A 1-year-old male neutered mixed breed dog presented to a Teaching Hospital Small Animal Internal Medicine Service with a history of unilateral uveitis, symmetrical atrophy of the temporal and masseter muscles, and leukotrichia and leukoderma of the top of the head. Four months before presentation, the dog developed partial alopecia involving the dorsal aspect of the head with subsequent development of leukotrichia in the affected area (Fig. 1A-C), as well as leukotrichia along all four distal limbs. Two weeks prior to presentation, the dog was seen by a veterinary ophthalmologist and diagnosed with chronic anterior uveitis OD and prescribed prednisolone acetate 1% drops (2 times daily OD, 4 times daily OS), meloxicam (dose not stated), and doxycycline (7.7mg/kg PO once daily). The primary care veterinarian submitted serum samples for a combined ELISA test (4DX, IDEXX Laboratories, Inc., Westbrook, ME) for Dirofilaria immitis antigen, and Borrelia burgdorferi, Ehrlichia canis, Ehrlichia ewingii, Anaplasma spp. antibodies, which was negative.
On presentation to the teaching hospital, the dog was bright and alert with unremarkable vital parameters with moderate symmetric temporal and masseter muscle atrophy. Serum biochemistry panel and a complete blood count (CBC) revealed mildly elevated activities of alanine transaminase (ALT; 170; reference range 21–72 IU/L) and creatine kinase (CK; 530; reference range 55–257 IU/L), with no other abnormalities noted. Serum antibodies (IgG and IgM) against Toxoplasma gondii were not detected. An indirect fluorescent antibody test for Neospora caninum was low level positive at 1:40, and considered unlikely to reflect active infection. Serology for type-2M muscle fiber antibodies was equivocal for masticatory muscle myositis (1:100, Neuromuscular Lab, University of California San Diego; <1:100 negative for MMM, 1:100 borderline antibody titer, > 1:100 consistent with MMM).
A complete ophthalmic examination at the time of the next visit (2 weeks later) included slit lamp biomicroscopy and binocular indirect ophthalmoscopy before and after pupil dilation with 1% tropicamide. Both eyes were open and appeared comfortable, with normal globe position and movements OU. The dog was isocoric with brisk but incomplete direct and consensual pupillary light reflexes OU. Menace response, dazzle reflex, and palpebral reflex were normal OU, and the dog behaved as if visual in photopic conditions. The most striking abnormality was marked approximately sectoral heterochromia OU (Fig. 2A-B). In both eyes, there was a gradation of iridal melanosis from peripheral to axial with the iris root and ciliary zone being a steely blue-grey, the collarette more golden brown, the pupillary zone a dark brown-black, and the pupillary ruff a typical jet black. Dilated fundic examination revealed multifocal to coalescing areas of pigment absence throughout the non-tapetal fundus OU. Evidence of inflammation OD was limited to 1 + cell in the anterior chamber and 2 + pigmented cell in the vitreous, as well as posterior synechial remnants over the anterior lens capsule. In the left eye, the sole inflammatory finding was 1 + pigmented vitreous cell. There was no aqueous flare or conjunctival or episcleral hyperemia OU. The ophthalmic diagnosis was historic/controlled panuveitis OU consistent with uveodermatologic syndrome.
A neurological examination at the same visit revealed bilaterally absent maxillary lip pinch response, and delayed pupillary light reflexes in both eyes, localizing to brain or cranial nerve 5 (trigeminal nerve). Magnetic Resonance Imaging (MRI) pre- and post-contrast of the skull revealed marked muscle atrophy with T2 hypersensitivity and contrast enhancement of temporalis, masseter, and pterygoid muscles, suggestive of severe MMM. MRI images also revealed mild to moderate bilateral lymphadenopathy of the mandibular and medial retropharyngeal lymph nodes. Cytological examination of a fine needle aspirate from the submandibular lymph node was consistent with reactive lymphoid hyperplasia. Evaluation of cerebral spinal fluid collected via cerebromedullary cisternal puncture was cytologically evaluated and assessed to be within normal limits.
Given the bilateral uveitis and ocular and cutaneous depigmentation, UDS was suspected, and Six-mm skin biopsies were collected from affected areas on the dorsal aspect of the head and the lateral aspect of the left pelvic limb at the level of the tibia. Histopathologic evaluation of hematoxylin- and eosin- (H&E-) stained tissue sections revealed severe melanin clumping within the epidermis, follicular epithelia, and hair shafts, as well as perifollicular and superficial melanin-laden macrophages (pigmentary incontinence) consistent with a dilute hair coat. There was no evidence of active inflammation in any of the biopsies or characteristic dermatopathologic pattern associated with UDS, despite the clinical suspicion. Systemic immunosuppressive therapy was initiated with prednisone at this point (2mg/kg/day PO for 2 weeks, tapered to 1.5mg/kg/day PO for 3 weeks, tapered to 1mg/kg/day PO for 2 weeks).
Over a period of two months, no improvement in ocular or dermatologic signs was documented, and the clinical signs of masticatory muscle atrophy progressed. Corticosteroid therapy was discontinued after 8 weeks due to lack of clinical improvement, marked side effects, and the development of a cutaneous opportunistic fungal infection with Scedosporium spp. on the left thoracic limb after 1 week of corticosteroid treatment, which prompted treatment with voriconazole (10mg/kg/day PO for 4 months). Lesions improved on voriconazole over a period of three months.
Dermatologic exam six months following presentation revealed progressive moderate to marked diffuse leukotrichia involving the face, chest, dorsum, and distal extremities (Fig. 1C). In addition, depigmentation of the mucocutaneous junctions and paw pads was noted. At this time, additional skin biopsies were collected due to development of subcutaneous-dermal nodules along the ventral neck, oral cavity, pinnal margins, and distal limbs. Six-mm biopsies from the ventral muzzle revealed severe, interstitial to diffuse, predominantly neutrophilic dermatitis admixed with lymphocytes, plasma cells, and mucin, as well as moderate periadnexal pigmentary incontinence and clumped melanin within follicles. Fungal culture and mycobacterium culture results were negative, and together with the biopsy results was suggestive of a secondary infectious process or sterile neutrophilic dermatitis.
Nine months post initial presentation to the teaching hospital, the dog developed progressive oral and pharyngeal dysphagia with inability to close the mouth and ptyalism. Thirteen months post presentation, a repeat type-2M muscle fiber antibody was performed, and the results were negative (< 1:100, Neuromuscular Lab, University of California San Diego). A video fluoroscopic swallow study (performed sixteen months post presentation) using food admixed with barium (liquid barium, soft food, and kibble) revealed a gas-dilated pharynx, and documented base of the tongue and rostral pharyngeal weakness consistent with severe pharyngeal and lingual dysphagia. There was no evidence of gastroesophageal reflux or esophageal dysmotility.
An electromyogram (EMG) of major muscles of the head, limbs, and trunk was also performed on this visit, and revealed moderate to marked increased spontaneous activity in the temporalis, pharyngeal, lingual, and orbicularis oculi muscles, as well as increased insertional activity in the cranial tibial muscle. Muscle biopsies of the right temporalis muscle and the lingualis proprius muscle were also performed. Histopathological review of the temporalis muscle revealed complete replacement of muscle fibers by adipose and fibrous tissue with no inflammatory cells present. H&E-stained slides of the lingualis proprius muscle revealed a marked increase in connective tissue, small myofiber size, numerous necrotic myofibers, several central nuclei, extensive and multifocal cellular infiltration with macrophages and other mononuclear cells, consistent with severe, chronic myositis and end-stage scarring.
Sixteen months following initial presentation, the dog had generalized leukotrichia and leukoderma, marked iridal depigmentation, generalized muscle atrophy including signs of temporomandibular disorder with jaw-closing weakness, and subsequent ptyalism (Fig. 3A-B). A repeat serum biochemistry revealed mildly elevated activities of ALT (104; reference range 21–72 IU/L), aspartate aminotransferase (AST; 83; reference range 20–49 IU/L), and CK (1189; reference range 55–257 IU/L). In light of negative tests for infectious diseases and histopathological findings, progressive peripheral immune-mediated polymyositis involving masticatory, lingual, and pharyngeal muscles was suspected. Treatment with cyclosporine (10mg/kg/day PO for 3 months) followed by mycophenolate (25mg/kg/day PO for the subsequent 2 months) did not lead to clinical or biochemical improvement. The dog’s dysphagia progressed, resulting in significant weight loss and prompting endoscopic placement of a percutaneous endoscopic gastrotomy (PEG) tube nineteen months after presentation.
Four years after initial presentation, the dog was maintaining stable body weight while being palliatively managed with nutritional needs and hydration provided via a PEG tube and cisapride (1mg/kg/day through the PEG tube). Leukotrichia had progressed to involve the entire dog resulting in an entirely white hair coat and depigmentation of epidermis, as well as iridal depigmentation of both eyes (Fig. 1D, 2C-D). A serum anti-nuclear antibody test was performed on this visit and found to be negative.