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 12 REFERENCES 1. Maggs DJ, Miller PE, Ofri R, Slatter DH. Slatter's Fundamentals of Veterinary Ophthalmology. 5th ed. St. Louis, MO: Elsevier, 2013. 363-364. 2. Kenny PJ, Vernau KM, Puschner B, Maggs DJ. "Retinopathy Associated with Ivermectin 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. 4. 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