CE Article #2

Granulomatous
Meningoencephalomyelitis
in Dogs
P. Filippo Adamo, DVM, DECVNa
William M. Adams, DVM, DACVR (Radiology, Radiation Oncology)
Howard Steinberg, VMD, PhD, DACVP
University of Wisconsin

ABSTRACT: Granulomatous meningoencephalomyelitis (GME) is a nonsuppurative inflammatory

disease of unknown origin that affects the central nervous system of dogs. GME is characterized
histologically by large perivascular cuffs of mononuclear cells in the parenchyma and meninges
of the brain and spinal cord. If left untreated, it is usually fatal. Immunosuppressive doses of
glucocorticosteroids have been the mainstay of treatment for GME; however, new and more
effective therapies have recently been proposed.This article reviews the pathology, origin, clinical
signs, therapeutic response, and outcome of GME in dogs.

ranulomatous meningoencephalomyelitis (GME) is a nonsuppurative inflammatory disease of the canine central

nervous system (CNS).17 Its cause is unknown.
This devastating disease was first called reticulosis by Koestner and Zeman in 1962.8 The term
GME was proposed by Braund and colleagues
in 1978.9 GME has a worldwide distribution
and accounts for 5% to 25% of all CNS disorders in dogs.3,10

PATHOLOGY
GME is thought to account for most lesions
previously described as reticulosis. 5,11,12 The
term reticulosis refers to an
abnormal increase in cells
derived f rom, or related to,
monocyte macrophages (i.e.,

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aDr. Adamo

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San Leandro, California.

678

histiocytes). 3 Because GME lesions contain

histiocytes, GME may, by definition, represent
a form of reticulosis.3 In 1972, reticulosis was
divided into three categories: inflammatory
(granulomatous) reticulosis, neoplastic reticulosis, and microgliomatosis.13 More recently,9 the
inflammatory form has been referred to as
GME,2,46,9,10,14,15 and neoplastic reticulosis has
been reclassified as lymphoma or malignant
histiocytosis.11
At necropsy, gross lesions of GME are evident if the angiocentric inflammatory reaction
is sufficient to produce changes of the normal
brain symmetry (i.e., falx deviation or compression of surrounding structures).5 Lesions are
seen as areas of swelling and yellow to gray discoloration and are predominantly found in
white matter; however, gray matter and leptomeninges also may be affected.4,5 Meninges
may appear thickened and cloudy. In some
cases, optic nerves are grossly enlarged.2
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Figure 1. Histopathology section of a canine brain with disseminated GME. (Courtesy of Dr. A. Armien)

* *
*
Hematoxylin and eosin stain shows tightly aggregated whorls of
lymphocytes, spindle-shaped phagocytes, and collagen deposition
around demonstrated (arrow ) or presumed vascular structures
(asterisks).The lesions consist of single or clustered aggregates of
perivascular inflammatory cell accumulation.The presumed
vessels are occluded by eosinophilic amorphous material, with
scarce spindle cells (fibroblasts). Original magnification 10.

Microscopically, lesions of GME are characterized by

perivascular cuffs of lymphocytes, varying numbers of
macrophages, and plasma cells in the parenchyma and
meninges of the brain and spinal cord3,4,9,11,12,14,16 (Figure 1).
Sometimes the cells are arranged in a whorled pattern
around the central vessels, a feature that is emphasized by
reticulin stain17 (Figure 1). In some areas, the perivascular
cells are predominantly lymphocytes; in other regions,
macrophages predominate.14 Lymphocytes are predominantly CD3 antigen positive, and nearly all lymphocytes
and macrophages express major histocompatibility complex class II antigen.15 Macrophages may differentiate into
epithelioid cells, which often form a discrete nest within
the cuff.5 Infiltration of all these cells into the CNS
parenchyma is typically minimal; however, as the perivascular population around several vessels expands and coalesces, the intervening parenchyma is progressively
compressed and obliterated. Such cases are grossly evident
at necropsy.5 The neuropil surrounding GME lesions
shows modest glial cell reaction and edema.4,5 Prolonged
cases have lesion confluence, vascular proliferation, and
reparative changes.2,9,1416
Based on the site and distribution of lesions, GME is
classified as one of three morphologic forms: disseminated, focal, or ocular.35,10,12 In disseminated GME, the
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Reticulin stain shows that the spindle cells are rich in

extracellular reticular fibrin deposition. Original magnification
20.

white matter of the cerebrum, caudal brainstem, cerebellum, and cervical spinal cord is primarily affected; however, vascular lesions may also be found in gray matter,
leptomeninges, and choroid plexus. 4,5 If multiple
perivascular cuffs coalesce, a solitary granuloma may
form, representing the focal form of GME.3,4,11,17 Focal
lesions most commonly occur in the brainstem, especially in the pontomedullary region, and in cerebral
white matter.3,4,11,17 A focal form of GME associated
with multifocal, smaller lesions throughout the neuraxis
has been reported.18 The focal form of GME should be
differentiated from CNS malignant histiocytosis and
primary CNS lymphosarcoma.11,19,20 The ocular form of
GME affects the retinal or postretinal portions of the
optic nerve.5 Dogs with ocular GME may subsequently
develop the disseminated or focal form of the disease.10

ORIGIN
The cause of GME is unknown.36,12,21 Autoimmune,
infectious, and neoplastic causes have been theorized; an
autoimmune cause is considered most likely.15 Recent data
indicate that the inflammatory lesions in GME consist of
a T-cellmediated delayed-type hypersensitivity reaction
with organ-specific autoimmune disease.15 Lesions of the
optic nerve also support this hypothesis. An antiastrocyte
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however, other breeds have been affected.14,16,21 The disease frequently affects young to middle-aged dogs, with
a mean age around 5 years (range: 6 months to 12
years).5,21 A female predisposition has been observed,
with a female:male ratio ranging from 1.8:1 to 3:1.4,15,21,28
One study (21 dogs) reported a higher incidence in
males, with a male:female ratio of 1.5:1.6

Figure 2. Postcontrast sagittal T1-weighted MRI image

of a dog with necropsy-confirmed disseminated GME.

Note the multiple irregularly shaped, contrast-enhanced foci in
the ventral brainstem (yellow arrow), caudal cerebellum (green
arrow), and C1C2 spinal cord (white arrow).

autoantibody was recently identified in the cerebrospinal

fluid (CSF) of dogs with GME or necrotizing meningoencephalitis (NME), indicating a possible relationship
between these two diseases and the autoantibody.22 How-

CLINICAL SIGNS
GME usually has an abrupt onset and an inexorably
progressive course. If left untreated, it is usually fatal in a
few days or weeks.46,21 Clinical signs are variable and
reflect the morphologic type of GME and the site of
the lesion in the neuraxis.
Disseminated (Multifocal) Form
In dogs with disseminated GME, several areas of the
CNS are damaged and any combination of clinical signs
reflecting lesions in multiple CNS areas is likely. Dogs are
determined to have multifocal involvement if they display
signs referable to at least two of the following structures
of the nervous system: optic nerve, forebrain, cerebellum,
brainstem, spinal cord, or meninges21 (Figure 2). Occasionally, fever may accompany neurologic signs.14 Cervical

The cause of GME is unknown. Autoimmune, infectious, and neoplastic causes

have been theorized; an autoimmune cause is considered most likely.
ever, it remains unclear whether the autoantibody is the
cause or the consequence of the inflammation.22
Pathologic features and lesion distribution distinguish
GME from idiopathic encephalitides of small-breed
dogs, such as NME of young pugs and Maltese terriers
and the necrotizing leukoencephalitis of Yorkshire terriers and Chihuahuas.12,16,23,24 NME of pugs and Maltese
terriers is histopathologically characterized by inflammatory changes with lymphocytic, plasmacytic, and histiocytic infiltration and extensive parenchymal necrosis
restricted to the cerebral hemispheres.2426 Necrotizing
leukoencephalitis of Yorkshire terriers has similar
necrotic lesions on histopathologic evaluation, but brainstem lesions occur in addition to cerebral lesions.23,26,27

INCIDENCE AND PREDISPOSITION

The disease has been described more commonly in
small-breed dogs, especially in toy breeds and terriers;
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hyperesthesia may be associated with disseminated or

focal GME.3

Focal Form
The focal form of GME causes clinical signs suggestive of a single, space-occupying lesion. If the lesion is
in the forebrain, the clinical signs are usually seizures,
behavior and mental status change, ataxia, circling, pacing, head pressing, and central visual impairment with
normal pupillary reflexes.14 If the lesion involves the
midbrain, mental depression and mydriasis unresponsive to light with normal vision are typical clinical
signs. 14 If the lesion involves the pons or medulla
oblongata, clinical signs may include hemiparesis ranging to tetraplegia; multiple cranial nerve deficits, such
as depressed palpebral, corneal, and gag reflexes; facial
and trigeminal nerve paralysis; and central vestibular
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ticity, goose-stepping gait, and intention tremor are

common clinical signs.14

Ocular Form
Ocular GME is the least commonly reported form of
GME. 14 It is characterized by acute onset of visual
impairment, with unilateral or bilateral dilated pupils
that are unresponsive to light stimulation as a result of
optic neuritis.14 Funduscopic examination may reveal a
hyperemic, edematous disk (Figure 3). Vessels may be
dilated, and focal hemorrhage may be present.14
DIAGNOSTIC APPROACH
Signalment, history, neurologic and ophthalmic
examinations, and progression of the neurologic signs
may be typical, but definitive diagnosis of GME
requires brain biopsy or necropsy.2932 A presumptive
diagnosis of GME is usually made on the basis of compatible findings on CSF analysis and magnetic resonance imaging (MRI) or computed tomography (CT)
in a dog with a characteristic signalment and suggestive
clinical signs.
Minimum Database
A minimum database for a dog with clinical signs of
CNS dysfunction should include a hemogram, serum
chemistry panel, and urinalysis to help differentiate
GME from metabolic encephalopathies. Survey radiographs of the thorax and abdominal ultrasonography
can help diagnose malignant neoplasia.33,34 An ante-

Figure 3. Fundic appearance of the left eye of a 6-year-

old, intact female Brittany spaniel with a history of

acute neck pain and bumping into objects. Optic neuritis
is demonstrated by optic nerve head swelling, loss of the
physiologic cup, and indistinct disk margins. (Courtesy of Dr.
R. Carter)

Cerebrospinal Fluid Analysis

Analysis of CSF collected f rom the cerebellomedullary cistern usually reveals a high protein concentration and an elevated total nucleated cell count
(pleocytosis).3,4,21 A total nucleated cell count less than 3
cells/l and a protein concentration less than 25 mg/dl
are usually considered normal CSF values.36,37 In dogs

Based on the site and distribution of lesions, GME is classified as one of

three morphologic forms: disseminated, focal, or ocular.
mortem presumptive diagnosis of GME may be
obtained via CSF analysis, CT or MRI, and elimination
of other encephalitides, such as those produced by protozoal infections (e.g., neosporosis, toxoplasmosis) and
fungal infections (e.g., blastomycosis, histoplasmosis,
coccidiomycosis, cryptococcosis, aspergillosis), using
serologic testing.3,35 Canine distemper viral encephalitis
may be ruled out by negative results of CSF neutralizing
antibody titer and urine reverse transcriptasepolymerase chain reaction assay; however, in some cases,
definitive diagnosis of canine distemper encephalitis
requires necropsy.
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with GME, the total nucleated cell count usually ranges

from 50 to 900 cells/l2; however, there is marked variability (from 0 to 11,840 cells/l), and in one study,6
about 10% of dogs had a normal value.

Cytology
In pleocytosis associated with GME, the cells are predominantly mononuclear, including small lymphocytes
(60% to 90%), monocytes (10% to 20%), and large
macrophages2 (Figure 4). Neutrophils usually make up
1% to 20% of the cell population; occasionally, they are
the predominant cell type, accounting for 50% to 60%
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Figure 4. Cytocentrifugation preparation of CSF. There

is a predominance of small lymphocytes (black arrows), with

smaller proportions of vacuolated macrophages (red arrows) and
nondegenerate neutrophils (green arrows). (Courtesy of Dr. R.
Dickinson)

of the cell type differential.2,21,28 Fewer lymphocytes than

monocytes are reported in some cases.38 Mononuclear
pleocytosis is more common in the disseminated form
of GME, although in one report,21 17% of dogs had a
predominantly neutrophilic inflammation, emphasizing
the variability in CSF findings that can be encountered
with GME. CSF pleocytosis can develop in dogs with
focal disease if lesions are close to the ventricular system
or meninges.3,21

Protein
The protein concentration in the CSF may increase
because of the breakdown of the bloodbrain barrier with
subsequent extravasation of serum protein and intrathecal
antibody production.4,39 Protein levels are variable in dogs
with GME, usually ranging from 40 to 400 mg/dl.2
Imaging
Magnetic Resonance Imaging
Magnetic resonance features of GME consist of single or multiple lesions that are hyperintense on T2weighted and fluid-attenuated inversion recovery
(FLAIR) images and mildly to moderately hypointense
on T1-weighted images, relative to adjacent brain tissue40 (Figure 5). Meningeal enhancement may also be
evident.41 If affected, optic nerves and the optic chiasm
may be more identifiable than usual (Figure 6).
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Figure 5. Two sets of brain MRI images, taken 49 days

apart, of a 13-year-old spayed dachshund. First study: (A)

A postcontrast T1-weighted image shows an area of hypointensity
in the ventral temporal lobe (between arrows); note the lack of
contrast enhancement. (B) On a FLAIR image, there is diffuse
hyperintensity in the white matter of the left cerebral cortex.This
dog was treated for presumed infarction. In the weeks following
tapering of corticosteroid therapy, clinical signs progressed. Second
study: (C) On a postcontrast T1-weighted image, there are now
bilateral foci of marked contrast enhancement in the cerebral
cortex. (D) On a FLAIR image, multiple bilateral hyperintense foci
are seen in the cerebral cortex.These findings are consistent with
progressive GME, distemper, or fungal granulomas. GME was
confirmed by CT-guided needle biopsy (Figure 8) and 17 months
later at necropsy. (The dog was treated with a combination of
corticosteroids and cyclosporine.)

Computed Tomography
Although not as sensitive as MRI in imaging brain
and meningeal lesions, CT can provide evidence of
GME. Both focal and disseminated forms of GME
show contrast enhancement, and the mass effect may be
indirectly observed by displacement of surrounding
brain tissue.4245 Meningeal and optic nerve contrast
enhancement may also be seen on high-quality images.
GME lesions in the forebrain may show contrast
enhancement42,43 (Figure 7), but brainstem lesions are
more difficult to see due to beam-hardening artifacts
from the petrous temporal bones.34,46
Brain Biopsy
Although infrequently performed, brain biopsy can be
a very useful diagnostic test in an animal with GME.21
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Figure 6. T1-weighted, contrast-enhanced MRI images of a 9-year-old spayed dachshund that presented with acute

blindness and absent pupillary reflexes in both eyes.

CSF analysis showed increased protein concentration and

lymphocytic pleocytosis. On this dorsal view, both optic disks are
enlarged and hyperintense (arrows) and extend into the vitreous.

On this sagittal view, there is an ill-defined area of hyperintensity

(arrow) at the rostral base of the brain, extending just cranial to
the hypophysis (asterisk), corresponding to the area of the optic
chiasm.

Brain biopsy can be performed via stereotactic CTguided technique (Figure 8) or by open surgical resection.2932

TREATMENT PROTOCOLS AND

PROGNOSIS
Various treatment protocols have been suggested for
GME, including glucocorticosteroids, radiation therapy,
cytosine arabinoside, procarbazine, leflunomide, and
cyclosporine. Common adverse effects, median survival
time, and approximate cost of therapy are summarized
in Table 1.
Glucocorticosteroids
Administration of immunosuppressive doses of glucocorticosteroids, particularly prednisone (2 mg/kg/day
PO) tapered with response over the following months
to achieve the lowest dose possible to control signs,47 is
the traditional primary treatment. Response is variable;
clinical signs often recur quickly with tapering doses;
and the prognosis for permanent recovery is poor,
causing overall results to be unsatisfactory.9,21,48 Longterm, high-dose corticosteroid treatments predispose
patients to gastrointestinal ulceration, pancreatitis, and
iatrogenic hyperadrenocorticism.9,21,48 A median surNovember 2007

On this axial view, the area of hyperintensity extends just caudal

to the optic chiasm (asterisk) and dorsolaterally and bilaterally in
the optic tract region of the pyriform lobe. A presumptive
diagnosis of ocular GME was made. Clinical signs and CSF
abnormalities resolved with cyclosporine therapy.

vival time for 15 dogs with focal clinical signs treated

with corticosteroids alone was 41 days in one report
(range: 3 to >1,215 days).21 In this report, a difference
in survival was noticed on the basis of clinical signs:
dogs with multifocal signs had a median survival time
of 8 days.
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Figure 7. CT image of an 8-year-old female Chihuahua

that presented with acute onset of blindness 1 month
previously, episodic cervical pain, and recent progression
to right-sided head tilt, pacing, and right circling. Left
facial sensation and left limb conscious proprioception were
decreased. Neurologic signs were consistent with multifocal
lesions involving optic tracts and the right forebrain. On this
image of the brain following administration of intravenous
contrast medium, there is enhancement in the right parietal lobe
(arrow) and left shift of the falx cerebri with compression of the
right lateral ventricle (mass effect).

Radiation Therapy
Radiation has been proposed as an alternative treatment for focal GME on the basis of the assumption
that the focal form may actually be primary B-cell lymphoma of the CNS. 21,49 Although this assumption
remains unproven, in one study,21 six dogs treated with
radiation therapy for focal forebrain signs had significantly longer survival times (median: >404 days) than 15
dogs with the focal form treated with steroids only
(median: 41 days). In the same study, 12 of 21 dogs with
multifocal signs died before any therapy could be initiated, and eight of the remaining nine dogs had such
debilitating neurologic signs that they were not considered suitable candidates for radiotherapy.
Acute radiation reactions of incidentally irradiated
normal tissue are self-limiting and generally well tolerated. Such reactions include epilation, otitis, and (when
the eyes are included in the treatment field) conjunctivitis, keratoconjunctivitis, and corneal ulcers. Acute radiation side effects subside within 3 to 5 weeks after
completion of therapy.50 An important consideration in
the use of radiation therapy is delayed adverse radiation
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Figure 8. CT-guided needle brain biopsy of the dog in

Figure 5. Histopathology of the collected sample confirmed the

diagnosis of GME.

effects. Early delayed effects can occur from 2 weeks to

3 months after treatment and may be due to transient
demyelination. Animals with early delayed effects may
present with signs similar to those of the initial presentation, or they may be generally stuporous. These effects
are infrequently encountered, are usually transient, and
respond to systemic corticosteroids. 50 Late delayed
effects can occur 6 months to years after treatment; the
most serious is brain necrosis. 50,51 The risk for late
delayed effects increases with the size of each radiation
fraction and with a higher total dose.

Cytosine Arabinoside
Cytosine arabinoside (cytarabine) is an antineoplastic
drug with immunosuppressive effects. In conjunction
with prednisone or as a sole agent, it has been reported
to be effective in some dogs with GME.35,52 Cytarabine
acts on mitotically active cells by inserting itself into
DNA molecules, causing premature chain termination.
Due to the ability of the drug to cross the bloodbrain
barrier and its effect on immunosuppression, it has been
theorized that cytarabine may be useful in treating GME
in dogs.35 The drug is administered as a subcutaneous
injection of 50 mg/m2 twice a day for 2 consecutive
days. 35,53 This regimen is initially repeated every 3
weeks.35,53 Gloves should be worn during the administraNovember 2007

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Table 1. Various Therapies for Granulomatous Meningoencephalomyelitis in Dogs

Median
Survival Survival
Time
Range
(days)
(days)

Number
of Dogs

Therapy

Coates et al54

11

No treatment

18

Coates
et al54,b

20

Procarbazine
prednisone

Myelosuppression,
hemorrhagic
gastroenteritis

450

NA

2550 mg/m2/
day PO

$60$120/moc

Munana
and
Luttgen21

15

Prednisone

Gastrointestinal
ulceration, pancreatitis,
iatrogenic Cushings
syndrome

41d

3
>1,215

0.252 mg/kg
PO bid

$3$7/mo

Munana
and
Luttgen21

Radiation
therapy +
prednisone

Demyelination (early
delayed); brain necrosis
(late delayed)

404d

NA

Total 4049.5
Gy, divided in
2.4- to 4.0-Gy
fractions

$4,000 for full

cycle

Zarfoss
et al53,e

10

Cytarabine
prednisone

Myelosuppression

531

45
1,025

50 mg/m2 bid SC
for 2 consecutive
days, repeated
initially q3wk,
then once
q23mo

$10 for each

drug per cycle f
+ professional
fee for the two
injections per
cycle

Adamo
et al63,g

10

Cyclosporine
corticosteroids

Gingival hyperplasia,
hypertrichosis,
excessive shedding,
vomiting, diarrhea

930d

60
>1,290

Starting dose: 6
mg/kg PO bid;
adjust to obtain
blood trough
cyclosporine
level of 200400
ng/ml

$60/moh +
serial CSF and
cyclosporine
blood level

Adamo
et al63,g

10

Cyclosporine +
ketoconazole

Gingival hyperplasia,
hypertrichosis,
excessive shedding,
vomiting, diarrhea

930d

60
>1,290

Cyclosporine
(5 mg/kg) +
ketoconazole
(8 mg/kg) sid

~$28/moh +
serial CSF and
cyclosporine
blood level

Study

Side Effects

Dose

Cost of
Therapy a

NA: not available.

aCost of therapy is approximated for a 13.2-lb (6-kg) dog.
bIn this study, the prednisone dose was reduced or discontinued in 17 dogs.
cProcarbazine is available as 10- to 80-mg capsules; the approximate price is $2 for a 10- or 20-mg capsule and $3 for a 30-mg capsule;
the price increases progressively to $8 for an 80-mg capsule. The drug is also available as an aqueous solution or oil-based suspension
(Diamondback Drugs, Scottsdale, AZ); the price for these formulations is the same as for the capsules.
dAs calculated by Kaplan-Meier analysis.
eInitially in combination with prednisone (1 mg/kg q12h); after the second round of cytosine injections, prednisone therapy is reduced
and, in some cases, discontinued. In this study, 8 dogs received long-term prednisone (01.7 mg/kg bid) treatment, and 2 dogs received
tertiary immunosuppressive chemotherapeutics (procarbazine and leflunomide) in addition to the prednisonecytarabine regimen.
f Cytarabine is supplied as a 20 mg/ml injectable solution in 5-ml (100-mg) vials ($10/vial).
g In this study, 7 dogs were treated with cyclosporine alone or in combination with ketoconazole, and 3 dogs were treated with
cyclosporine and corticosteroids. Because of the small total number of cases in the study, all data were grouped together.
hCyclosporine is available in 10-, 25-, 50-, and 100-mg capsules; it may also be reformulated in capsules from oral solution (Neoral;
Novartis). The approximate price is $1 for a 25-mg capsule and $6 for a 100-mg capsule. A generic formulation could cost approximately one-third to one-half of the wholesale price.

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Figure 9. Brain CT studies of the dog in Figure 7 after 7 months of cyclosporine treatment. Absence of contrast
enhancement indicates resolution of the previous lesion. CSF analysis confirmed resolution of the previous abnormalities.

Before contrast injection.

After contrast injection.

tion of this agent because it can be absorbed through the

skin.35 A complete blood count (CBC) is conducted 10
to 14 days after the first course of cytarabine therapy and
periodically throughout the course of treatment (usually
once every 2 to 3 months).35 To increase treatment efficacy, cytarabine is usually used initially in combination
with prednisone (1 mg/kg bid); after the second round of
cytarabine injection, prednisone therapy is reduced.35 The
most significant side effect is myelosuppression. Other
side effects include vomiting, diarrhea, and hair loss.35 In
one study,53 the use of cytarabine was investigated in 10
dogs with suspected GME. Eight dogs received longterm prednisone (0 to 1.7 mg/kg bid) treatment, and
tertiary immunosuppressive chemotherapeutics (procarbazine and leflunomide) were added to the prednisonecytarabine regimen in two dogs (Table 1).53 In
this study, the median survival time was 531 days (range:
46 to 1,025 days), and five of the 10 dogs were alive at
the time of the studys conclusion.

Procarbazine
Procarbazine, an antineoplastic drug with multiple
sites of action, has been used as an adjunct therapy to
prednisone or as a single agent.35,54 It inhibits incorporation of small DNA precursors as well as RNA and protein synthesis. Procarbazine can also directly damage
DNA through an alkylation reaction.35,55 Procarbazine is
lipid soluble and crosses the bloodbrain barrier.35,55 In
one study,54 procarbazine and prednisone were investigated in 20 dogs with suspected GME, and the results
were compared with those of an untreated control group
(11 dogs) with histopathologically confirmed GME
(Table 1). In this study, the prednisone dose was reduced
or discontinued in 17 dogs, and the median survival
time was 15 months.54 Procarbazine has been used orally
at a dose of 25 to 50 mg/m 2/day. 35,54 The main side
effect associated with procarbazine therapy (usually
associated with the higher dose) is myelosuppression
(30% in one study).54 The CBC should be monitored

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Figure 10. Adverse effects of cyclosporine in the treatment of GME.

Hypertrichosis after 7 months of cyclosporine therapy in the dog

in Figure 7.

Gingival hyperplasia after 2 years of cyclosporine therapy.

once weekly for the first month, then monthly thereafter.35 Other side effects include hemorrhagic gastroenteritis (15% in one study 54), nausea, vomiting, and
hepatic dysfunction.35,54

cyclosporine concentration is most likely present in

affected areas of the CNS.44 In addition, as the T-cell
response is initiated in the peripheral lymphoid organs
in autoimmune disease,59 there may not be a need for
cyclosporine to cross the bloodbrain barrier to suppress
the pathological immune repsonse to the CNS. In dogs,
it is recommended to administer cyclosporine either 1
hour before or 2 hours after feeding to guarantee consistent and best absorption.60 Cyclosporine is not nephrotoxic or hepatotoxic in dogs and cats unless extremely

Cyclosporine
The rationale for using cyclosporine in GME arose
f rom recent data suggesting that GME is a Tcellmediated, organ-specific, autoimmune disease.15
Cyclosporine has profound immunosuppressive proper-

GME usually has an abrupt onset and an inexorably progressive course. If left untreated,
it is usually fatal in a few days or weeks.
ties and suppresses T-cellmediated immune responses
through inhibition of synthesis of interleukin (IL)-2
and other cytokines.56,57 Cyclosporine also suppresses
activation of macrophages and monocytes and the production of other cytokines (IL-3, IL-4, IL-5, tumor
necrosis factor-, and interferon), thus indirectly
inhibiting antigen presentation by class I and II major
histocompatibility complex, mononuclear cell function,
mast cell and eosinophil production, and growth and
differentiation of B cells.58 The bloodbrain barrier permeability of cyclosporine is poor; however, because
GME is a perivascular disease and the bloodbrain barrier is disrupted during inflammation, therapeutic
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high blood concentrations (>3,000 ng/ml) are maintained.61,62

In a retrospective study 63 of 10 dogs with presumptive
GME treated with cyclosporine alone or in combination
with corticosteroids and/or ketoconazole, cyclosporine
either alone or in combination with ketoconazole was
found to be effective (Table 1). In this study, no significant
abnormalities were detected on serial CBC and serum
chemistry panel in any dog. Serial CSF analysis showed a
marked improvement in inflammation in all dogs (Figure
9). Side effects of cyclosporine therapy at the therapeutic
dose included excessive shedding, gingival hyperplasia, and
hypertrichosis (Figure 10); signs of overdose included gasCOMPENDIUM

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trointestinal signs (e.g., vomiting, diarrhea, anorexia). The

overall median survival time for all dogs in the study was
930 days (range: 60 to >1,290 days), and five dogs were
still alive at the time of the studys conclusion. Based on
the results of this study, we recommend cyclosporine as
monotherapy at a starting dose of 6 mg/kg PO q12h, with
a blood cyclosporine trough level target of 200 to 400
ng/ml. The blood cyclosporine trough level should be
tested after 5 to 7 days and reevaluated together with CSF
after 1 month and every 4 or 6 months thereafter, or any
time the patient neurologically deteriorates.

Cyclosporine and Ketoconazole

If cyclosporine monotherapy is cost prohibitive, coadministration of cyclosporine and ketoconazole has been
suggested.44 Ketoconazole has been shown to decrease
the systemic clearance of cyclosporine in dogs through
inhibition of hepatic cytochrome P450 3A microsomal
enzymes.64 We found the coadministration of ketoconazole and cyclosporine clinically effective using a starting
dose of 5 mg/kg PO q24h of cyclosporine and 8 mg/kg
of ketoconazole. The target trough blood cyclosporine
level and serial monitoring are similar to the protocol
described for cyclosporine used as monotherapy. This
combined treatment has the advantage of being given
only once daily. No significant side effects from ketoconazole were observed after 2 years in one dog and 14
months in two other dogs after receiving this combined
therapy. This combination protocol is not recommended
if liver enzyme levels are elevated or any other medical
condition that might exacerbate liver insufficiency is
present at the time of diagnosis or during treatment.
Leflunomide
Leflunomide is an immunomodulator used in a preliminary clinical study in three dogs with inflammatory
or malacic brain lesions of unknown cause.65 In this
study, leflunomide replaced an effective treatment with
immunosuppressive doses of glucocorticosteroids, which
had to be discontinued due to the onset of iatrogenic
Cushings syndrome. This study indicated a favorable
response in all three dogs that survived more than 12
months after starting leflunomide therapy.
Surgery
Surgical removal of brain GME lesions has also been
reported.1 Surgical intervention is not a typical treatment
modality for inflammatory or infectious brain disorders;
however, it is suggested that the mass removal and the
COMPENDIUM

decrease in intracranial pressure afforded by craniotomy

may benefit the patient. 1 Surgical removal may also
enable histologic confirmation of GME, which then may
be followed by the most appropriate medical treatment.1

CONCLUSION
Untreated GME is invariably fatal, and the disseminated form carries the worst prognosis.21 Radiation therapy combined with corticosteroids has been shown to
significantly increase survival time in dogs with the focal
form presenting with forebrain signs. Leflunomide therapy is promising; however, prospective evaluations of a
larger treatment group with a longer follow-up to substantiate these initial findings is warranted. Cytarabine,
procarbazine, and cyclosporine treatment for GME may
result in better long-term outcomes than those previously reported with glucocorticosteroid treatment alone.
ACKNOWLEDGMENTS
The authors thank Drs. R. Carter, A. Armien, and R. Dickinson for providing the images of the fundus of the eye, the histopathology of brain section, and the cytology of CSF, respectively.

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1. The histopathologic appearance of GME is characterized by

a. necrotic changes in the brainstem.
b. necrotic changes in the cerebral cortex.
c. perivascular cuffs composed of lymphocytes, a varying number of macrophages, and plasma cells in the
parenchyma and meninges of the brain and spinal
cord.
d. diffuse brain necrotic changes with perivascular accumulation of polymorphonucleated cells.
2. Which statement regarding the signalment for
GME is most correct?
a. Pugs, Maltese, and Yorkshire terriers appear to be
predisposed.
b. Large-breed dogs appear to be predisposed.
c. Any breed of dog of any age and either sex may be
affected; however, older dogs appear to be predisposed.
d. Any breed of dog of any age and either sex may be
affected; however, young to middle-aged, female,
small-breed dogs appear to be predisposed.
3. Based on the site and distribution of the lesions,
GME is classified into
a. two morphologic forms: disseminated and focal.
b. three morphologic forms: disseminated, focal, and
ocular.
c. four morphologic forms: disseminated, focal, ocular,
and cerebellar.
d. none of the above
4. What is the most likely cause proposed for GME?
a. virus
c. neoplasia
b. autoimmune disease
d. protozoa

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5. Definitive diagnosis of GME requires

a. viral isolation.
b. detection of a histopathologic lesion on brain biopsy
or necropsy.
c. detection of inclusion bodies in lymphocytes in the
CSF.
d. detection of unidentified protozoa in macrophages in
the CSF.
6. CSF analysis in dogs with GME is characterized by
a high total protein concentration and an elevated
total nucleated cell count with a predominance of
a. macrophages.
c. small lymphocytes.
b. neutrophils.
d. eosinophils.
7. Characteristic MRI features of GME consist of
a. single or multiple lesions, primarily involving the white
matter, that are hyperintense on T2-weighted and
FLAIR images and hypointense on T1-weighted images.
b. single or multiple lesions, primarily involving the white
matter, that are hypointense on T2-weighted and
FLAIR images and hypointense on T1-weighted images.
c. single or multiple lesions, primarily involving the white
matter, that are hyperintense on T2-weighted and
FLAIR images and hyperintense on T1-weighted
images.
d. No characteristic MRI features have been described
for GME.
8. The following new alternative therapies have
been proposed for GME:
a. cytarabine, procarbazine, radiation therapy, leflunomide, and cyclosporine.
b. cytarabine, amphotericin B, radiation therapy, and
cyclosporine.
c. cytarabine, cyclophosphamide, procarbazine, and radiation therapy.
d. cytarabine, itraconazole, radiation therapy, and
cyclosporine.
9. _________ is the most significant side effect of
cytarabine when used in the treatment of GME.
a. Myelosuppression
c. Renal failure
b. Papillomatosis
d. Hepatic failure
10. The most common side effects of cyclosporine in
the treatment of GME are
a. gingival hyperplasia and hypertrichosis.
b. lymphopenia and anemia.
c. hepatic and renal failure.
d. gingival hyperplasia and hepatic failure.

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