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Paper Abstract

Gliomas in Neurofibromatosis

Overview

Neurofibromatosis (NF) is not a single disease entity but refers to three distinct conditions (NF1, NF2, and Schwannomatosis) with the development of tumors of the brain, spinal cord, and the nerves that transmit signals between the brain, spinal cord, and all other parts of the body. The most common form of NF is Neurofibromatosis Type 1 (NF1). Gliomas are a common type of tumor originating in the brain. About 33% of all brain tumors are gliomas, which originate in the glial cells that surround and support neurons in the brain, including astrocytes, oligodendrocytes, and ependymal cells. These gliomas are termed intra-axial brain tumors because they grow within the substance of the brain and often mix with normal brain tissue. Gliomas may range from low to high grades, based on their histological characteristics. The most common central nervous system tumors in NF1 are low grade gliomas, with the optic pathway glioma being a hallmark tumor.

In this regard, low-grade gliomas (LGGs) predominate in children, while high-grade gliomas are more commonly seen in young adults with NF1. The gliomas in NF1 may occur along the optic nerve pathway, brainstem, and cerebellum.  But the most common is the optic pathway gliomas (OPGs) and brainstem gliomas (BSGs).

Clinical presentation

Most of the tumors that arise in NF1 are OPGs and have a distinct predilection to involve the optic nerve, chiasm, and hypothalamus. These optic pathway gliomas are typically found in young children, afflicting 15% to 20% of patients with NF1. Although these tumors seem to have a more indolent behavior and may even regress without treatment, they can cause significant morbidity and progress in some patients. Bilateral optic gliomas are nearly characteristic in NF1 patients. NF1 Optic pathway glioma patients present with symptoms that include ophthalmological abnormalities, such as strabismus (squint/crossed eyes), visual field defects, decreased visual acuity, abnormal pupillary function, decreased color function, optic nerve atrophy or proptosis ( forward placement) as well as a diencephalic syndrome and precocious puberty, especially in optic chiasmatic tumors. Other symptoms include headaches, seizures, personality changes, weakness in the arms, face, or legs, numbness, problems with speech, dizziness, nausea, and vomiting.

The brainstem is the second most common location of gliomas associated with NF1. Patients with BSGs usually present with classic brainstem symptoms such as ataxia (loss of coordination of muscles, especially extremities) long tract signs, cranial nerve deficits, or any blend of them. Even though symptoms may vary upon the tumor localization, typically, the presence of any cranial nerve dysfunction accompanied by long tract signs is usually suggestive of a BSG. Patients may also present with headaches and signs of increased intracranial pressure if the cerebrospinal fluid drainage is obstructed by the tumor, which may cause hydrocephalus (accumulation of fluid within the cranium). In NF1 patients, brainstem tumors are most often found in the lower medulla, followed by the pons, and finally in the midbrain. BSGs in NF1 are also most often asymptomatic like optic pathway gliomas and show a low frequency of clinical progression.

Diagnosis

Diagnosis of gliomas associated with NF1 is mainly based on a thorough medical history followed by a general physical examination which includes details about the patient’s symptoms, and personal and family health history. A neurological evaluation followed by tests for vision, hearing, speech, strength, sensation, balance, coordination, and reflexes is performed, followed by a complete ophthalmological assessment. Magnetic resonance imaging (MRI) is the preferred imaging modality that helps in assessing the progression of the tumors as well as aid in treatment planning. The final diagnosis for OPGs as well as BSGs is based on the clinical findings, and neuroimaging studies using MRI followed by histological confirmation.

Research over the past 20 years has revealed numerous risk factors that can alter NF1-associated glioma formation and progression. These include the germline NF1 gene mutations, patient age and sex, background genomics (ethnicity/race), co-existing atopic (sensitivity to allergens, which can be familial) conditions (eczema, asthma), tumor location within the neuroaxis, the presence of additional somatic mutations in the tumor, and prior tumor treatment (radiation therapy).

Management

The gliomas associated with NF1 are preferable, managed by a multidisciplinary team of specialists as they involve a varied spectrum of manifestations. The majority of NF1-associated gliomas can be approached conservatively and often close observation may be sufficient in asymptomatic patients. However, for patients with diagnostic clinical symptoms and radiographic findings, treatment should be planned accordingly. NF1-associated tumors are often benign, secondly, it is difficult to predict which tumors will result in clinical symptoms, and thirdly current therapies, especially radiation, may increase the risk of secondary tumors or malignant transformation of benign tumors. Surgery and/or chemotherapy are the preferred interventional standard treatment approaches over radiotherapy, considering the deleterious post-irradiation complications. The most common OPGs should be treated with a multidisciplinary approach to decide the timing and form of treatment while taking into account visual function and tumor progression.

Brainstem gliomas are typically benign and progress clinically in only one-third or fewer of the patients. Similar to OPGs, NF1-associated brainstem gliomas are more indolent than those not associated with NF1 and most often do not require clinical intervention or treatment, suggesting that conservative management is optimal. Despite the higher incidence of symptomatic presentation, very few NF1-associated BSGs will exhibit further growth on MRI after the initial diagnosis, and even fewer will demonstrate symptomatic progression. For this reason, observation is recommended for asymptomatic children with NF1-associated BSGs.

Quality of life

Quality of life (QOL) is presented as an index of all factors affecting the quality of life of the patient to map the disease’s progress. It is possible to examine the effect of the illness on QOL through questionnaires specific to the disease or general questionnaires. A systematic review and meta-analysis reported that QOL in all subdomains of physical function, mental and emotional status, social functioning status and general health has decreased significantly in adult NF patients. Also, there was some strong evidence suggesting that children affected by NF have low-level QOL compared to the general population.

Many promising trials are underway to create therapies that are more specifically targeted to NF1-related tumors. However, future studies are still needed to better predict which tumors will remain benign and which will progress further to cause clinical losses in order to start treatment as early as possible and thus help to focus on improving the quality of life of patients with gliomas associated with NF1.

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