Wednesday, 9 January 2013

Brainstem gliomas in childhood

Roger J Packer MD, contributing editor. Dr. Packer of the Children's National Medical Center and George Washington University has no relevant financial relationships to disclose.

Publication dates
Originally released October 14, 1996; last updated September 5, 2012; expires September 5, 2015
Key points
  • Brainstem gliomas occur most frequently in children, with the majority being diffuse pontine gliomas.
  • Approximately 20% of childhood brainstem gliomas are not diffuse pontine tumors; these non-diffuse pontine lesions, such as tectal gliomas and exophytic cervicomedullary tumors, are often low-grade gliomas and have a relatively good prognosis.
  • Over 90% of children with diffuse pontine gliomas will die of disease within 18 months of diagnosis.
  • Radiotherapy remains the only effective, albeit transient, therapy for diffuse pontine gliomas.

Historical note and nomenclature
Brainstem gliomas are, by definition, glial tumors that primarily arise within the brainstem. Concepts concerning brainstem gliomas have changed remarkably since the advent of MRI. Although the majority of brainstem gliomas arise in the pons, subsets of patients have been identified with more caudal or rostral tumors (Packer et al 1993a; 1993b). In addition, MR has more clearly identified the extent of lesions and the tendency of some brainstem tumors to infiltrate the diencephalon, the cervical cord, and even the cerebellum (Barkovich et al 1991).

The pathology of brainstem gliomas is complex. Although pure low-grade and high-grade tumors do exist, more commonly a mixed glial pattern is seen, with areas of low-grade glioma in contiguity with regions of frank anaplasia (Littman et al 1980). For unclear reasons, the location of the tumor within the brainstem is often related to pathology, as benign lesions tend to occur more frequently in the mesencephalon and the low medulla. Therefore, brainstem gliomas are separated into 3 relatively distinct, but overlapping, groups: (1) diffuse pontine gliomas, (2) tectal lesions, and (3) cervicomedullary masses.

Diffuse intrinsic brainstem gliomas almost always involve the pons, with or without extension to other brainstem sites, and constitute the majority of childhood tumors. These primarily pontine or diffuse intrinsic tumors make up approximately 80% of all brainstem gliomas and are highly resistant to treatment. Pathologically intrinsic diffuse brainstem tumors usually display mixed features, including areas of malignancy.

Up to 10% of brainstem gliomas arise in the medulla or at the cervicomedullary junction (Epstein and McCleary 1986; Stroink et al 1987). These tumors tend to be dorsally exophytic and histopathologically low-grade—the majority being pilocytic astrocytomas. Such cervicomedullary tumors carry a more favorable prognosis and may be amenable to total, or near-total, surgical resection.

Focal, or localized, tumors of the mesencephalon may also occur. Such lesions, especially those of the tectum, are often indolent and histopathologically low-grade (Vandertop et al 1992).

Children with neurofibromatosis type 1 are at increased risk to develop apparent brainstem gliomas (Milstein et al 1989; Pollack et al 1996). The patterns of growth and presentation for children with brainstem lesions and neurofibromatosis are variable, with some patients being asymptomatic at the time when lesions are radiographically identified and others having stable neurologic deficits. Once again, the understanding of brainstem gliomas in children with neurofibromatosis has changed dramatically since the advent of MRI, especially with routine screening of asymptomatic newly diagnosed patients with neurofibromatosis. It is now believed that many such lesions are hamartomas that will not grow over time. In any event, all lesions in children with neurofibromatosis should be evaluated circumspectly, and treatment should only follow documented progression.

Despite the initial variability in clinical presentation and histopathologic features at the time of diagnosis, later in the course of disease, the majority of patients with progressive brainstem gliomas will be found to harbor tumors that show areas of malignancy. It is unclear whether this finding represents a dedifferentiation of the tumor or whether malignant foci were present in the tumor at the time of diagnosis. At the time of progression, intrinsic brainstem gliomas tend to be extremely bulky and infiltrative, essentially destroying the normal architecture of the brainstem. Leptomeningeal dissemination is not rare at the time of disease progression, occurring in up to one third of patients at initial relapse.
Clinical manifestations
Diffuse intrinsic brainstem gliomas classically present with the triad of cranial neuropathies, ataxia, and long tract signs (Panitch and Berg 1970). The type of neurologic compromise present is obviously dependent on the location of the tumor. Because the majority of diffuse intrinsic brainstem gliomas arise in the pons, sixth and seventh nerve dysfunction are most frequent. Lower cranial nerve deficits may also occur but are infrequently the first sign of diffuse intrinsic lesions. Rarely, patients will present with an isolated cranial neuropathy, such as peripheral seventh nerve palsy. The majority of patients will have some type of gait disturbance at the time of diagnosis. This disturbance is often an intermixture of long tract signs and ataxia. The classical presentation of crossed hemiparesis, with a seventh nerve palsy on one side and arm and leg weakness on the other side, clearly points to intrinsic lateralized brainstem involvement.

The duration between the onset of symptoms and the diagnosis of a brainstem lesion has changed with the improvement in neuroimaging techniques (Barkovich et al 1991; Kaplan et al 1996). The majority of patients are now being diagnosed within 2 months of the insidious onset of symptoms, whereas prior to CT and MRI, most patients were diagnosed between 3 and 6 months of clinical presentation. Approximately one third of patients with brainstem tumors will have headache associated with nausea and vomiting. Although brainstem tumors can be bulky at diagnosis, with both anterior and posterior extension, only one third of patients will have hydrocephalus. Interestingly, patients may also experience significant personality changes prior to diagnosis. The reasons for such personality changes are unclear but may be due, in part, to the interruption of thalamic projections. In children less than 5 years of age, unexplained irritability is a frequent initial symptom.

The presentation of patients with localized cervicomedullary lesions differs from that of patients with diffuse intrinsic tumors. The patients with cervicomedullary lesions often have long histories of nonspecific headaches and vomiting (Stroink et al 1987). The headaches and vomiting rarely just occur early in the morning and are likely to occur at variable times during the day. Vomiting is usually projectile and is often unrelated to food intake. At time of diagnosis, patients may have little in the way of focal neurologic deficits or may have swallowing difficulties associated with lower cranial nerve (9, 10, 11, 12) dysfunctions. Swallowing difficulties and drooling tend to occur in young children.

Tumors of the midbrain or upper tectum often present with little, if any, focal neurologic deficits (Vandertop et al 1992; Pollack et al 1994; Robertson et al 1995). Tectal masses most commonly result in hydrocephalus with associated headaches, nausea, and vomiting. After diversion of cerebrospinal fluid, there may be a complete disappearance of symptoms. Less frequently, patients with tectal lesions will have frank extraocular movement dysfunction including Parinaud syndrome (paralysis of upgaze, lid retraction, convergence nystagmus, and pupils that react better to accommodation than to light).

Occasionally, focal pontine lesions will arise, presenting with isolated seventh nerve palsies. These lesions are usually pilocytic astrocytomas and seem to carry a better prognosis (Edwards et al 1994).