Vincristine Induced Peripheral Polyneuropathy in a Golden Retriever
Contributed by Eric Hans, DVM; Joseph Mankin, DVM, DACVIM (Neurology); Meighan Daily, DVM, DACVIM (Oncology), Jonathan M. Levine, DVM, DACVIM (Neurology)
Texas A&M College of Veterinary Medicine
College Station, TX
Clinical History
A 14 year-old castrated male Golden Retriever (32.4kg) was examined by the Texas A&M University Neurology Service for clinical signs of generalized weakness.Clinical signs were first noted 2 weeks prior to evaluation and consisted of difficulty rising, ambulatory weakness, and occasional collapse.The owners considered the weakness to be static in progression.Three months prior to the onset of weakness a diagnosis of multicentric lymphoma was made.Treatment was initiated shortly thereafter with a CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) chemotherapy protocol.
Physical and Neurological Examination
The general physical examination was unremarkable aside from significant dental calculus. On neurologic examination the dog had difficulty rising and a gait characterized by short-strided ambulatory tetraparesis. Mentation was appropriate and the cranial nerve exam revealed no abnormal findings. Postural reactions were delayed in the thoracic limbs and absent in the pelvic limbs. An absent withdrawal reflex was found in all four limbs and patellar reflexes were reduced bilaterally. Generalized muscle atrophy was present, with the pelvic limbs most significantly affected. Based on these findings, a generalized neuromuscular disease was suspected.
Diagnostic Tests
Complete blood profile and routine chemistry panel - performed prior to presentation by the referring veterinarian and revealed no remarkable abnormalities
Urinalysis - slightly dilute urine (USG 1.023) and trace proteinuria.
Additional tests were performed to better define the generalized neuromuscular disease.
Acetylcholine receptor antibody test: 0.10 nmol/l; within normal reference range
Creatine kinase: 174 U/L; within reference range
Electromyography was performed under general anesthesia. Abnormal spontaneous muscle activity in the form of fibrillation potentials and positive sharp waves were detected, suggestive of either a myopathy or peripheral axonopathy (Figure 1)
Figure 1: Electromyogram from the cranial tibial muscle. There are abundant fibrillation potentials with occasional positive sharp waves.
Motor nerve conduction studies were also performed under general anesthesia.In both the ulnar (Figure 2) and peroneal nerves motor conduction velocity was diminished (peroneal MNCV 29 m/sec and ulnar 27 m/sec), and compound motor unit action potentials had reduced amplitude with pathologic temporal dispersion.These findings were most consistent with a polyneuropathy resulting from peripheral demyelination and/or loss of large diameter axons.
Figure 2: Ulnar motor nerve conduction study. The compound motor unit action potentials have prolonged latency, reduced amplitude, pathologic temporal dispersion, and polyphasia.
Muscle and nerve biopsies
Open biopsy under general anesthesia was obtained from the right pelvic limb. A portion of the cranial tibial muscle was sampled along with a portion of the peroneal nerve. The cranial tibial biopsy revealed generalized myofiber atrophy with most fibers having polygonal to anguloid shape. Resin embedded sections of the peroneal nerve showed a marked depletion of myelinated fibers, with approximately 40-50% of the expected population remaining (Figure 3). Endoneurial fibrosis was prominent. A small number of remaining nerve fibers were undergoing axonal degeneration, with no regenerative changes observed.
Figure 3: Toluidine blue stained resin embedded sections from the peroneal nerve showing marked nerve fiber loss.
Outcome
Vincristine induced polyneuropathy or neurotoxicity is well described in human medicine, especially amongst pediatric cancer patients and patients with lymphoma1, 2. It has also been experimentally generated in mice, rats, and rabbits3-5. A case report of vincristine induced peripheral neuropathy in a dog has been published6.In that dog, collapse, pelvic limb weakness, and reduction in spinal reflexes were described.Histologically, vincristine induced polyneuropathy is characterized by axonal loss, demyelination, and endoneurial fibrosis; these changes may be severe.
The diagnosis of vincristine induced neuropathy may be challenging as there are no definitive hallmarks of the disease. For example, tetraparesis and axonopathy could occur due to paraneoplastic neuropathy. Several features of this case, however, strongly suggest that vincristine exposure was the most likely underlying reason for the neuropathy.First, the clinical signs began after drug administration and closely resembled those that have been previously described in dogs administered vincristine. Second, electrophysiologic and histologic features of this case were similar to those recognized in humans and domestic species exposed to vincristine.Finally and perhaps most importantly several weeks after vincristine was discontinued, the clinical signs abated.