Urgent question Polina is very sick

[lillymae]

Originally Posted by omichka

after she has started to take a prednisolon, she is a normal dog, as used to be, even more active, but.... her blindness makes me worried a lot. Even her eyes's color is changed. It is a bad sign as I was told by vet.


Tomorrow morning we are going to neurologist for MRI and spinal exam.

I will let you know, thanks you

Never thought I'd be saying this, but I hope she has Chiari and not a tumor.
If Chiari and she gets the rite meds the sight will probably come back. The cyst or tumor is pressing on the optic nerve, with the rite meds if Chiari the cyst will resolve. If tumor it will not.
Praying this baby will be OK and we get good news tomorrow.

[dwerten]

Good luck today with your little one

[bailie]

sending prayers to u and ur little furbaby xx

[omichka]

Our news are bad ....

suspected necrotizing leukoencephaloelitis (NLE) possible Necrotizing meningoencephalomyelitis (NME)

They did find extra fluids.


Neurologist said that this is worst case of GME (aka general GME) , and .... we do not know how long she will live - a few months or maximum a couple years.

I have not read about it yet, but doctor said that I should be still optimistic.

she was given new medication, including prednisolon, but they increased doses A LOT. Polina is 6.7 pounds only.

the list of medication:

1. prednisolon 3mg/ml, dose increse to 1ml for 5 days twice daily, then reduce to 0.5 91.5mgtwice daily for 3 weeks, then .5 once a day, then .5 ml every other day.

What I do worry that she is much better after prednisolon, EVEN more active then used to be. IMO, dose already probably high for her, why MORE????

2. Clindamycin. 25 mg/ml. Twice 3ml. Antibiotic. 3 weeks only

3. Doxycycline. 10mg/ml. Twice 3ml. Antibiotic. 3 weeks only

4. Zonisamide. 25mg. Twice one pill.

[dwerten]

Originally Posted by omichka

Our news are bad ....

suspected necrotizing leukoencephaloelitis (NLE) possible Necrotizing meningoencephalomyelitis (NME)

They did find extra fluids.


Neurologist said that this is worst case of GME (aka general GME) , and .... we do not know how long she will live - a few months or maximum a couple years.

I have not read about it yet, but doctor said that I should be still optimistic.

she was given new medication, including prednisolon, but they increased doses A LOT. Polina is 6.7 pounds only.

the list of medication:

1. prednisolon 3mg/ml, dose increse to 1ml for 5 days twice daily, then reduce to 0.5 91.5mgtwice daily for 3 weeks, then .5 once a day, then .5 ml every other day.

What I do worry that she is much better after prednisolon, EVEN more active then used to be. IMO, dose already probably high for her, why MORE????

2. Clindamycin. 25 mg/ml. Twice 3ml. Antibiotic. 3 weeks only

3. Doxycycline. 10mg/ml. Twice 3ml. Antibiotic. 3 weeks only

4. Zonisamide. 25mg. Twice one pill.

ok i think you need to ask neurologist if he has heard of Dr Sisson and his protocol and I think you need to join the GME group i referred you to as they know a ton about this and what works. If it is a bad case then your dog needs to be on chemo drug and steroids so please join this group tonight as they will help you understand everything and tell you what the latest protocol is and what they are using to get their dogs in remission. It can take a year but if she goes into remission then she will be ok.

Also no more vaccines so you may need to look into getting a rabies vaccine waiver when it comes due but definitely no DHPP or any other vaccine

Please join this group i am on it and they know alot about this disease. I also have a friend with gme as well and her dog is doing much better. Her dog gained weight from the pred so expect this but the pred is necessary to keep swelling down on the brain. I provided alot of good info below so check it all out.

Be strong and she will be ok just educate yourself so you can get her the best protocol you can to get her better.

[dwerten]

Originally Posted by dwerten

NewGMEDogs : NewGMEDogs

you can post your info on this group and ask what they think as they have dogs with gme and went through mri and spinal taps and neurological testing and i am sure they can answer your questions in regards to that as well

here is the group please join ASAP - they are really nice

[TwoforFun]

Best wishes on your road to your baby recovery.

[omichka]

Thanks, I did join same day as you recommended and have read, and receive news.. Just did not post yet, but I will.

I will read more careful again.

Now. So do you think this treatment is not right?

I really worry about high doses

[dwerten]

Originally Posted by omichka

Thanks, I did join same day as you recommended and have read, and receive news.. Just did not post yet, but I will.

I will read more careful again.

Now. So do you think this treatment is not right?

I really worry about high doses

you have to do high doses to get her inflammation down. Post everything to the group and they will help you. Also ask for dr sisson paper and welcome letter and read it and review it with your neurologist. Many have had great success with dr sisson protocol as he is an expert with this disease. NME and GME i think means the entire spinal chord is being affected along with brain. The will tell you the differences as they know and you can read old messages as well.

I think she definitely has a chance now that you have a firm diagnosis. Yorkie prayers are amazing too I have seen it happen many times.

[dwerten]

just in case no one is awake i am going to post the paper by dr sisson so hang tight so i can post it as cannot post all in one post

[dwerten]

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 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, is often effective in causing permanent remission of neutrophilic and eosinophilic meningitis or focal brainstem or forebrain GME. If these conditions relapse when prednisone therapy is reduced or discontinued, then other chemotherapeutic agents such as lomustine (used for 1 year) and/or microemulsion cyclosporine (used for 1.5 years) can be added 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, lomustine, cytarabine and cyclosporine modified from the outset if they are to survive long-term. Leflunomide therapy can also be used to treat resistant cases that relapse despite combination therapy with other drugs.


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.

[dwerten]

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 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. This drug could be used if lomustine was not effective or not tolerated well. 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 nadir is not below 3,000.

Leflunomide is an immunomodulatory drug that has been shown in 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 know, 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 and hemorrhagic colitis. In humans hepatotoxicity has been reported16 but this has not been reported in dogs so far. The author has used leflunonmide to treat autoimmune CNS disease of dogs by adding it to prednisone, lomustine, cyclosporine and cytarabine combination therapy in the few cases in which relapse occurs each time prednisone therapy has been withdrawn. 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 The author has found that a few dogs that have failed conventional therapy for autoimmune CNS disease have been able to be maintained in remission with addition of leflunomide therapy.

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.

[dwerten]

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 6 mg/kg every 12 hours of Neoral 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 8 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 my 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 Neoral should only be considered for an owner that cannot possibly afford Neoral therapy any other way.

Generally Neoral 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 Neoral is used in combination with prednisone and lomustine. In this situation the prednisone is used for 6 months, the lomustine for one year and the Neoral for 1.5 years. Used this way the permanent remission rate of autoimmune CNS disease of all types approaches 99 percent.

[dwerten]

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 50 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 and less than 3,000 cells. 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 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 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 to prednisone in these cases the long-term remission rate is approaching 90 percent.

Cyclosporine is also an effective immunosuppressive drug that can be used in place of, or more often combined with, prednisone and lomustine to achieve maximum immunosuppression.
The microemulsified form (Neoral®), 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 cyclosporine-binding 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 T-cell 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 chroid 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

[dwerten]

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/.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.