Download Granulomatous Meningoencephalomyelitis in Dogs

644
Vol. 23, No. 7 July 2001
Email comments/questions to
[email protected]
or fax 800-556-3288
CE
Article #3 (1.5 contact hours)
Refereed Peer Review
Granulomatous
Meningoencephalomyelitis
in Dogs
KEY FACTS
Louisiana State University
■ Acute-onset blindness is the
most common manifestation of
ocular granulomatous
meningoencephalomyelitis
due to optic neuritis.
■ Cytologic evaluation of
cerebrospinal fluid generally
reveals a nonsuppurative
inflammation; however, a high
number of neutrophils may be
seen in some cases.
■ The immunosuppressive drug
leflunomide may be a reasonable
alternative treatment in steroidsensitive dogs.
Kirk Ryan, DVM
Steven L. Marks, BVSc, MS, DACVIM
Sharon C. Kerwin, DVM, MS, DACVS
ABSTRACT: Granulomatous meningoencephalomyelitis (GME) is an acute, progressive disease
causing focal to multifocal neurologic signs or sudden blindness in dogs. Typically, GME affects middle-aged, small-breed dogs. Classic histologic findings include perivascular cuffs of
mononuclear inflammation in the brain and spinal cord with a predilection for white matter. A
tentative diagnosis of GME is based on supportive history, physical examination, cerebrospinal
fluid analysis, and cross-sectional imaging of the brain or spinal cord. This diagnostic testing is
also indicated to exclude the diagnosis of similarly presenting infectious, inflammatory, and
neoplastic diseases. Confirming a diagnosis of GME requires histologic examination of the central nervous system via brain biopsy or at necropsy. Corticosteroids remain the mainstay of
therapy. However, radiation therapy and new immunosuppressive drugs may induce a transient
remission of clinical signs. Currently, the prognosis for prolonged recovery is poor. Recurrence
and progression of neurologic signs frequently result in death or necessitate euthanasia.
G
ranulomatous meningoencephalomyelitis (GME) is an inflammatory
disease of unknown etiology that affects the central nervous system
(CNS) of dogs. It is a common diagnostic differential for dogs with focal or multifocal neurologic disease. The description of GME in the veterinary
literature frequently overlaps with that of reticulosis (Box 1), a broad category of
historically important infiltrative CNS diseases.
Clinical signs vary and depend on the neuroanatomic location of the lesions.
Although largely considered an inflammatory disease, several different etiologies
have been hypothesized. The histopathologic lesions of GME share features with
infectious, neoplastic, and immune-mediated diseases.
PATHOLOGY
Histopathology remains the basis of our current understanding of GME. Classic GME lesions are characterized by perivascular cuffs of proliferating monocytes, macrophages, lymphocytes, and plasma cells (Figure 1).1–5 These perivascular cuffs often merge at adjacent vessels to form cellular whorls, which evolve
into nodular granulomas that mimic space-occupying masses.1,3,4,6 Occasionally,
Compendium July 2001
Small Animal/Exotics 645
BOX 1
Reticulosis
The term central nervous system (CNS) reticulosis is
used to describe a group of neoplastic and idiopathic
inflammatory diseases of the reticuloendothelial system
of the CNS (including GME).11,16–18,20 The definition
of reticulosis emphasizes the shared perivascular
orientation and histiocytic appearance of lesions in this
group of diseases.18 However, some confusion exists in
the literature regarding the proper designation of these
diseases.
Although a few sources distinguish inflammatory
reticulosis from neoplastic reticulosis,11,16 many cases
previously designated only as reticulosis are probably
cases of GME.21 Inflammatory reticulosis (focal and
multifocal) has been distinguished from GME
(disseminated) on the basis of lesion distribution.18
Occasionally, the term reticulosis is used primarily
to refer to neoplastic diseases.12 The use of terms
such as neoplastic GME and inflammatory GME
is characteristic of the overlapping definitions found
in the literature.15
This confusion highlights the difficulty in clinically
differentiating GME from similar neoplastic and
inflammatory CNS lesions. Neoplastic processes can
incite a significant inflammatory response. Chronic,
severe inflammation may take on histopathologic
characteristics of neoplasia. Recently, immunohistochemical studies have been used to further classify
the inflammatory cells within GME lesions.5,22 One
such study concluded that GME may be an immunemediated disease caused by a T-cell–mediated, delayedtype hypersensitivity reaction to CNS antigens.5
Likewise, some cases of reticulosis have been further
classified as primary lymphomas of the brain.22 This
debate over disease classification is clinically relevant
because the key to effective treatment is accurate
diagnosis.
granulomas develop that are not associated with blood
vessels.1,3 Rarely, the inclusion of neutrophils within lesions has been described.2,4 In general, classic perivascular cuff lesions of varying severity are found throughout
the brain and cervical spinal cord.1,2 GME lesions have
been localized to the eye, cerebrum, brain stem, cerebellum, and cervical spinal cord.1,2,4,7–10 Within the CNS,
lesions generally affect the white matter more than the
gray matter.1,3,11,12 Meningeal inflammation has been reported in association with underlying lesions.5
Microscopically, ophthalmic GME is characterized by
marked nonsuppurative inflammatory infiltrates and
granuloma formation within the optic nerve from the
optic disk to the optic chiasm.13,14 Similar lesions may be
noted in the retina and choroids.14–17 Retinal atrophy
with accumulation of pigment and adhesions to the underlying choroid may also occur.13,14 Occasionally, classic
perivascular lesions may extend into the sclera.15,17
The origin of inflammatory cells in GME is controversial. These cells may result from the migration of
blood-derived inflammatory cells or, more likely, represent a proliferative reaction within the CNS reticuloendothelial system.1,5,6 Regardless of origin, these cells accumulate in the space surrounding the vessels that
penetrate the brain (Virchow-Robin space).6,18,19 This
space is outlined by perivascular invaginations of the
pia mater around small vessels entering the brain and is
normally lined with a low number of reticuloendothelial cells.19 The normal reticuloendothelial cells of the
CNS include microglia and blood-derived monocytes.12
CLINICAL SIGNS
Clinical signs vary with the location and severity of
GME lesions. In general, GME should be suspected in
any mature dog that develops progressive signs of focal
or multifocal neurologic dysfunction, including the following4,23,24:
■
■
■
■
■
Seizures
Depression
Blindness
Head tilt
Circling
■
■
■
■
■
Cranial nerve dysfunction
Weakness
Ataxia
Cervical pain
Proprioceptive deficits
SYNDROMES
Focal GME lesions mimic space-occupying masses
(Figure 2). Clinical signs of focal disease occur secondary to nodular granuloma formation, but these cases may have disseminated lesions as well.3,4 The focal
form of GME may have a slower onset and progression
(3 to 6 months) than disseminated GME.1
Figure 1—Photomicrograph demonstrating the classic histo-
logic lesion of granulomatous meningoencephalomyelitis.
646 Small Animal/Exotics
Compendium July 2001
Figure 2—Sagittal brain sections demonstrating the extent of a
Figure 3— Optic neuritis consistent with granulomatous
gross granulomatous meningoencephalomyelitis lesion (arrows).
meningoencephalomyelitis.
Multifocal or disseminated GME progresses more
rapidly and is reported to have an acute onset (2 to 6
weeks) with more varied clinical signs.1 Some authors
have attempted to loosely define a number of clinical
syndromes associated with the location of lesions or
disease progression.1,4,16 One author reported five clinical syndromes associated with focal lesions in the cerebrum, midbrain, pons/medulla, vestibular system, and
cerebellum.1 The clinical relevance of these syndromes
has been questioned because many cases present with
multifocal neurologic signs.3
Ocular manifestations of GME have been well recognized and documented in the literature.13–15,17 Frequently,
this syndrome is characterized by acute blindness with
some cases later developing neurologic signs with CNS lesions.8,13–17 The acute blindness is attributed to optic neuritis characterized by dilated pupils, no menace response,
and no pupillary light response.13,14,17 Severe anterior and
posterior uveitis may also occur.15 Acute signs of optic
neuritis that may be recognized during ophthalmic examination include swollen elevated optic disks with blurred
margins, hyperemia, and no physiologic cup (Figure
3).11,13,14,17 In more chronic cases, optic nerve atrophy may
be evidenced by a shrunken optic disk with gray discoloration.13 Retinal detachment and petechial hemorrhage
may also be noted during fundic examination.14 GME
usually affects both eyes but may be unilateral.18
on signalment and clinical signs facilitates the diagnosis
of GME. Although any age and breed may be affected,
the disease classically affects middle-aged, small-breed
dogs (Figure 4).1,3,8,23 Male and female dogs appear to
be equally affected based on inconsistent reports of sex
predilection.1,3,8,23 An appropriate diagnostic plan leading to a definitive diagnosis of GME includes laboratory testing, cerebrospinal fluid (CSF) analysis, advanced
imaging, and histopathologic confirmation.
Common laboratory tests (e.g., complete blood cell
count, serum chemistry, urinalysis) are often within
normal limits because GME is not usually a multisystemic disease.1,3,15 Complete blood cell count results
consistent with both inflammation and stress have been
reported.4,25
Cerebrospinal fluid analysis represents one of the
most important diagnostic tests for GME because it is
readily performed and frequently abnormal. However,
mild disease may not disrupt the blood–brain barrier
enough to allow exfoliation of cells into the CSF.16 Classic CSF abnormalities include a mononuclear pleocytosis with elevated protein (mostly globulin) concentration. 1,3,8,23,24 Lymphocytes and macrophages are the
predominant cell types with a variable number of
mononuclear cells (Figure 5).1–3,8,23,24 Dogs with GME
may have a significant number of neutrophils in the
CSF and may also demonstrate polymorphonuclear cells
within classic lesions.3,23,24 In one study of 22 dogs with
GME, total CSF leukocyte counts ranged from 9.0 to
5400 cells/µl (normal, less than 10 cells/µl), while CSF
protein ranged from 13.0 to 1119 mg/dl (normal, less
than 25 mg/dl).24 In this study, abnormalities were more
DIAGNOSIS
The clinical signs of GME are not pathognomonic,
and a number of diagnostic differentials (Box 2) must
be considered. A high level of clinical suspicion based
Compendium July 2001
Small Animal/Exotics 647
BOX 2
Diagnostic Differentials
A diagnosis of GME is supported by the exclusion
of neoplastic, infectious, and inflammatory central
nervous system (CNS) diseases causing similar clinical
signs. A variety of infectious diseases are included on the
list of diagnostic differentials. A few of these merit
specific attention. It has been suggested that GME is
caused by an as yet unidentified infectious agent.21
Viral encephalitides (e.g., rabies and distemper) are
important considerations, especially in unvaccinated pets
from endemic areas. Distemper virus has been associated
with encephalitis of mature dogs and may be capable of
persistent, latent infection.28 CNS lesions associated with
canine distemper virus are characterized in part by
mononuclear perivascular cuffing and a predilection for white
matter that mimics the lesions of GME.29,30 GME cases have
been reported with rabieslike or distemperlike inclusion
bodies.31 In fact, distemper virus was once considered a likely
etiologic agent for GME based on a case report
demonstrating large amounts of distemper virus antigen
within classic GME lesions.32 In general, a diagnosis of
distemper is confirmed by demonstration of viral antigen in
brain tissue by immunohistochemistry.29 Positive
cerebrospinal fluid (CSF) distemper titers provide strong
supportive evidence but may be negative in some cases of
distemper encephalitis.25,30 False-positive CSF titers may be
obtained in association with blood contamination of the CSF
sample. In addition, CSF analysis in distemper often yields
less dramatic pleocytosis (less than 25 cells/µl) than GME.24
Protozoal encephalomyelitis may occur secondary
to infection with Toxoplasma gondii or Neospora
caninum.33,34 Although affected animals may present
with multifocal neurologic signs that mimic GME,
these agents frequently cause clinical signs in other body
systems as well.33,34 CSF abnormalities are nonspecific
and include an elevated protein concentration and
an increased nucleated cell count (predominantly
lymphocytes and mononuclear cells).33,34 CSF and serum
antibody titers may be useful in excluding this diagnosis.
However, normal dogs may have high serum titers.33,34
Serologic tests may be performed on CSF samples,
but their diagnostic value has not been completely
evaluated.25 This is especially true when the integrity
of the blood–brain barrier is in question. Cytologic
marked in the cisternal CSF compared with the lumbar
CSF. The effect of blood contamination and previous
steroid therapy on CSF parameters is debatable but
should be considered when normal CSF results are
found in a patient with severe clinical disease.3,24 Prior
identification of these organisms in the CSF is definitive,
but the diagnosis is most commonly made at necropsy.33,34
Idiopathic breed-specific CNS inflammatory
diseases are important diagnostic differentials.25 This is
particularly true of the necrotizing meningitis seen in
pugs, Maltese terriers, and Yorkshire terriers.35–37 Affected
animals present with the classic signalment, clinical signs,
and diagnostic test results associated with GME. These
diseases generally progress despite therapy and carry a
poor prognosis. Antemortem differentiation of GME
from breed-specific necrotizing meningitis may be
difficult without biopsy but may be clinically important as
advances in the diagnosis and treatment of GME occur.
Meningoencephalitis may occur secondary to
infection with the yeast organism Cryptococcus
neoformans.38 In endemic areas, this is an important
consideration prior to initiating immunosuppressive
therapy. Various cytologic abnormalities (i.e.,
pyogranulomatous and eosinophilic inflammation) have
been reported in the CSF of dogs with cryptococcal
meningitis.39 Ideally, the diagnosis is based on cytologic
identification of characteristic yeast organisms in the
CSF or other sites.39 In addition, the latex agglutination
serologic test for Cryptococcus identifies capsular
antigen.39 Consequently, a positive test result is
indicative of an active infection; tests can be performed
on serum and CSF samples.39
Neoplasia is one of the primary differential
considerations in the diagnosis of GME. The classic
inclusion of GME with neoplastic disease under the
larger term reticulosis underscores the fact that these
diseases can appear clinically and histologically very
similar.11,12,16 The clinical signs and diagnostic imaging
of certain neoplasms (e.g., meningioma) and focal GME
parallel each other. Immunohistochemical evidence
suggests that some cases diagnosed as focal GME
are actually B-cell lymphoma or primary histiocytic
neoplasia.22 Ideally, the neoplastic cell of origin should
be determined by immunohistochemistry whenever a
neoplastic process is suspected.
Many diseases capable of causing optic neuritis
(e.g., infectious, inflammatory, neoplastic, and idiopathic
disease) are diagnostic differentials of ocular GME.
steroid therapy has been suspected to decrease the diagnostic yield of CSF cytology.1 In at least one study, previous steroid therapy and/or blood contamination did
not appear to interfere with the detection of pathologic
changes.24
648 Small Animal/Exotics
Figure 4—Toy-breed dogs represent the typical signalment
for granulomatous meningoencephalomyelitis. However, idiopathic breed-specific necrotizing meningoencephalitides are
separate entities to be considered.
Cerebrospinal fluid pressure measurement is occasionally performed at the time of sample collection.
Both normal and increased values have been obtained
and probably depend on the severity of the disease and
the skill of the clinician performing the measurement.16,24 Rarely, CSF protein electrophoresis is performed to further identify increased proteins.4 At this
time, such information does not appear helpful in the
diagnosis and treatment of GME as disruption of the
blood–brain barrier and leakage of serum proteins are
hallmarks of the disease.
Although a presumptive diagnosis of GME based on
history, signalment, physical examination, and supportive CSF findings is often sufficient to begin treatment,
advanced imaging and histologic confirmation are
required to make a definitive diagnosis. Advanced
imaging modalities identify lesions consistent with focal and multifocal GME.7,9,10 Magnetic resonance imaging (MRI) has significant advantages over computed
tomography (CT) when used for generating images of
the brain. 9 Specifically, MRI images have greater
anatomic detail and fewer artifacts associated with bony
structures.9 In addition, MRI technology allows the
production of images from any geometric plane.9
There are few published case reports documenting
the advanced imaging of histologically confirmed
GME. Contrast enhancement of focal GME lesions on
CT has been reported.7,10 In a review of three cases diagnosed via CT, GME lesions were less enhanced than
meningiomas following contrast administration.7 In another retrospective study, nonspecific CT abnormalities
that correlated well with lesion localization included
hydrocephalus, edema, falcial deviation, and asymmetry of ventricles.10 In a report of two GME cases confirmed histologically and by brain MRI, one dog had a
focal lesion with features consistent with both inflam-
Compendium July 2001
Figure 5—Photomicrograph of cerebrospinal fluid from a dog
with granulomatous meningoencephalomyelitis. Lymphocytes and macrophages are the prominent cytologic cell types.
mation and neoplasia. 9 In T 1-weighted images, an
isointense space-occupying mass was delineated by a
hypointense margin. In T2-weighted images, the mass
was hyperintense compared with surrounding normal
brain tissue.9 The second dog developed an enhancing
lesion that was not evident on T1- and T2-weighted images prior to contrast administration.9
Unfortunately, MRI and CT cannot always completely differentiate neoplastic from nonneoplastic diseases of
the CNS.7,9,10 Although antemortem diagnosis of GME
is possible, histologic confirmation of the diagnosis is
often not obtained until necropsy. Surgical brain biopsy
following MRI or CT has been described with varying
rates of morbidity.7,8 Some of these cases involve dogs
taken to surgery for excision of suspected neoplasia.7 In
addition, CT-guided (free-hand or stereotactic) brain
biopsy has been used in clinical cases to differentiate
neoplastic from nonneoplastic disease.26,27 Tissue for microscopic examination should be obtained whenever
possible (antemortem or postmortem).
TREATMENT
Central Nervous System GME
Treatment may begin once a diagnosis of GME has
been established. Corticosteroid therapy remains the
standard treatment of GME despite eventual progression of clinical signs in most cases.1,3,8,23 Information regarding the dosage and efficacy of different corticosteroids in the treatment of GME is lacking. Many
authors report the use of prednisone or prednisolone at
a dose of 1 to 2 mg/kg sid or bid.1,16,17,23 In general, an
immunosuppressive course of prednisone should be followed by a slow taper over 4 months until the lowest
therapeutic dose is reached. Discontinuation of therapy
is rarely achieved in true cases of GME. The use of cytotoxic agents is not routine. Cyclophosphamide, specifi-
Compendium July 2001
cally, is poorly distributed to the CNS.40
Recently, leflunomide (Arava™, Aventis Pharmaceuticals, Bridgewater, NJ), a de novo pyrimidine synthesis inhibitor,41 has been used to treat immune-mediated and inflammatory diseases in dogs.42 Activated T
lymphocytes synthesize pyrimidine primarily through
the de novo pathway and may be especially sensitive to
leflunomide.41 This information is noteworthy because
GME may be a T-cell–mediated autoimmune disease.5
Although experience with this drug is still limited, it
has been advocated in the treatment of certain CNS
diseases in dogs that were experiencing severe side effects from glucocorticoid therapy.43 In humans, leflunomide has been associated with alopecia, diarrhea, and
leukopenia.41 At the present time, the significant cost of
this drug limits its use in many cases.
Radiation therapy may be a useful treatment modality for some cases of GME.8,44 A definitive assessment
of the efficacy of radiation therapy for cases of
histopathologically confirmed GME is lacking. However, a recent report suggests that radiation therapy prolonged the survival of dogs with focal GME.8 In addition, complete resolution of clinical signs and CT scan
abnormalities following radiation therapy has been reported in a small number of confirmed cases of GME.44
Absence of histologic GME lesions at necropsy has
been reported in a small number of cases that had confirmatory antemortem brain biopsies followed by radiation therapy.8 Total doses of radiation ranged from 40.0
to 49.5 Gy.8,44 In one report, these doses were divided
into 2.4- to 4.0-Gy fractions and administered via a 6mV linear accelerator or a cobalt-60 teletherapy unit.8
Complications of radiation therapy for CNS diseases
include infarction, necrosis, cataracts, and keratoconjunctivitis sicca. 45 Infarction and resulting necrosis
commonly manifest as seizures but may not be apparent for 5 to 6 months.45 The use of radiation therapy in
nonneoplastic diseases is controversial, and the hazards
of such therapy should be considered in addition to the
potential benefit.
Anticonvulsant agents may be valuable in select cases to control seizure activity.16,23 Diazepam at standard
doses may be administered intravenously or per rectum
to terminate ongoing seizure activity. Other drugs, such
as phenobarbital and potassium bromide, may be used
for maintenance anticonvulsant therapy. A thorough
evaluation for other causes of seizures is indicated.
Ocular GME
The treatment of ocular GME is similar to that of
CNS GME. Oral corticosteroids alone or in conjunction with locally administered corticosteroids have been
used to induce remission of clinical signs.1,13,14,16,17 Ther-
Small Animal/Exotics 649
apy for glaucoma and other sequelae to ocular inflammation may be necessary in conjunction with corticosteroid therapy.
PROGNOSIS
In general, GME has a poor prognosis.1,4,8,16,46 Among
dogs with severe seizure disorders, pets diagnosed with
GME are more likely to be euthanized or die during
hospitalization.46 Disseminated GME reportedly has an
acute onset and progresses rapidly to death or euthanasia within 6 weeks.1,16 The focal form of this disease
may have a more insidious onset and progresses slowly
over 3 to 6 months.1 In a recent study, dogs with focal
GME had a median survival time of 114 days (range, 3
to more than 1215 days).8 Dogs with multifocal signs
had a median survival time of 8 days (range, 1 to 274
days).8 Corticosteroid therapy may induce a transient
remission of clinical signs and prolong survival in some
patients.1,3,8,16 Positive prognostic indicators reportedly
include clinical and histopathologic evidence of focal
disease and treatment with radiation therapy.8
In ocular GME, the prognosis for permanent return
of visual function is poor.13,14,17 However, transient improvements in vision may occur following corticosteroid therapy.13,14,17 In a recent report, ocular GME
rarely progressed to a fatal neurologic disease.8 Other
authors frequently cite ophthalmic signs in combination with severe neurologic impairment.13,14,16,17
CONCLUSION
GME is a frequent consideration in the diagnosis of
dogs with neurologic disease. A presumptive diagnosis
is based on signalment, history, physical and neurologic
examination, and supportive diagnostic tests or advanced imaging. Definitive diagnosis requires tissue
sampling for microscopic evaluation via brain biopsy or
postmortem examination. Immunohistochemical studies will most likely be the source of information needed
to further our understanding of the disease. Standard
treatments for GME consist of corticosteroids and anticonvulsants. Novel immunosuppressive drugs and radiation therapy are useful in some cases. Currently, the
prognosis for prolonged recovery is poor.
REFERENCES
1. Braund KG: Granulomatous meningoencephalomyelitis.
JAVMA 186:138–141, 1985.
2. Braund KG, Vandevelde M, Walker T, et al: Granulomatous meningoencephalomyelitis in six dogs. JAVMA 172:
1195–1200, 1978.
3. Thomas J, Egger C: Granulomatous meningoencephalomyelitis in 21 dogs. J Small Anim Pract 30:287–293, 1989.
4. Sorjonen D: Clinical and histopathological features of granulomatous meningoencephalomyelitis. JAAHA 26:141–147,
1990.
650 Small Animal/Exotics
5. Kipar A, Baumgartner W, Vogl C, et al: Immunohistochemical characterization of inflammatory cells in brains of dogs
with granulomatous meningoencephalitis. Vet Pathol
35:43–52, 1998.
6. Russo M: Primary reticulosis of the central nervous system
in dogs. JAVMA 174:492–500, 1979.
7. Speciale J, VanWinkle T, Steinberg S, et al: Computed tomography in the diagnosis of focal granulomatous meningoencephalitis: Retrospective evaluation of three cases.
JAAHA 28:327–332, 1992.
8. Munana K, Lutgen P: Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982–
1996). JAVMA 212:1902–1906, 1998.
9. Lobetti R, Pearson J: Magnetic resonance imaging in the diagnosis of focal granulomatous meningoencephalitis in two
dogs. Vet Radiol Ultrasound 37:424–427, 1996.
10. Plummer S, Wheeler S, Thrall D, et al: Computed tomography of primary inflammatory brain disorders in dogs and
cats. Vet Radiol Ultrasound 33:307–312, 1992.
11. Koestner A, Jones T: Malignant lymphoma or lymphosarcoma: Primary in central nervous system, in Jones T (ed): Veterinary Pathology, ed 6. New York, Williams and Wilkins,
1997, pp 307–309.
12. Jubb K, Huxtable C: The nervous system, in Jubb K,
Kennedy P, Palmer N (eds): Pathology of Domestic Animals,
ed 4. San Diego, Academic Press, 1993, pp 267–439.
13. Fischer C, Liu S: Neuro-ophthalmologic manifestations of
primary reticulosis of the central nervous system in a dog.
JAVMA 158:1240–1248, 1971.
14. Smith J, DeLahunta A, Riis R: Reticulosis of the visual system in a dog. J Small Anim Pract 18:643–652, 1977.
15. Smith R: A case of ocular granulomatous meningoencephalitis in a German shepherd dog presenting as bilateral uveitis.
Aust Vet Pract 25:73–78, 1995.
16. Cuddon P, Smith-Maxie L: Reticulosis of the central nervous system in the dog. Compend Contin Educ Vet Pract
6:23–32, 1984.
17. Garmer N, Naeser P, Bergman A: Reticulosis of the eyes and
the central nervous system in a dog. J Small Anim Pract
22:39–45, 1981.
18. Vandevelde M: Primary reticulosis of the central nervous
system. Vet Clin North Am 10:57–63, 1980.
19. Braund KG: Encephalitis and meningitis. Vet Clin North
Am 10:31–57, 1980.
20. Fankhauser R, Fatzer R, Luginbuhl H, et al: Reticulosis of
the central nervous system (CNS) in dogs. Adv Vet Sci Comp
Med 16:35–71, 1972.
21. Vandevelde M: Neurologic diseases of suspected infectious
origin, in Greene C (ed): Infectious Diseases of the Dog and
Cat. Philadelphia, WB Saunders Co, 1998, pp 530–532.
22. Vandevelde M, Fatzer R, Fankhauser R: Immunohistological
studies on primary reticulosis of the canine brain. Vet Pathol
18:577–588, 1981.
23. Sarfaty D, Carrillo J, Greenlee P: Differential diagnosis of
granulomatous meningoencephalomyelitis, distemper, and
suppurative meningoencephalitis in the dog. JAVMA 188:
387–392, 1986.
24. Bailey C, Higgins R: Characteristics of cerebrospinal fluid
associated with canine granulomatous meningoencephalomyelitis: A retrospective study. JAVMA 188:418–
421, 1986.
25. Tipold A: Diagnosis of inflammatory and infectious diseases
of the central nervous system in dogs: A retrospective study.
J Vet Intern Med 9:304–314, 1995.
Compendium July 2001
26. Koblik P, LeCouteur R, Higgins R, et al: CT-guided brain
biopsy using a modified Pelorus Mark III stereotactic system: Experience with 50 dogs. Vet Radiol Ultrasound
40:434–440, 1999.
27. Harari J, Moore M, Leathers C, et al: Computed tomographic-guided, free-hand needle biopsy of brain tumors in
dogs. Prog Vet Neurol 4:41–44, 1994.
28. Lincoln S, Gorham J, Davis W, et al: Studies of old dog encephalitis. Vet Pathol 10:124–129, 1973.
29. Palmer D, Huxtable C, Thomas J: Immunohistochemical
demonstration of canine distemper virus antigen as an aid in
the diagnosis of canine distemper encephalomyelitis. Res Vet
Sci 49:177–181, 1990.
30. Thomas W, Sorjonen D, Steiss J: A retrospective evaluation
of 38 cases of distemper encephalomyelitis. JAAHA
29:129–132, 1992.
31. Cameron A, Conroy J: Rabies-like neuronal inclusions associated with a neoplastic reticulosis in a dog. Vet Pathol
11:29–37, 1974.
32. Vandevelde M, Kristensen B, Greene C: Primary reticulosis
of the central nervous system in the dog. Vet Pathol
15:673–675, 1978.
33. Dubey J: Toxoplasmosis in dogs. Canine Pract 12:7–28,
1985.
34. Ruehlmann D, Podell M, Oglesbee M, et al: Canine
neosporosis: A case report and literature review. JAAHA
31:174–183, 1995.
35. Stalis I, Chadwick B, Dayrell-Hart B, et al: Necrotizing
meningoencephalitis of Maltese dogs. Vet Pathol
32:230–235, 1995.
36. Tipold A, Fatzer R, Jaggy A, et al: Necrotizing encephalitis
in Yorkshire terriers. J Small Anim Pract 34:623–628, 1993.
37. Cordy D, Holliday T: A necrotizing meningoencephalitis of
pug dogs. Vet Pathol 26(3):191–194, 1989.
38. Berthelin CF, Bailey CS, Kass PH, et al: Cryptococcosis of
the nervous system in dogs, Part 1: Epidemiologic, clinical,
and neuropathologic features. Prog Vet Neurol 5:88–97,
1994.
39. Berthelin CF, Legendre AM, Bailey CS, et al: Cryptococcosis of the nervous system in dogs, Part 2: Diagnosis, treatment, monitoring and prognosis. Prog Vet Neurol
5:136–146, 1994.
40. Stanton M, Legendre A: Effects of cyclophosphamide in
dogs and cats. JAVMA 188:1319–1322, 1986.
41. Smolen J, Kalden J, Scott D, et al: Efficacy and safety of
leflunomide compared with placebo and sulphasalazine in
active rheumatoid arthritis: A double-blind, randomized,
multicentre trial. Lancet 353:259–266, 1999.
42. Gregory C, Stewart A, Sturges B, et al: Leflunomide effectively treats naturally occurring immune-mediated and inflammatory diseases of dogs that are unresponsive to conventional therapies. Proc 16th ACVIM Forum:716, 1998.
43. Sturges B, LeCouteur R, Gregory C, et al: Leflunomide for
treatment of inflammatory or malacic lesions in three dogs:
A preliminary clinical study. Proc 16th ACVIM Forum:697,
1998.
44. Sisson A, LeCouteur R, Dow S, et al: Radiation therapy of
granulomatous meningoencephalomyelitis of dogs [abstract].
J Vet Intern Med 3:119, 1989.
45. Gavin P, Fike J, Hoopes P: Central nervous system tumors.
Semin Vet Med Surg (Small Anim) 10:180–189, 1995.
46. Bateman S, Parent J: Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156
cases (1990–1995). JAVMA 215:1463–1468, 1999.
Compendium July 2001
ARTICLE #3 CE TEST
The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from
the Auburn University College of Veterinary
Medicine. Choose the best answer to each of the following questions; then mark your answers on the
postage-paid envelope inserted in Compendium.
CE
1. Which of the following is the treatment of choice for
GME?
a. corticosteroids
b. vincristine and cyclophosphamide
c. radiation therapy
d. NSAIDs
e. broad-spectrum antibiotics
2. By which of the following are GME lesions most commonly characterized?
a. pyogranulomatous inflammation
b. eosinophilic inclusion bodies
c. retinal degeneration
d. focal lesions of the thoracolumbar spinal cord
e. nonsuppurative perivascular cuffing
3. Clinical signs of GME include which of the following?
a. vomiting, diarrhea, weight loss
b. lower motor neuron hindlimb reflexes
c. seizures, head tilt, ataxia, blindness
d. cervical pain, proprioceptive deficits
e. c and d
4. A complete diagnostic plan for GME includes which
of the following?
a. an ophthalmic examination
b. CSF analysis
c. MRI or CT
d. histologic confirmation
e. all of the above
5. Which of the following radiographic studies is most
useful in the diagnosis of GME?
a. skull radiography
d. MRI
b. ultrasonography
e. CT
c. myelography
6. The term reticulosis (when discussing the CNS) refers
to which of the following?
a. accumulation of reticulin fibers with meningeal inflammation
b. a group of diseases characterized by proliferation of
cells associated with the CNS reticuloendothelial system (including inflammatory and neoplastic diseases)
c. nonsuppurative inflammation of the thalamic reticular nucleus
Small Animal/Exotics 651
d. an uncommon form of GME
e. a degenerative disease of the peripheral nervous system
7. An idiopathic breed-related necrotizing meningitis
that mimics GME has been reported in which of the
following?
a. whippets, greyhounds, salukis
b. poodles, schnauzers, West Highland white terriers
c. small, white, toy-breed dogs
d. pugs, Maltese terriers, Yorkshire terriers
e. golden retrievers, Labrador retrievers
8. Leflunomide is
a. a classic NSAID.
b. a chemotherapeutic agent.
c. an alternative immunosuppressive agent.
d. a dietary supplement.
e. a potassium-sparing diuretic.
9. A worse prognosis for GME is associated with which
of the following?
a. focal GME
b. cervical spinal cord GME
c. multifocal GME
d. ophthalmic GME
e. treatment with radiation therapy
10. Ophthalmic GME is frequently characterized by
which of the following?
a. corneal opacity
b. rapid progression and death
c. acute blindness due to optic neuritis
d. keratoconjunctivitis sicca
e. retrobulbar granulomatous inflammation