Optic Neuritis in a One Year Old French Bulldog
Amanda M. Nicklin
Basic Science Advisor: Dr. Thomas Kern
Clinical Advisor: Dr. Meghan Slanina
Senior Seminar Paper
Cornell University College of Veterinary Medicine
February 26, 2014
Key words: optic neuritis, granulomatous meningoencephalitis, GME, optic neuropathy
ABSTRACT
A one year old female spayed French Bulldog presented to the Ophthalmology Service at
Cornell University for evaluation of a one week history of vision loss. On ophthalmic
examination, the pupils were mydriatic but responsive and the palpebral reflexes were intact OU,
while the menace response and dazzle reflex were absent OU. The adnexal structures and
anterior segment appeared normal. On fundic examination, the optic discs and the retina
surrounding them were slightly edematous and elevated OU. An electroretinogram recorded
normal retinal function, and the dog was subsequently transferred to the Neurology Service.
Magnetic resonance imaging of the brain revealed swollen and T2-hyperintense optic
tracts and optic chiasm that displayed marked contrast enhancement. Cytologic analysis of
cerebrospinal fluid revealed a mild lymphocytic pleocytosis. The dog was presumptively
diagnosed with optic neuritis caused by granulomatous meningoencephalitis (GME) and
treatment was begun with an immunosuppressive dose of oral prednisone. The dog had regained
some vision by her recheck examination 2 weeks later but was exhibiting side effects of the
prednisone. Treatment with oral cyclosporine was added and her prednisone dosage was reduced
two weeks following initiation of the cyclosporine. Three months following discharge from the
hospital, the dog still retained vision which the owner reported to be at 80% from prior to her
onset of blindness. Her dosage of prednisone was further tapered and the cyclosporine was
continued.
INTRODUCTION
A one year old female spayed French Bulldog presented to the Cornell University
College of Veterinary Medicine Ophthalmology Service for evaluation of a one week history of
2
vision loss. The dog reportedly had fallen down the stairs and was running into other animals in
the household. The owner also reported that the dog had been head shaking, was less responsive
to commands, and had an increase in mucoid ocular discharge. The dog had been otherwise
healthy, was up to date on rabies and distemper vaccinations, and consumed a partially raw diet.
On presentation the dog was bright, alert, responsive, and very anxious. Her heart rate
was 140 bpm, temperature was 102.4 F, and she was panting. A general physical examination
was unremarkable. On ophthalmic examination the adnexal structures and anterior segment were
normal bilaterally. The pupils were mydriatic but responsive, and the palpebral reflex was intact
OU. The menace response and dazzle reflex were absent OU and the dog behaved as if blind.
The intraocular pressures were normal at 15 mmHg OU. The retina surrounding the optic nerve
head was slightly edematous and elevated, and the optic discs were slightly swollen bilaterally.
The retina otherwise appeared normal, and the remainder of the ophthalmic examination was
normal.
CLINICAL FINDINGS
Differential diagnoses for dogs presenting with acute blindness include glaucoma, retinal
detachment, ivermectin toxicosis, sudden acquired retinal degeneration syndrome (SARDS),
optic neuropathy, and other neurologic dysfunction.1 This dog had normal intraocular pressures
and no clinical evidence suggestive of glaucoma, ruling out this differential diagnosis.
Furthermore, the fundus had a normal appearance with the exception of the slight retinal edema
and elevation, with no signs of detachment. Dogs generally develop blindness due to ivermectin
toxicosis within a day of ingestion of a toxic dose.2 Toxicosis usually arises from a medication
overdose or ingestion of horse manure following deworming with ivermectin.2 This patient had
3
not had any contact with horses or ivermectin administration for at least 2 weeks prior to
presentation.
SARDS is a disease of unknown etiology causing sudden blindness in generally middle
age to older dogs. The blindness is usually bilateral and irreversible, though thought to be nonpainful. In approximately 60% of cases, the
dogs experience polyuria, polydipsia, and
polyphagia prior to vision loss.3 While the
patient did not experience these often
Figure 1: Electroretinogram from this patient. The
first waveform for each eye around 50 ms
indicates the electrical potential produced when
light hits the retina. The remaining waveforms are
motion artifact.
associated signs, SARDS could not be ruled
Figure 2: Electroretinogram from a dog
diagnosed with SARDS. No electrical activity is
produced from light striking the retina.
out. Optic neuropathies and other neurologic
dysfunction also remained differential diagnoses.
An electroretinogram was performed to assess retinal function and rule in or out a
diagnosis of SARDS. The electroretinogram in this patient was almost normal (Fig. 1); the peak
was slightly shorter and wider than a completely normal electroretinogram. However, a dog with
SARDS displays a flat-line ERG (Fig. 2). At this point the dog was transferred to the Neurology
Service for further workup.
4
DIAGNOSIS
Initial neurologic examination revealed similar cranial nerve findings: absent menace response
and dazzle reflex, intact palpebral reflex, and mydriatic but responsive pupils. Furthermore, there
was pain on palpation of the cranial thoracic and cervical spine, as well as the craniocervical
junction, and head, leading to the neurolocalization of multifocal spinal pain and cranial nerve II
deficits. Blood was drawn for a complete blood count and chemistry panel which revealed a
stress leukogram (lymphopenia and eosinopenia) as well as a slight hyperphosphatemia and mild
elevation in ALT.
Two-view spinal radiographs showed abnormalities of all the thoracic vertebrae and at
least two lumbar vertebrae (fig 3.). The spinous processes of T5-7 and T8-9 were fused. The
thoracic and lumbar spine contained mild to moderate scoliosis and probable focal kyphosis at
L1-2. Theses abnormalities were likely causing extradural compression of the spinal cord and
nerve roots resulting in the multifocal spinal pain noted on neurologic exam. However, these
Figure 3: Left lateral spinal radiograph. All thoracic vertebral bodies and at least two of the lumbar vertebral
bodies are malformed. The spinous processes of T5-7 and T8-9 are fused. L1 is wedge-shaped and there is
malalignment and probable kyphosis at L1-2.
5
abnormalities do not explain the dog’s sudden loss of vision. Therefore, magnetic resonance
imaging (MRI) of the brain was performed.
MRI revealed swollen and T2-hyperintense optic tracts and chiasm that were markedly
contrast enhancing; indicative of a process that disrupts the blood-brain barrier (Fig. 4 & 5). The
remainder of the brain imaging appeared normal.
Figure 4: T1-weighted transverse image
following contrast injection. Optic chiasm is
markedly swollen and contrast enhances.
Figure 5: T1-weighted dorsal section
following contrast injection. The optic tracts
are markedly enlarged and contrast
enhancing.
A sample of cerebrospinal fluid (CSF) was submitted for analysis. While there was
extensive blood contamination, there was a nucleated cell count of 18 cells/μL (normal is less
than 5 cells/μL); 81% of these cells were lymphocytes and 14% were non-degenerate
neutrophils. Had the increase in white cell count been due to blood contamination a higher
percentage of neutrophils, rather than lymphocytes, would have been expected. No neoplastic
cells or infectious agents were seen. Therefore, the tap was interpreted as a mild lymphocytic
pleocytosis, which is commonly seen with inflammatory CNS disease. A total protein could not
be performed because a large enough sample volume had not been obtained.
6
The appearance of the MRI and results of the CSF tap led to a diagnosis of optic neuritis.4
Optic neuritis is characterized by sudden loss of vision and can be localized to intrabulbar or
retrobulbar. With intrabulbar optic neuritis, the optic disc appears edematous and hyperemic,
with indistinct margins. There can be retinal hemorrhage or edema adjacent to the disc, and loss
of the physiologic cup.5 Retrobulbar optic neuritis is characterized by a normal fundus
appearance.5
Causes of optic neuritis include infection, inflammation, neoplasia, and trauma.
Infectious causes include canine distemper virus, tick-borne encephalitis virus, mycotic
infections (cryptococcosis, blastomycosis, and histoplasmosis), toxoplasmosis, ehrlichiosis, and
rickettsial infections.8 Granulomatous meningoencephalitis (GME) is the most common
inflammatory cause of optic neuritis.1,3 Primary neoplasia such as meningioma, glioma, and
lymphoma can invade the optic tracts causing vision loss.5,7 Orbital tumors can secondarily
invade the optic nerves, and other pathologies of the orbit including orbital cellulitis and
abscessation can compress the optic tracts.5 However, these extraorbital causes are much less
likely to be bilaterally symmetrical. Traumatic optic neuritis occurs following proptosis of the
globe or other head trauma.5
GME is the most common cause of optic neuritis in dogs, and was the most likely
differential diagnosis in this case.1,3 The dog was up to date on distemper vaccination, displayed
no evidence of orbital pathology, and did not have a history of trauma. While neoplasia can
occur in dogs of any age, infectious and inflammatory etiologies are more likely in a one year old
dog. Infectious disease testing was not performed in this case because the signalment (young,
spayed female), appearance of the MRI, and results of CSF analysis were highly suggestive of an
underlying inflammatory cause.4,6,7 Furthermore, the complete blood count and chemistry panel
7
were not suggestive of a systemic infection. Therefore, the dog was presumptively diagnosed
with optic neuritis due to GME.
TREATMENT RATIONALE
GME is an inflammatory disease of the central nervous system (CNS) of dogs.5-7,9-12 The
etiology is unknown but infectious, neoplastic, and autoimmune causes have been proposed.6,7
Currently an aberrant immune-mediated reaction of T-cell mediated delayed hypersensitivity is
in favor.6,7 Histopathology demonstrates granulomatous perivascular accumulations of
lymphocytes, plasma cells, epithelioid cells, and occasional neutrophils.7,10,11 These lesions are
generally confined to the white matter, which can include the optic tracts.4,10,11,13
There are three forms of GME: focal, disseminated, and ocular. 4,9,10,11 The ocular form
is the least commonly reported, and is usually characterized by acute blindness with signs of
intrabulbar optic neuritis or amaurosis.5,7,9-11 The disseminated form has multifocal lesions
throughout the CNS, while the focal form characterizes a single lesion.6,9-11 Animals with the
disseminated and focal forms generally present with clinical signs that neurolocalize to the area
of the CNS containing the lesion(s).11
Histopathology is the only method of definitively diagnosing GME, however, a
presumptive ante-mortem diagnosis can be made on the basis of clinical findings.10,12 Results of
CSF analysis most commonly show a markedly increased total protein as well as a mononuclear
pleocytosis.5-7,9,11 In this case a lymphocytic pleocytosis was determined on CSF analysis, and a
total protein could not be established due to insufficient volume. Furthermore, the optic nerves
were swollen and displayed contrast-enhancing hyperintensities on MRI consistent with
GME.4,7,9
8
GME is most commonly diagnosed in female, young to middle-age, small and toy breed
dogs.5-7,9-12 A definitve diagnosis of GME is made based on histopathology, either post-mortem
or via a biopsy. As obtaining a biopsy is an invasive procedure, treatment is often initiated
empirically based on signalment and clinical findings.
TREATMENT
As a presumed autoimmune disease, immunosuppression is the goal of treatment for
GME, and immunosuppressive doses of corticosteroids are the mainstay of therapy.3,6,7,11 The
patient was subsequently started on 2 mg/kg/day of oral prednisone to be administered as 1
mg/kg BID. Common side effects associated with high doses of corticosteroids include polyuria,
polydipsia, polyphagia, and weight gain.9
Other immunosuppressive therapies have been advocated for the treatment of GME
including cyclosporine (6 mg/kg PO BID), azathioprine, chemotherapeutics (including cytosine
arabinoside and procarbazine), and radiation therapy.3-7,9,11,12 Cyclosporine is a fungal
polypeptide that inhibits transcription of α-interferon, a cytokine implicated in macrophage and
monocyte signaling. 9 Side effects can include vomiting, diarrhea, anorexia, weight loss, gingival
hyperplasia, hypertrichosis, and excessive shedding.9
Cytosine arabinoside (CA) is a chemotherapeutic that readily crosses the blood-brain
barrier (BBB).6,12 While CA, like other chemotherapeutics, can cause extreme myelosuppression,
it has the benefit of not requiring daily administration.6 In one study of a dog presenting with
multifocal areas of CNS inflammation consistent with GME, treatment with prednisone and CA
resulted in a survival time of over one year.6
9
Radiation therapy has been used mainly for the treatment of focal, mass-like lesions, with
some apparent success.11 Histopathologic evidence of GME was no longer present post-mortem
in dogs treated with radiation that had been previously diagnosed with the focal form of GME
via biopsy.11 Radiation therapy has not reportedly been used for the treatment of ocular GME.
These alternative therapies have been used in combination with, and in place of,
corticosteroids for animals that display side effects of chronic steroid use that are unacceptable to
owners. 3,6,7,9,11,12
The patient also had evidence of fluid in the ears bilaterally on MRI. She was empirically
started on a 6 week course of oral cephalexin in case of an otitis media since she was going to be
immunosuppressed. These changes may explain the head shaking and decrease in response to
commands reported by the owner.
PROGNOSIS
The overall prognosis of GME is guarded to poor.14 For dogs treated with corticosteroids,
the survival time ranges from 7 – 1000+ days.9 However, one study of 42 dogs sites a median
survival of 14 days for all dogs in the study.11 The intense variability in survival is related to the
form of GME. Disseminated GME carries a far graver prognosis than focal GME, and this can
often be attributed to dogs that die before treatment can be instituted.11
One source groups ocular GME with the disseminated form in carrying a graver
prognosis than the focal form.4 However, another source suggests that mortality due to the ocular
form is low.10 This discrepancy may arise from the fact that the ocular form can degenerate into
the disseminated form by developing further CNS lesions.11 Montgomery and colleagues
10
reported that about 33% of dogs regained vision following diagnosis of optic neuritis, and that
optic neuritis due to GME carries a graver prognosis than other causes.3
Approximate survival time of dogs treated with cyclosporine is 930 days, with
procarbazine is 420 days, with cytosine arabinoside is 531 days, and with radiation therapy is
404 days.4 These data are given for GME as a whole, however due to its relative rarity; there are
not survival times specific to the ocular form of GME.
OUTCOME
The patient returned for a recheck appointment two weeks following discharge from the
hospital. Her owner reported that she had regained some of her vision at home; however she had
become food aggressive toward the cat in the household. Ophthalmic examination revealed the
palpebral and pupillary light reflexes had remained intact, and the pupils were now mid-range at
rest. The patient had a negative dazzle reflex; this was presumed to be behavioral because her
menace response was intact bilaterally. The retina and optic nerve appeared normal OU.
The food aggression was attributed to the high dose of corticosteroids the dog was
receiving so the owner was advised to continue this dosage for another two weeks then reduce to
a 1.6 mg/kg/day dose. Cyclosporine ((3.3 mg/kg PO BID) was prescribed in addition.
The patient returned for another recheck examination 3 months following initial
discharge from the hospital. At this visit the owner reported that the patient had regained about
80% of her vision but still had difficulty with depth and night vision. The dog remained food
aggressive but had improved. At this visit the ophthalmic examination was again normal but the
dog had gained 0.4 kg and appeared overweight. The prednisone dosage was tapered to 1.3
mg/kg/day and the dose of cyclosporine was continued.
11
DISCUSSION
While GME can only be definitively diagnosed with histopathology, a presumptive ante-mortem
diagnosis can be made based on signalment and clinical findings.10,12 In this patient, the severely
swollen, T2-hyperintense, and markedly contrast-enhancing optic nerves seen on MRI, the
lymphocytic pleocytosis noted on CSF analysis, together with her signalment, was highly
suggestive of a diagnosis of the ocular form of GME.4-7,9,11
This patient’s favorable response to immunosuppression with prednisone supports the
notion that GME is caused by an aberrant T-cell mediated immune reaction.6,7 Only about onethird of patients diagnosed with optic neuritis regain their vision and relapses are common
particularly while therapy is being tapered.6,7,9 This patient’s fortuitous return to vision may be
due to her short course of clinical signs (one week) prior to presentation and early diagnosis and
treatment. However, relapses are common and this dog will need to be monitored closely while
her medications are tapered.6,7,9
Fundus changes in this dog were quite subtle and the ERG recordings were critical in
distinguishing SARDS from optic neuritis. Use of an ERG for differentiation is particularly
important in patients, such as this one, where the signalment is not typical for a dog with
SARDS.3
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Toxicosis in Two Dogs." Journal of the American Veterinary Medical Association 233.2
(2008): 279-284.
3. Montgomery KW, van der Woerdt A, Cottrill NB. "Acute Blindness in Dogs: Sudden
Acquired Retinal Degeneration Syndrome versus Neurological Disease (140 Cases, 20002006)." Veterinary Ophthalmology 11.5 (2008): 314-320.
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