Assessment Anatomic diagnosis

Etiologic diagnosis—Disorders considered for sudden-onset seizures in a dog of middle to old age included neoplasia, inflammation, degenerative disease, vascular disease, and injury. The initial diagnostic plan included a CBC, serum biochemical analysis, urinalysis, coagulation profile, and thoracic and abdominal radiography; echocardiography was performed to evaluate the previously diagnosed pulmonary hypertension and heartworm disease. Additional diagnostic testing included ultrasonography of the abdomen and MRI of the head.

Diagnostic test findings—The CBC revealed slight neutropenia (2,964 neutrophils/μL; reference range, 3,000 to 11,500 neutrophils/μL). Serum biochemical analysis values were within reference intervals. Urinalysis revealed a urine specific gravity of 1.060, mild proteinuria, and a moderate number of spermatozoa. Coagulation pathways were considered functional on the basis of the coagulation profile results.

Thoracic radiographic findings were consistent with the previously diagnosed chronic heartworm disease. Echocardiography confirmed resolution of the previously identified pulmonary hypertension and mild mitral and tricuspid valve insufficiencies. Results of abdominal radiography were unremarkable except for likely benign prostatic hypertrophy.

On day 1, the dog was anesthetized, and an MRI examination of the head was performed with a 3-T scanner.^a Initial scan sequences (T2-weighted fast spin echo, T1- and T2-weighted fluid-attenuated inversion recovery, diffusion-weighted, and 3-D fast spoiled gradient echo sequences) revealed a mass effect in the rostral portion of the right cerebral hemisphere, which distorted the ventricles and shifted the midline slightly to the left and caused direct compression of the right optic nerve. Following IV injection of contrast medium,^b subsequent 3-D fast spoiled gradient echo and T2-weighted fast spin echo sequences revealed enhancement in the right rostral region of the cerebrum and olfactory bulb with areas of edema throughout the right cerebral hemisphere (Figure 1). Image characteristics were indicative of an intra-axial tumor, and a glial tumor and a metastatic lesion were considered the differential diagnoses.

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Axial 3-D fast spoiled gradient echo images (obtained before [A] and after [B] IV administration of contrast medium^b) of the head of a Belgian Malinois that was evaluated following a 2-week history of seizures and mentation changes. Notice the large, round to irregularly shaped, intra-axial, ring-enhancing mass with an isointense center in the rostral portion of the cerebrum that has caused a midline shift to the left. The findings are most consistent with glioma or a metastatic lesion.

Citation: Journal of the American Veterinary Medical Association 253, 5; 10.2460/javma.253.5.559

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Surgical intervention with postoperative chemotherapy and radiation therapy were recommended as the treatment of choice for the intracranial mass. A transfrontal craniotomy was performed. Portions of the ethmoid turbinates were removed for cytologic examination and bacterial culture. Samples of the mass were collected for histologic and cytologic examinations and bacterial culture.

After removal of the mass, the nasal cavity opening from the frontal sinus was packed with bone wax^c and gelatin sponges prior to closure. The dog received IV administration of isotonic crystalloid fluid, levetiracetam, famotidine, furosemide, and buprenorphine hydrochloride. The dog's postoperative neurologic status remained unchanged from the preoperative status. Four days after surgery, the furosemide and buprenorphine treatments were discontinued and prednisolone administration was initiated. In addition, treatment with sildenafil was reinitiated as previously prescribed.

The bacterial cultures of the ethmoid turbinates and mass specimens yielded no growth after 48 hours, whereas cytologic examination of the ethmoid turbinate specimens revealed no atypical cells. Impression smears of the mass contained predominantly highly pleomorphic round cells that had marked anisokaryosis and anisocytosis, admixed with fewer lymphocytes. The large round cells in the impression smears had several features of malignancy, indicating a neoplastic process. Histologic examination of sections of the mass revealed parts of the tumor that had uniform small vacuolated cells with a honeycomb pattern with some glomeruloid vessels. However, other parts had extreme pleomorphism with large sometimes multi-nucleated tumor giant cells and pseudopalisades around blood vessels and areas of necrosis. These findings were consistent with a glioblastoma with a high degree of anaplasia on the basis of the World Health Organization classification of CNS tumors.¹ Immunohistochemical analyses of sections of the tumor for glial fibrillary acidic protein (GFAP), vimentin, and S100 were undertaken to further support the diagnosis of glioblastoma. Some, but not all, cells were positive for GFAP. There was strong positivity for vimentin, consistent with astrocytoma. Tumor cell reactivity for S100 was weak. The tumor sections were stained for CD18 to evaluate for histiocytic sarcoma. No stain update was identified, thereby decreasing the likelihood of histiocytic sarcoma.

The dog was discharged from the hospital 8 days after surgery, and the owners were instructed to administer levetiracetam and sildenafil as previously prescribed. The dog was returned 1 week later for radiation therapy and chemotherapy. Radiation therapy (linear accelerator^d) consisted of a total dose of 54 Gy applied in 18 weekday doses of 3 Gy (Monday through Friday). Two weeks into radiation therapy (9 treatments), the dog started having seizures, and examination revealed myoclonic twitches in the fore-limbs and thoracic muscles, decreased mentation, ataxia, proprioceptive deficits of the left forelimb and hind limb, and the previously noted lack of menace response and pupillary light reflex in the right eye. Results of MRI indicated the presence of hemorrhage in the right frontal lobe and at the site of the tumor and cerebral edema. Radiation therapy was discontinued, and the dog was started on furosemide as no rapid changes in intracranial pressures necessitating emergent use of a hypertonic saline (3.0% NaCl) solution or mannitol were identified. The dog continued to have seizures in the face of treatment, and the levetiracetam dosage was increased and phenobarbital was added to the treatment regimen to control the seizures. After 48 hours with no seizure activity, chemotherapy with temozolamide (80 mg/m², PO, q 24 h for 5 days) was initiated. Two days after the start of temozolamide administration, the dog developed diarrhea and was administered metronidazole. The owners were instructed to administer levetiracetam, phenobarbital, sildenafil, and metronidazole, as previously prescribed, to the dog at home.

By day 42 after diagnosis, all the dog's lately developed neurologic deficits had resolved with only slight proprioceptive deficits in the left hind limb; the previously noted absent menace response and pupillary light reflex in the right eye persisted. The dog was returned 1 month later for reevaluation, at which time the phenobarbital and sildenafil treatments were discontinued. The dog continued to be treated with levetiracetam and temozolamide at home for 5 days every 3 weeks for 5 additional treatment periods. The dog continued to be monitored by the primary care veterinarian, and survived for 4 years, 3 months, and 28 days (1,581 days) following diagnosis of glioblastoma before being euthanized because of chronic renal disease. The only long-term neurologic deficits noted were those associated with the right eye.

Comments

A glioblastoma is categorized as a high-grade astrocytoma in veterinary medicine and as a grade IV malignancy in human medicine.^1,2 In humans and canids alike, glioblastoma is considered one of the most aggressive intracranial tumors. Astrocytomas represent approximately 10% of all CNS tumors in dogs, and glioblastoma comprises only approximately 5% of astrocytomas.²

In dogs, the mean age at the time of evaluation for glioblastomas is 8.4 years (range, 2 to 11 years).³ Clinical signs of glioblastoma are consistent with those of other intracranial tumors and include seizures, ataxia, circling, head pressing, and mentation or behavioral changes. The median time from onset of clinical signs to evaluation for glioblastoma is 21 days, with the most common clinical sign being seizures.³

Magnetic resonance imaging often allows for identification of intracranial tumors through location and imaging characteristics. Characteristics of glioblastoma include consistent peritumoral edema, sharp borders, ring enhancement, heterogeneous T2-weighted signal intensity, iso- to hypointense appearance on T1-weighted images, necrosis, and cyst formation. Many of these features are also evident in the human tumor counterparts.² However, a definitive diagnosis cannot be made by use of MRI and relies on histologic examination of sections of the mass. Histopathologically, glioblastoma is characterized by a heterogeneous cellular phenotype, necrosis with pseudopalisading of tumor cells around necrotic areas, marked microvascular proliferation, and occasional multi-nucleated cells. No histopathologic feature is more impactful in predicting poor prognosis than intratumoral necrosis of variable extent and distribution.⁴ Immunohistochemical detection of GFAP in astrocytes is often noted. The presence or absence of GFAP may help in the classification of astrocytic tumors, but that difference cannot be considered an absolute criterion, especially in poorly differentiated tumors.⁴

For dogs with any type of intracranial mass that are receiving only palliative care, the median survival time is approximately 1 to 10 weeks.⁵ For supratentorial tumors, the median survival time is approximately 25 weeks.⁵ Surgical intervention alone often adds months to survival time. Whereas specific data are limited, surgery combined with radiation therapy is reported to have improved outcome, compared with that achieved with radiation therapy alone.⁵ The use of chemotherapy in treatment of intracranial tumors is still somewhat new in veterinary medicine, and its effectiveness is often debated. Temozolamide, a novel oral alkylating agent, has become the standard of care as an adjuvant treatment or monotherapy for high-grade gliomas and other tumors in humans.⁵ Canine glioma cell lines appear to have responses similar to those of human glioma cell lines against commonly used chemotherapeutic agents, such as lomustine (CCNU), camptothecin-11 (CPT-11), and temozolamide. It is likely that the moderate advantages of adjuvant chemotherapy seen in human patients would apply to their canine counterparts.⁵ Reports of and data for median survival time associated with this multimodal protocol in dogs are limited. Reports of survival time have ranged from 3 to 8 months when chemotherapy has been given alone or in combination with radiotherapy or surgical debulking.⁴ In humans, the morbidity and mortality rates for all gliomas are poor overall, with survival times ranging from 7 to 24 months, even with combination (surgery, radiation therapy, and chemotherapy) treatment.⁶ For canine patients, such as the dog of the present report, the authors usually provide owners with a 12-month expected survival time following multimodal treatment.

The multimodal treatment used in the case described in the present report included a transfrontal craniotomy for debulking of the mass, radiation therapy, and chemotherapy with temozolomide. For the dog of this report, a survival time after diagnosis of 4 years, 3 months, 28 days (1,581 days) was achieved. During the 1,581-day period, the owners reported that the dog had a good quality of life and no additional seizures. The only long-term neurologic deficits were the lack of pupillary light reflex and menace response in the right eye. Toward the end of the survival period, the dog's quality of life declined as a result of chronic renal disease. The case described in the present report supports the use, benefit, and clinical application of a multimodal approach, similar to that currently used in human medicine, for treatment of dogs with gliomas.