Feline Seizures. With Dr. Laurent Garosi. Specialist in Veterinary Neurology. July 2016

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1 The 7 th Annual Vet Education International Online Veterinary Conference Feline Seizures With Dr. Laurent Garosi Specialist in Veterinary Neurology July 2016 Vet Education is proudly supported by Hill s Pet Nutrition (Australia) and Lyppard Australia Pty Ltd

2 PECULIARITIES OF SEIZURES IN CATS Dr Laurent Garosi DVM, Dip ECVN, MRCVS RCVS & European Specialist in Veterinary Neurology President European College of Veterinary Neurology Head of neurology/neurosurgery Davies Veterinary Specialists, England RECOGNITION OF AN EPILEPTIC SEIZURE An epileptic seizure is the physical manifestation of an excessive and/or hypersynchronous abnormal neuronal activity within the cerebral cortex. It is important to recognise that an epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder. Similarly, the term epilepsy is not a specific disease but the term use to define recurrent epileptic seizures. Seizure types can be classified into two major categories: partial and generalised. Compared to dogs, cats commonly exhibit partial seizures. The focal nature of this seizure type is associated with a higher incidence of focal intracranial pathologic change in cats. These can be focal (partial motor or more often partial complex seizure) seizures: unaltered consciousness with asymmetric localised motor signs such as eyelid or facial twitching, clonus of muscle groups of one limb or psychomotor (complex partial) seizures: behavioural seizures pattern involving the limbic system which may be seen as growling, vocalization, rage, aggression without provocation, running in circles, floor licking, tail chasing Compared to dogs, cats tend to experience high seizure frequency whatever the underlying cause. The recognition of an epileptic seizure is essentially based on the owners description of the event. Apart for the unequivocal description of a generalised tonico-clonic seizure, the recognition of a partial or psychomotor seizure can be a real challenge for the clinician. Video footage obtained by the owner can be for that particular reason of precious help. An epileptic seizure can be suspected based on the peracute and unexpected (except cases of reflex seizures where seizures are observed in response to specific stimuli such as auditory reflex seizures which we are currently investigating) onset and offset, stereotypical pattern (i.e. each seizures are fairly similar in following the same pattern), presence of involuntary motor activity and/or abnormal mentation and behaviour and/or autonomic signs (salivation, urination and/or defecation), and elimination of other paroxystic events (syncope, acute vestibular attack, myasthenia gravis). CLINICAL EVALUATION OF A CAT WITH SEIZURES An epileptic seizure is not a disease entity in itself but a clinical sign generally indicative of a forebrain disorder. Neurological examination should therefore focus on detecting forebrain signs (evaluation of mental status, presence of circling gait, postural reaction testing, assessment of menace response and response to nasal stimulation). Causes of seizures can be classified as being intracranial or extracranial in origin. Intracranial causes are further subdivided into those where a structural lesion is identified (vascular, inflammatory/infectious, traumatic, anomalous, neoplastic disease) and those where no such lesion is present that is primary (functional or idiopathic) epilepsy.

3 The detection of forebrain signs on neurological evaluation in the inter-ictal period rules-out as a general rule the hypothesis of primary epilepsy. The only exceptions to this rule are ischaemic necrotic brain lesions secondary to violent seizures (excitotoxicity phenomenon). Such lesions are particularly found in cats in the NMDA receptor-rich brain region such as the hippocampus. Inter-ictal neurological deficits frequently observed include mainly behavioural changes (aggression, fear, hyperexcitability, uncontrolled biting, chasing ). GENERATING A LIST OF DIFFERENTIALS Seizures refer to a forebrain disorder. Their causes may originate outside (extra-cranial) or inside (intracranial) the brain. Causes of seizures found outside the brain (extra-cranial) may be found outside the body (toxic disorder) or inside the body (metabolic disorder). In both instances, the cat may have normal or abnormal neurological examination in the interictal period. If neurological signs are seen, they are typically symmetrical and nonlocalising in term of anatomic diagnosis. Common metabolic causes include hepatic encephalopathy (either due to portosystemic shunt or to cirrhosis), renal encephalopathy, ionic imbalance (hypocalcemia, hyponatremia, hypernatremia, hypomagnesemia or hyperkaliemia), hypoglycaemia, polycythemia, and hyperthyroidism. Common toxic or nutritional disorder seen in cats include lead, ethylene glycol, organophosphate and methaldehyde poisoning and thiamine deficiency. Intracranial causes of epileptic seizures can further be divided into functional and structural forebrain disorder. Most cats with structural forebrain disorder show neurological signs in the interictal period. These signs are often asymmetric and can localise the lesion. They can refer to a forebrain disorder (ipsilateral circling, contralateral postural reaction deficit, contralateral menace response loss with normal pupillary light reflex, contralateral abnormal response to stimulation of the nostril, abnormal behaviour) or to a multifocal disorder (cranial nerve or spinal cord involvement). The exception to this is a structural lesion in a silent area of the brain (region of the brain which causes only seizures with no other localising signs such as the olfactory lobe or prefrontal lobes) or in the early stage of an enlarging (and eventually slowly growing) mass. Structural brain diseases include: cerebrovascular accident (common known causes in cats include cardiomyopathy, glomerulopathy, hyperthyroidism, intoxication by anti-coagulant and parasitism), infectious encephalitis (Feline Infectious Peritonitis, FIV, FeLV-associated CNS lymphoma, Toxoplasmosis, Borna disease and bacterial meningoencephalitis), immune-mediated encephalitis, post-head trauma, primary and metastatic brain tumour, and anomalous (hydrocephalus). A syndrome of complex partial seizures with orofacial automatism (FEPSO) has been described in cats who will display signs of salivation, facial twitching, chewing, growling, rapid turning This syndrome has been associated with hippocampal pathology. In human, similar syndrome is seen with autoimmune limbic encephalitis and is associated with antibody against VGKC (voltage-gated potassium channel complex). Similar pathology has been documented in cats and it is also suspected VGKC complex antibody may play an important role in naturally occurring seizure disease in this species. Brain MRI showed bilateral hippocampal T1 hypo- and isointensity and T2 hyperintensity.

4 The term primary (or idiopathic) epilepsy implies a functional forebrain disorder causing recurrent epileptic seizures with a normal interictal period and no identifiable toxic, metabolic or structural intracranial causes. This type of epilepsy is considered less common in cats as compared to dogs. The diagnosis of primary epilepsy is unfortunately a diagnosis of exclusion. There is to date no definitive diagnostic test to confirm this diagnosis. DISEASE MECHANISMS (VITAMIN D AS ACRONYM) (COMMON CAUSES IN CATS ARE HIGHLIGHTED IN BOLD) Vascular Inflammatory/ Infectious Trauma Toxic Anomalous Metabolic Idiopathic Neoplastic Nutritional SPECIFIC DISEASES Ischemic stroke Hypertension Polycythemia High-grade atrioventricular dysfunction Infectious encephalitis (Toxoplasma, Bacterial, FIP, Cryptococcus, Blastomycosis, FIV, Aberrant parasitic migration, FeLV) Meningo-encephalitis of unknown aetiology (presumed immune-mediated) Auto-immune limbic encephalitis Head injury - may be chronic response to earlier trauma Lead, organophoshate, ethylene glycol toxicities Hydrocephalus Hepatic encephalopathy, hypoglycaemia, hypocalcemia, hyperthyroidism, renal (uraemic) encephalopathy Primary epilepsy Primary and metastatic brain tumour Thiamine deficiency Degenerative Lysosomal storage disease CHOOSING THE APPROPRIATE DIAGNOSTIC WORK-UP Baseline blood work including a complete blood count, chemistry profile, thyroid profile, bile acids, blood pressure as well as a urinalysis should be performed in all cats with seizures. These non-invasive tests may help to diagnose metabolic causes of seizures and are useful in planning anesthesia for any potential advanced imaging. The typical evaluation of an animal with idiopathic epilepsy includes normal neurologic and physical examinations, a history of seizures with normal behaviour, normal interictal periods and normal blood work. Dog with idiopathic epilepsy typically begin to seizure between 1 and 5 years of age and, therefore, a dog meeting these criteria is presumptively diagnosed with idiopathic epilepsy and advanced diagnostics are often

5 not necessary. Because such typical guidelines are not available for the feline idiopathic epileptic, advanced diagnostics are usually recommended for the seizuring cat, even when idiopathic epilepsy is suspected. Such diagnostics include advanced imaging such as MRI or CT and potentially a CSF tap. A CSF tap is indicated if the imaging is normal or the imaging is suggestive of intracranial disease and the cat is believed to have normal intracranial pressure. If there is a large space occupying mass or there is evidence of brain herniation, a CSF tap is contraindicated. Normal CSF is clear and colorless with less than 5 cells/µl of CSF and less than 27mg/dL protein (for a cisterna magna sample). Abnormalities on CSF are very sensitive to intracranial disease, but often not specific. However, when evaluated in conjunction with the MRI/CT imaging, it can be a helpful diagnostic tool. Cultures and infectious disease titers (Cryptococcus, toxoplasmosis and FIP) may also be useful tests to be performed on CSF. When finances are limited? If the cat has no abnormal inter-ictal signs and no abnormalities on neurological examination, once systemic/metabolic causes have been excluded, it is not unreasonable to start management (as below) without having performed advanced imaging. However, the owners should be warned that intra-cranial disease can not be excluded and clinical signs may progress. In cases with evidence of intra-cranial disease where finances limit further investigation, managing the seizures alone can maintain quality of life for a reasonable period of time in some cases (e.g. meningiomas are the most common brain neoplasms in cats and are usually very slow growing). However owners should be advised that the treatment is only palliative and clinical signs will progress. In this situation, euthanasia should be considered once a good quality of life is no longer sustained. MAINTENANCE THERAPY The aim of any anti-epileptic treatment is to control the seizures by reducing their frequency, intensity and severity with minimum side effects. Decision to start anti-epileptic treatment is still a subject of controversy. Cats with a single seizure or isolated seizures separated by longs period of time do not require treatment. Treatment is indicated when: The first seizure is life-threatening (status epilepticus or severe clusters), multiple seizures are observed in a short period of time, seizures occur more than once a month and/or owners objects to their frequency, the seizures are becoming more frequent or more severe, an underlying progressive disorder has been identified as the cause of the seizures. The choice of anti-epileptic drug in a particular species depends on the pharmacokinetic, efficacy, safety and cost of the treatment. Commonly used anti-epileptics in cats are: phenobarbitone (3 mg/kg q12hrs orally), levetiracetam (20 mg/kg q8hrs orally), zonizamide (5 to 10 mg/kg q24hrs orally) and pregabalin (2 to 4 mg/kg q8 to 12 hrs orally). Phenobarbitone is the first choice of many clinicians for cats with seizures. In dogs, repeated phenobarbitone administrations are known to alter estimated steady state serum concentration as a consequence of enzyme induction. This results in the need to progressively increase oral dosage with time in order to maintain steady state therapeutic level. This phenomenon of enzyme induction following repeat administration of

6 phenobarbitone is negligible in cats. The elimination half-life is stable at around 34 to 43 hours and therefore drug concentration of phenobarbitone are not expected to decrease in cats receiving long-term therapy without changing the oral dosage. Monitoring of serum level is only justified shortly after the onset of treatment (when steady state level is reached after 10 to 15 days) due to the differences in elimination kinetics of phenobarbitone between population of cats or when drugs that might interfere with phenobarbitone s pharmacokinetic are added. Recommended therapeutic ranges have not been properly defined in cats but are considered similar to the recommended one in dogs [20 to 35 ug/ml]. Cats should not be considered as refractory to treatment until serum concentrations reach 35 ug/ml unless unacceptable side effects persist. Side effects of phenobarbitone in cats include: sedation, ataxia, polyphagia, weight gain, neutropenia, thrombocytopenia, coagulopathy, severe cutaneous eruptions and marked lymphadenopathy (idiosyncratic delayed hypersensitivity). The author does not recommend the use of oral bromide in cats due to the high incidence of side effect in this species and in particular clinical and radiographic signs similar to feline asthma such as coughing and/or difficulty breathing. EMERGENCY APPROACH TO STATUS EPILEPTICUS The emergency approach to SE consists in sequentially stabilize and initiate drug therapy, institute maintenance anti-epileptic treatment, treat recurrent seizures and look for an underlying cause. Systemic stabilization All cases of status epilepticus (SE; seizure activity lasting 5 minutes or more or multiple seizures without recovery inbetween) or cluster seizures (2 or more seizures within 24 hours, between which the cat regains consciousness) should be treated as trauma patients. While stopping the seizures is the ultimate aim, it is essential to maintain a patent airway (place an endotracheal tube if concern occurs), support proper breathing patterns and oxygenation (X Ref QRG 12 Administering oxygen therapy), provide circulatory support, and maintain body temperature. All these measures are paramount since the combination of circulatory collapse, organ hypoperfusion, and energy depletion that may occur due to SE can lead to severe, irreversible renal, cardiac and hepatic organ failure. Cessation of seizure activity Place IV catheter if possible Intravenous diazepam (DZP; mg/kg) or midazolam ( mg/kg) bolus as first line emergency therapy. If intravenous access is not available, diazepam can be given rectally and midazolam can be given intramuscularly at same dosage Obtain blood sample for emergency database (see below) If the bolus of DZP or midazolam is successful in ceasing seizure activity, but additional seizures occur, two additional boluses of these drugs, or a continuous rate infusion (CRI) of DZP or midazolam may be administered. A CRI of DZP at mg/kg/hour or midazolam at 0.2 mg/kg/hour can be provided; these drugs are administered diluted in 5% dextrose in water (D5W) in a volume

7 corresponding to the maintenance requirements (50 ml/kg/day), to maintain a seizure-free state. An infusion pump or syringe driver must be used for accuracy. Careful monitoring of heart rate, blood pressure and respiratory rates as well as diligent nursing care is needed while cats are being treated with diazepam or midazolam CRIs due to their cardiorespiratory depressant effects. Once seizurefree for approximately 6 hours, the infusion should be slowly tapered, by 25% every 6 hours, to avoid potential withdrawal-induced seizure activity, while carefully monitoring for additional seizure activity. Concerns regarding aqueous solubility, formation of deposits and adsorption onto polyvinyl chloride tubing have been raised with DZP. Compatibility should be checked before combining DZP with any other medication or intravenous fluid as formation of precipitates is common (e.g. with calciumcontaining fluids). Never administer if a precipitate forms. Use of midazolam in lieu of DZP circumvents many of these concerns; however this is far more expensive. If DZP is used the administration set should be protected from light by covering with a bag or bandaging, and changed every 2 hours. If diazepam is unsuccessful in ceasing seizure activity, other options include phenobarbital and propofol. Phenobarbital can be used as an initial IV bolus dose of 3 mg/kg but it must be stressed that the effect is not immediate, but rather can take minutes, so overdosing needs to be avoided, and its use needs to be considered early on in a patient presenting in status epilepticus or with cluster seizures. Using phenobarbital as an emergency drug is useful when phenobarbital is the chosen maintenance drug. Phenobarbital can also be used as an intravenous loading dose of 18 mg/kg. However, it is recommended to administer smaller boluses (2-4 mg/kg) to avoid excessive sedation, repeating every minutes, to effect but not exceeding 18 mg/kg over 24 hours. Note that recovery from phenobarbitone or propofol sedation/anaesthesia may include paddling movements of the limbs, which should not be confused with recurrent seizure activity. Differentiation between the two can be achieved by turning the cat in a different recumbency. Motor activity caused by propofol will be expected to stop while an epileptic seizure cannot be stopped. A CRI of propofol can be considered if the above fails to control the seizures. Propofol is very successful in quickly ceasing seizure activity when diazepam has failed to achieve this, and an initial bolus of 1-4 mg/kg can be used to effect followed by a constant rate infusion of mg/kg/min titrated to effect. Once seizure-free for approximately 6 hours, the infusion should be slowly tapered, by 25% every 6 hours, to avoid potential withdrawal-induced seizure activity. In addition to causing apnoea, propofol is also a cardiovascular depressant so, this too requires careful monitoring. Propofol is a phenol and thus capable of causing oxidative injury to RBC of the cat resulting in Heinz body formation and possible haemolytic anaemia, although this is rarely clinically significant following seizure management. All of the above drugs, though useful emergency drugs, cause sedation of varying degrees, which is undesirable. Intravenous levetiracetam is a viable alternative, not causing sedation and having no known side effects in cats. Levetiracetam is administered in 20 mg/kg intravenous boluses. Its intraveinous use may be effective for 8 hours, at which time it can be repeated if necessary. It is not a veterinary licensed drug and is expensive so is unlikely to be on the shelf in most veterinary clinics.

8 However, it may be possible to obtain on prescription from a chemist or local hospital if urgent need arises. Once the seizures stop, institution of a maintenance antiepileptic treatment (phenobarbitone 3 mg/kg orally or intramuscular (if oral intake is not possible due to excessive sedation) q12hr) is critical to prevent seizure recurrence. In a cat already receiving phenobarbitone, oral phenobarbitone dosage can be increased by 25 to 30% if serum level is low and re-checked days later and/or a 2 nd or 3 rd anti-epileptic drug be started: levetiracetam (20 mg/kg orally q8hr), zonizamide (5 to 10 mg/kg orally q24hr) and pregabalin (2 to 4 mg/kg orally q8 to 12 hr). Identify and treat underlying condition Alongside initial management of the seizures, investigations should begin for treatable underlying causes, with investigations initially including an emergency database (PCV, total solids, blood glucose and electrolytes) and blood pressure assessment. Hypoglycaemia should be treated if this is severe (<3.0 mmol/l) and has resulted in seizure. Medical history should be reviewed, including potential toxin exposure and possibility of trauma. Further investigations such as advanced imaging of the brain (CT/MRI) and CSF analysis are only considered when SE is controlled and the cat is systemically stable.