Cerebral cysts of ependymal or ventricular origin in a juvenile rhesus macaque (Macaca mulatta) with neurologic signs

Abstract

Naturally occurring neurologic disease in non-human primates may be attributable to a wide-range of causes, including infectious agents, congenital or acquired malformations, degenerative diseases, and, rarely, neoplasia. We report a case of ataxia and paresis in a juvenile rhesus macaque with ependymal-lined cerebral cysts.

1. INTRODUCTION

Nervous system disorders in rhesus macaques (Macaca mulatta), as in other veterinary species, range from naturally occurring infections to congenital and developmental diseases to metabolic derangements to primary and metastatic neoplasms, although the latter are relatively rare in non-human primates (NHPs).¹ In addition, rhesus macaque models of human neurologic conditions such as Parkinson’s disease, multiple sclerosis, and stroke have been developed.¹ Ataxia, paresis or paralysis, and seizure are common neurologic signs associated with non-specific nervous system disorder in NHPs. Investigating the cause of neurologic disease often requires antemortem testing, including neurologic examination, cerebrospinal fluid analysis, and magnetic resonance imaging, as well as postmortem examination. We report a case of ependymal-lined cerebral cysts noted on postmortem examination in a juvenile rhesus macaque with ataxia and paresis.

2. SUBJECT AND METHODS

All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the Oregon National Primate Research Center (ONPRC). The ONPRC is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.

A 3-year-old, 3.8 kg, female rhesus macaque (Macaca mulatta), outdoor group housed at the ONPRC, presented for favoring left front and left hind limbs. The macaque was a non-experimental animal and considered specific pathogen free by yearly serological testing for simian retrovirus, simian T-cell leukemia virus, simian immunodeficiency virus, Macacine herpesvirus 1, and measles. Left forearm muscle atrophy was noted on sedated physical exam (10 mg/kg intramuscular [IM] ketamine; Henry Schein Brand pharmaceuticals, Dublin, OH). Radiographs of all limbs revealed no obvious bone abnormalities. Complete blood count (CBC) showed mild thrombocytosis (510 × 10³/mm; reference interval [RI] 119–471 × 10³/mm) and lymphocytosis (5.74 × 10³ μL; RI 1.13–3.77 10³ μL). Serum blood chemistry was unremarkable. Following a loading dose of oral meloxicam (0.2 mg/kg; CEVA Animal Health, Lenexa, KS) and 2 days of IM meloxicam maintenance doses (0.1 mg/kg), left hind limb lameness resolved and the macaque was returned to the social group. The animal was ambulating well with no gait abnormalities, although she continued to preferentially grasp treats with the right hand and used the left front limb only to climb and swing.

Two weeks after initial presentation, the macaque presented with ataxia and hypermetria of the forelimbs. General observation revealed normal mentation. The animal was sedated (5 mg/kg IM Telazol; Zoetis, Troy Hills, NJ). Indirect and direct pupillary light reflexes were intact and otoscopic examination of both ears was unremarkable. Cerebrospinal fluid (CSF) collected from the cisterna magna was clear and submitted for aerobic and anaerobic cultures. Repeat CBC showed absolute neutrophilia (15.57 × 10³ μL; RI 2.38–9.61 × 10³ μL), lymphocytosis (5.28 × 10³ μL; RI 1.13–3.77 × 10³ μL), monocytosis (1.48 × 10³ μL; RI 0.19–0.92 × 10³ μL), and basophilia (0.32 × 10³ μL; RI 0.02–0.1 × 10³ μL). Serum chemistry panel showed mild hypoproteinemia (5.8 g/dL; RI 6.0–7.9 g/dL).

Although aerobic and anaerobic CSF cultures yielded no growth, therapeutics, including a morning dose of intravascular (IV) metronidazole (20 mg/kg; APP Pharmaceuticals Schaumburg, IL), an evening dose of oral metronidazole (25 mg/kg), once-daily IV ceftriaxone (50 mg/kg; Hikma Phramaceuticals, Eatontown, NJ), and once-daily IM meloxicam (0.1 mg/kg), continued prophylactically for possible bacterial meningoencephalitis. Emesis and persistent retching occurred during initial administration of diluted IV ceftriaxone given over 10 minutes. IV ondansetron (0.125 mg/kg; Hikma Pharmaceuticals) and famotidine (0.5 mg/kg; West-Ward, Eatontown, NJ) were administered, and signs of nausea ceased. Before subsequent ceftriaxone administrations, pre-sedation IM ondansetron (0.125 mg/kg) was administered. Breakthrough emesis occurred during one treatment.

Seven days after initiating antibiotic therapy, intermittent head tossing, clockwise turning, dull mentation, and piloerection were observed. Due to poor prognosis, the animal was euthanized and underwent postmortem examination.

3. RESULTS

On gross examination, there was one large cyst in each of the cerebral hemispheres, asymmetrically expanding both the occipital and temporal lobes. The right cerebral cyst markedly dilated and distorted the caudal occipital lobe (Figure 1a), while the left cerebral cyst protruded from the rostral temporal lobe (Figure 1b). The cysts each contained 10–15 mL of clear, red-tinted fluid that was negative on bacterial culture. On cross section, the cysts communicated with the lateral ventricles (Figure 1c). Sagittal section revealed a compressed cerebral aqueduct (image not shown). Along the surface of the cerebellum and the brain stem were brown to tan foci, consistent with pressure necrosis or hemorrhage from the space occupying cysts. No cranial or vertebral deformities were observed.

Figure 1:

Dorsal (A) and ventral (B) aspects of the brain highlight right occipital and left temporal fluid-filled cysts (asterisks). A cross section of fixed cerebrum at the level of the occipital lobes (C) shows markedly dilated ventricles.

Microscopically, the cysts were lined by epithelial cells consistent with ependymal cells, and the cells were occasionally ciliated and had multifocal degeneration and necrosis. (Figure 2a–b). Rarely, ependymal cells formed rosettes within the subependyma (Figure 2c). In adjacent neuroparenchyma, there were acute and chronic hemorrhages, scattered neuronal necrosis, moderate numbers of glial cells consistent with gemistocytic astrocytes (Figure 2d), myelin degeneration, axonal loss, and swollen and/or degenerate axons (Figure 2e).

Figure 2:

Cysts in the temporal-occipital lobes are lined by ependymal-like cells (A) with multifocal cilia (B) and occasional subependymal rosette formation (C). Within the neuroparenchyma are glial cells consistent with gemistocytic astrocytes (D, arrows), along with axonal degeneration (E, arrow).

Other significant postmortem findings included increased thickness at the parenchyma at the hilar region of the lung lobes, compatible with a history of emesis under sedation and subsequent aspiration, and chronic-active proliferative typhlocolitis with acute renal tubular injury, consistent with chronic colitis of macaques and diarrhea-induced renal hypoperfusion.²

4. DISCUSSION

The ependymal lining and location of the cerebral cysts are compatible with hydrocephalus or periventricular ependymal cysts that communicated with the lateral ventricles. Although the cerebral cysts did not resemble the symmetrically bilateral ventricular dilatations typically associated with hydrocephalus, congenital hydrocephalus is the most likely etiology in this case.

Ependymal cysts, which are generally rare, benign, and not associated with clinical signs, have been reported in several veterinary species, including one cynomolgus macaque³ and rats.⁴ In humans, space occupying ependymal cysts have been occasionally associated with neurologic signs such as ataxia, vomiting, and pain.^5–10 The rosette formation by ependymal cells in the subependyma in Figure 2c lends some credence to the possibility of periventricular ependymal origin. However, although no midbrain abnormalities were noted, the cerebral aqueduct was grossly compressed, suggesting obstruction of CSF circulation and subsequent CSF accumulation, rather than two separate space-occupying cysts.

Hydrocephalus can be obstructive due to a congenital malformation or may be secondary to trauma, infarction, or other insult. Cerebral aqueduct stenosis is the most common lesion associated with hydrocephalus.¹¹ Congenital hydrocephalus has been reported in a rhesus macaque neonate,¹² and late onset of clinical signs are documented in both rhesus macaques and humans.^13–14. Additionally, there was no inflammation consistent with underlying bacterial or viral infection and no organisms were cultured from the cystic fluid indicative of bacterial invasion to suggest secondary hydrocephalus.

We conclude that cerebral cysts of ependymal or ventricular origin, whether congenital or acquired, although rare, can lead to clinically significant neurological disease and that late onset congenital hydrocephalus is another differential to consider in non-neonatal rhesus macaques with neurologic signs.