Intracranial Meningioma with Ophthalmoplegia in a Rhesus Macaque (Macaca mulatta)

Abstract

A 21-y-old female rhesus macaque presented with signs of internal and external ophthamoplegia, including anisocoria and ptosis. Ophthalmoplegia is the paralysis or weakness of one or more intraocular or extraocular muscles that control the movement of eye; this condition can be caused by neurologic or muscle disorders. The macaque was euthanized due to progression of clinical symptoms, and postmortem gross examination revealed a mass at the base of the brain attached to the meninges. Histopathologic examination led to the diagnosis of intracranial meningioma. Here we describe a case of intracranial meningioma with internal and external ophthalmoplegia in a rhesus macaque (Macaca mulatta).

Meningioma is a tumor that develops in the meninges, including the dura mater, arachnoid mater, and pia mater, all of which surround the brain and spinal cord. In humans, meningioma is the most frequently encountered primary intracranial neoplasia and accounts for approximately 35% of all reported primary brain tumors in the United States.^5,7 Clinical manifestations are dependent on the size and location of the tumor.^3,23 To our knowledge, only 3 cases of naturally occurring meningioma in nonhuman primates have been reported; these cases affected 2 baboons and 1 collared brown lemur.^17,19,21 The meningiomas of 2 of these previous cases were described only briefly as part of a disease survey of neoplasia in 100 free-ranging baboons and a captive prosimian population.^17,21 The third report focused on the pathologic features of the meningioma described with no mention of the clinical signs in the baboon, although its location was similar to that of the case we describe here.¹⁹

In the current case report, we describe the clinical manifestations, postmortem examination, and diagnosis of an intracranial meningioma in a rhesus macaque (Macaca mulatta).

Case Report

A 21-y-old female rhesus macaque was presented due to anisocoria. The animal was individually housed indoors at the California National Primate Research Center (Davis, CA). The facility is AAALAC-accredited, and all animals are maintained in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act.^1,10 Physical examination revealed anisocoria with mydriasis of the left eye that was enhanced with light (Figure 1). The differential diagnoses for unilateral mydriasis include palsy of cranial nerve III, tonic pupil, pharmacologic mydriasis, and iris damage. Pharmacologic dilation of the pupil was ruled out because the macaque had no history of receiving drugs that could affect pupil size. Slit-lamp biomicroscopy did not reveal any abnormalities in the structure of the iris. CBC and serum biochemistry data revealed no significant findings.

Figure 1.

Anisocoria with mydriasis of the left eye.

The left eye had a sluggish direct and absent consensual pupillary light reflexes. The right eye had normal direct and consensual pupillary light reflexes. These reflexes involve 2 pathways, afferent and efferent.^24,25 The afferent pathway is activated by light stimulating the retinal photoreceptors and causing a signal to pass along the optic nerve to the pretectal area of the midbrain. From here, signals pass bilaterally to the right and left Edinger–Westphal nuclei, where the efferent pathway of the pupillary light reflex begins. From the Edinger–Westphal nuclei, the signal passes along the oculomotor nerve to the ciliary ganglion, from which the postganglionic fiber innervates the constrictor muscles of the iris. Evaluation of the response of the iris to light allows assessment of both the afferent and efferent pathways via direct and consensual pupillary light reflexes. In an animal with a normal pupillary light reflex, the light shined into an eye will cause the pupils in both that eye (direct pupillary light reflex) and the opposite eye (consensual pupillary light reflex) to constrict. If a unilateral afferent lesion is present, signals produced by light shined into the affected eye will not reach either Edinger–Westphal nucleus, so there will be neither direct nor consensual pupillary light reflexes from light directed into the affected eye; however, light directed into the unaffected eye will elicit both direct and consensual pupillary light reflexes. In the case of a unilateral efferent lesion, light in the affected eye will result in only a consensual pupillary light reflex, whereas light in the unaffected eye will cause only a direct pupillary light reflex. In this macaque, the lack of a direct pupillary light reflex to light in the left eye combined with a weak (left) consensual response to light in the right eye inconclusively suggested an efferent lesion on the left side.

Two weeks after the initial presentation, the macaque was reassessed. Physical examination revealed a remarkable ptosis and a progressed mydriasis, with complete absence of direct and consensual pupillary light reflexes in the left eye. Instillation of 0.1% pilocarpine ophthalmic solution in the left eye caused pupil constriction, thereby ruling out iris damage. Tonic pupil was ruled out, because this condition does not usually include ptosis. Ultrasound examination revealed no evidence of orbital neoplasia or inflammation. At this point, given the clear results after light stimulation, a left-sided efferent lesion (palsy of cranial nerve III) was considered to be the most likely cause of the mydriasis and ptosis, because activity in this nerve is responsible for controlling not only the iris sphincter muscle (sphincter pupillae) but also the upper eyelid muscle (levator palpebrae superioris). Because no clinical improvement was noted after 7 d of treatment with prednisone (2 mg/kg PO every 12 h), the macaque was euthanized by sodium pentobarbital overdose and submitted for diagnostic necropsy.

At gross necropsy, the macaque was thin with prominent anisocoria because of left-sided mydriasis (Figure 1). Examination of the cranial cavity revealed a firm, off-white, well vascularized, irregularly ovoid, 2.0 × 1.5 × 1.5 cm, bosellated mass adherent to the meninges at the base of the brain, centered approximately over the left lateral-most aspect of the sella turcica (Figure 2). The mass compressed the midbrain superiorly and slightly medially (Figure 3) and placed pressure on cranial nerves III and IV where they penetrate the dura mater to enter the cavernous sinus before gaining access to the orbit through the superior orbital fissure. Other findings at gross necropsy included a soft, ovoid (1.0 cm in greatest dimension), subcutaneous mass on the dorsal aspect of the right wrist (consistent with lipoma), multifocal gastric mucosal erythema (gastritis), a thick-walled cyst in the liver, and a proximal colonic ulcer.

Figure 2.

A large, ovoid and lobular mass is located caudal to the optic chiasm and firmly attached to the meninges which, in turn, have remained attached to the base of the skull.

Figure 3.

Ventral view of the brain. Note the indentation in the left lateral aspect of the midbrain.

Tissues were fixed in 10% neutral buffered formalin, processed routinely, and embedded in paraffin. Sections (5 µm) were mounted on glass slides and stained with hematoxylin and eosin. Histologically, the mass was composed of sheets, streaming ribbons, and whorls of cells having indistinct borders and generally small to moderate amounts of pale eosinophilic cytoplasm (Figure 4). Nuclei varied from round to oval in the sheet formations to elongate or spindle-shaped in the ribbon and whorl formations. Nuclear chromatin was finely stippled. The nuclei often contained a single nucleolus (rarely 2 nucleoli), and mitoses were uncommon, numbering less than 3 per 10 high-power (400×) fields. Anisocytosis, anisokaryosis, and pleiomorphism were mild to moderate, and multinucleate cells were present but rare. Indistinct tumor lobules were delineated by thin bands of fibrous connective tissue, and small blood vessels were frequent, often with thickened, hyalinized walls. Areas of necrosis undergoing dystrophic mineralization were scattered throughout the mass. No evidence of tumor invasion into the brain was detected, nor was there any evidence of hyperostosis of the skull, as is sometimes associated with meningioma in humans.^2,18,20 The World Health Organization describes 16 histologic subtypes of meningioma; the histologic characteristics of the tumor we describe here are consistent with a diagnosis of a meningothelial meningioma.^14,15

Figure 4.

Meningothelial meningioma composed of round to spindle-shaped cells arranged in islands, sheets, and indistinct whorls. Bar, 100 µm.

Discussion

Meningothelial meningioma is classified as a grade I tumor, according to criteria from the World Health Organization.^14,15 Most meningiomas are grade I benign tumors with clinical signs dependent on the size and location of the tumor and usually as a result of the tumor compressing surrounding neurovascular structures. Meningiomas are thought to derive from arachnoidal cap cells⁶ and can potentially develop at any site in the meninges. In humans, the majority of meningiomas are located in the supratentorial region.⁶ In both a previously reported case in a baboon (in which the site was reported)¹⁴ and the present case in a rhesus macaque, the tumors were found at the base of the brain. Cranial nerves III, IV, and VI and the ophthalmic branch of cranial nerve V all converge at the cavernous sinus and enter the orbit through the superior orbital fissure. Although the tumor we describe here likely placed pressure on the point where these nerves converge (on the left side), only signs associated with cranial nerve III were observed. Because cranial nerves IV and VI are responsible for contracting the superior oblique muscle and lateral rectus muscle, respectively, the clinical presentation associated with these nerve palsies includes esotropia, accompanied by diplopia. The ophthalmic branch of cranial nerve V carries only sensory nerve fibers, so damage to the nerve causes the absence of corneal and palpebral reflexes. In the present case, none of these signs was observed. The tumor compression probably caused damage only to cranial nerve III, although histologic examination of cranial nerves was not performed. In both humans and dogs, females are more likely to develop meningioma;^5,6,11,19 in humans, the ratio is approximately 2:1.^5,6,11 Several studies suggest an association between the increased incidence in women and sex hormones, based on the presence of estrogen, progesterone, or androgen receptors (or their combination) in meningiomas,^{4,8,9,12,13,16,25} although the association is not consistent. The fact that the previously reported baboon and lemur were female,^17,19,21 as was the rhesus macaque we describe here, suggests the possibility that nonhuman primates may mirror the predominance of meningioma in female humans, although the number of cases in these animals is small as yet.