BRAIN AND ORBITAL TUMOR

Signs and Symptoms

Brain and orbital tumors may either be primary lesions or the result of metastasis from primary tumors originating elsewhere. Brain tumors can directly and indirectly affect the systemic and visual systems.1-4 They can occur spontaneously and idiopathically or as part of a genetic hereditary syndrome.1-3 When they grow large enough, intracranial masses have the ability to displace or compress functional elements inside the cranium (both tissue and vascular) impacting structure and function.1-4 Depending upon the tumor location, different functions may be affected. For example, patients with brain tumors may experience aphasia, ataxia, weakness, memory loss and hallucinations, among other things.5-9 When a tumor impacts the visual pathway, visual acuity or visual field loss will ensue.3-10

These defects occur in seven cardinal locations, with variations:

(1) Unilateral optic nerve location, resulting in ipsilateral central acuity and field loss.

(2) Anterior chiasmal location, resulting in ipsilateral optic nerve and crossing contralateral nasal retinal axon impingement creating an ipsilateral central loss in conjunction with a contralateral temporal hemifield defect.

(3) Chiasmal location, creating the classic bitemporal hemianopic defect, denser superiorly.

(4) Posterior chiasmal syndrome, which can have three presentations: central bitemporal, bitemporal denser inferiorly, and incongruous homonymous hemianopia.

(5) Parietal lobe location, creating a contralateral, relatively incongruous, inferior homonymous quadrantanopia sometimes referred to as “pie on the floor.”

(6) Temporal location, creating a contralateral superior homonymous quadrantanopia sometimes referred to as “pie in the sky.”

(7) Occipital lobe location, creating contralateral congruous homonymous quadrantanopia or hemianopia with or without macular sparing depending upon the location.

As tumors enlarge inside the closed cranial vault, they compress brain tissue and may elevate intracranial pressure either directly or through ventricular blockage, with resultant hydrocephalus.11,12 This can create symptoms of increased intracranial pressure such as nausea, vomiting, headache (often waking the patient from sleep, or worsening throughout the day), transient visual obscurations and pulsatile tinnitus (in the ears). The most telling sign of increased intracranial pressure is bilateral optic disc edema (papilledema).

Tumors requiring formidable vascular supply can induce anemia or ischemic cerebrovascular accident (ischemic stroke CVA) along with all of its systemic and ocular sequelae.14,15 If they or their vascular supplies hemorrhage, they can induce hemorrhagic cerebrovascular accident (hemorrhagic stroke CVA) along with its consequences.13,16,17

Diplopia and ophthalmoplegia occurring from cranial nerve III, IV or VI palsy, Horner syndrome, internuclear ophthalmoplegia, nystagmus and skew deviation, to name a few, may occur from an intracranial mass lesion impinging on various structures. Orbital tumors may present with loss of visual acuity, dyschromatopsia, relative afferent pupillary defect and proptosis.

Pathophysiology

The common brain tumors affecting the eye and visual pathway include pituitary adenoma, meningioma, glioma/astrocytoma and neurofibromas and hemangioblastoma (Von Hippel-Lindau vascular tumors).1,2

Pituitary adenomas can be either non-secreting or secreting in nature. The vast majority are non-secreting. Those that are secreting are traditionally named for the hormone that is errantly excreted when they grow. Prolactinomas (growth hormone adenomas) are among the most common types of hormone-secreting pituitary adenomas.18,19 Patients with secreting pituitary adenomas may present initially with symptoms of endocrine dysfunction such as infertility, decreased libido and galactorrhea with or without neurologic symptoms such as headache and visual changes.18,19 Patients with non-secreting tumors typically have no endocrine dysfunction.

Oversecretion of hormones from a dysfunctional pituitary gland may result in classic syndromes, the most common of which are hyperprolactinemia (from oversecretion of prolactin), acromegaly (from excess growth hormone) and Cushing’s disease (from overproduction of adrenocorticotropic hormone).18,19 Prolactinomas are more common in men.19 Amenorrhoea is a common occurrence in women.19 Acromegaly (gigantism, enlargement of the tongue) occurs in growth hormone-secreting tumors.20

When pituitary tumors bleed, they pose a life-threatening emergency known as pituitary tumor apoplexy.21 The clinical features include abrupt onset of severe headache, nausea, vomiting, deteriorating consciousness, cranial neuropathies with ophthalmoplegia, visual impairment and endocrine deficiency.21

Meningiomas are tumors of the meninges.22-24 Optic nerve sheath meningiomas (ONM) account for one third of all intrinsic tumors of the optic nerve.22-24 Despite being histologically benign, they often cause progressive visual loss that can lead to blindness if left untreated.22,23 Optic atrophy and optic disc collateral vessels are other presenting signs. Diffuse segmental optic nerve sheath thickening or globular growth is noted upon imaging.23 Calcification is a sign that the tumor is slow growing.23 OMN with posterior components have the potential for intracranial extension. Younger sufferers often demonstrate faster growth.23

Gliomas and astrocytomas are named for their cell types.26-29 Both are common tumors of the central nervous system (CNS).24 These tumors constitute a heterogeneous class of related neoplasms that are associated with a variety of molecular abnormalities affecting angiogenesis and the extracellular matrix.25 Both tumors (glioma>astrocytoma) have been associated with neurofibromatosis type 1 (NF-1) and may be seen with or without the classic skin lesion known as the “café-au-lait” spot.26 Any time optic nerve glioma is diagnosed, testing for NF-1 is advised.26-28

Astrocytomas are documented as being able to “seed” the retina, leading to retinal astrocytoma.29 There are several grades of astrocytomas, from the least aggressive (grade 1) to the most aggressive (grade 4)—notably glioblastoma multiforme (GBM), which is a rapidly growing and spreading grade 4 tumor that may not produce symptoms until it is very large. Its infiltrative nature prevents complete surgical removal, giving GBM a very grim prognosis.

Hemangioblastomas (HB) are rare, indolent CNS vascular tumors that may occur sporadically or in association with von Hippel-Lindau (VHL) disease with associated lesions occurring in many organs.30-35 VHL disease is characterized by the occurrence of primary hemangioblastic tumors in the nervous system.30 While the origin has not yet been entirely clarified, patients with VHL carry an autosomal dominant germline mutation tumor-suppressor gene.31

Dysfunction of the VHL protein causes accumulation and activation of hypoxia-inducible factor (HIF), which is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells.31 The result is endolymphatic sac tumors, which arise from proliferation of endolymphatic duct/sac epithelium.30,32 These tumors may originate in or extend into the brain.30 The tumors typically grow in the young adult population.33

The disease is associated with renal carcinoma, pheochromocytoma, paraganglioma, pancreatic neuroendocrine tumor and retinal capillary hemangioma, and is seen as discrete, circumscribed, orange-red vascular lesions found in either the peripheral or juxtapapillary retina.34 These hemangiomas constitute one of the diagnostic criteria of VHL.34

Despite being slow growing—if they grow at all—the retinal lesions are capable of causing significant visual morbidity via exudative or tractional effects (tumor induces retinal striae and distortion) on the surrounding retina.34

Management

Neurologic diseases can be diagnosed by the company they keep. Proper understanding of anatomical correlates and advancing signs and symptoms can permit approximate localization of the lesion. Clinicians armed with this knowledge can direct neuroimaging to the specifically suspected location. Neuroimaging can be completed with or without the use of intravenous contrast-enhancing dyes. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and magnetic resonance venography (MRV), under the guidance provided by the practitioner, can correctly concentrate on the proper anatomic area of suspicion. Once the lesion is located it can be identified based upon patient profile, neuroimaging features, systemic signs and symptoms, appearance, behavior, location or cell type if biopsy is possible.

Once the lesion is identified, treatment can begin. Generally, there are five strategies for the treatment of tumors:

(1) Monitor and treat symptoms; small, slow-growing non-malignant tumors may not require removal or modification, as their rate of change is so slow they may never impact a patient’s quality of life. Here, patients are educated to report for annual imaging and clinical examinations to reassess the size, location and functional impact of the tumor. Patients whose tumors impact the visual system can be monitored with serial automated perimetry, photography and neuroimaging, and can be given home-based tools such as an Amsler grid to monitor themselves for changes in acuity or field.18,19

(2) Surgical removal; resection must be done with great care, as collateral damage may impact quality of life as much as or more than allowing the tumor to remain.29

(3) Irradiation; accurately aimed internal beam radiation systems have the ability to thermally destroy tumors inside the cranium without being surgically invasive. Computer-driven systems direct tumor destruction with minimal collateral damage.22,23

(4) Medical therapy; chemotherapy is a traditional avenue for tumor treatment when surgical resection is not possible due to location or patient frailty. It works by selectively attacking tumor cells chemically. The great trick to the engineering of chemotherapeutic agents is building them so they attack bad cells while leaving the good (the magic bullet). The biggest drawback of this approach is that the medications induce substantial side effects, including hair loss, loss of appetite, fatigue, wasting and opportunistic infection. In some instances, medications exist that stabilize or stop tumor advancement. Other medications, for slow-growing tumors, are designed to reduce symptoms.18-21

(5) Deprive the blood supply; vascular endothelial growth factor (VEGF) inhibitors can involute tumor vascular systems and are effective for some tumors, with minimal side effects.31-35

Clinical Pearls

Altered mentation, slurred speech and facial droop are classic signs of stroke, requiring emergent investigation and hospitalization. They are also signs of tumor, making neuroimaging a necessary diagnostic test.

Screening visual fields are excellent tools for uncovering gross neurological visual losses.

Automated perimetry should be completed for all patients known to have brain injury (tumorous or other). The test establishes baseline parameters; subsequent evaluations will chart improvements, stability or regression.

Any time bilateral disc edema is seen, neuroimaging is indicated. Lumbar puncture cannot be performed until a space-occupying mass lesion is ruled out. Lumbar puncture in the presence of an intracranial tumor can cause life-threatening brain herniation through the foramen magnum, with subsequent respiratory arrest.

Retinal hemangiomata from VHL can be treated with observation or tumor disruption via laser photocoagulation, cryotherapy, photodynamic therapy, radiation or surgical tumor excision.

Vomiting can be seen as a response meant to dehydrate the body and relieve intracranial pressure.

1. Louis DN, von Deimling A. Hereditary tumor syndromes of the nervous system: overview and rare syndromes. Brain Pathol. 1995;5(2):145-51.

2. de Ribaupierre S, Vernet O, Vinchon M, Rilliet B. Phacomatosis and genetically determined tumors: the transition from childhood to adulthood. Neurochirurgie. 2008;54(5):642-53.

3. Lanphear J, Sarnaik S. Presenting symptoms of pediatric brain tumors diagnosed in the emergency department. Pediatr Emerg Care. 2014;30(2):77-80.

4. Jardón J, Delgado L, Izquierdo NJ. Neuroophthalmology meets oncology: a case report. Bol Asoc Med P R. 2012;104(4):41-4.

5. Kundu B, Penwarden A, Wood JM, et al. Association of functional magnetic resonance imaging indices with postoperative language outcomes in patients with primary brain tumors. Neurosurg Focus. 2013;34(4):6.

6. Czapiewski P, Szmuda T, Dzierżanowski J. Pseudo-stroke manifestation of multiple myeloma: a report of two cases with literature review. Folia Neuropathol. 2013;51(1):87-91.

7. Lim A, Weir P, O’Brien TJ, Kaye AH. Complex visual hallucinations as a presentation of temporal low-grade glioma. J Clin Neurosci. 2011;18(1):157-9.

8. Lee TS. Transient and spontaneously-remitting complex hallucinations in a patient with melanoma and brain metastases. Psychosomatics. 2010;51(3):267-70.

9. Kan E, Kan EK, Atmaca A, et al. Visual field defects in 23 acromegalic patients. Int Ophthalmol. 2013;33(5):521-5.

10. Obuchowska I, Mariak Z. Homonymous hemianopsia. Klin Oczna. 2012;114(3):226-9.

11. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care. 2011;15(3):506-15.

12. Passi N, Degnan AJ, Levy LM. MR imaging of papilledema and visual pathways: effects of increased intracranial pressure and pathophysiologic mechanisms. AJNR Am J Neuroradiol. 2013;34(5):919-24.

13. Tamhankar MA, Biousse V, Ying GS, et al. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: a prospective study. Ophthalmology. 2013;120(11):2264-9.

14. Anila KR, Nair RA, Koshy SM, Jacob PM. Primary intravascular large B-cell lymphoma of pituitary. Indian J Pathol Microbiol. 2012;55(4):549-51.

15. Iglesias P, Castro JC, Díez JJ. Clinical significance of anaemia associated with prolactin-secreting pituitary tumours in men. Int J Clin Pract. 2011;65(6):669-73.

16. Gempt J, Gerhardt J, Toth V, et al. Postoperative ischemic changes following brain metastasis resection as measured by diffusion-weighted magnetic resonance imaging. J Neurosurg. 2013;119(6):1395-400.

17. Sattler MG, Vroomen PC, Sluiter WJ, et al. Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone. Int J Radiat Oncol Biol Phys. 2013;87(1):53-9.

18. Lake MG, Krook LS, Cruz SV. Pituitary adenomas: an overview. Am Fam Physician. 2013;88(5):319-27.

19. Delgrange E, Raverot G, Bex M, et al. Giant prolactinomas in women. Eur J Endocrinol. 2013;170(1):31-8.

20. Jallad RS, Bronstein MD. The place of medical treatment of acromegaly: current status and perspectives. Expert Opin Pharmacother. 2013;14(8):1001-15.

21. Zieliński G, Witek P, Koziarski A, Podgórski J. Spontaneous regression of non-functioning pituitary adenoma due to pituitary apoplexy following anticoagulation treatment – a case report and review of the literature. Endokrynol Pol. 2013;64(1):54-8.

22. Shapey J, Sabin HI, Danesh-Meyer HV, Kaye AH. Diagnosis and management of optic nerve sheath meningiomas. J Clin Neurosci. 2013;20(8):1045-56.

23. Saeed P , Rootman J, Nugent RA, et al. Optic nerve sheath meningiomas. Ophthalmology. 2003;110(10):2019-30.

24. Hallinan JT, Hegde AN, Lim WE. Dilemmas and diagnostic difficulties in meningioma. Clin Radiol. 2013;68(8):837-44.

25. Nicholas MK, Lukas RV, Jafri NF, et al. Epidermal growth factor receptor – mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res. 2006;12(24):7261-70.

26. Curless RG, Siatkowski M, Glaser JS, Shatz NJ. MRI diagnosis of NF-1 in children without café-au-lait skin lesions. Pediatr Neurol. 1998;18(3):269-71.

27. Chateil JF, Soussotte C, Pédespan JM, et al. MRI and clinical differences between optic pathway tumours in children with and without neurofibromatosis. Br J Radiol. 2001;74(877):24-31.

28. Segal L, Darvish-Zargar M, Dilenge ME, et al. Optic pathway gliomas in patients with neurofibromatosis type 1: follow-up of 44 patients. J AAPOS. 2010;14(2):155-8.

29. Cohen VM, Shields CL, Furuta M, Shields JA. Vitreous seeding from retinal astrocytoma in three cases. Retina. 2008;28(6):884-8.

30. Vortmeyer AO1, Falke EA, Gläsker S, et al. Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms. Acta Neuropathol. 2013;125(3):333-50.

31. Capitanio JF, Mazza E, Motta M, et al. Mechanisms, indications and results of salvage systemic therapy for sporadic and von Hippel-Lindau related hemangioblastomas of the central nervous system. Crit Rev Oncol Hematol. 2013;86(1):69-84.

32. Pavesi G, Feletti A, Berlucchi S, et al. Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: benefits, risks and outcome. J Neurosurg Sci. 2008;52(2):29-36.

33. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617-23.

34. Wong WT1, Chew EY. Ocular von Hippel-Lindau disease: clinical update and emerging treatments. Curr Opin Ophthalmol. 2008;19(3):213-7.

35. Hawasli AH, Rubin JB, Tran DD. Antiangiogenic agents for nonmalignant brain tumors. J Neurol Surg B Skull Base. 2013;74(3):136-41.