Chronic Compressive Myelopathy and Progressive Neurologic Signs Associated with Melarsomine Dihydrochloride Administration in a Dog

Introduction

Melarsomine dihydrochloride is an organic arsenical used commonly for the treatment of canine heartworm disease. Neurologic complications associated with this drug have been reported previously, but most reactions occur acutely after administration of the drug. The purpose of this report was to describe a dog that developed melarsomine-associated compressive myelopathy causing clinical signs that were chronic and progressive in nature, ultimately requiring spinal decompressive surgery.

Case Report

A 7 yr old castrated male Great Dane presented to the North Carolina State University College of Veterinary Medicine Neurology and Neurosurgery service for evaluation of progressive spinal hyperesthesia and ataxia lasting > 3 wk. The dog was acquired by the owner from a rescue organization 3 wk prior to presentation and was reported to have mild hind limb ataxia at that time. Over the next 3 wk, the dog displayed progressive pelvic limb gait abnormalities, seemed painful to the owner, and would cry when attempting to either sit or stand. Previous medical history was scarce, save the fact that the dog had a positive antigen test for Dirofilaria immitis when he was surrendered to the rescue organization. The dog had received two injections of melarsomine dihydrochloride^a (dose not recorded) 24 hr apart in the left and right lumbar paraspinal musculature 5 wk prior to adoption (8 wk prior to presentation). The exact anatomic location of the injections was not noted in the dog’s medical record.

A complete physical examination revealed no significant abnormalities. On neurologic examination, the dog was ambulatory but paraparetic, with the right pelvic limb more affected than the left. A marked general proprioceptive ataxia was present in the pelvic limbs. Postural reactions, including proprioception and hopping, were decreased bilaterally in the pelvic limbs but normal in the thoracic limbs. Spinal reflexes were normal in all four limbs, and the cutaneous trunci reflex was present to the level of the fourth to fifth lumbar vertebrae. On spinal palpation, significant paraspinal hyperesthesia was present at the level of the thoracolumbar junction. The dog also exhibited mild atrophy of the infra- and supraspinatus muscles bilaterally and had decreased range of motion on flexion of the caudal cervical spine. Cranial nerve examination and the remainder of the neurologic examination were unremarkable. The primary neuroanatomic localization was from the third thoracic to the third lumbar spinal cord segments, with suspicion of a lesion located at the thoracolumbar junction. Additionally, a cervical myeloradiculopathy was suspected, but felt to be of lesser significance. Differential diagnoses for the thoracolumbar myelopathy included neoplasia, discospondylitis, intervertebral disc disease, meningomyelitis, and either spinal cord inflammation or compression related to aberrant heartworm migration. Given the chronicity of the dog’s signs, myelopathy secondary to melarsomine administration was considered less likely. The dog’s cervical myeloradiculopathy was suspected to be related to common degenerative spinal diseases in the breed, such as cervical spondylomyelopathy, Hansen type II degenerative disc disease, or a synovial cyst; however, a multifocal disease process could not be completely excluded.

A complete blood count, serum biochemical analysis, urinalysis, and thoracic radiography were performed and were within normal limits. Radiographs of the cervical and thoracolumbar spine were performed and revealed multifocal spondylosis deformans, articular process degenerative joint disease, but no evidence of lytic vertebral lesions. MRI of both the cervical and thoracolumbar spine was performed using a 1.5T magnet^b. Imaging consisted of T1- and T2-weighted sequences performed in sagittal, dorsal, and transverse planes, as well as sagittal short TI inversion recovery and half-Fourier acquisition single-shot turbo-spin echo sequences. During imaging of the thoracolumbar spine, IV contrast was administered^c and postcontrast T1-weighted sequences were acquired in three imaging planes.

In the cervical spine, there was desiccation of multiple cervical discs, and collapse of the sixth to seventh cervical intervertebral disc space with associated spondylosis deformans and mild ventral spinal cord compression at that site. Those findings were consistent with Hansen type II degenerative intervertebral disc disease. Imaging of the thoracolumbar spine revealed an extradural compressive mass lesion at the thoracolumbar junction causing moderate right-sided spinal cord compression. After contrast medium was administered, the mass showed strong peripheral contrast enhancement (Figure 1). Additionally, marked hyperintensity on T2-weighted and short T1 inversion recovery sequences were noted within the paraspinal musculature at the level of the right 13th thoracic (T13) to first lumbar (L1) intervertebral foramen. An irregular periosteal reaction was present on the transverse process of L1. A second area of T2 hyperintensity and contrast enhancement was apparent within the left subcutis at the level of T13. The appearance on MRI was most consistent with an inflammatory process and paraspinal and epidural abscessation. Either an infectious abscess or sterile abscessation associated with melarsomine administration was considered most likely. Additionally, given the dog’s history, the left-sided subcutaneous lesion was suspected to represent a previous injection site.

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Collection of cerebrospinal fluid from the lumbar cistern revealed a mild increase in protein (0.56 g/L; reference range, < 0.45 g/L) with a total nucleated cell count of 2 cells/μL (reference range, ≤ 5 cells/μL). Cytologic evaluation of the cerebrospinal fluid was unremarkable. An ultrasound-guided aspirate of the mass within the paraspinal musculature was performed under general anesthesia, and cytologic examination of a small amount of fluid obtained from the intramuscular portion of the lesion was consistent with suppurative inflammation, but no infectious organisms were identified. The fluid was submitted for aerobic and anaerobic culture but produced no bacterial growth.

Initially, a conservative course of treatment was undertaken, consisting of pain management (3 mg/kg tramadol^d per os [PO] q 8 hr, 14 mg/kg methocarbamol^e PO q 8 hr, and 6 mg/kg gabapentin^f PO q 8 hr) and activity restriction. Antibiotic therapy was not initiated at that time because culture results were pending. Three days after initial discharge from the hospital, the dog showed a significant decline in pelvic limb function and presented to the hospital with a nonambulatory paraparesis. Other neurolocalizing signs were consistent with the previous examination.

Surgical exploration of the paraspinal and epidural lesions was undertaken via a dorsal approach to the thoracolumbar spine, and a right hemilaminectomy was performed at T13–L1. Overt changes to the paraspinal muscles were difficult to identify intraoperatively, but muscle adjacent to the site of compression was removed and submitted for histopathology. Upon removal of the inner cortical bone at T13–L1, a mass was identified within the epidural space. The mass appeared thin-walled and cystic. On manipulation, a clear brown fluid was observed to leak from the cyst. The mass was removed and submitted for culture and histopathology along with several small pieces of bone from the margin of the laminectomy. The cultures were negative for bacterial growth.

Histopathologic examination of the surgically removed material revealed skeletal muscle with degenerative and necrotic myofibers bordered by a variably thick band of mature fibrous connective tissue. The mature fibrosis blended into immature fibrosis, which was interwoven at right angles with small caliber blood vessels, consistent with granulation tissue. Infiltrating the granulation tissue and extending into a central area of necrotic debris were numerous degenerative and nondegenerative neutrophils, foamy macrophages, and fewer lymphocytes and plasma cells. That pyogranulomatous inflammation was mixed with fibrin and scattered areas of hemorrhage. No infectious agents were observed (Figure 2).

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The postoperative recovery was uneventful, and the patient showed rapid improvement in neurologic status after recovery. At the time of discharge (4 days postsurgically), the patient was comfortable and ambulatory with some assistance; however, the dog maintained an upper motor neuron bladder and was unable to void voluntarily. That problem persisted for several wk postoperatively. Bladder emptying was aided pharmacologically with phenoxybenzamine^g (0.4 mg/kg PO q 12 hr) and intermittent (q 8 hr) urinary catheterization by the owner. At a follow-up evaluation performed 3 wk postoperatively, the owner reported that the dog had only begun to void on his own within the last few days. During an examination performed 3 mo postoperatively, the dog maintained a persistent moderate ambulatory paraparesis and general proprioceptive ataxia of the pelvic limbs.

Discussion

This report describes an unusually chronic, progressive myelopathy associated with administration of melarsomine dihydrochloride, an organic arsenical used commonly for the treatment of canine heartworm disease. The drug is typically administered as an intramuscular injection in the epaxial musculature between the third and fifth lumbar vertebrae^h. Previously reported common adverse effects include injection site reactions, local myalgia, depression, lethargy, anorexia, fever, pulmonary congestion, vomiting, and pulmonary thromboembolism.^1,2

Infrequently, neurologic complications such as severe paraspinal hyperesthesia, acute paresis and ataxia, fecal incontinence, seizures, and death have been reported.³ Potential mechanisms of neurologic complication include inadvertent administration of melarsomine into the epidural space or spinal cord, chemically induced vasospasm and segmental spinal cord ischemia, or sterile epidural abscess formation, presumably from migration of the compound either along fascial planes or along nerve roots into the epidural space.³ Epidural inflammation and fat necrosis induced by the compound may lead to a secondary compressive myelopathy.³ The case reported here displayed imaging and intraoperative findings consistent with the last mechanism of neurologic injury. Specifically, neurologic signs in this patient appeared to originate due to a progressively expansile sterile epidural abscess and adjacent granulation tissue that developed secondary to melarsomine administration approximately 8 wk earlier. Although the precise site of melarsomine injection was not recorded in this dog, temporal association of clinical signs, imaging, and intraoperative findings similar to those previously reported, and the histologic findings of sterile, chronic, active pyogranulomatous inflammation make melarsomine-associated abscess the most likely explanation.³ Other previously reported causes of myelopathy related to heartworm disease include aberrant heart worm migration and thromboembolic events.^4–7 Although those diagnoses were originally considered as differentials in this case, imaging and intraoperative findings were not consistent with those diagnoses. This patient also had clinical and imaging findings suggestive of a mild cervical myeloradiculopathy secondary to Hansen type II degenerative disk disease, and the contribution of that lesion to his presentation and persistent clinical signs could not be ignored. However, the acute deterioration of pelvic limb function in conjunction with rapid patient improvement after surgical decompression indicated that the dog’s thoracolumbar lesion was of primary significance.

A unique feature of this case is the chronic progressive nature of the dog’s clinical signs. The time between melarsomine injection and development of nonambulatory status in the patient was approximately 8 wk. Although previous reports alluded to chronic signs, the only previously published case series described signs that were acute to subacute in nature, with signs generally developing within hours of injection. Indeed, the chronicity of previously published cases was only 1 wk at most.³ The chronicity of signs in this reported case may be partially attributed to the fact that the dog was in a new home immediately after melarsomine treatment and had little known previous medical history. As such, identification of subtle changes in gait may have been difficult. Additionally, some of the dog’s initial clinical signs may have been attributed to a cervical myelopathy, common in the breed, and incidentally present in this case. For those reasons, the dog’s clinical signs may have been allowed to progress longer than typical; however, the acute exacerbation of clinical signs just prior to surgery and the histopathologic findings suggest an active inflammatory process, not just residual abnormalities from prior acute neurologic injury.

Medical management was originally recommended in this case because of previous reported success; however the patient deteriorated, and surgical decompression resulted in prompt improvement in neurologic signs.³ That result suggests that surgical decompression is an effective approach in this disease, particularly in dogs whose clinical signs are either progressive over more than a brief period of time or in cases where neurologic signs are severe.

Several factors have been suggested to decrease the risk of neurologic complications in dogs treated with melarsomine. Those include administering the drug only by deep intramuscular injection and only between the third and fifth lumbar vertebrae regions, as well as limiting the volume of injected melarsomine to < 4 mL/site^h.³ The location of this patient’s paraspinal and epidural abscesses suggest that it was not treated according to the manufacturer’s instructions for administration of melarsomine, and it is possible that the location of administration influenced the development of neurologic complications in this case. Because the volume of melarsomine administered was not recorded, the authors cannot draw conclusions on what effect volume may have had.

Conclusion

Melarsomine-associated epidural abscess should be considered in any patient who shows progressive spinal pain and ataxia even several weeks after treatment of heartworm infection. Based on this and other reports, abscesses are sterile in nature, but may cause significant spinal cord compression and myelopathy. Decompressive laminectomy should be considered in patients with progressive clinical signs and can lead to a good outcome even in those that are severely affected.