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and alopecia. These side effects may be mild and transient, but can also be progressive and even persistent
with structural brain damage on MRI scanning. Neurocognitive decline, especially memory dysfunction,
is a major complaint following brain radiotherapy. In the United States, approximately 200,000 patients
[1]
receive brain irradiation each year . Due to both tumour progression and treatment, up to ninety percent
[1]
of these patients experience cognitive dysfunction . The treatment-related neurocognitive decline is
[2]
poorly understood , but causes a severe decline in the quality of life of these patients. Radiation injury
is a multifactorial and complex event, characterized by vascular modification, inflammation, gliogenesis
abnormalities and, when high-dose radiation is administered, even necrosis.

The incidence of radiation necrosis generally rises with an escalating radiation dose, fraction size and the
[3]
administration of chemotherapy . The precise mechanism of the neurotoxicity remains to be answered.
However, two hypotheses (the vascular hypothesis and the glial hypothesis) explaining this neurocognitive
[4]
decline have arisen . The vascular hypothesis suggests that radiation induces vascular injury which
leads to vascular inadequacy and so contributes to neurotoxicity. This neurotoxicity will eventually lead
to neurocognitive decline. The degree of vascular inadequacy seems correlated to the extent of cognitive
[3]
impairment . The second hypothesis, the glial hypothesis, states that radiation therapy leads to a hold
of gliogenesis because of a microglial inflammatory response induced by IL-6, inducing demyelinative
necrosis. White matter networks are essential for cognitive function. By damaging these networks, as caused
[3]
by demyelinative necrosis, cognitive impairment may occur . However, in experimental animal studies,
gliogenesis occurred to be fairly spared following radiation therapy, making this hypothesis less plausible.
In contrast to this sparing of astrocytes and oligodendrocytes, a 97% reduction in “newborn” neurons was
[5]
found in neurogenesis after brain irradiation .
Whole brain radiotherapy (WBRT) or prophylactic cranial irradiation (PCI) exposes the whole cerebrum to
a modest dose of radiation. Since the influence of brain irradiation on the long-term cognitive performance
is a concern, several strategies, such as partial brain irradiation, hippocampal avoidance irradiation and the
[6]
use of neuroprotective agents, aim to prevent or reduce radiation-induced cognitive deterioration .

[7]
[9]
[8]
Memantine , donepezil and methylphenidate have been widely studied in Alzheimer’s disease and
influence cognition. Memantine was reported to be effective in the treatment of moderate to severe
Alzheimer’s disease, whereas donepezil reduces the likelihood of progression of cognitive impairment at
12 months significantly (P = 0.004). In addition, these agents are suggested to be neuroprotective [6,10,11] ,
thereby possibly limiting cognitive deterioration after brain radiotherapy. This led to the following research
question: are memantine, methylphenidate and donepezil successful in sparing cognitive functioning after
cerebral radiotherapy-treatment?

A literature study was performed to determine the effect of memantine, methylphenidate and donepezil on
the neurocognitive function of patients after partial or whole-brain radiotherapy.

LITERATURE SEARCH STRATEGY
A search in PubMed was conducted to evaluate the effect of memantine, methylphenidate and donepezil on
cognition after brain-radiation therapy. In the Supplementary Table 1 you will find the details on the search
strategy. The search date was January 2018. The articles had to be in English language. This search provided
58 articles. After applying the filters “human subjects” and “clinical trials”, only eight articles were selected
[Figure 1]. Each publication was carefully examined and identified to fit the research question based on the
eligibility criteria. Including criteria for studies consisted of “human beings”, “cranial irradiation therapy”,
“brain tumours or -metastases”, the use of “memantine”, “methylphenidate” or “donepezil” and “cognitive
assessment”. In addition, the trials had to be clinical trials, written in the English language.