Neurofibromatosis type 1 - Ophthalmologic Exam is recommended
Short Summary

5-year-old boy was diagnosed with neurofibromatosis type 1 (NF1) eight months after birth. He has displayed café-au-lait spots, axillary freckling, macrocephaly, sphenoid dysplasia, brain hamartomas, right temporal arachnoid cyst, and optic glioma. Visual evoked potentials showed evidence of bilateral functional deficit.

Patient's Questions
1)    Do you agree with the need for starting a therapy at the present stage of disease? as advised by the Policlinico San Matteo in Pavia? 
2)    Do you think that the proposed therapeutic indication from the Hospital San Matteo in Pavia is correct?
Medical Background

Date of birth - May 2004. 
4-year 9-month-old boy has a history of neurofibromatosis type 1 (NF1), diagnosed since January 2005. He has displayed typical manifestations of NF1 so far, namely café-au-lait spots, axillary freckling, macrocephaly, sphenoid dysplasia, brain hamartomas and right temporal arachnoid cyst, and most notably here, thickened and kinked optic nerves, left more than right, with enlargement of the chiasm, predominantly on left, i.e., an optic glioma.
Visual evoked potentials (VEPs) were performed on January 2009 with “evidence of bilateral functional deficit.” 

Expert's Opinion

I do not have any indication of the child’s clinical exam by the pediatric ophthalmologist, specifically measurement of visual acuity or assessment of visual fields. Such data are crucial (see rationale below). If such information is available, I would be most willing to review; if not performed, such data are crucial and should be sought in every way possible unless the child is completely unamenable to ophthalmologic exam.
In reference to the lesion of the optic nerves and enlarged chiasm, unbiopsied but referred to here as optic glioma, the patient's MRI on July 2008, compared to July 2007, was substantially unchanged except for small increase at the right suprasellar cistern. In other words, the child was felt to have stable disease. Now the February 2009 MRI shows slight increase in size of the sellar-suprasellar portion (approximately 2 x 2.5 cm) of the optic glioma. On my view, the lesion is a bit more cystic with more enhancement but not radically different in overall size. 
(1) Does Alessandro need to start treatment with chemotherapy for this optic glioma? 
No, not necessarily so, but the clinical circumstances here are highly important.
In general, many, many children with NF1 have thickened optic nerves, and some kinked, even scary-looking nerves or chiasm, yet normal visual function as far as acuity and fields. Again, a number of NF1 children have the appearance of optic glioma at the chiasm that may or may not need treatment. 
The decision of if and when to initiate treatment hinges on the child’s ophthalmologic exam, namely the acuity and visual fields. In the United States we do not rely on visual evoked potentials to make this decision, as such are poor markers of acuity and fields, unless there is a radical and drastic reduction in the electrical signals by VEPs. We should recognize that because of the white matter abnormalities, hamartomas, subcortical spots and MRI changes we see in so many children with NF1, we expect just about any child with NF1 to have some abnormality of VEPs.
Thus, if this child has close to normal visual acuity and fields, as determined by a pediatric ophthalmologist, and has not displayed some definitive reduction of acuity and/or fields, we would NOT commence chemotherapy based on simply the small change on MRI.
However, if the child has clear decline of visual function by acuity or fields, or has acuity less than the United States measurement of 20/40-20/50 OU, then we would commence chemotherapy.
The internationally regarded neuro-ophthalmologist William Hoyt from UCSF cautioned decades ago, prior to MRI or computed tomography (CT), not to overreact or over-treat optic gliomas in NF1. His advice remains true today. We know that many NF1 children have MRIs that look worrisome, but if there visual acuity and fields are acceptably normal, we watch and wait, and do not give chemotherapy or radiotherapy. There are even case reports of spontaneous waxing and waning of optic glioma size and visual function on NF1 patients. The lesson is clear: do not treat unless the medical team is convinced of a change in visual function.
 
(2) Would the SIOP induction carboplatin/vincristine chemotherapy be the correct plan if treatment is necessary, i.e., if the medical team is convinced of a change in visual function.
Yes. The mainstay of treating optic gliomas in all children under age 10 years is carboplatin/vincristine. Other chemotherapeutics have been used, but in the child with NF1 we almost always choose these drugs because of their lower potential of inducing leukemia in the child with NF1. In the United States there has been debate about monthly (Pediatric Oncology Group, POG) vs. weekly carboplatin (Packer regimen). These two different ways of administering carboplatin have the same efficacy, though the monthly administration has less chance of allergic reaction and other side effects (J Clin Oncol 2002;20:2951-8).
It should be noted too that carboplatin and vincristine do not tend to reverse these tumors, but instead stabilize the tumor until a child is older and radiotherapy can be given. The carboplatin and vincristine chemotherapy data in optic gliomas (NF1 and non-NF1 together) collectively show approximately the following effectiveness: chance of complete disappearance of tumor (complete response) 2-5%; chance of shrinkage on the order of 25% to 50% or more (minor or partial response) 30-35%; no change in size whatsoever (stable disease) 50%; and optic glioma growth (progressive disease) 10-15%. Recall again that many optic gliomas, in NF1 especially, do not change even when no treatment is administered, and the same holds true for many low-grade gliomas/astrocytomas (Pediatr Blood Cancer 2008;51:245-50).

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