GRANULOMATOUS MENINGOENCEPHALITIS (GME)

Granulomatous Meningoencephalitis (GME)

Most people have never heard of GME or any other form of central nervous system reticulosis until they have a dog with a brain disease that is gradually getting worse. Frequently what the owner is told is that GME is an inflammatory disease that acts in many ways like cancer and that very little is known about it. We understand how frustrating this is and hope to provide a summary of this condition in an understandable form. The general process of inflammation involves the infiltration of normal tissues by cells of the immune system. These cells are like the armed police of the body. They go to the area where they are called and release destructive biochemicals with the goal of obliterating an area of invasion by infectious organisms or of dead or diseased tissues. Granulomatous inflammation involves infiltration by cells called "mononuclear cells." These cells normally engulf and destroy debris. In GME, these cells form cuffs around the blood vessels of the brain and spinal cord (mostly in the white matter). The cuffs join at adjacent vessels forming actual masses/nodules. We do not know where the cells of infiltration come from in GME. They may come from the circulation or come from local proliferation of cells already present. Current understanding is that GME is an immune-mediated disease that seems to involve T-lymphocytes sending out inappropriate signals and starting this entire inappropriate cascade of brain blood vessel circulation.

Cambridge Natural History Diagrams of the Canine Brain (Photocredit: Public Domain image via Wikimedia Commons)

Originally the term "reticulosis" was used to refer to infiltrative diseases of the nervous system including GME, cancerous cell infiltrations and other diseases. There was a great deal of confusion and overlap of terminology and the expression "reticulosis" is no longer used. GME is complicated enough without including other conditions in its umbrella. GME is not a cancerous process and it is distinct from other inflammatory brain diseases. Unfortunately, obtaining a definitive diagnosis requires analysis of a piece brain tissue and since this is not likely to occur in a living patient, the term "MUE" which stands for "meningoencephalitis of unknown etiology" is often used to include all the inflammatory brain conditions. Luckily, there are diagnostic procedures short of brain biopsy which can take us closer to the diagnosis than simply saying "MUE."

THE CLINICAL PICTURE OF GME

The classical patient is a young to middle-aged small breed dog though any dog of any breed can be affected. What sort of neurologic signs are seen depend totally on what area of the nervous system is involved. Seizures, neck pain, drunken gait, walking in circles, blindness, listlessness, tilted head, facial abnormalities, and weakness can be seen. This does not leave out much in the way of neurologic symptoms. Symptoms can come on acutely or be more chronic.

Breeds felt to have a genetic predisposition to GME are:

TYPES OF GME

There are three types of GME: focal (limited to one location in the nervous system); disseminated or multifocal (involving many locations in the nervous system); and ocular (involving the optic nerve/eye). A patient may have more than one type. The disseminated form is the most common.

The focal type of GME typically has a slower onset (3-6 months) while the disseminated form is more rapid (2-6 months). Obviously, the disseminated form has a larger variety of signs within the same patient since many areas of the brain are involved. Dogs with the disseminated form have a poor prognosis with median survival times (without treatment) ranging from 8 days to 30 days from the time of diagnosis depending on the study. Prognosis is better for the focal form but, regardless of the form, GME is not curable and life-long medication is necessary (see below). The ocular form most commonly shows up as sudden, generally permanent blindness. It can affect one or both eyes but is not of a life-threatening nature.

It is important to realize that GME is considered to have a fair prognosis with treatment in most cases with 44-75% of dogs responding (depending on the study). Best outcomes are seen when multiple medications are employed. Worse outcomes are seen when there are seizures or when there is a mass effect on brain imaging.

MAKING THE DIAGNOSIS

MRI is an important part of the brain diagnostic process.
In this GME patient, the affected areas look like white cloud-like structures in the brain.
(Diagnostic image courtesy of animalmr.com, used with permission.)

When presented with a patient with brain-related symptoms, a database will be needed to establish the patient's general health as well as define the nature of the neurologic disease. A basic blood panel/urinalysis is important for any sick pet (not to mention for the monitoring of healthy elderly pets). These tests (along with the physical examination) form the foundation of evaluation and determination of what medication can be used, and what other systems must be considered. After this a spinal tap and MRI will be needed to sort out the different brain issues.

Tapping of the cerebrospinal fluid (spinal tap) enables evaluation of cells in the CSF fluid. Cancer cells may be found as can be infectious organisms or the inflammatory cells typical of GME. General anesthesia is required to tap fluid from the nervous system and the procedure is not entirely without risk. Still, the cells of GME should be findable in the fluid if they are present in the brain. Since the immune-suppression needed to treat GME would be disastrous in the case of an infection, it is very important to distinguish these two situations hence the special importance of this test.

Conditions that might present similarly include:

• Viral encephalitis (including canine distemper and rabies) though further spinal fluid testing is generally more revealing.
• Parasitic encephalitis (such as toxoplasmosis)
• Fungal encephalitis (such as caused by Cryptococcus neoformans)
• Cancer

MRI (magnetic resonance imaging) is able to image the brain in such detail that it is considered nearly a confirming test for GME. CT (CAT scanning) is not as definitive. If the diagnosis is felt to still be questionable after spinal tap, MRI should be considered despite expense.

The only way to confirm GME with 100% certainty is by biopsy though, obviously, diagnostics do not get any more invasive than brain surgery. For this reason, confirmation is frequently post-mortem.

TREATMENT

Immune-suppression with corticosteroids (such as prednisolone) remains the center of therapy for GME. Once the disease is controlled, one may begin to gradually drop the steroid dose until the minimum dose required to control the disease is reached. This process can be expected to require 4 months or so and is fraught with relapses. Response to prednisolone is variable and results are much better if additional medications are added.

Cytosine arabinoside, an agent of chemotherapy, can be added to prednisolone for a much better response. Monitoring for bone marrow suppression is needed with a medication as strong as this but, in one study with 10 affected dogs, all were able to achieve remission and median survival time was 531 days.

Similarly, another chemotherapy agent called procarbazine has been combined with prednisone to improve the length of GME remission. A study by Dr. Joan Coates et al. from the University of Missouri was published in the January/February 2007 issue of the Journal of the American College of Veterinary Internal Medicine. In this study, 21 dogs with GME were treated with both procarbazine and prednisone and outcomes compared to those of 11 dogs who were found to have GME on post-mortem and had received no treatment. Median survival time of the treated dogs was 14 months compared to less than one month for dogs receiving no treatment. Of the 21 dogs, 17 were able to reduce their steroid use or even discontinue it. Of the 21 dogs, 7 developed bone marrow suppression side effects and 3 dogs developed serious gastrointestinal side effects (hemorrhagic gastroenteritis). Although researchers concluded that procarbazine and prednisone was a more effective combination than prednisone alone, they did not actually include a group of dogs treated with prednisone alone in this study.

Cyclosporine is an immunomodulator somewhat different from the chemotherapy agents described above. It can be combined with prednisolone to treat GME without the bone marrow suppression side effects of concern above. In a small study of 10 dogs, median survival time was 930 days. Another study got 620 days. Both results are highly respectable in a disease where median survival without treatment was 30 days.

A new drug called leflunomide has been released to treat immune-mediated diseases of a type that includes GME. This is a relatively expensive treatment, which has limited use but it remains as a possible alternative to corticosteroid use for dogs that do not tolerate corticosteroid side effects.

Results with any of these agents have been encouraging. For example, the GME protocol used at Cornell University (oral prednisone, oral cyclosporine, and cytosine arabinoside infusions) has led to remission within 36 hours in the majority of patients and the average survival time is 2-3 years.

If the GME is focal or localized, radiotherapy may be helpful. Radiation of the head or face can lead to infarction (abnormal clotting), which can in turn lead to seizures for periods as long as 5 to 6 months after therapy. Cataracts and dry eye are common results of radiotherapy should the eyes be included in the field of radiation. That said, many cases of focal GME have enjoyed complete resolution after radiation.

If seizures have been a manifestation of GME, either disseminated or focal, medication will be used to control the seizures. Anti-seizure medication is the same regardless of the cause of the seizures so something specific for GME seizures is not needed. For a review of anti-seizure medication see the section on seizure disorders.

Ophthalmic GME also uses oral corticosteroids for therapy but may also employ topical ones. If glaucoma results from GME then therapy for this is necessary. Again, therapy for this result of GME is addressed in a standard way; no specific GME glaucoma therapy is needed.
 

Page last updated: 7/17/2021