الفهرس 
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Abstract
Non-Hodgkin lymphoma results from malignant proliferation of cells of lymphocytic lineage. Although malignant lymphomas are generally restricted to lymphoid tissue, it is not uncommon to find bone marrow involvement in children. For cancer therapy, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. Chemotherapy is commonly associated with harmful effects to multiple organ systems, including the central nervous system. Neurotoxicity may manifest as both acute and delayed complications, which is particularly a concern for long-term survivors.
Cognition is the set of all mental abilities and processes related to knowledge: attention, memory, judgement, reasoning, computation, problem solving & decision making, comprehension & production of language, etc. Cognitive processes use existing knowledge and generate new knowledge.
The aims of our study were to evaluate the effect of intrathecal methotrexate on neurocognitive function in NHL treated children, and its relation to risk factors and to develop a suitable and applicable model to evaluate neurocognitive function in children.
Our study included 35 subjects, 25 non Hodgkin’s lymphoma cases treated with methotrexate and 10 controls.
The majority of our participants were males (more than 70%). The mean age of our cases was 9.5±4.1 years, which is a little higher than that of controls (8.7±3.2 years), but this difference was not significant.
Comparison between cases and controls according to Stanford-Binet Intelligence Scale in our study revealed that the verbal and quantitative sub-scales were significantly better among controls compared to cases; while the abstract/visual and short term memory were better among controls but non significantly different from cases. The total Stanford-Binet Intelligence Scale was significantly higher among controls compared to cases. Comparison between cases and controls according to other tests (Attention, Language expression, Language perception, Bender gestation and Visual perception) did not show any significant difference between cases and controls.
The comparison between age at disease onset and verbal subscale of Stanford-Binet Intelligence Scale showed that it was better among older ages and the difference was significant. On the other hand, Comparison between age at disease onset and quantitative subscale of Stanford-Binet Intelligence Scale revealed that it was non significantly better among older ages. Comparison between verbal and quantitative subscales of Stanford-Binet Intelligence Scale and the number of intrathecal injections did not show any significant relation.
Conclusion
Methotrexate has harmful adverse effect on congnitive functions of children treated for NH L( in verbal and quantitave ), and this effect increases when MTX treatment started at younger age.
Recommendation
As intrathecal chemotherapy is mandatory in prophylaxis and treatment in some pediatric malignancy and until now no alternative therapy to it so understanding the risks of central nervous system (CNS) toxicity is critically important in long-term follow-up of childhood cancer survivors.
Many survivors experience learning difficulties in school, which can be ameliorated with an appropriate individualized education plan (IEP) implemented by the school(Armstrong et al,2009)
A neuropsychologist familiar with the CNS effects of treatment for childhood cancer can perform a neurocognitive assessment and
identify specific strengths and weaknesses in the childhood cancer survivor. These can be used to formulate interventions that can compensate for any weaknesses. Such interventions may include extra time on tests to compensate for reduced processing speed, sitting at the front of the class and having tests taken in isolation to compensate for attention deficits, or tutoring to bolster a specific weakness(Diller et al,2009)
Without the knowledge of the risks of therapy, subtle learning problems may be easily overlooked, potentially leading to poor school performance, reduced self-confidence, lower education achievement, lower earning potential and a lower quality of life (Diller et al,2009)
Children treated before 5–6 years of age, especially those treated before 3 years of age, are at a higher risk for developing cognitive impairments than those treated after the age of 8–10 years.
It is important to get a good interval history and physical examination and important diagnostic test for possible CNS toxicity include:
• Neurocognitive assessment
• Neuroradiologic studies
• EEG (Armenian et al,2015)
Neurocognitive evaluation is essential to detect learning disability. It should be performed in all school-aged children who have received cranial irradiation, intrathecal chemotherapy, or high-dose systemic methotrexate therapy. It should be performed early in therapy to
establish a baseline, at the end of therapy and at entry into long-term follow-up. If any abnormalities are noted, more frequent assessment may be needed to maintain up-to-date recommendations for the school’s individual educational plan (IEP) (Armenian et al,2015)
Neuroradiologic studies should include either CT or MRI as indicated based on physical examination, history and neurocognitive assessment. MRI is the preferred imaging modality because of its greater sensitivity in delineating white matter damage. Mild change presents as occasional punctate areas of signal abnormality, moderate as large or multiple areas of damage and severe as confluent areas of white matter damage. (Lanzkowsky et al,2016)
Patients with severe white matter damage manifest impairment in mentation, motor deficits and seizures.EEG abnormalities are relatively nonspecific, but can be useful to identify seizure activity should that be suspected based on history or physical examination. (Lanzkowsky et al,2016)
Management of any CNS deficits should include working directly with the school to produce a functional IEP designed to enhance the strengths and ameliorate the weaknesses identified in each child (Lanzkowsky et al,2016)
Some centers tested the hypothesis that mathematics training during treatment improves executive function, children with ALL were randomized to intensive individualized training in solving math problems or standard care while on treatment. While the standard care group had higher scores in applied mathematics at baseline, the intervention group improved such that it performed statistically significantly better in applied mathematics and visual memory at the end of intervention and at six-month follow-up. The standard care group did not improve in any
area, and declined in seven of 11 domains, illustrating the natural history of cognitive decline. This study shows that early intervention is feasible, beneficial, and durable ( Moore IM et al,2012)
As the childhood cancer survivor population increases, future studies will require: 1) continued refinement of CNS-directed therapies; 2) early intervention with both psychoeducational tools and novel pharmacotherapies; 3) novel pharmacologic and nonpharmacologic neuroprotective strategies during cancer therapy; 4) and resources to assess and individualize neuropsychologic intervention in the highest-risk patients. A common theme across all these is the need for consensus on less burdensome screening assessments for uniformity in practice and in clinical trials.