key: cord-0041575-gjwoezfa authors: Cherubini, Giunio Bruto; Platt, Simon title: Neurology: Seizures in younger dogs and cats date: 2010-09-30 journal: nan DOI: 10.1111/j.2044-3862.2008.tb00543.x sha: a7c22256df98fd4f0b004d8d28e536f86e8aadbf doc_id: 41575 cord_uid: gjwoezfa nan Seizure disorders are becoming more frequently diagnosed in younger dogs and cats in clinical practice; however there is a lack of definitive data about the real frequency. The specific development characteristics of younger animals have to be considered. The underlying cause of seizures has to be investigated with particular attention to congenital, degenerative or metabolic disorders and inflammatory/infectious diseases. Anti-epileptic treatment is recommended and should be started in addition to the treatment of the underlying disorder where present. For the purpose of this article, younger animals are defined as those less than six months old.This article will address the approach and treatment of younger dogs and cats with recurrent seizure activity. Young animals have more permeable blood brain barriers than adults (Hellmann et al., 1982) . The consequence of this is a significantly increased risk of cerebral exposure to toxins, drugs and metabolites. Thus, the characteristic inquisitive behaviour of younger animals and the absence of a routine eating habit may increase the risk of neurotoxicosis. The immature brain may also be more susceptible to seizures due to the changes occurring during natural development and maturation for two main reasons. Firstly, there is a decrease in the inhibitory neurotransmitter system (GABA) function relative to an overdeveloped excitatory system (glutamate) when compared with an adult brain (Young et al., 1990; Fritschy et al., 1994) . The maturity of the inhibitory neurotransmitter GABA is crucial for the cessation of the seizure activity and to balance the glutamate excitatory system. Secondly, incomplete brain myelination (myelination begins in the last stage of gestation and continues for the first six months of age) contributes to the increase risk of seizures in the immature brain (Kubova et al., 1994) . Drug use in younger animals requires special consideration of the organ systems responsible for drug metabolism and elimination. Younger animals have a rapidly changing body weight and body surface area which has to be kept in mind when dosing anti-epileptic drugs (AEDs) whose dose is based on body weight, in order to avoid sub-therapeutic or toxic AED blood concentrations.The absorption of AEDs depends on the route of administration (oral or parenteral). The reduced GI absorptive capabilities of younger animals can lower the systemic AEDs serum level and efficacy (Boothe and Tannert 1992) . The increase in percentage of body water content can affect the distribution of water soluble AEDs such as bromide. Younger animals have a lower serum protein concentration that can lead to an overdosage of protein bound AEDs (phenobarbitone and diazepam). Additionally, the immature liver is responsible for decreased metabolism of phenobarbitone, diazepam and gabapentin (one third of which is metabolised by the liver in dogs), leading to an increased risk of AED toxicosis. Finally, reduced renal clearance present in immature dogs can be particularly important when using the water soluble AEDs such as bromide and gabapentin. Although there is a lack of data in younger dogs and cats, the overall seizure incidence during the life time varies from 0.5 to 5.7% of all dogs and from 0.5 to 1% of all cats (LeCouteur and Child 1989). On evaluation of a patient with a history of seizures, it is necessary to evaluate the comprehensive history. Many of the seizure episodes are not witnessed by the veterinarian and can be confused by the owner with other 'events' such as syncope, narcolepsy/ cataplexy, vestibular and even behavioural disorders. Physical examination should be complete, with particular attention paid to the cardiorespiratory and gastrointestinal systems, and body temperature; palpation of the calvarium should be performed looking for open fontanelles.The examination of the eye is an essential part of the neurological examination in case of suspected intracranial diseases. The eyes are the 'window to the brain'; in fact the retina and the optic disc are the only directly visible part of the nervous system. In cases of neurological disease, the neuro-ophthalmological examination helps in localising the disease process, in detecting primary disease such as chorioretinitis (i.e. associated with inflammatory diseases) or secondary signs such as papilloedema resulting from increasing intracranial pressure (i.e. secondary to meningoencephalomyelitis of unknown aetiology (MUA) or hydrocephalus or brain tumour). An exhaustive neurological examination is mandatory. Idiopathic epileptic animals are usually neurologically normal in between seizures. However, animals with ÇSMALL ANIMAL G NEUROLOGY ### UK Vet -Vol 13 No 9 November 2008 2 secondary seizures may have detectable neurological abnormalities in this inter-ictal period. In the immediate post-ictal period it is common to temporarily have so called 'post-ictal signs', i.e. blindness, behaviour changes, ataxia and lack of menace response. Younger animals are less likely than adults to suffer from idiopathic epilepsy and an identifiable cause of seizures should be carefully investigated (Podell et al., 1995) .The differential diagnosis in younger dogs and cats for seizure events should include metabolic disease, i.e. portosystemic shunt, juvenile hypoglycaemia (due to breed and or severe intestinal parasitism), as well as toxicity ( Table 1 ). The initial diagnostic evaluation, following an isolated seizure episode, should include a haemogram, a biochemistry profile including serum glucose, cholinesterase (the poisonous effect of organophosphorous and carbamate pesticides comes about through the inhibition of cholinesterase) and lead level, urinalysis, and serum bile acids. Faecal examination should be part of the minimum database in younger animals, where an intestinal parasitic burden can induce anaemia, hypoglycaemia, and hypoproteinaemia and ultimately trigger seizure activity. Skull radiographs, and cerebral ultrasound through an open fontanel can help in identifying the presence of trauma and ventriculomegaly respectively. Cerebral MRI and cerebrospinal fluid (CSF) analysis are recommended to investigate intracranial congenital disorders, such as hydrocephalus or lissencephaly, inflammatory disease and congenital brain tumours even if rarely reported (Smith et al., 2007) . When infectious disease is suspected, additional tests to perform on CSF include PCR, titres and culture (Table 2) . Additionally, blood and urine should be analysed for storage disorders if other tests have proven negative. Haemorrhage due to coagulopathy (i.e. secondary to Angiostrongylus vasorum) Infectious Virus Any -see Table 2 Although seizures in younger dogs and cats are often secondary to an intracranial or extracranial disease, the possibility of an early manifestation of idiopathic epilepsy should not to be ruled out (Jokinen et al., 2007; Hoskins 2001) . Recurrent seizures can effect the brain's development. Accumulating human data suggests that neonatal seizures may be associated with or cause brain damage in the immature brain and increase the risk of subsequent seizure-induced injury, predisposing to epilepsy in adulthood. Moreover, the main factor that determines more persistent epilepsy, following on from early seizures, is protracted seizure episodes (Schimd et al., 1999; McCabe et al., 2001; Dulac et al., 2007) . Early and rational anti-epileptic treatment should be instituted in younger patients with a history of more than one seizure, cluster seizures or status epilepticus, despite the underlying cause. In fact, better seizure control and satisfactory long-term management are achievable where early, appropriate and aggressive anticonvulsant treatment is initiated. If and when an underlying cause can be identified and remedied (i.e. toxin exposure), anticonvulsant treatment can be slowly withdrawn over time; the suggestion is to reduce the dose by 25% every 3-4 weeks up to 5-6 months if the puppy or kitten has remained seizure free (Hoskins 2001) . It is important to make the owner aware of the difficulty in attaining acceptable seizure control in some patients despite appropriate AED treatment. In cases with cluster seizure activity and status epilepticus, phenobarbitone and diazepam can be given per rectum, intravenously, intranasally, or via intraosseus and intraperitoneal routes; bromide can also be given per os or per rectum but has a much longer half life generally prohibiting its use in emergent situations. Because there is a lack of clinical information regarding administration of AEDs in immature animals, the pharmacokinetics and drug disposition data have to be interpreted with caution before establishing an anti-epileptic protocol. Adult AED dosing protocols can be used as a guideline in younger animals. However, it has to be adjusted in view of the continuing growth, organ maturation and changing volume distribution to maintain the desired therapeutic serum level (Table 3 ).The owner should be made aware of the infrequent but potentially severe, life-threatening complications associated with each AED (Table 4) . Bromide (Br) is the oldest AED used in humans (Lancet, 1857); it has been recently reinstituted as AED in children with refractory epilepsy with no apparent long-term side effects (Takayanagi et al., 2002) . It can be used as first choice AED in dogs. 30-40 mg/kg q 24h~30 mg/kg q 24h Phenobarbitone 0.5-2 mg/kg q 24h /q 12h 0.5-2 mg/kg q 24h Diazepam 0.5-1 mg/kg q 8h 0.5-1 mg/kg q 8h Gabapentin 10-20 mg/kg q 8h 10-20 mg/kg q 8h Levetiracetam 10-30 mg /kg q 8h 10-30 mg/kg q 8h bound and does not undergo hepatic metabolism. It is eliminated by the kidneys in a manner similar to chloride; consequently, diets with high chloride content can increase the bromide excretion and lower the serum Br concentration, increasing the risk of seizures. Bromide may be an attractive AED in younger puppies with immature liver function. The reduced renal function allows shortening of the bromide halflife (~ 25 days in adult dogs), reaching steady state earlier and improving the seizure control (Bergman and Coates 2005). Typical side effects reported in adults are polydipsia, polyuria and polyphagia with the possible increased risk of pancreatitis. Bromide has been recently reported to have a very efficacious anticonvulsant activity in cats (Volk et al., 2006) , with the advantage of not being metabolised by the liver. However, Br has been associated with a high frequency of respiratory complications (~ 70%), similar to feline asthma syndrome. Respiratory complications can develop at any time during the treatment and may or may not be steroid responsive. Discontinuation of Br can resolve the respiratory signs in approximately 50% of the cases. However, the respiratory side effects have been severe in several cases, related to a fatal eosinophilic bronchopneumonia (Boothe and George, 2002) . The owner should be made aware of this potentially severe, life threatening complication associated with Br therapy in cats. Phenobarbitone is the most commonly used AED and has been proven to be as effective as bromide as an anticonvulsant. Phenobarbitone does not have significant protein binding (40-50%); 25% is eliminated unchanged by the kidney and it has a predominant hepatic metabolism. Phenobarbitone induced hepatotoxicity is well described in the literature and the risks are more elevated in immature dogs, due to the incomplete liver development and slow Pb elimination. Phenobarbitone is a hepatic P450 enzyme inducer, consequently the half-life and efficacy decreases with long-term treatment. Phenobarbitone may also have a detrimental effect on the normal development of the nervous system with mental impairment and disturbance in the full brain growth documented in rats and children (Burgeois, 1995) . Hoskins (2001) suggested the following protocols: phenobarbitone 0.5 mg/kg sid for animals younger than three months, 1 mg/kg bid for animals between three and six months of age, and 2 mg/kg bid for animals older than six months; bromide 40-80 mg/kg daily to increase if necessary to 120 mg/kg with serum level monitored at four and eight weeks after initiation and then every two months. Parental diazepam is considered the first AED for emergency seizures treatment. However, its short half-life, increased hepatic enzyme induction, physical dependence and risk of acute and chronic liver failure, makes it less ideal as an AED for chronic seizure control. Gabapentin and levetiracetam have not yet been fully evaluated in dogs and cats, However, due to the lack of hepatic enzyme induction and lack of significant reported side effects, they may be particularly promising AEDs in the younger animal. Gabapentin has minimal protein binding, and does not induce hepatic enzymes. Gabapentin is eliminated unchanged by the kidney and its Temporary lethargy and sedation are quite common. Gabapentin is a safe AED that has been proven efficacious in reducing seizure frequency and severity as an 'add-on' drug (Platt et al., 2006) in refractory cases. It has been anecdotally used with success as monotherapy in cases of focal sensorimotor seizures. Levetiracetam (LEV) is a new generation nonenzyme inducing AED. LEV has a high absorption rate, does not bind to plasma protein, is poorly metabolised, and lacks significant drug-drug interaction making it a favourable AED in younger animals. Initial sedation is the only minimal side effect reported in people. Multiple studies have recently shown that LEV exerts neuroprotective effects reducing the amount of inflammation and neuronal death that occurs with seizures (Hannon and Klitgaard 2001). Levetiracetam has been used as an adjunctive AED in refractory dogs with a few anecdotal reports suggesting its safety and efficacy (Volk et al 2007) .The authors have successfully used levetiracetam in cats without significant side effects. • A younger animal is more prone to seizures than an adult due to a more vulnerable developing brain. • Seizure activity has to be considered an emergency and appropriate treatment established quickly. • It is important to carefully rule out possible underlying causes that can lead to unsatisfactory treatment. • The owner should be made aware of the potential adverse effects characteristics of each AED. 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