Canine and Feline Epilepsy. Luisa De Risio
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Clinical presentation
Neurological signs in cats include disorientation, ataxia, seizures and blindness (Caylor and Cassimatis, 2001). Neurological signs in dogs are characterized by cerebellar and central vestibular dysfunction (Dow et al., 1989; Evans et al., 2003). Neurologic signs may be preceded or associated with anorexia, vomiting and/or diarrhoea.
Diagnosis
Diagnosis is based on the history of metro-nidazole administration, clinical signs and resolution of signs following metronidazole discontinuation.
Management
Treatment involves metronidazole discontinuation, symptomatic and supportive care. In dogs, diazepam has been reported to markedly improved recovery times of animals with metronidazole toxicosis. Diazepam was administered at an initial dose of 0.2–0.5 mg/kg IV followed by 0.3–0.5 mg/kg PO every 8 h for 3 days (Evans et al., 2003). Mean response time (defined as the time to resolution of the debilitating clinical signs) was 4.25 days for untreated dogs to 13.4 h for treated dogs, and mean recovery time (defined as the time to resolution of all residual clinical signs) was 11 days for untreated dogs and 38.8 h for treated dogs (Evans et al., 2003).
Prognosis
Prognosis is generally excellent, with most animals recovering within 2 weeks. However, sometimes recovery can be prolonged in severely affected animals.
Ivermectin and other macrocyclic lactones
Overview
The macrocyclic lactones, including avermectins (abamectin, ivermectin, eprinomectin, doramectin and selamectin) and milbemycins (moxidectin, milbemycin and nemadectin), are parasiticides able to kill a wide variety of arthropods and nematodes. Ivermectin is commonly used as heartworm preventative in dogs and cats, as ear miticide in cats, as treatment of sarcoptic and demodectic mange in dogs, and as anthelminthic in ruminants, swine and horses. Intoxication can occur when ivermectin is inadvertently overdosed by the owner or veterinarian or when dogs or cats are exposed to products intended for large animals (including by ingestion of contaminated faeces), which contain a higher concentration of ivermectin than small animal products. In addition, subpopulations of herding type breeds, primarily collies as well as Shetland sheepdogs and Australian shepherds, old English sheepdogs, German shepherds and some mixes of these breeds have a unique sensitivity to macrocyclic lactones and other drugs due to an autosomal recessive mutation in the ATP-binding cassette (ABC) B1 (ABCB1) gene (formerly named multidrug resistance 1 (MDR1) gene). This mutation results in a lack of functional permeability glycoprotein (P-gp) (Nelson et al., 2003; Merola and Eubig, 2012). P-gp is a member of the ATP-binding cassette (ABC) superfamily of transporters and represents an important neuroprotective component of the blood-brain barrier as it limits the entry of macro-cyclic lactones and other xenobiotics into the CNS. The defective P-gp results in accumulation of relatively high concentrations of P-gp-substrate drugs in the CNS, even when relatively low doses of drug are administered.
Mechanism of action
Ivermectin and other macrocyclic lactones cause toxicity in mammals by acting as GABAA-receptor agonists in the CNS. Low CNS concentrations of macrocyclic lactones produce stimulatory CNS effects (e.g. tremors, seizures), whereas higher concentrations result in inhibitory CNS effects (e.g. ataxia, obtundation, stupor, coma).
Clinical presentation
Clinical signs of ivermectin toxicity have been reported at dosages ranging from 0.1 to 0.4 mg/kg PO in ABCB1 gene mutation-susceptible canine breeds, 0.2–2.5 mg/kg PO in non-susceptible canine breeds and of 0.3 mg/kg SC in cats (Merola and Eubig, 2012). Clinical signs include obtundation, disorientation, hypersalivation, muscle tremors, ataxia, blindness, mydriasis, seizures, stupor and coma (Hopper et al., 2002; Nelson et al., 2003; Kenny et al., 2008; Merola et al., 2009). Due to the long half-life of macro-cyclic lactones (from 2 days for ivermectin to 19 days for moxidectin), clinical signs of toxicosis may persist for days to weeks, depending on the agent, dose and the breed involved. Death may occur from respiratory arrest if no therapeutic intervention takes place.
Diagnosis
The clinical diagnosis is based on the history of exposure or over-dosage and clinical signs. A genetic test for the ABCB1-1Δ mutation is commercially available and can help to identify susceptible dogs. Plasma or stomach contents can be submitted to a veterinary diagnostic laboratory for quantification of ivermectin. Post-mortem diagnosis can be reached by analysis of ivermectin concentration in frozen brain, liver and fat.
Management
There is no specific antidote for ivermectin toxicity. Treatment involves decontamination including multiple doses of activated charcoal (Table 4.1) to interrupt the enterohepatic recirculation of ivermectin; a saline cathartic (Table 4.1), supportive care (intravenous fluids, ventilator support, cardiovascular, respiratory and neurologic monitoring, nursing care), AEMs (see Table 4.1 and Chapters 12 and 24) and myorelaxants in animals with tremors. Induction of emesis (Table 4.1) can be considered in animals with no neurologic signs and recent oral exposure. Historically, GABA agonists AEMs (such as benzodiazepines and barbiturates) were not recommended in animals with ivermectin-induced seizures as ivermectin is also a GABA agonist and exacerbation of clinical signs was a concern. However, this no longer seems to be the case. AEMs with a different mode of action such as levetiracetam (see Table 4.1 and Chapter 16) may be used.
Intravenous lipid emulsion (IVLE) administration has been suggested as a treatment that may shorten the duration of clinical signs of macrocyclic lactones and other lipophilic compound toxicosis. It is hypothesized that the IVLE acts as a ‘lipid sink’ and draws lipophilic compounds into the plasma lipid phase, thereby removing the compound from the target tissues and promoting its elimination (Merola and Eubig, 2012). Intralipid 20% preparation for intravenous infusion administered at 1.5 ml/kg as initial slow bolus followed by a constant rate infusion of 0.25 ml/kg/min over a 30–60 min period has been reported to result in rapid recovery in dogs and one cat with ivermectin toxicosis (Pritchard, 2010; Clarke et al., 2011; Bates et al., 2013; Epstein and Hollingsworth, 2013). IVLE does not seem beneficial to dogs that are homozygus for the ABCB1-1Δ mutation, possibly because of pre-existent high brain tissue concentration of ivermectin (Wright et al., 2011). Physostig-mine and flumazenil may also be beneficial in the treatment of ivermectin toxicity. In severely affected animals intensive nursing care including respiratory, cardiovascular and nutritional support are necessary for several days.
Prognosis
Recovery may occur, however it is often prolonged (>3 weeks). Blind animals may recover vision (Kenny et al., 2008). Exposure to ivermectin doses >5 mg/kg carries a guarded prognosis. Outcome is likely to be more favourable when decontamination measures are instituted soon after exposure and good supportive care is provided.
Levamisole
Overview