Emerging treatments for granulomatous meningoencephalomyelitis (Proceedings)

Granulomatous meningoencephalomyelitis is a commonly diagnosed idiopathic inflammatory disease of the central nervous system (CNS) in dogs. Incidence of GME reportedly ranges from 5 to 25% of all CNS disorders in dogs. Granulomatous meningoencephalomyelitis has a progressive clinical course and often is fatal. Although the cause of GME is unknown, infectious, autoimmune, and neoplastic causes have been proposed. Current literature supports evidence for a delayed-type T-cell mediated hypersensitivity of an organ-specific autoimmune disease process. Meningoencephalomyelitis of unknown etiology (MUE) has been termed to categorize a group of diseases that include granulomatous meningoencephalomyelitis (GME), necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), or infectious meningoencephalitis for which the cause has not been identified. The MUEs may represent a spectrum of CNS inflammatory diseases with similar pathogeneses.

Prevalence of GME is higher in female dogs in some studies; however both sexes can be affected. Granulomatous meningoencephalomyelitis is frequently diagnosed in young to middle-aged, toy breed dogs with a mean age of 5 years.

Classification of GME consists of three clinical forms: multifocal (disseminated), focal, and ocular. Multifocal GME is characterized by acute onset and rapid progression of neurologic dysfunction. Dogs with focal GME tend to have more insidious or slower progression of neurologic signs. Affected dogs can have neurologic signs reflecting disease of a focal area of the CNS. The forebrain is commonly involved in focal GME. Forebrain signs include seizure, behavioral change, visual deficits, and postural deficits. Seizure is the most common clinical manifestation of forebrain disease. Brain stem signs include cranial nerve deficits, central vestibular dysfunction, and gait deficits. The focal form also may primarily involve the cerebellum and cause dysmetria and intention tremors. Spinal cord involvement produces mild to severe gait deficits leading to paresis or paralysis. Disseminated or multifocal involvement of the nervous system leads to signs of at least two areas of the CNS: forebrain, brain stem, cerebellum, spinal cord, and meninges. Dogs with multifocal GME will commonly manifest forebrain and brainstem signs. The ocular form alone is not as common, but often is concurrent with the multifocal form. The ocular form can present with acute onset of blindness, dilated pupils, and absent pupillary light reflex. Acute optic neuritis is recognized by a swollen optic disk with poorly defined margins. Chronic signs of optic neuritis are recognized by atrophy of the optic nerve and sunken optic disks. Fundoscopic examination can reveal retinal detachment and hemorrhage. Dogs with ocular GME can subsequently develop CNS involvement.

Definitive diagnosis of GME is based upon histology of CNS tissue obtained by biopsy or necropsy. Neuropathologic lesions consist of perivascular infiltrates of mononuclear cells in the white matter and meninges of the brain and spinal cord. A presumptive diagnosis of GME is based on signalment, brain imaging, CSF analysis, and excluding other excluding regional causes of infectious encephalitides. The combined diagnostic approach with advanced brain imaging and cerebrospinal fluid analysis is informative for a presumptive antemortem diagnosis of GME. Cerebrospinal fluid analysis is characterized by a predominantly mononuclear pleocytosis with variable presence of neutrophils. Advance brain imaging results may be normal, or show solitary or multiple heterogeneous contrast-enhancing lesions.

Treatment options

GME patients typically require lifelong immunosuppressive therapy. Combination therapy of glucocorticoids and other immunosuppressive agents will potentially allow for reduction or elimination of glucocorticoid treatment. Megavoltage irradiation of GME lesions has shown efficacy in some dogs with clinical signs suggesting focal involvement. Side effects include mucositis, keratitis, brain necrosis (early effect), and bone necrosis (late effect). Radiation treatment is costly and requires general anesthesia.

Immunosuppressive doses of glucocorticoids have been the mainstay of treatment for GME; however, clinical response has been variable and neurologic signs often recur. Immunosuppressive doses of prednisone, 1 to 2 mg/kg PO bid are initiated for 2 to 4 weeks and the dose is gradually reduced or tapered every 4 weeks when clinical signs stabilize or improve. The ultimate goal is alternate-day therapy at the lowest dose as clinical signs stabilize. Animals often respond initially, but relapses are common. Treatment is not curative, and life-long therapy is often required. High-dose corticosteroid therapy leads to undesirable side effects such as gastric ulceration, hepatic dysfunction, and iatrogenic hyperadrenocorticism. Previously reported median survival times in dogs administered glucocorticoids with focal and multifocal GME were 114 and 8 days respectively. Dogs with focal forebrain dysfunction had the longest survival times.

A goal of using other immunomodulatory therapies is to allow discontinuation or reduction in glucocorticoid dose. Immunomodulatory therapies that have shown clinical usefulness for GME include leflunomide, procarbazine, cytosine arabinoside and cyclosporine. Limited numbers of dogs have restricted abilities to statistically evaluate outcomes in earlier studies of cytosine arabinoside, procarbazine, cyclosporine and leflunomide. Another major limitation of recent studies is lack of histopathologic confirmation of GME patients. All drugs have potential risks for myelosuppression.

Leflunomide

Leflunomide is a de novo pyrimidine synthesis inhibitor and has been used to treat GME in dogs. Until recently the drug has been cost prohibitive. A recommended dosage is 4-6 mg/kg/day by mouth. It is recommended to monitor the CBC and serum biochemistry for undo side effects on a regular basis.

Procarbazine

Procarbazine is a potent monoamine oxidase inhibitor that is lipid soluble and crosses the blood brain barrier (BBB). Its cytotoxic effects alter DNA, RNA and protein synthesis. Procarbazine has been used as an adjunctive therapy to prednisone or alone. Survival times of longer than 12 months were reported for these immunosuppressive therapies, thus, may provide options as replacement or complementary therapies for glucocorticoids. The most clinically relevant side effect is myelosuppression. Procarbazine is well absorbed from the gastrointestinal tract. Procarbazine is administered 25 mg/m2 PO sid. A CBC is monitored once weekly for the first month and monthly thereafter. Initially, procarbazine is administered with prednisone 1 mg/kg, bid and when clinical signs stabilize the prednisone is tapered and discontinued. Procarbazine is available in capsule form. Due to the small size of veterinary patients, procarbazine is reformulated into an elixir (10 mg/ml) oil based solution: five 50 mg capsules, oil-base flavor (liver, chicken, fish) drops, 0.25 tsp silica gel (to keep in suspension), and gradually qs ad 25 ml sesame oil. Procarbazine offers advantage over cytosine arabinoside by its oral route of administration versus subcutaneous injection.

Cytosine arabinoside

Cytosine arabinoside, an arabinose-containing nucleoside, will cross the BBB in normal dogs. It acts on active cells by inserting into DNA molecules. It has been used in the treatment of GME as the sole treatment or as an adjunct to prednisone. The most significant side effect is myelosuppression. The protocol consists of a dose of 50 mg/m2 SC twice daily or 100 mg/m2 once daily for 2 consecutive days. The regimen is repeated every 4 to 6 weeks. The injection intervals can be extended once the disease is considered to be in remission. A CBC is performed 10 to 14 days after the first course of cytosine therapy and prior to each injection through the treatment (every 2 to 3 months).

Cyclosporine

Cyclosporine inhibits transcription of alpha-interferon, a cytokine that amplifies macrophage and monocyte activation. Dosage has been dosed as 3 to 15 mg/kg PO every 12 h when used alone or 5 to 12 mg/kg q 24 h when combined with ketoconazole 8 mg/kg q 24 h. Benefits of cyclosporine over cytosine arabinoside and procarbazine include less risk of myelosuppression and hepatic dysfunction. It is recommended to monitor the CBC and serum biochemistry. Target level for immunosuppression is 200 to 400 ng/ml.

Prognosis

Prognosis for definitively diagnosed cases of GME has been considered poor. Dogs with presumptively diagnosed GME may go into remission with combination immunosuppressive therapy of prednisone and other immunomodulatory drugs. The therapeutic regimen is tailored to the patient and the ability of the pet owner to follow through with proper monitoring. Future studies are needed for evaluating long term outcome of these therapies in dogs with a definitive diagnosis using histopathology.