The Use of Botulinum Toxin for the Treatment of Generalized Myoclonus in a Dog^S

Introduction

Myoclonus is defined as shock-like contractions of a portion of a muscle, an entire muscle, or a group of muscles restricted to one area of the body or appearing synchronously or asynchronously in several areas. Together with the appropriate history and signalment, myoclonus can be considered extremely suspect for canine distemper encephalomyelitis (CDE).

This case report describes a dog with myoclonus so debilitating that it hindered her ability to ambulate, thereby promoting all the comoribund conditions noted in recumbent patients. The generalized myoclonus was treated symptomatically using a novel therapy not previously reported before in the dog. The treatment resulted in ambulation, the ability to eat, and overall well-being. The use of botulinum toxin to treat myoclonus should be considered as a treatment modality in future cases of debilitating myoclonus.

Case Report

A 13 mo old spayed female mixed-breed dog weighing 20.1 kg was referred to the Small Animal Hospital at The University of Florida’s Veterinary Medical Center due to tetraparesis. Eight months previously, the owner had found the dog alongside a road extremely cachexic, weighing only 9 kg. With nursing care, the dog made a rapid recovery. Demodectic mange was diagnosed by the primary veterinarian, and the dog was treated^a for 6 wk. Once the hair began to grow back, the client discontinued the medication. Two months before presenting to The University of Florida’s Veterinary Medical Center, the owner noticed the dog’s jaw and head muscles contracting, and within 2 days of this observation, the dog began whimpering. Three days after the whimpering began, the muscle contractions started to involve the shoulders. Over the next 2 days, the contractions intensified, and the dog’s motor skills continued to decline, resulting in what was described by the referring veterinarian as “walking with an ataxic hypermetric gait resulting in difficulty in ambulation.” A canine distemper virus titer (serum) was negative for immunoglobulin (Ig) M but positive for IgG at 1:120. After an internet search, the owner located a veterinarian in a nearby state who claimed to have a treatment for canine distemper.

At that veterinarian’s hospital, the dog weighed 20.8 kg and her temperature was 39.06°C. The dog was hospitalized, and the second veterinarian treated the alleged canine distemper by administering an intrathecal injection of Newcastle vaccine (0.6 mL of an unknown concentration) via the cisterna magna. The dog was also treated with doxycycline (150 mg q 12 hr), phenobarbital (65 mg q 12 hr), one capsule of a nutritional supplement containing S-adenosylmethionine^b q 24 hr, an omega-3 fatty acid supplement^c (one chew q 24 hr), and 2 mL IV diazepam q 8 hr. In addition, 0.4 mL ivermectin^d per os (PO) 3 times/wk to treat the demodectic mange. After 5 days in the hospital, the dog was walking with the same hypermetric, ataxic gait as at the time of admission. The dog was eating well but was becoming increasingly aggressive and resistant to handling. The muscle contractures remained unchanged and were noted in the medical record as myoclonus. The dog was discharged with phenobarbital, the S-adenosylmethionine supplement, doxycycline, and oral diazepam (10–20 mg PO to help her sleep at night). Over the next 1 wk, she worsened from and became nonambulatory. The myoclonus worsened to become quite debilitating, contributed to her not being able to sleep even with diazepam administration. During that time, the owner attempted to treat the myoclonus with unknown doses of levetiracetam, gabapentin, midazolam, and pregabalin, all prescribed by the original veterinarian. None of those medications gave lasting relief, but only a temporary response.

On presentation to The Veterinary Medical Center, the dog weighed 17.5 kg and her body temperature was 39.2°C. She was nonambulatory and unable to stand even with assistance. There were multiple superficial abrasions associated with wear points aggravated by the persistent generalized myoclonus and a mild generalized pyoderma. A neurologic examination revealed a tetraparetic, nonambulatory patient that was bright and alert with normal cranial nerve function; however, the intense tone of the masseter muscles made opening the mouth difficult. The paresis was worse on the right side and worse in the thoracic limbs. Spinal segmental reflexes were intact and of normal amplitudes. The postural responses were difficult to evaluate due to the myoclonus; however, they were reduced to absent in the thoracic limbs, worse on the right side, and reduced in the pelvic limbs. The most remarkable aspect of the exam was the constant debilitating myoclonus. The myoclonus was generalized, but most severe around the thoracic limbs and head and less evident in the pelvic limbs (see Supplementary Video I).

The dog was treated with lidocaine^e (one 35 mg bolus followed by a constant rate infusion [CRI] at 0.4375 mg/hr) and midazolam^f (4.38 mg IV pro re nata) in an effort to control the myoclonus while awaiting further diagnostics. The lidocaine and midazolam had minimal effects. Administered alone, the midazolam had some effect in helping her sleep despite the myoclonus. Hand feeding was necessary because the myoclonus prevented her from prehending food. A complete blood cell count revealed a mild nonresponsive anemia, hyperfibrinoginemia, mild neutrophilia, mild lymphopenia, and monocytosis. Those findings were consistent with chronic infection/inflammation. Serum biochemical profile had minor liver enzyme elevations, a marginally low albumin, and a slight elevation in cholesterol, which were consistent with phenobarbital use. A skin scrape was negative for demodex. Because of a purulent vaginal discharge, an abdominal ultrasound was performed that revealed a mildly hyperechoic liver and no indication of a stump pyometra.

After premedicating the dog with methadone^g and midazolam, general anesthesia was induced with propofol^h and maintained with a propofol CRI. Electromyographyⁱ (EMG) demonstrated bursts of spontaneous activity appearing as large compound motor unit action potentials as previously described in dogs with myoclonus.¹ Nerve conduction velocities were not performed because the severity of the persistent myoclonus caused too much interference. Neither electroencephalography nor an electroencephalography-EMG jerk-locked back averaging were performed.

MRI^j of the brain was acquired with some difficulty because despite a surgical level of anesthesia, the myoclonus remained severe enough to require the use of IV atracurium^k (1.75 mg was administered q 15 min for the duration of the MRI). That allowed the acquisition of images without movement artifact. Cervical T2-weighted images showed that the central canal of the cervical spinal cord had a well-defined hyperintensity extending from the level of the first cervical vertebra to the cranial aspect of the third cervical vertebra, measuring 2.1 mm at its greatest diameter. On the T1-weighted images, the lesion was hypointense, and there was no contrast enhancement. There was no evidence of a compressive lesion within either the cervical or thoracic spinal cord. The cervical lesion was interpreted as syringohydromyelia. Cerebral spinal fluid (CSF), obtained by an atlanto-occipital tap, had 1 nucleated cell/μL, 0 red blood cells, and a protein of 11 mg/dL. Serum distemper titers measured via an indirect fluorescence immunoassay were 1:1,250 for IgG and < 1:5 (negative) for IgM. Titers on the CSF was 1:2 for IgG and, < 1:1 (negative) for IgM.

After recovery from anesthesia, treatment with IV midazolam was continued because oral midazolam alone did not curtail the myoclonus. While waiting to start treatment with botulinum toxin, the dog was discharged with cephalexin^l (500 mg PO q 12 hr), a combination of antioxidant vitamins (200–300 vitamin C^m PO q 12 hr, 200–400 IU vitamin Eⁿ PO q 12 hr, and 8,000–10,000 IU vitamin A^o q 12 hr), diazepam^p (10 mg PO pro re nata to help with sleeping), and diet augmentation with yogurt.

One wk later, the dog returned to the Veterinary Medical Center for the first treatment with botulinum toxin^q (botulinum toxin type A). The dog weighed 17.3 kg and she was normothermic. The skin infection was clearing having only residual crusts from the previous pyoderma. The owner noted periods of reduced myoclonus when 10 mg diazepam PO was administered, but the effect was short lived. She was still nonambulatory and the myoclonus was as severe as before.

A CRI of propofol was administered for anesthesia, and a total of 100 U of botulinum toxin were divided among the muscles most severely affected with myoclonus. Using a 25 gauge needle, the toxin was dispersed to multiple sites within each muscle. At first, EMG was used to try to identify which muscles were most affected; however, it ultimately proved easier to simply use digital palpation. In total, 12 U were injected into the left masseter muscle, 16 U into the left infraspinatus muscle, 22 U into the left biceps brachialis muscle, 20 U into the left triceps brachii muscle, 8 U into the left cranial tibialis muscle, 14 U into the left quadriceps muscle, and 8 U into the right biceps femoris muscle. There were no complications encountered either during or immediately after the injections, and the patient was discharged the same day with the same recommendations and prescriptions as previously described.

Five hr later, the owner noted that, with assistance, the dog stood for the longest duration of time so far. Her right thoracic limb was not curling under her as often as it had, her ears were articulating much more naturally, and she was able to eat without resting her head on the ground. Approximately 11 hr postinjection, the dog was reportedly uncomfortable, whimpering and trying to move around. She was able to sleep that night; however, the irritation persisted into the following day.

The referring veterinarian monitored rectal temperature, and at 48 hr postinjection, a temperature of 39.4°C was noted. Despite the fever, the dog took several steps using both thoracic limbs and had a dramatic increase in strength, standing for longer than 30 sec. On the owner’s scale of myoclonus intensity (ranging from 1 to 10, where 10 was her status at the start of treatment), the dog was assigned a score of 5. Twelve days postinjection, the dog slept deeply for the first time without the aid of midazolam. Eighteen days after the botulinum injections, it was decided to repeat the injections because of the continued myoclonus and to treat the muscles that either were not treated the first time and muscles that, despite treatment, continued to have debilitating myoclonus.

Re-evaluation at the Veterinary Medical Center showed a body weight of 17 kg, normothermia, resolution of the previous vaginal discharge, improved skin condition, and persistence of the generalized myoclonus. The patient was still tetraparetic, with the right thoracic limb the most severely affected. A CRI of propofol was used to maintain anesthesia, and the muscles were again palpated. Affected muscles were again palpated and the affected muscles injected at multiple sites with botulinum toxin. In total, 24 U were injected into the abdominal muscles (bilaterally), 12 U into the pectoral muscles bilaterally, 8 U into the quadriceps muscle (bilaterally), 8 U into each masseter muscle, 8 U into the right triceps brachii muscle, 12 U into the left triceps brachii muscle, 8 U into the left biceps femoris muscle, and 8 U in the left cranial tibialis. A total of 140 U were administered.

A skin scrape at that time was positive for demodex, and milbemycin^r (11.5 mg PO q 24 hr for 5 days then 23 mg PO q 24 hr) was prescribed. In addition, a urine sample was submitted for distemper polymerase chain reaction (PCR) test. The result was negative.

Two days after the second botulinum treatment, the dog continued to gain strength. The myoclonus was still evident, but at a lower intensity that allowed her to stand and chase a ball for a short time. Four days after the second set of injections, she was sleeping through the night. The dog was walking on all four limbs she was able to run short distances holding her head up and starting to place the right thoracic limb paw appropriately instead of standing on its dorsal aspect. The improvement in function may have been either because of imperceptible improvement of conscious proprioception or the improved muscle strength.

Eight days after the second set of botulinum injections, the myoclonus started to intensify and her use of the right thoracic limb was deteriorating. The owner had been administering the milbemycin as prescribed, but because the drug may have been either stimulatory or tremorigenic, the owner was instructed to stop the drug. Discontinuation resulted in a lessening of the myoclonus intensity. Fifteen days after the second botulinum treatment, the dog was walking 50 yards while carrying her ball; however, she was showing weakness in the thoracic limbs. The weakness was interpreted as a possible sign of botulinum toxin overdose. Twenty-five days after the second treatment, her strength was improving. The dog could stand for long periods of time, she was placing her right thoracic limb paw in the correct position consistently, and the myoclonus was a 3 on the owners scale. The skin was continuing to improve. Forty-five days after the second treatment, the dog was running well on all four limbs. She could run for 30 min at a time. Fifty-six days after the second treatment, she ran three miles on the beach. One hundred fifty days after the second treatment, she continued to improve. The myoclonus was subsiding in intensity and was only being problematic when she was standing still (it caused the right forelimb to move under the thorax). By one hundred eight days after the second treatment, the myoclonus was starting to intensify, and plans were made to repeat the treatment of select muscles in 1–2 mo. Two hundred ten days after the second treatment, the owner reported that the myoclonus was subsiding significantly. Plans for the third treatment were put on hold.

Discussion

Myoclonus is defined as shock-like contractions of a portion of a muscle, an entire muscle, or a group of muscles restricted to one area of the body or appearing synchronously or asynchronously in several areas. Myoclonus is considered highly suggestive for CDE because it is a residual characteristic sign of CDE.^2,3 In one series of 19 cases of confirmed distemper in dogs, myoclonus was the most common neurologic sign (seen in 13 of 19 dogs).⁴ In another series of confirmed distemper cases, myoclonus was seen in 36 of 84 dogs (43%)⁵ In that report, myoclonus was seen with other inflammatory diseases of the central nervous system, including unclassified viral encephalitis, protozoal encephalitis, bacterial encephalitis, steroid-responsive encephalitis, and granulomatous encephalomyelitis.⁵ The prevalence of myoclonus in the nondistemper inflammatory diseases ranked from 5% to 14%. Myoclonus has also been reported in a case of lead toxicity in a dog and associated with canine Lafora disease.^6–8

The antemortem diagnosis of distemper in the patient described in this report was based on the compatible history, signalment, neurologic signs, and the two positive serum IgG titers and one positive CSF titer. The corresponding CSF had a protein level of 11 mg/dL, 1 white blood cell/μL, and 0 red blood cells/μL making blood contamination not impossible, but unlikely. Other potential diagnostic tests for distemper such as skin biopsy, conjunctival scrapings, or PCR on the CSF were not performed. The lack of a positive finding on urine PCR test was due to the time between infection and sampling because the virus sheds for only up to 90 days.^9,10 On the T2-weighted MRI, none of the findings that have previously been described in patients with distemper were noted (e.g., bilaterally symmetrical hyperintensity of the cortical gray-white matter junction of the parietal and frontal lobes and the arbor vitae of the cerebellum being hyperintense with partial loss of the cerebellar cortical gray-white matter demarcation). Dural enhancement dorsal to the frontal and parietal lobes can also be seen on postcontrast images of the distemper patient.¹¹ In the article by Griffin et al. (2009), the cervical spinal cord was not imaged. The cause of the syringohydromyelia in the cervical spinal cord seen on the MRI in the dog described in this case may not be determined based on MRI alone. It could either have been a sequela to CDE gray matter disease with resultant loss of neurons, gliosis, and resultant cavitation or it may have been an anomaly. The largest diameter measured was 2.1 mm in diameter. There were no caudal fossa changes present that may have contributed to the mild syringohydromyelia, and there were no cervical compressive lesions that could have resulted in its formation.

The origin of myoclonus is thought to involve the formation of an autonomous pacemaker in the lower motor neuron despite the fact that the pathologic changes in the lower motor neuron are mild.⁵ In humans with spinal myoclonus, the mechanism is thought to entail a loss of local inhibitory spinal interneuron function, allowing for the repetitive discharge of the ventral horn cells.¹² In this patient, the myoclonus proved quite debilitating, affecting both ambulation and sleep. Myoclonus has been implicated as a cause of pain in one human report.¹³

Botulinum toxin is used frequently in human medicine in the subspecialty of interventional neurology. The symptomatic treatment with botulinum toxin is safely used for strabismus, blepharospasm, hemifacial spasm, spasmodic torticollis, palatal tremor, childhood myoclonus, and spinal myoclonus.^14–20 Multiple dosing regimens have been used with no apparent standard, including 30 U/muscle, 10–20 U/muscle, 45 U/muscle, and for the treatment of palatal tremor, doses as low as 0.03–0.06 U/muscle (very small muscles) are reported.^13,15,19,20 There are fewer reports of the clinical use of botulinum toxin in dogs and cats. Reported instances have been for blepharospasm, experimentally as a model for human laryngeal dysfunction, and one report in a cat for congenital spasticity/contracture of the gastrocnemius muscle.^21–23 In those cases and in the case described herein, there were no reported deleterious effects from the injections of botulinum toxin. The patient in this report did have one episode of hyperthermia 48 hr postinjection. Hyperthermia is noted as a potential side effect in humans when botulinum is used to treat hyperhydrosis, otherwise side effects are reportedly rare in people. In this case, the patient did have one postinjection sign that the authors interpreted as a potential overdose: weakening of the thoracic limbs. The weakness became evident 15 days after the second treatment and was transient in nature, lasting only 2 days. The onset of action of botulinum toxin may be as soon as minutes to hours postinjection. Variables include proximity of the injection to the end plates, concentration of toxin, and tissue diffusion properties.²⁴ The effects of botulinum treatment reportedly last anywhere from 3 mo to 6 mo before retreatment is required.¹⁹ There have been previous reports that dogs may be resistant to the effects of botulinum toxin, with a greater resistance to type C than to type A. Dogs are sensitive to the effects of botulinum toxin, but they are most resistant to C and do show clinical signs with type A, however, the type A needs to be either injected or a large oral dose given to induce clinical signs.^25,26 Botulinum type A was used in the patient described herein. Because the incidence of naturally acquired botulism is low in dogs compared with other species, it may be possible that dogs do not absorb as much toxin from the gut. Botulism in cats is exceedingly rare, although reported in cats, it’s paucity is thought to be due to the cat’s selective feeding habits.²⁷ Once in the circulation, there are also species variations in the motor neuron receptors to which the toxin binds, which may lead to more variation in sensitivity to the toxin.²⁸ Research looking at discrepancies in the toxin’s effect between mice and humans concluded that the effect/injected U of toxin was the same. It was generally packaging and dilution differences that resulted in the perceived differences.²⁴ Because of this unknown variability, the authors of this study chose to initiate treatment in a multistep, gradient fashion. Location of the toxin injection may influence effect, and EMG-assisted placement of the toxin near the motor end plate has shown better clinical results; however, in the presence of muscle contractions such as myoclonus locating motor end plates by searching for end plate noise would be difficult.²⁹ In humans, EMG-guided botulinum injection is still the gold standard, but with either small targets or hard to reach targets, use of the point-touch technique is gaining favor. The benefits of the point-touch technique are that not all clinicians have access to EMG and if injections are being administered through small ports (i.e., via laryngoscope), less working space is needed. The technique is based on targeting using known landmarks. In human patients with adductor spasmodic dysphonia, botulinum toxin injection using the point-touch technique was comparable to the EMG-guided technique with respect to clinical outcome.³⁰ Repeated treatments are often necessary because botulinum toxin binding is eventually negated by new neuronal sprouting.³¹

Conclusion

The patient described in this report presented with a compatible history and clinical signs (e.g., myoclonus) often seen with canine distemper. The patient’s myoclonus was debilitating, hindering her ability to recover by contributing to her inability to ambulate. All the comoribund conditions seen in the recumbent patient occurred in this case. The myoclonus was also deleterious to her well-being by not allowing her to eat or sleep well. Her neurologic condition was treated symptomatically with a novel therapy of botulinum toxin type A, and the dog demonstrated improvement in both ambulation and general well-being. The use of botulinum toxin to treat myoclonus in this case was without serious side effects and promotes the concept that botulinum toxin treatment is safe, effective, and should be considered as a treatment modality in future cases of debilitating myoclonus.