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.
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 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 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, 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 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 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.
GME: A Deadly Condition You Probably Never Heard Of
Have you heard of Granulomatous Meningoencephalomyelitis, more commonly known as GME? I hadn’t until recently. And I consider myself fairly knowledgeable about dogs.
There is also an even more severe from of this called Necrotizing Meningoencephalitis or NME.
What it is in layman’s terms is an autoimmune disorder that affects mostly small dogs. Which is why we as Chi parents need to be aware of this. It can be deadly.
Margaret’s Story of Cricket
I first learned about this issue through one of our Facebook group members Margaret Ditty. She has a precious little Chihuahua named Cricket who has had very rough time of it since she developed GME and NME.
Margaret and her husband Rich have spent thousands trying to get help for their little girl. It’s been a long tough road for the Ditty’s and I admire their dedication to their fur baby Cricket.
Causes of GME
GME is an inflammatory disease of the central nervous system . It usually won’t develop in older dogs over the age of 8.
Most vets will tell you that they really don’t know the cause of GME but there are some that believe it is caused by repeated vaccination.
Did you know that the same amount of a vaccine given to a 120 pound dog is often given to a 5 pound dog? That is just crazy!
Since I am not a doctor, I will let you watch Dr. Becker here in this video explain about this condition:
Symptoms of GME (your dog may have some of these symptoms or all of them)
- Head Pressing: The dog will press their head against things
- Weakness in legs
- Behavior changes
- Head tilting
- Unsteady walk or gait
It is imperative that you get your dog in to see your veterinarian right away if you suspect GME or are seeing these symptoms in your dog. Without treatment, dogs can die within a day or so after the symptoms start.
How GME is Diagnosed
A basic blood panel and urinalysis and a spinal tap (done under anesthesia) is required. Also sometimes a MRI is needed.
Treatments for GME
Depending on what areas are affected, treatment may consist of:
- Corticosteroids (prednisone)
- Radiation therapy (if the GME is localized)
- In severe cases, hospitalization will be required
Dr. Becker also believes in some alternative therapies to speed up the healing process. She had a consultation with Margaret Ditty and gave her some ideas of what she could do to help Cricket and she also gave Margaret permission to share the call. You can listen to it here:
How to Prevent GME
While some dogs just seem to predisposed to this condition, repeated vaccinations seem to bring it on or make it much worse.
So before your dog’s next vaccinations, you might want to have your vet do a titer test to see if your dog still has the antibodies for the disease your dog would be vaccinated against. If there are antibodies present, there is no need for the vaccine.
While the titer test can be expensive, Dr. Becker believes you should call around and find a vet who will do the test at a cheaper price. You can read more about the titer test here .
You can also find a holistic veterinarian here.
Margaret also suggests that you should be prepared for this or any other pet emergency in advance by getting pet insurance while your pet is healthy and applying for Care credit which is used specifically for veterinary bills and doesn’t have to be paid back right away.
That way if an emergency should arise, you can use the Care credit until you are reimbursed from the insurance plan. Then you would pay the Care credit bill.
Of course, it would also be a good idea to start an emergency savings fund and save the money yourself.
If you or someone you know has a dog with GME and/or NME and would like support, you can join the Pet Parents Fighting NME & GME “Educate, Encourage, Share” group here .
I want to thank Margaret and Rich Ditty and Dr. Becker for providing me with much of the information for this article. I pray that it helps save doggy lives. As Margaret says “Educate, Encourage and Share”.