Update

Georgie was on the heavy Pred dose for 4 days and as of Thursday evening she has been back on a 5 mg tab in the morning and a 5 mg tab in the evening. She is so lethargic from the high doses of Pred but she still manages to jump up and down with excitement when I come home or I mention the word sweetie. She is still wagging her tail and that at least puts a smile on my face.

Poor little baby is still totally blind but she does manage very well considering.

It's Cytosar weekend again so we can only hope that it will assist in getting the relapse under control.

Rollercoaster ride

After little Georgie's last relapse she stablilised quite quickly. I reduced her Pred to one a day again as I just can't bear to see her so down and uncomfortable. Things were going really well for 2 weeks and then I started noticing little signs of another relapse. From there things went backwards pretty quickly. She has now completely lost her vision again and is completely disorientated and falling over. Absolutely heartbreaking! I immediately put her on the higher Pred dose again and then last night decided to up it even further to Dr Sisson's 4 day dosage to kick start the process. I also put her back on Leflunomide (5mg once a day) with the hope that she won't have any GI issues from it. My poor little baby. Fortunately she is an absolute fighter and if anyone can get back on her feet it is my baby girl. This time I am certainly not going to make the mistake of lowering her Pred dosage so quickly. She is due for another round of Cytosar this weekend which I am pleased about.

I forgot to mention that inbetween these 2 relapses I had to rush Georgie off to the vet as there was a lot of blood in her stools...so much so that it was dripping out of her bum quite badly. The vet seemed to think it might have been the Leflunomide as it can be a side effect. So we stopped the Leflunomide. The level she was on didn't stop her from relapsing anyway. I made a call though to add it back when she had this last relapse. We need all the help we can get.

Catch Up

I haven't written on my blog for a few months. Georgie was doing really well...brilliantly in fact. The vet reduced her Pred to one 5mg tab per day and then also reduced her Cyclosporine to once a day (0.10 ml) and the Cytosar injections to once every 6 weeks. All was well. 2 Weeks ago we decided to reduce the Pred further to one tablet every second day...BIG MISTAKE..poor Georgie started relapsing. I was absolutely heartbroken. I immediately upped her Pred to the initial dose of one tablet twice a day and upped the Cyclosporine to twice a day again (0.12ml). I phoned the vet and we agreed that we need to keep the levels of everything else high while reducing the Pred down the line. She goes for her 3 weekly Cytosar injections this weekend.

Fortunately Georgie's relapse isn't nearly as bad as the original symptoms but I think I watch her so closely that we caught it very early.

It is very worrying for me that she clearly can't cope without the Pred. Of all the meds I was really hoping to get her down to as little as possible on Pred. Maybe with the higher Cyclosporine and Cytosar doses we will be able to down the line.

SuperYorkie

She did it!!!!! She just jumped onto the low couch...with a little inspiration from one of her favourite treats. Took her about 10 to 15 tries but by Georgie she got it.

Next step lounge couch glory

General update

On the Georgie front she is still on Prednisone, Cyclosporine, Leflunomide and her 3 weekly Cytosar injections (next round this weekend). She is still improving in terms of her GME symptoms and I am thrilled. I can only pray that the day we decide to do the first pred reduction she will still continue to improve.

She is now quite the pro at jumping off the couch and the bed is now also seemingly a breeze. I think she just needs to get some confidence to jump onto the couch. I am going to try and coax her to jump on a lower couch with some of her favourite treats. I think that might do the trick. Hopefully once she has mastered that she will have the confidence to try the couch in the lounge.

Oh and Dr Strydom has been convinced for a while now that Georgie has some sort of vision in her left eye. We have suspected it too and even more so after last night. There was a cow hoof on the floor in the kitchen (out of place) and she tentatively snuck up to it and ran away repeatedly as if it was something strange. It gives me comfort to think that she can still see something no matter how little.

FYI, I recieved not one reply from any of the places I emailed for research feedback.

Research

I have been trying to find out more about any research going on into GME. Thanks to another blogger I have seen that there is a research grant open through the AKC Canine Health Foundation.

01731: A Novel Approach to Understanding How Meningoencephalomyelitis Develops In Dogs:

Abstract
This project is aimed at finding a cause of 'meningoencephalomyelitis of unknown etiology', otherwise known as 'MUE', which is a summary term for diseases such as 'GME'. This group of conditions causes serious neurologic disease in dogs, especially small breeds, including blindness, loss of balance, seizures and paralysis - but the cause is currently unknown. A recent experimental breakthrough has incriminated bacteria in the digestive system as triggers for a similar disease in laboratory mice and rats. The main purpose of this project is to find out whether imbalances in the number or type of digestive system bacteria might also be a cause for MUE in dogs. If it was to be true it would open a whole new avenue of approach to treatment of affected dogs and might also produce information useful for treating neurologic disease in humans. To carry out this investigation we will analyze fecal samples collected from affected dogs for their content of bacteria. We will then compare the numbers and type of bacteria with those we find in fecal samples from unaffected dogs. Because we will be examining many dogs with MUE we will also be able to ask owners other questions about their dogs' recent medications and medical history to determine whether there are other risk factors that might be associated with MUE.

Anyone interested in donating can do so via the website http://www.akcchf.org/research/funded-research/1731.html or by ordering one of the Fight GME bracelets on the Fight Granulomatous Meningoencephalitis Facebook page.

Anyway, I am still interested to know what other research is taking place and how the research findings are distributed to vets, particularly internationally. I have mailed the Foundation to find out more. I have also mailed the University of Pretoria in South Africa to find out if any research is being done here at home. The only snippets of papers I can find on the internet from a local perspective seem to be a good few years old and based on the fact that dogs are being treated differently nowadays I was hoping things would also be moving with the times in terms of research.

I am also going to try and find out generally how new breakthroughs and medications are shared here in South Africa. I will speak to Dr Strydom about that at some point as well. Surely if dogs are responding well to treatment there must be a means of sharing with other vets.

Holding thumbs for some responses

Vacuum cleaner

Boy oh boy is Georgie hungry. She is a real little vacuum cleaner. I would recommend Prednisone for anyone with anorexia. She acts like every meal is her last one. I don't even think she gets a chance to taste anything she eats so quickly. I am thinking of maybe getting one of those bowls that slow their eating down. I honestly think if I gave her an unlimited supply of food she would carry on all day.

I think she is permamently hungry. She starts moaning for food in the early early afternoon and I only feed her at 5. I am scared to give her snacks in between in case she gets fat...although I do give in and sneak in a few grain free dog biscuits here and there as a treat.

Oh and at 3 a.m. and 5 a.m. on Sunday morning she woke me up. I took her outside for a wee but soon realised she was actually waking me up to give her food. Poor little monkey. I know I get grouchy when I'm hungry. Hopefully one day when we start the Pred reduction it will start to ease of a bit.

This morning she only woke me up once, at 4 a.m. so I was grateful.

Leap of faith

I forgot to mention that Georgie jumped off the bed on Saturday morning....and with a perfect landing. Big step for her. She has also jumped off the couch a few times. I am positive she is going to jump on the couch again within the next 2 weeks. She hasn't done that since early Jan.

Go Georgie, Go!!!

New haircut

Little Georgie hasn't had a haricut since the week before she went blind and was getting rather full of knots. I thought it might be stressful for her to go to the parlour since she can't see and I also don't really want her around too many strange dogs while her immune system is so low. So I went and bought some clippers and did a home job. She wasn't thrilled with the exercise but it didn't turn out too badly.

Look at her go...

A good night's sleep

Great news...Georgie hasn't vomited again since reducing the amount of new food. She had a good night's sleep with no restlessness. She is really looking good.

GME Support

The reason I started this blog is to provide support to other 'parents' with GME dogs. I personally found it helpful and encouraging to read posts from other people who are going through this.

Some of the resources I use are:


careforcoby.blogspot.com
aishainthebay.blogspot.com
gmedogs.freeforums.org
www.yorkietalk.com
http://www.yorkieencephalitis.com/
www.yorkieangelpatrol.com
https://www.facebook.com/FightGME

 
You can also donate to GME research on the Facebook page by buying bracelets.
 

 

I can also recommend watching this clip on You Tube. It has given me a lot of hope.

 

http://www.youtube.com/watch?v=Afz1qXtCw74

 

 

What a night!

Poor little Georgie vomited during the night; at 2 a.m. and again at 4 a.m. I have a feeling it is my fault and that I gave her too much of the new food without adding it gradually. I did get some punishment in the form of very little sleep. I am going to add the pellets very gradually to the chicken and see how she goes along. Feel pretty bad.

New food

So after taking grains out of Georgie's diet and only feeding her chicken I wanted to make sure she was still getting a balanced diet. I have previously made her home cooked meals with veggies etc but she wasn't quite as excited about it as I was. So I Googled grain free dog food and found Orijen which I thought I would try. I bought a trial bag today and Georgie went mad for it...although the Pred makes her so hungry nowadays I think she would go mad for cardboard at this stage.

Dr Sisson's paper

 

TREATMENT OF AUTOIMMUNE DISEASES OF THE CENTRAL

NERVOUS SYSTEM OF DOGS

Allen Sisson DVM, MS, Diplomate ACVIM (Neurology)

Angell Animal Medical Center, Boston, Massachusetts

Several inflammatory, primary central nervous system (CNS) derangements of dogs have

been described such as: 

1. Granulomatous Meningoencephalomyelitis (GME)

2. Necrotizing Encephalitis of mostly Pug, Maltese and Yorkshire terrier dogs

3. Corticosteroid-Responsive or Neutrophilic Meningitis

4. Eosinophilic Meningoencephalomyelitis

5. Idiopathic Tremor Syndrome or Cerebellitis

6. Pyogranulomatous Meningoencephalitis

7. Meningoencephalomyelitis of undetermined etiology 

The two things these conditions have in common are that they are considered to be idiopathic, since no causative agent or infectious organism has been found,10,17 and they all respond, to some degree, to immune suppressive therapy. Because of this, most people now believe that these diseases are either autoimmune or neoplastic in nature. However, an autoimmune etiology is most likely since in most cases with aggressive immunosuppressive therapy permanent remission can be achieved which would be unlikely if they really were of neoplastic origin.

Depending on where in the brain and spinal cord these diseases start, and how rapidly they

progress, they can cause a wide variety of signs. The most common presenting clinical signs are:

1. Progressively worsening central vestibular signs

2. Progressively worsening seizures and behavior abnormalities

3. Progressively worsening neck and or back pain

4. Progressively worsening para or tetraparesis

5. Progressively worsening generalized severe intention tremor

6. Acute onset of blindness

These signs can progress at various rates, but surprisingly they are often acute (1-2 days) to

peracute (8-12 hours) in duration on initial presentation. In the peracute form these autoimmune brain and spinal cord diseases can be one of the most serious neurological emergencies. It is possible for a dog with GME involving the brain stem to progress from mild vestibular ataxia to severe violent rolling to opisthotonos, coma and death within 12-24 hours from the first onset of clinical signs. A dog with GME involving the cervical spinal cord may progress from signs of mild ataxia to full tetraplegia in 1-2 days mimicking a cervical disc herniation. Pugs, Maltese terriers and Yorkshire terriers with necrotizing encephalitis commonly present with only 1-2 days or even a few hours of pacing, demented behavior followed by near constant seizure activity and death within 12 to 24 hours.

 

Although in most cases a neurological patient should be stabilized and diagnostic tests

evaluated before treatment is started, a dog with rapidly progressive GME or necrotizing

encephalitis may be dead, or permanently neurologically damaged, if treatment is withheld for 8-12 hours so a cerebrospinal fluid (CSF) analysis and advanced imaging can be evaluated before treatment is begun. It is therefore imperative that a high index of suspicion be maintained for autoimmune CNS disease when dogs are presented with unusually rapidly developing seizures, vestibular signs, tetraparesis, violent generalized tremors or blindness. Frequent, accurate neurological examinations will indicate if rapidly progressive or static to improving disease is present. For this reason, it is not a good idea to admit a dog that appears to have acute onset geriatric vestibular disease with plans to re-evaluate the dog the next morning. If the dog has GME death may occur by then. If rapid neurologic deterioration is noted on repeat examination then immediate referral to a 24-hour emergency center or aggressive immune suppressive therapy should be started until a CSF analysis and advanced CNS imaging can be done to confirm the diagnosis. Increased cellularity of a CSF analysis is not likely to be altered by corticosteroid or other immunosuppressive therapy for 12 to perhaps 24 hours; so an accurate diagnosis can still be made after glucocorticoid therapy has begun. However, if CSF is collected after 12-24 hours of glucocorticoid therapy false negative results may be obtained. Therefore it is best to begin, or refer the dog for, diagnostic testing as soon as possible after initiating therapy in such an emergency situation. 

High dose, long term, immunosuppression is the key to successful therapy for all autoimmune diseases of the CNS. For this reason it is imperative that infectious causes of CNS inflammation be ruled out by diagnostic testing since immunosuppressive therapy would obviously worsen these conditions. The following therapies have been found to have efficacy in treating CNS autoimmune disease: 

1. Corticosteriods in immunosuppressive doses1,2,3

2. Azathioprine20

3. CCNU (Personal communication March, P, Ohio State University)4

4. Cyclosporine Modified by Microemulsion5,6

5. Cytarabine7,18

6. Leflunomide15

7. Procarbazine7,19

8. Radiation Therapy8,3

Corticosteroids, primarily prednisone, is the drug of first choice and is on rare occasion used as the sole therapy. It is important that immunosuppressive doses be used initially, and therapy be sustained at high doses, very gradually tapered over many months or relapses are likely to occur.

A six-month tapering dosage schedule of prednisone that is generally effective is as follows:


1 mg/lb Q 12 hours for 4 days

0.5 mg/lb Q 12 hours for 17 days

0.5 mg/lb Q 24 hours for 35 days 

0.25 mg/lb Q 24 hours for 60 days 

0.25 mg/lb Q 48 hours for 60 days

Dogs weighing less than 5 kgs are dosed as 5 kg dogs, and dogs weighing 5 to 10 kgs are dosed as 10 kg dogs. Dogs weighing over 35 kg are dosed as 35 kg dogs. Prednisone alone, used in the above dosage schedule, in about 75 percent of cases will cause long-term remission when neutrophilic or eosinophilic meningitis or focal GME of the posterior or rostral fossa of the brain are treated; however the addition of at least leflunomide to prednisone therapy is recommended since it improves the odds of sustained remission.

Prednisone alone or in combination therapy causes many adverse effects. When these adverse effects are severe they may require the prednisone dose to be reduced prematurely or even stopped entirely and another immune suppressive drug used in its place or combined with a reduced prednisone dose. The adverse effects that can occur are:

 

1. Severe polyuria, polydipsia, polyphagia and panting
 

2. Urinating in the house or urinary incontinence and weight gain

3. Colitis type diarrhea, vomiting and anorexia

4. Gastrointestinal (especially colonic) ulceration/perforation

5. Life threatening steroid hepatopathy

6. Urinary tract and skin infections and other infections

7. Severe mental depression and lethargy

8. Hyperexcitable, energetic, aggressive

9. Muscle atrophy and weakness

10. Endocrine alopecia

11. Hypertension

12. Calcinosis Cutis
 

Some of the more common adverse effects listed above can be prevented by some simple

instructions to the owner. If the dog has normal renal function, the owner should limit the dog's water consumption to 20 ccs/pound of body weight divided three times a day. This will prevent the excess drinking that causes the dog to urinate in the house and be urinary incontinent. If the dog does start urinating in the house despite this, the dog's urine should be cultured using a cystocentesis urine sample to be sure a urinary tract infection has not developed. The dog should not be fed more than the amount of food he was fed before prednisone therapy. That should be no more than 20 calories of food per pound per day. Feeding a high fiber, low fat food, such as canine or feline RD or feline WD, prevents weight gain and prevents the steroid induced colitis diarrhea that is very common unless this diet is used. The dog should have a 12 hour fasted serum chemistry profile collected in all cases 10 to 14 days after this prednisone schedule is started. If the serum bilirubin is elevated above the normal range, the prednisone dose should be immediately reduced to 0.5 mg/lb once a day and the steroid hepatopathy should gradually start to resolve. In those cases in which the dog becomes severely mentally depressed on prednisone or has severe muscle weakness or an intolerable personality change, prednisone may have to be discontinued permanently or the dose drastically reduced and other immune suppressive drugs considered.

Azathioprine is an immunomodulatory drug that primarily acts by interrupting purine
metabolism leading to inhibition of DNA synthesis and mitosis. It is most effective to inhibit cell mediated immunity and is less effective against the humoral response. Azathioprine seemed to have some effectiveness to treat immune mediated CNS disease of dogs in one study.20 This drug has been used very effectively to treat many other immune mediated diseases of dogs including myasthenia gravis. The author has used both azathioprine and leflunomide to treat a wide variety of immune mediated diseases of dogs including immune mediated CNS disease, and has found azathioprine generally less effective and more toxic than leflunomide in most cases. The adverse effects of azathioprine include bone marrow suppression, hepatotoxicosis and acute pancreatitis.

The bone marrow suppression resulting in leukopenia, thrombocytopenia and anemia are generally dose related and can be resolved with dosage adjustments based on hemogram monitoring. However, the hepatotoxicosis and acute pancreatitis often occur abruptly in the early days of therapy in susceptible dogs, and are not dose related effects. It is impossible to predict before therapy which dogs will experience these often severe hepatic and pancreatic reactions to azathioprine which can be life threatening. In general, the adverse reactions to leflunomide are less severe and can be corrected more rapidly than the adverse reactions to azathioprine. For this reason, leflunomide is the drug of first choice with azathioprine only used if leflunomide is not tolerated due to a drug eruption and other medications such as cytarabine and lomustine in addition to prednisone therapy are not able to maintain remission. Azathioprine is initially administered at 2 mg/kg orally once a day, and in 2 to 4 weeks the dosage is reduced to 2 mg/kg orally every 48 hours. However, this dosage may have to be adjusted to a lower or less frequent interval based on hemogram and serum chemistry profile monitoring. Initially hemograms should be done every 2 weeks then monthly for the duration of therapy. Neutrophil counts less than 3,000/uL warrant a dosage reduction. 

CCNU (Lomustine) is a very effective addition to or replacement for prednisone immune
suppression in prednisone resistant cases, for cases that relapse off of prednisone or when
prednisone adverse effects are too severe. Lomustine is a nitrosourea compound used in the
treatment of certain neoplasic diseases and is a potent immune suppressor primarily due to its toxic effect on lymphocytes. It alkylates DNA and RNA but is not cross resistant with other alkylating agents such as Cytoxan. Since the drug has high lipid solubility and it is not ionized at physiological pH, it crosses the blood-brain barrier very well reaching 50 percent or greater than plasma levels. Lomustine is most commonly used to treat brain tumors and lymphosarcoma. The primary toxicity of the drug is bone marrow suppression causing leukopenia and delayed thrombocytopenia. The toxic effects on the bone marrow are cumulative. The delayed thrombocytopenia is only a problem if the drug is dosed once every three weeks rather than every four weeks. Using every 4-week dosing thrombocytopenia does not occur. Some dogs, toward the end of one year of therapy, start to become too leukopenic on a dose that previously did not cause this. For this reason hemograms should be watched closely toward the end of therapy.

 
The only other major toxicity is gastrointestinal causing vomiting and diarrhea especially if the dose is high enough to cause excess myelosuppression. If the dog has severe neutropenia and gastrointestinal bleeding from a lomustine overdose, shock, sepsis and death can occur quickly.

Lomustine is reported to be hepatoxic in dogs at times when used at high doses of 90 mg/meter squared every 3 to 4 weeks at the same time other hepatotoxic drugs like trimethoprim-sulfadiazine or drugs that interfere with its hepatic metabolism such as cimetidine are given.14 It is very unlikely this hepatotoxicity will occur at the immunosuppressive doses used for autoimmune disease as long as therapy does not exceed one year. Serum chemistry monitoring for hepatotoxicity can be done after the first treatment then every three months thereafter. The initial dosage of lomustine for dogs weighing 20 pounds or less is 30 mg/meter squared once a month. For dogs weighing more than 20 pounds the initial dosage is 35 to 40 mg/meter squared once a month. However when the dosage calculation is made the dosage should always be rounded downward to the closest even 2.5 mg increment for dogs weighing 20 pounds or less, and rounded downward to the closest even 10 mg increment for dogs over 20 pounds. Lomustine is supplied as 10 and 40 mg capsules. For small dogs the capsules must be compounded into a smaller size than 10 mg. The capsules should always be handled with gloves by the owner and hospital staff. Some dogs are very sensitive to bone marrow suppression by this drug and others are very resistant. Because of this the first dosage used should be very conservative. A hemogram should be done exactly 6 days after the first treatment. The goal is to have a granulocyte (neutrophil) count nadir of over 1,000/uL and less than 3,000/uL. The dose should be gradually raised each month until this range is achieved. Each time the lomustine dose is increased a hemogram needs to be done 6 days later. Once the correct dose is found and the same dose is being given each month the hemogram 6 days post treatment is no longer needed. A hemogram should also be done 21 to 29 days after each treatment, and it should reflect a neutrophil count at least over 3000/uL to safely give the drug again at 30 days. Lomustine therapy is generally used for one year to treat autoimmune CNS disease.
 

Lomustine is used initially combined with prednisone, leflunomide and cytarabine in all cases of necrotizing encephalitis, and all cases of GME that involve the spinal cord or that cause blindness since these forms of autoimmune CNS disease seem to almost always relapse or not go into remission at all if prednisone only is used. By adding lomustine initially as part of the treatment combination in these cases, the long-term remission rate approaches 90 percent for GME and 70 to 80% for necrotizing encephalitis. 

Cyclosporine is also an effective immunosuppressive drug that can be used in place of, or more often combined with, prednisone, leflunomide, cytarabine and lomustine to achieve maximum immunosuppression. The microemulsified form (Atopcia® Novartis Animal Health US, Inc., Greensboro, NC 27408), or its generic equivalent (cyclosporine modified), should always be used since its dose is less and the blood level achieved is more uniform due to better intestinal absorption than Cyclosporine USP, Sandimmune® (Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936).9 Cyclosporine acts primarily by strongly suppressing T lymphocyte activation and proliferation. Cyclosporine binds to the cytosol of lymphocytes with cyclosporinebinding proteins and blocks calcium-dependent signal transduction blocking T-cell activation.9 In addition it prevents synthesis of several cytokines such as interleukin-2, which further inhibits Tcell proliferation.9 It has been shown by immunohistochemical studies that the bulk of lymphocytes in GME lesions of the brains of dogs are CD3 antigen positive T lymphocytes.10 The data from these studies strongly suggests that canine GME is a T-cell-mediated delayed-type hypersensitivity, organ-specific autoimmune disease.10 Therefore, cyclosporine's T-cell specificity makes it a good choice to treat GME. Cyclosporine is lipophilic and has poor blood-brain barrier permeability; however it may be trapped in the endothelial cells and the choroid plexuses of the CNS since it concentrates mostly in intracellular compartments including of erythrocytes and leukocytes.11 GME primarily creates perivascular lesions in the CNS; so it is likely that cyclosporine would enter the intracellular compartment of the lymphocytes and macrophages in these perivascular granulomas.6

Cyclosporine is a very rapidly acting immune suppressor. Effective steady state blood levels can be measured in 24 to 48 hours after starting therapy.9 In most cases a dosage of 3 mg/kg every 12 hours of Atopica will achieve serum concentrations high enough to be therapeutic for GME.6 Whole blood concentrations should be measured soon after starting therapy since there is considerable biological variation in absorption of this drug from one patient to the other. Ideally cyclosporine concentrations of 400 - 600 ng/ml would be achieved 12 hours post pill.9 However it has been shown serum concentrations of only 200 - 400 ng/ml are often effective for GME.6 It appears from blood level testing the half-life of cyclosporine is short in dogs. Generally blood levels 2 to 3 hours post pill are in the 400 - 600 ng/ml range, but 4 to 8 hours post pill the levels are often 200 - 400 ng/ml and 8-12 hours post pill are often less than 200 ng/ml. When this is found it is sometimes necessary to use 6 mg/kg every 12 hours to achieve consistent serum concentrations of cyclosporine over 200 ng/ml throughout the treatment period in dogs. In general cyclosporine is a safe drug in dogs with few adverse effects. The most common adverse effect is diarrhea, anorexia or vomiting if the dose is too high for a given individual.12
 

Dividing the dose more evenly throughout the day often resolves this. However, on occasion other adverse effects have been seen such as gingival hyperplasia, papillomatosis, hirsutism, excessive shedding, and insulin resistance or inhibition of insulin release which may require the drug to be discontinued.12 Unlike in humans, the drug is not nephrotoxic or hepatotoxic unless blood levels greater than 3,000 ng/ml are achieved,9 which would be very difficult to do in dogs. Cyclosporine is metabolized by cytochrome P-450. Since phenobarbital induces this enzyme phenobarbital will decrease cyclosporine blood levels.12 However, ketoconazole significantly lowers the dose of cyclosporine needed to achieve an effective blood level and seems to make the blood level more even throughout the day.12 A dose of 10 mg/kg once a day of ketoconazole often allows a 50 to 80 percent reduction in the cyclosporine dose which can result in considerable financial savings since cyclosporine is quite expensive.12 However, it must be kept in mind that ketoconazole has several adverse effects in some dogs. The most common adverse effects are anorexia, vomiting and diarrhea. On occasion the drug can be hepatotoxic. It is teratrogenic; so it should never be given to  pregnant dogs. It also lowers gonadal and steroid hormone levels. For these reasons ketoconazole administration with Atopica should only be considered for an owner that cannot possibly afford Atopica therapy any other way. Generally Atopica is only used in the most resistant cases such as necrotizing encephalitis and spinal cord or blindness form of GME. It may also be used for GME cases that relapse when steroids are withdrawn or when steroids cause too severe adverse effects. Most commonly Atopica is used in combination with prednisone, leflunomide, cytarabine and lomustine. In this situation the prednisone is used for 6 months, the lomustine and cytarabine for one year and the Atopcia and leflunomide for 1.5 years. Used this way the long-term remission rate for GME is close to 95% and for necrotizing encephalitis 80 to 85%.

 

Cytarabine (Cytosine Arabinoside) is an antineoplasitc agent mostly used to treat lymphosarcoma of dogs. It has been shown to cross the blood-brain barrier of normal dogs.7 There are a few reports of its use, combined with other medications, to treat GME successfully in dogs.7,13,18 The dose recommended is 50 mg/meter squared, subcutaneously, every 12 hours for 2 days every 3 weeks indefinitely.7 The drug causes a nadir in 7-14 days since it is myeolsuppressive. It can cause vomiting, diarrhea and hair loss. Adverse effects are generally rare and myelosuppresion is less than with lomustine. The author has used cytarabine at the increased dose of 100 to150 mg/meter squared, subcutaneously, every 12 hours for 2 days every 4 weeks for one year alternated two weeks apart with monthly lomustine as described above. When using cytarabine for the first time the dose should not exceed 100 mg/meter squared. The dose can be increased to 150 mg/meter squared if the 6 days post medication neutrophil nadir is not below 3,000/uL.

Leflunomide is an immunomodulatory drug that has been shown to be effective in treating several autoimmune diseases of dogs, including autoimmune CNS disease, that were unresponsive to conventional therapy.15 It is leflunomide’s active metabolite teriflunomide (A77 1726) that seems to cause the immune suppressive effects.15 All the effects of this metabolite are not known, but it is thought that teriflunomide inhibits pyrimidine biosynthesis and inhibits cytokine and growth factor receptor associated tyrosine kinase activity thus inhibiting T and B lymphocyte proliferation and function.15 The effective dose range of leflunomide is 1.5 to 4 mg/kg once a day, but this dose needs to be individually adjusted for each dog base on their teriflunomide blood level measured 24 hours after a dose is given.15 In humans the peak blood level of the active metabolite is obtained 6 to 12 hours after dosing, and the drug has a very long half-life of about 2 weeks.16 Therefore, it can take up to two months to reach full steady-state.16 An initial loading dose could be used to raise the blood level more rapidly, but to date the author has not done this because of the fear of inducing severe, abrupt adverse effects. The primary adverse effects of this drug observed by the author have been thrombocytopenia, hemorrhagic colitis and in about 10% of dogs a rapidly developing cutaneous, ulcerative drug eruption occurs. This drug eruption is most common on the  nasal plane, face or food pads, but on occasion will occur on the neck or truncal skin. This drug eruption rapidly resolves if leflunomide therapy is discontinued. In humans hepatotoxicity has been reported16 but this has not been reported in dogs so far. Currently the author uses prednisone in combination with leflunonmide to treat all autoimmune CNS diseases of dogs. In most cases cytarabine is also added using a three drug combination at the onset of diagnosis. Whenever a relapse occurs or when necrotizing encephalitis is suspected lomustine, and in some cases cyclosporine, is added using the five drugs in combination. Blood levels are measured every 2 to 4 weeks after initiating therapy to adjust blood levels into the safe therapeutic range of 20 to 40 mcg/ml of teriflunomide measured by high-pressure liquid chromatography.15

Procarbazine is another antineoplastic alkylating agent used to primarily treat lymphosarcoma. It is lipid-soluble and crosses the blood-brain barrier. It is myelosupressive causing thrombocytopenia and leukopenia. It comes as 50 mg capsules that almost always have to be compounded as an oil base, flavored solution for use in dogs.7 It is given orally as 25 to 50 mg/meter squared once a day.7,19 Hemograms are monitored weekly for the first month then monthly thereafter.7 After the first month, if possible, the dose is reduced to every other day unless disease relapse occurs.7 It might be possible to use this drug carefully at the same time lomustine or cytosine arabinoside are given, but this has not been tried to date.  

Radiation therapy has been used to treat GME of dogs in the past.8 However, it was not always effective in dogs that relapsed when prednisone therapy was discontinued.8 With the advent of therapies such as leflunomide, cytarabine, lomustine and cyclosporine there is little indication to use radiation therapy to treat autoimmune CNS disease of dogs since these chemotherapeutic agents seem to be more effective.

Summary: Prednisone alone, in immunosuppressive doses, tapered slowly over 6 months, may be effective in causing permanent remission of neutrophilic and eosinophilic meningitis or focal brainstem or forebrain GME; however a combination of prednisone for 6 months and
leflunomide for 1.5 years increases the chance of long term remission and is now always used. If these conditions relapse when prednisone therapy is reduced or discontinued, then adding other chemotherapeutic agents along with the leflunomide such as lomustine and cytarabine (both used for 1 year) can be done to achieve permanent remission. Dogs with GME involving the spinal cord or visual pathways or that have necrotizing encephalitis should be treated with combination therapy of prednisone, leflunomide, cytarabine and lomustine from the outset if they are to survive longterm.

Therapy with microemulsion cyclosporine (used for 1.5 years) can also be added to treat

resistant cases that relapse despite combination therapy with the four drugs described above.

References:

1 Braund KG, Vandevelde M, Walker TL, et al.: Granulomatous meningoencephalomyelitis in six

dogs. J Am Vet Med Assoc 172(10):1195-1200, 1978. 

2 Meric, SM: Canine meningitis a changing emphasis. J Vet Int Med 2(1): 26-35, 1988.

3 Munana KR, Luttgen PJ. Prognostic factors for dogs with granulomatous

meningoencephalomyelitis: 42 cases (1982-1996). J Am Vet Med Assoc 212(12): 1902-1906,1998.

4 Sisson A: Encephalitis. In: Tilley LP, Smith FWK, eds. The 5-Minute Veterinary Consult Canine

and Feline 3rd edition. Philadelphia: Lippincott Williams & Wilkins 2004:398-399.

5 Sisson A: Encephalitis In Tilley LP, Smith FWK, eds. The 5-Minute Veterinary Consult Canine

and Feline 2nd edition. Lippincott Williams & Wilkins 2000:650-651.

6 Adamo FP, O'Brian RT: Use of cyclosporine to treat granulomatous meningoencephalitis in three

dogs. J Am Vet Med Assoc 225(8):1211-1216, 2004.

7 Cuddon PA, Coates JR, Murry M: New treatments for granulomatous meningoencephalomyelitis.

In: Proceedings. 20th Am Coll Vet Intern Med Forum 2002:319-321.

8 Sisson AF, LeCouteur RA, DowSW, Gillettte EL: Radiation therapy of granulomatous

meningoencephalomyelitis of dogs. J Vet Int Med 3(2):119, 1989.

9 Gregory CR: Immunosuppresive agents. In: Kirk RW, Bonagura JD eds. Current veterinary

therapy XIII. Small animal practice. Philadelphia: WB Saunders Co. 2000:509-513.

10 Kipar A, Baumgartner C, Vogl K, et al: Immunohistochemical characterization of inflammatory

cells in brains of dogs with granulomatous meningoencephalitis. Vet Pathol 35:43-52, 1998.

11 Begley DJ, Squires LK, Zlokovic BV, et al:Permeability of the blood-brain barrier to the

immunosuppressive cyclic peptide cyclosporin A. J Neruochem 55:1222-1230, 1990.

12 Robsin D: Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in

people, dogs and cats. Vet Rec 152:739-748, 2003.

13 Nuhsbaum MT, Powell CC, Gionfrido JR, et al: Treatment of granulomatous

meningoencephalitis in a dog. Vet Ophthalmol 5(1):29-33, 2002.

14. Kristal O, Rassnick KM, Gliatto JM, et al: Hepatotoxicity associated with CCNU (Lomustine)

chemotherapy in dogs. J Vet Intern Med 18:75-80, 2004.

15. Gregory CR, Stewart A, Sturges B, et al: Leflunomide effectively treats naturally occurring

immune-mediated and inflammatory diseases of dogs that are unresponsive to conventional

therapy. Transplantation Proceedings, 30: 4143-4148, 1998.

16. Leflunomide. Antirheumatic agents. In: Hebel SK ed. Drug Facts and Comparisons. St. Louis:

Facts and Comparisons. January 2000:1593-1595.

17. Schatzberg SJ, Haley NJ, Barr SC, et al: Polymerase chain reaction screening for DNA viruses

in paraffin-embedded brains from dogs with necrotizing meningoencephalitis, necrotizing

leukoencephalitis, and granulomatous meningoencephalitis. J Vet Intern Med 19:553-559, 2005.

18. Zarfoss M, Schatzberg S, Venator K, et al: Combined cytosine arabinoside and prednisone

therapy for meningoencephalitis of unknown aetiology in 10 dogs. J Sm An Prac 47:588-595, 2006.

19. Coates JR, Barone G, Dewey CW, et al: Procarbazine as adjunctive therapy for treatment of

dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21

cases (1998-2004). J Vet Intern Med 21:100-106, 2007.

20. Wong MA, Hopkins AL. Meeks JC, et al: Evaluation of treatment with a combination of

azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology: 40

cases (2000-2007). J Am Vet Med Assoc 237(8):929-935, 2010.

 

Update

Georgie started vomiting last Thursday (3 days before the Leflunomide arrived). I was getting very worried that this might be due to the toll the Prednisone was taking on her. Although the vet gave her a drug called Losec Mups to assist with the gastro Pred side effects it is still a concern. Her tummy was rock hard and you could see she was desperately uncomfortable. I had been giving Georgie her meds without food to improve the effect of the Cyslosporine. She vomited Thurdsay, Friday and Saturday. She even vomited after her first Leflunomide tablet on Saturday night. I was heartbroken. I made a decision to start giving the meds with her food to try and reduce the harshness of it all.

Since Sunday I have given her meds with food and also decided to remove grain from her diet. I had a feeling she was battling to digest her food because of all the meds. I fed her boiled chicken instead of chicken and pellets.

From that point on she has managed to keep her food down and she has now successfully had 4 doses of Leflunomide.

I don't know if the Leflunomide is working incredibly quickly, whether her new diet has helped or whether the other meds have finally started to take effect, but what a change. In the last 4 days Georgie has gone from lethargic, uncomfortable and showing many signs of the disease to a energetic, happy little girl with significantly less noticeable neurological symptoms. I can finally breathe a sigh of relief that something seems to be working.

Next Steps

Unfortunately after the MRI and spinal tap Georgie seemed even worse than before she had the procedures. The vet immediately upped her dosage of Prednisone and scheduled her for her first sessions of Cytosar injections (Cytarabine) on the weekend. The injections are given 12 hours apart and given over a 48 hour period, i.e. 4 injections over the weekend.

I immediately got to work trying to find out as much as I could about GME. Unfortunately a lot of the information on the internet is fairly outdated and based primarily on the use of Prednisone as treatment. Prednisone is extremely tough on the body and does a lot of damage if used for a long period of time. In many cases Prednisone alone is not sufficient to stop the disease and once the dosage is reduced the symptoms quickly return and often more aggressively than before, Fortunately I found forums and other more up to date information that gave me a bit more hope.

Georgie wasn't responding much to the increased Prednisone and Cytosar. The vet (Dr Frikkie Strydom) suggested upping the Prednisone to a higher dose and adding the drug Cyclosporine to the mix. I readily agreed, desperate to try and help my little girl. Unfortunately she vomited a few times and cried beforehand so we took her back to the vet to check it out. He booked her in for the weekend to rule out any seizures and monitor her. Fortunately they didn't pick up any seizures and it seemed like the vomiting was just an initial response to the Cyclosporine. It stopped before she was discharged. 3 weeks after the initial Cytosar sessions she was due for her next round. We continued with this method of treatment and I continued to research as much as I could and was in regular contact with my vet who I must say is absolutely incredible and puts up with me telling him everything I have researched. The hospital he is a partner in is of a very high standard and treat a lot of these cases (Fourways Vet Hospital in Johannesburg, South Africa). Regardless of their experience and my lack of experience he has always been open to whatever I have had to say.

 

After very little improvement even after the 3rd round of Cytosar I decided to send the vet a paper from Veterinary Neurologist Dr Sisson in the USA. Dr Strydom was already using 3 of the drugs in the paper and I asked him whether we could look at the others Dr Sisson uses, primarily Leflunomide which he now uses in all GME cases. Dr Strydom researched what I had sent him and immediately made arrangements to order to Leflunomide and find out about the necessary blood tests being analysed at a human lab (the veterinary labs in South Africa don't test Teriflunomide levels).

Georgie's background

Little Georgie was born on the 1st May 2012. She came into my life on the 15th July 2012. She was a healthy, happy and sociable little girl. On the 17th of November 2012 we noticed that she wasn't responding to anything visually and rushed her off to the emergency vet. He was equally concerned about her vision and referred us to the Animal Eye Hospital for tests. The eye specialist confirmed that our baby was blind and diagnosed her with Sudden Acquired Retinal Degeneration Syndrome (SARDS), a disease that causes blindness over a very short space of time. We went away with the comfort that she was in no pain and would adjust extremely quickly. The specialist was right. Within less than 2 weeks she was running around as if nothing was wrong whatsoever.

In December 2012 I knew I needed to get Georgie spayed and booked her in for surgery. The day before the surgery I took her in for blood tests just to make sure there were no underlying health issues and she was given the all clear. On the 19th of December she had her surgery and the next day was back to her normal lively self. A few days later we started to notice her walking a bit strangely and presumed it was to do with the surgery and her stitches possibly pulling. 9 days after the surgery we took her to have her stitches out but she continued to walk strangely and started tilting to one side and circling. On 31st December we took her back to the vet as we were very concerned about her behaviour. The vet hoped that it was Vestibular disease but did mention the chance that it might be neurologial. He treated her with antibiotics and Prednisone.

Within a week Georgie was back to herself and the vet started reducing the dosage of Prednisone. About a week later she started going downhill again. I immediately took her back to the vet and he booked her in for an MRI and spinal tap the next day. I was beside myself with worry. We got the results of the MRI the same day and the vet diagnosed her with suspected Granulomatous Meningoencephalitis (GME). She had a fairly large lesion on her brain. The results of the spinal tap confirmed his suspicions. Here began our journey with GME.