Histopathology of lesions important for GME diagnosis

Histopathology of lesions important for GME diagnosis

Feb 01, 2003
Q: Could you provide a brief review on the causes and management of granulomatous meningoencephalomyelitis (GME) in dogs?

A: Granulomatous meningoencephalitis (GME) occurs primarily in adult female dogs, most often in purebred small breed dogs. Disseminated granulomatous lesions primarily affect the white matter of the cerebrum, caudal brain stem, cerebellum and cervical spinal cord and cause multifocal forebrain signs, whereas seizures may be the primary sign if a focal granulomatous lesion is present in the cerebrum.

Animals with the disseminated granulomatous disease often show an acute and fulminating clinical course, whereas those with focal granulomatous disease tend to have subtle signs at the beginning and a more prolonged clinical course. GME is a progressive disease.

Definitive diagnosis of GME is difficult and involves histopathologic examination of lesions obtained by way of stereotactic biopsy, open surgical biopsy, or post-mortem examination. Ante-mortem diagnosis more commonly involves cerebrospinal fluid analysis, brain/spinal cord imaging with CT or MR imaging, and the elimination of other encephalitides such as caused by canine distemper, Neospora caninum, Toxoplasma gondii and the fungal infections (blastomycosis, histoplasmosis, coccidioidomycosis, cryptococcosis and aspergillosis) by specific serologic testing procedures. The cerebrospinal fluid collected from a suspected dog typically shows an elevated protein content (40-1,000 mg/dl) and increased white blood cell count (primarily of mononuclear cells, both lymphocytes and macrophages). The most consistent diagnostic findings from the cerebrospinal fluid analysis are obtained before any glucocorticoids are administered.

The cause of GME is still unknown; however, immune-mediated, infectious and neoplastic causes have been proposed. GME is most likely an immune-mediated disease of the nervous system.

Glucocorticosteroid and radiation therapy

Symptomatic therapy with glucocorticosteroids has proved successful in temporarily alleviating clinical signs and/or slowing disease progression.

Prednisone has been the most frequently used glucocorticoid; dosages ranging from 2 to 4 mg/kg daily appear to be adequate. Dexamethasone and methylprednisolone are useful too. The response to steroid therapy varies and cessation of glucocorticoid therapy is invariably associated with rapid and dramatic clinical deterioration, and therefore, glucocorticosteroids should not be discontinued.

Long-term, high-dose corticosteroid therapy commonly leads to undesirable side effects such as gastrointestinal ulceration, hepatic dysfunction, and either iatrogenic hyperadrenocorticism or iatrogenic hypoadrenocorticism. Radiation therapy may prove to be very beneficial for the treatment of focal GME. Dogs treated with radiation therapy for focal GME lesions may have significantly longer survival times (median >404 days) than dogs with focal GME lesions that do not undergo radiation therapy.

The dogs with multifocal GME tend to die either before or during radiation. Radiation therapy is costly and involves daily general anesthesia. Side effects of radiation include moist epithelial desquamation, mucositis, keratitis, keratoconjunctivitis and brain necrosis as early effects and blindness, cataracts, and bone necrosis as late effects.

New therapies

Because the long-term side effects of corticosteroids and the expense and relative unavailability of radiation therapy are less than desirable, new adjunctive and/or alternative medical therapies are preferred. For more specific details refer to the recent article: Cuddon PA, Coates JR, Murray M: New Treatments for Granulomatous Meningoencephalomyelitis. Proc 20th Annual Forum ACVIM 20:319-321, 2002.

Cytosine arabinoside therapy

Cytosine arabinoside (Ara-C) may be used in the treatment of GME in dogs, either as a sole treatment or in conjunction with prednisone. Ara-C, an arabinose-containing nucleoside, crosses the blood-brain barrier in dogs and acts on mitotically active cells by being inserted into DNA molecules that result in premature chain termination.

Ara-C has been used to treat CNS neoplasias in dogs and has been used alone or in combination with other drugs to treat systemic lymphoma and myeloproliferative disorders. Cytosine arabinoside has also been used intrathecally to treat CNS lymphoma and appears to effectively reduce the development of CNS metastases when administered systemically to cats with renal lymphoma. The reported dosage in dogs for the treatment of neoplasia is variable, ranging from 100 mg/m2 as an intravenous, constant rate infusion, or subcutaneous administered drug for four days with repeat dosing every three to four weeks up to 600 mg/m2 more than 48 hours and a repeat treatment course in three to four weeks. Others believe that the drug should be administered at a low-dose constant schedule at 10 mg/m2 daily or twice daily subcutaneously. The most significant side effect of ara-C in dogs is myelosuppression, which typically occurs at a nadir of seven to 14 days. Other reported side effects may include vomiting, diarrhea and hair loss.

An effective protocol for the long-term treatment of GME in dogs is subcutaneous injection of ara-C at a dose of 50 mg/m2 twice daily for a period of two consecutive days.

This regimen is repeated initially every three weeks. Gloves should be worn when administering this agent. A CBC is performed 10-14 days after the first course of cytosine therapy and then periodically throughout the course of treatment (usually once every two to three months). It is best to institute ara-C therapy initially in combination with prednisone (1 mg/kg orally twice daily). After the second round of ara-C injections, a reduction of the prednisone therapy is done by tapering the prednisone.

ara-C may also be used as a sole agent in some dogs with GME. ara-C (Faulding Pharmaceuticals, Elizabeth, NJ) is supplied as a 20 mg/ml injectable solution in 5 ml (100 mg) vials. The cost is about $1.88 per ml.

Procarbazine therapy

Procarbazine is an antineoplastic drug initially synthesized as a potential monoamine oxidase (MAO) inhibitor. Procarbazine is lipid-soluble, crosses the blood-brain barrier and alkylates DNA and affects RNA and protein synthesis. In veterinary oncology, procarbazine is infrequently used as an adjunctive treatment as part of the MOPP [mechlorethamine, oncovin (vincristine), procarbazine, prednisone] rescue protocol for lymphomas.

Procarbazine has now been used for treatment of GME as an adjunctive therapy to prednisone or alone. Procarbazine is well absorbed from the gastrointestinal tract and is metabolized by erythrocytes and by microsomal enzymes in the liver to azoprocarbazine. It is widely distributed in the body including the cerebrospinal fluid.

The kidney is the major excretion route and less than 5 percent of the drug is excreted unchanged. Myelosuppression, principally thrombocytopenia and leukopenia, may be a dose-limiting factor. The nadir of thrombocytopenia is usually about four weeks. Other side effects may include nausea, vomiting and hepatic dysfunction. Procarbazine can sometimes cause neurotoxicity resulting from the passage across the blood-brain barrier but also from its affects as a monoamine oxidase inhibitor.

Adverse effects may arise with co-administration with a number of drugs such as ephedrine, isoproterenol, epinephrine, tricyclic antidepressants such as imipramine and amitriptyline, narcotics, antihistamines, phenothiazines and barbiturates. Neurotoxic effects are associated with the peripheral and central nervous systems. Central nervous system effects include both sedation and agitation. The peripheral effects of procarbazine include loss of tendon reflexes, paresthesia and myalgia. The monoamine oxidase inhibitor effects cause an increased sensitivity to catecholamines. Procarbazine (matulane) is available as a 50-mg capsule (about $0.70/capsule).

Because of the small size of dogs affected with GME, procarbazine is reformulated into an elixir. It is recommended that a pharmacist re-compound the drug because of its toxicity in the powder form. To make a 10 mg/ml oil-based solution mix five 50 mg capsules, add some oil-based flavor (liver, chicken, fish) drops, 0.25 tsp silica gel (to keep in suspension), and gradually add and mix 25 ml of sesame oil. The expiration date is 30 days. Gloves should be worn when handling this agent. The oral hydrochloride salt is unstable in aqueous solutions. Procarbazine is administered orally at a dose of 25 to 50 mg/m2 daily.

The CBC should be monitored once weekly for the first month, then monthly thereafter. After the first month of therapy, attempt to reduce the frequency of the dose to every other day.