years of education on MoCA. Neuropsychiatric inventory (NPI) , Hamilton depression scale (HAMD), and Hamilton anxiety scale (HAMA) were used to evaluate the neuropsychiatric symptoms. Trained research staff administered these assessment scales in counterbalanced manner.
Descriptive statistics were calculated for all variables. For continuous variables, means and standard deviations were calculated. Descriptive statistics for categorical variables included the number and frequency in each category. Total scores for MMSE, MoCA, ADL, NPI, HAMD and HAMA were compared among the three groups using one-way analysis of variance (ANOVA) models, followed by Bonferroni test with significance level of 0.05. The chi square test was used to determine if there was a significant difference in cognitive function between the RT + CRN and RT-No-CRN group. The McNemar test was used to determine if there was a significant difference in the proportion of CRN patients deemed cognitively impaired by the MMSE and MoCA. MMSE and MoCA subdomain scores were compared between the RT + CRN and RT-No-CRN group using Wilcoxon rank sum test. Significance was defined as P < 0.05. The NPI frequency of symptoms was dichotomized (present or not) and compared between the three groups with Fisher’s exact test. Analyses were carried out with the SPSS, version 13.0.
Table 1 shows the demographic and major clinical characteristics of all subjects. There was no significant difference in terms of age (F = 1.261; P = 0.285), gender (χ 2 = 1.846; P = 0.397) and level of education (F = 1.638; P = 0.197) among the 3 patient groups. In addition, no significant difference was found between RT + CRN and RT-No-CRN patients in the mean total RT dosage (t = 0.562; P = 0.576), age at the completion of RT (t = -0.291; P = 0.771) and post-RT interval (t = -1.370; P = 0.172) (Table 1).
Total scores of impairment on neuropsychological tests
Total scores of impairment on neuropsychological tests
RT + CRN
(n = 36)
(n = 40)
(n = 40)
28.9 ± 1.9
28.6 ± 1.5
25.4 ± 4.6
Time to complete MMSE (min)
4.0 ± 1.1
5.9 ± 1.7
5.7 ± 1.4
27.2 ± 2.2
27.2 ± 3.0
21.8 ± 5.3
Time to complete MoCA (min)
6.4 ± 1.2
8.3 ± 2.3
8.1 ± 2.0
20.0 ± 0
20.0 ± 0
23.7 ± 9.5
3.5 ± 6.7
3.5 ± 4.5
15.6 ± 17.0
4.9 ± 4.1
2.9 ± 3.0
9.7 ± 6.3
5.5 ± 4.1
3.8 ± 2.8
10.7 ± 7.8
MMSE and MoCA subdomain scores
MMSE and MOCA subdomain scores in the CRN and RT-No-CRN group
RT + CRN
(n = 40)
(n = 40)
MMSE subdomain scores
10.0 ± 0
9.6 ± 1.4
3.0 ± 0
2.6 ± 0.9
Attention and calculation
4.3 ± 1.0
3.6 ± 1.7
2.5 ± 0.8
1.4 ± 1.3
8.8 ± 0.5
8.3 ± 1.2
MoCA subdomain scores
Visuospatial and executive
3.8 ± 1.0
3.2 ± 1.5
2.9 ± 0.3
2.5 ± 0.8
5.7 ± 0.5
5.0 ± 1.2
2.9 ± 0.3
2.3 ± 1.0
1.6 ± 0.6
1.4 ± 0.8
Memory and delayed recall
3.5 ± 1.3
1.2 ± 1.4
6.0 ± 0
5.7 ± 0.8
Frequency of impairment on NPI (overall and individual symptoms) in 3 groups
RT + CRN
(n = 36)
(n = 40)
(n = 40)
Presence of symptoms in past 4 weeks, n (%)
Aberrant motor activity
Night-time behavior disturbances
In this study, we have shown that the CRN patients who have received conformal radiation for NPC generally have manifestations in cognitive impairment and neuropsychiatric symptoms, and also found some typical characteristics that have not been reported previously.
We found that the CRN patients had significant change of cognitive function, mainly reflects in short term memory, delayed recall, language, attention, orientation, visuospatial and executive function. The results of our study are similar to those of Cheung [17, 18] and Hsiao  despite methodological differences. In these studies, RT had deleterious effects on cognitive function in NPC patients. For example, Cheung examined a group of NPC patients who had completed their radiotherapy previously, and found memory, language, motor ability, as well as executive functions were significantly impaired for those patients who developed temporal lobe necrosis after RT. Lesion volume was correlated significantly with the severity of cognitive deficits. Hsiao found that the cognitive functioning scores had significantly declined in the domains of short-term memory, language abilities, and list-generating fluency to patients at least 1year after completion of RT.
We also found a relatively high rate of general intelligence impairment among CRN patients, with 22.5% by the MMSE and 75% by the MoCA so affected. This result was inconsistent with Cheung`s study of remaining relatively intact general intelligence by the MMSE in CRN patients . It is possibly related to a longer post-RT interval of mean 4.3years and bigger total RT dosage of mean 70.7 Gy in our cohort, compared with about 1 year and 58.4 Gy in the former. It has been confirmed that post-RT interval and total RT dosage are correlated with more severe CRN as well as cognitive defect respectively .
Compared to the MMSE, the MoCA provided more information in identification of cognitive impairment in a cohort of CRN patients, and cost only about 8 minutes to complete. It can be explained by the inclusion of subtests that measure more demanding assessment of executive function, visuospatial function, new learning, attention, and information processing speed. This is one of the few studies to assess the MoCA in NPC survivors with CRN. Because the MoCA was so well tolerated and disagreed with the MMSE in such a significant proportion of subjects, we believe that the MoCA is a more sensitive CRN-related cognitive screen suitable for clinical practice . However, this study is limited by the lack of gold standard neuropsychological assessment, and a validation study further testing this preliminary hypothesis is warranted.
Another notable finding here is that CRN subjects have relatively more neuropsychiatric symptoms than those of their cerebral normal counterparts. The most frequent symptoms among subjects with CRN are irritability (87.5%), anxiety (72.5%) and depression (62.5%), with about 1 in 3 displaying agitation and apathy. Irritability, anxiety, depression, agitation, apathy and night-time behavior disturbances are significantly more frequent among subjects with CRN than those with normal MR image. Only subjects with CRN had psychotic symptoms including hallucinations and delusions.
The association between neuropsychiatric impairment and CRN has been recognized for some time, although lack of exact quantitative investigation. Nishimura reported clinical findings such as mental deterioration and motor abnormality in 12 NPC survivors with CRN . Armstrong reported depression appears to increase years after RT, possibly first peaking somewhere between 4 and 6 years posttreatment . Recently Tang examined a group of CRN patients with Self-Rating Anxiety Scale and Self-Rating Depression Scale, and found the patients with CRN got higher scores in both scales . This result was consistent with our study of negative emotions in CRN patients.
The temporal lobes that easily involved in CRN are responsible for cognitive, emotional and psychological function. Radiation-induced damage to progenitor populations responsible for maintenance of white matter integrity and adult hippocampal neurogenesis has been suggested to play a major role in the neurocognitive impairment many cancer survivors experience . The behavioral and psychological manifestations may, in part, be related to cerebral organic pathological changes (e.g., temporal lobe, limbic system, hippocampus) [26–28], and also social psychological attack (including RT adverse reaction, tumor deterioration) as well as cognitive dysfunction . Post-RT patients, especially CRN victims, exhibit characteristic irritability. Though the specific cause is yet to be verified, attention should be paid to this syndrome in the long term survivors to improve their quality of life.
CRN patients who have received conformal radiation for NPC generally manifest cognitive neuropsychiatric symptoms with typical characteristics. However the study was limited by the relatively small sample size, and the lack of statistical differences found between groups (i.e. abstraction, delusion, hallucination, and aberrant motor activity) may not be a function of lack of differences, so that the results should be confirmed in some larger sample size and better match studies. Meanwhile, MoCA may be a feasible instrument for routine cognitive screening, but the sensitivity and specialty are not yet confirmed due to lack of gold standard in the study.
In conclusion, we found that the CRN patients after RT for NPC have relatively high level of cognitive impairment and more frequent neuropsychiatric symptoms, which have their typical characteristics. The development of interventions to assist these persons in coping with such symptoms should also be a goal for CRN treatment and rehabilitation. The MoCA and NPI are feasible tests which are suitable for clinical practice. MoCA classifies more CRN patients as cognitively impaired than the MMSE, which led us to the hypothesis that MoCA would be a sensitive screen for CRN patients. Currently, this hypothesis still needs further study to confirm, and such study is now underway.
We wish to highlight some relevant information about the authors: HH has a Master’s in Neurology, with vast experience in research and health service systems. XW has a Master’s in Neurology, with research interest in radiation injury. MG is an oncologist, and specializes in the treatment of nasopharyngeal carcinoma.
Montreal cognitive assessment
Mini-mental state examination
Activity of daily living scale
Hamilton depression scale
Hamilton anxiety scale.
This work is financially supported by the Guangdong Province Science and Technology Program 2010B030700010.
- Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan DK, Tung SY, Thaw M, Ho JH: Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys. 1992, 23 (2): 261-270. 10.1016/0360-3016(92)90740-9.View ArticlePubMedGoogle Scholar
- Tuan JK, Ha TC, Ong WS, Siow TR, Tham IW, Yap SP, Tan TW, Chua ET, Fong KW, Wee JT: Late toxicities after conventional radiation therapy alone for nasopharyngeal carcinoma. Radiother Oncol. 2012, 104 (3): 305-311. 10.1016/j.radonc.2011.12.028.View ArticlePubMedGoogle Scholar
- Sumitsawan Y, Chaiyasate S, Chitapanarux I, Anansuthiwara M, Roongrotwattanasiri K, Vaseenon V, Tooncam H: Late complications of radiotherapy for nasopharyngeal carcinoma. Auris Nasus Larynx. 2009, 36 (2): 205-209. 10.1016/j.anl.2008.04.006.View ArticlePubMedGoogle Scholar
- Kim JH, Brown SL, Jenrow KA, Ryu S: Mechanisms of radiation-induced brain toxicity and implications for future clinical trials. J Neurooncol. 2008, 87 (3): 279-286. 10.1007/s11060-008-9520-x.View ArticlePubMedGoogle Scholar
- Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY: CNS complications of radiotherapy and chemotherapy. Lancet. 2009, 374 (9701): 1639-1651. 10.1016/S0140-6736(09)61299-X.View ArticlePubMedGoogle Scholar
- Dropcho EJ: Neurotoxicity of radiation therapy. Neurol Clin. 2010, 28 (1): 217-234. 10.1016/j.ncl.2009.09.008.View ArticlePubMedGoogle Scholar
- Chen J, Dassarath M, Yin Z, Liu H, Yang K, Wu G: Radiation induced temporal lobe necrosis in patients with nasopharyngeal carcinoma: a review of new avenues in its management. Radiat Oncol. 2011, 6: 128-10.1186/1748-717X-6-128.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang YX, King AD, Zhou H, Leung SF, Abrigo J, Chan YL, Hu CW, Yeung DK, Ahuja AT: Evolution of radiation-induced brain injury: MR imaging-based study. Radiology. 2010, 254 (1): 210-218. 10.1148/radiol.09090428.View ArticlePubMedGoogle Scholar
- Lee AW, Cheng LO, Ng SH, Tse VK OSK, Au GK, Poon YF: Magnetic resonance imaging in the clinical diagnosis of late temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Clin Radiol. 1990, 42 (1): 24-31. 10.1016/S0009-9260(05)81617-4.View ArticlePubMedGoogle Scholar
- National Cancer Institute. Common Terminology Criteria for Adverse Events v.4.0 (CTCAE). 2011, Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed June 14, 2011
- Folstein MF, Folstein SE, McHugh PR: Mini-mental state A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975, 12 (3): 189-198. 10.1016/0022-3956(75)90026-6.View ArticlePubMedGoogle Scholar
- Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969, 9 (3): 179-186.View ArticlePubMedGoogle Scholar
- Olson RA, Iverson GL, Carolan H, Parkinson M, Brooks BL, McKenzie M: Prospective comparison of two cognitive screening tests: diagnostic accuracy and correlation with community integration and quality of life. J Neurooncol. 2011, 105 (2): 337-344. 10.1007/s11060-011-0595-4.View ArticlePubMedGoogle Scholar
- Olson RA, Chhanabhai T, McKenzie M: Feasibility study of the Montreal Cognitive Assessment (MoCA) in patients with brain metastases. Support Care Cancer. 2008, 16 (11): 1273-1278. 10.1007/s00520-008-0431-3.View ArticlePubMedGoogle Scholar
- Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005, 53 (4): 695-699. 10.1111/j.1532-5415.2005.53221.x.View ArticlePubMedGoogle Scholar
- Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994, 44 (12): 2308-2314. 10.1212/WNL.44.12.2308.View ArticlePubMedGoogle Scholar
- Cheung MC, Chan AS, Law SC, Chan JH, Tse VK: Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma. Cancer. 2003, 97 (8): 2019-2026. 10.1002/cncr.11295.View ArticlePubMedGoogle Scholar
- Cheung M, Chan AS, Law SC, Chan JH, Tse VK: Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis. Arch Neurol. 2000, 57 (9): 1347-1352.View ArticlePubMedGoogle Scholar
- Hsiao KY, Yeh SA, Chang CC, Tsai PC, Wu JM, Gau JS: Cognitive function before and after intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: a prospective study. Int J Radiat Oncol Biol Phys. 2010, 77 (3): 722-726. 10.1016/j.ijrobp.2009.06.080.View ArticlePubMedGoogle Scholar
- Yuen HK, Sharma AK, Logan WC, Gillespie MB, Day TA, Brooks JO: Radiation dose, driving performance, and cognitive function in patients with head and neck cancer. Radiother Oncol. 2008, 87 (2): 304-307. 10.1016/j.radonc.2008.03.020.View ArticlePubMedGoogle Scholar
- Meyers CA, Wefel JS: The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol. 2003, 21 (19): 3557-3558. 10.1200/JCO.2003.07.080.View ArticlePubMedGoogle Scholar
- Nishimura R, Takahashi M, Morishita S, Sumi M, Uozumi H, Sakamoto Y: MR imaging of late radiation brain injury. Radiat Med. 1992, 10 (3): 101-108.PubMedGoogle Scholar
- Armstrong CL, Gyato K, Awadalla AW, Lustig R, Tochner ZA: A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev. 2004, 14 (1): 65-86.View ArticlePubMedGoogle Scholar
- Tang Y, Luo D, Rong X, Shi X, Peng Y: Psychological disorders, cognitive dysfunction and quality of life in nasopharyngeal carcinoma patients with radiation-induced brain injury. PLoS One. 2012, 7 (6): e36529-10.1371/journal.pone.0036529.View ArticlePubMedPubMed CentralGoogle Scholar
- Dietrich J, Monje M, Wefel J, Meyers C: Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist. 2008, 13 (12): 1285-1295. 10.1634/theoncologist.2008-0130.View ArticlePubMedGoogle Scholar
- Sultzer DL, Mahler ME, Mandelkern MA, Cummings JL, Gorp Van WG, Hinkin CH, Berisford MA: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease. J Neuropsychiatry Clin Neurosci. 1995, 7 (4): 476-484.View ArticlePubMedGoogle Scholar
- Lai MK, Chen CP, Hope T, Esiri MM: Hippocampal neurofibrillary tangle changes and aggressive behaviour in dementia. Neuroreport. 2010, 21 (17): 1111-1115. 10.1097/WNR.0b013e3283407204.View ArticlePubMedGoogle Scholar
- Amano N, Inuzuka S, Ogihara T: Behavioral and psychological symptoms of dementia and medical treatment. Psychogeriatrics. 2009, 9 (2): 45-49. 10.1111/j.1479-8301.2009.00284.x.View ArticlePubMedGoogle Scholar
- Casanova MF, Starkstein SE, Jellinger KA: Clinicopathological correlates of behavioral and psychological symptoms of dementia. Acta Neuropathol. 2011, 122 (2): 117-135. 10.1007/s00401-011-0821-3.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/14/10/prepub
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