Susan M. Cochrane, DACVIM (Neurology)
A seizure is defined as a transient paroxysmal episode of excessive and/or synchronous neuronal activity within the cerebral cortex resulting in a varied clinical manifestation. The initial seizure discharge can start in a single focal area or can involve both cerebral hemispheres synchronously from the start.
Seizure terminology is currently a controversial topic. Primaryepilepsy (hereditary or genetic epilepsy) is a functional disorder of the cerebral cortex that is typically age-related and is usually, but not always, associated with generalized motor seizures. Symptomatic or secondaryepilepsy results from a structural brain disorder such as neoplasia. Cryptogenicoridiopathicepilepsy occurs when seizures are suspected to have a structural etiology but the cause cannot be determined (e.g., microscopic disorder such as glial scar or cortical dysplasia). Primary and cryptogenic seizure patients are often grouped together since clinical distinction can be difficult and treatment options are often similar. Reactiveepilepsy refers to seizures caused by extracranial disorders such as hypoglycemia.
A seizure may be preceded by the prodrome, which is not part of the seizure based on EEG recordings. This period may last several hours to several days during which the patient's behaviour is abnormal (e.g., withdrawn, seeks owner). The aura, when present, is currently considered to be the true onset of the seizure and is thought to reflect partial seizure activity that then rapidly generalizes. This is a very important concept since lateralization during the aura can localize the seizure focus to the contralateral cerebral cortex and influences diagnostic approach and choice of antiepileptic drug (AED). Primary epilepsy is currently thought not to have an aura, while cryptogenic (idiopathic) epilepsy may have an aura. The ictus typically lasts 1-2 minutes and is varied in appearance, often including abnormal mentation, motor movement, and autonomic signs such as urination, defecation and/or salivation. The post-ictal period which follows the ictus lasts several minutes to hours and occasionally several days. Restlessness, increased appetite and thirst, disorientation, blindness and aggression can occur during this period.
Seizure classification is currently also under review. Generalized seizures involve both sides of the body usually with loss of consciousness and can be either convulsive (tonic-clonic often with autonomic release) or non-convulsive ("absence", brief loss of contact with environment without motor component). Non-convulsive seizures are thought to be uncommon or at least poorly recognized in veterinary medicine. Partial seizures are likely more common than originally suspected especially since it is currently suspected that the aura is a partial seizure. Simple partial seizures have lateralizing motor activity (e.g., eyelid and/or whisker movement) without altered consciousness, usually reflecting structural cerebrocortical disease. Complex partial seizures are more common than simple partial seizures. In addition to motor activity, they have altered level of consciousness sometimes with a behavioural (e.g., hallucination, rage) and autonomic component.
Diagnostic Approach to Seizures
Determining the cause of the seizures should start with evaluation of the patient's signalment, history including seizure type and pattern, physical examination, and neurological examination. When considering intracranial causes, using age grouping of 0 to 6 months, 6 months to 5 years and greater than 5 years of age, allows for a logical approach to the seizure patient.
The decision to start AED therapy should be based on each individual case. General recommendations for initiating therapy include a single seizure occurring more than once every 4-6 weeks, cluster seizure activity (i.e., greater than one seizure within 24 h) or status epilepticus regardless of frequency. The primary goal of therapy is to balance adequate seizure control with acceptable drug adverse effects. The owner should understand that complete elimination of seizure activity might be an unrealistic goal. We hope that AED therapy will decrease the severity, duration, and frequency of the seizure activity.
In general AEDs, act through enhancement of inhibitory processes via GABA (gamma aminobutyric acid), reduction of excitatory transmission and/or control of membrane cation conductance such as sodium and calcium. Factors influencing the choice of AED include general patient health, cost, owner lifestyle, dosing frequency, drug toxicity and seizure type and pattern. While monotherapy is preferred, 20-50% of patients will require multiple AED therapy. In general, the following formula can be used to calculate desired changes in AED dosages: New dose = (Actual drug dose divided by Actual serum [drug]) X Desired serum [drug].
Bromide (Br) usually as Potassium Bromide (KBr): Bromide (Br) is a safe and effective AED that can be used as a sole drug or as part of a multiple drug regimen. Although Br has traditionally been the second line AED, Br has emerged as a first line drug in the dog. This is especially the case in young dogs or dogs with liver disease. Br is not protein bound so drug interactions are minimal and Br does not undergo hepatic metabolism. It is renally excreted so should be used with caution in patients with renal disease. As the % chloride in the diet increases, the absorption of Br decreases and the renal excretion of Br increases, resulting in a decrease of the serum Br level. This important fact needs to be considered with any changes in diet and water. As a result of this link with chloride, intravenous NaCl and loop diuretics can be used to treat Br toxicosis.
Since Br has a long half-life (t ½) of 21-38 days and occasionally up to approximately 68 days, it can take several months to reach steady state serum levels. The recommended dose of KBr in the dog is 20-40 mg/kg q 24 h or 10-20 mg/kg q 12 h. Dogs will often tolerate higher doses such as 40-60 mg/kg/day if KBr is used as a single AED. Therapeutic Br serum levels are reported as 10-20 mmol/L but dogs will often tolerate serum Br levels up to 20-30 mmol/L especially if KBr is used as a single AED. Although usually well tolerated, adverse effects of Br include sedation, weakness especially pelvic limbs, ataxia, PU/PD, GIT irritation, pruritus and pancreatitis especially when used in combination with phenobarbital. In cats, the use of KBr has been associated with a potentially life-threatening asthma-like syndrome with eosinophilic pulmonary infiltrates so this drug is currently not recommended for use, or only with extreme caution, in this species.
To achieve serum Br levels more rapidly, an oral loading KBr dose of 400-600 mg/kg divided q 3-4 h over 24 h or alternatively 75 mg/kg PO q 12 h for 10 treatments followed by the maintenance Br dose can be used. This loading dose is often not necessary. If seizure control is required rapidly, I prefer an initial Br dose of 30 mg/kg PO q 12 h or very occasionally the 75 mg/kg dose q 12 h for 10 treatments alone or combined with short-term phenobarbital therapy. Based on the long t ½ of Br, serum Br levels should be measured 6-8 weeks after onset of therapy with follow-up level at approximately 3-4 months. If a loading dose of KBr is used, initially measure serum Br levels at approximately two weeks after onset of therapy. Routine serum Br levels, CBC and serum chemistries should be evaluated every 6-12 months pending progress.
Phenobarbital: Although phenobarbital (PB) has traditionally been the first line AED, it is now often the second line drug, used as an alternative to Br or add-on with Br. This shift from phenobarbital to Br is based on the potential for PB to have drug interactions, interfere with serum chemistries and laboratory testing (e.g., serum SAP level, ACTH stimulation and dexamethasone suppression), induction of p450 microsomal enzyme function and potential hepatotoxicity. Phenobarbital currently remains the AED of choice in the cat.
The recommended starting dose of PB in the dog is 2-2.5 mg/kg q 12 h and in the cat is 1-2 mg/kg (usually 3.25 to 15 mg/cat) PO q 12 h. In puppies, the starting dose of PB is higher at 5 mg/kg q 12 h. Based on a t ½ of approximately 40 h, steady state serum levels are achieved by10-12 days. Trough serum PB levels should be measured 2-3 weeks after initiating therapy and after each dose change. Although the laboratory reference range is approximately 85-185 umol/L, trough levels in the dog should not exceed approximately 140 umol/L to avoid hepatotoxicity. In the cat, therapeutic levels are likely lower than the dog at 50-100 umol/L. If serum PB levels are subtherapeutic but seizure control is good, then the PB dose does not need to be increased. Routine serum PB levels, CBC and serum chemistries should be measured every 6 months.
Potential adverse effects of PB in the dog include PU/PD/PP, sedation (usually transient), hepatotoxicity, pancreatitis and rarely, bone marrow suppression including severe neutropenia, thrombocytopenia and/or anemia. CBC should be assessed at one and three months after initiation of treatment to evaluate for these rare blood dyscrasias which are usually reversible.
In the event that PB therapy needs to be discontinued, the weaning process should be performed slowly, usually in 7.5-15 mg decrements alternating between morning and evening treatments every 2-3 weeks, usually taking approximately 16 weeks. Only in cases of bone marrow suppression or severe hepatic disease should PB withdrawal be performed rapidly.
Benzodiazepines: Benzodiazepines are not very useful as maintenance AEDs in the dog. Diazepam (DZ) in the dog has a short t ½ and rapid development of tolerance which limits its use to the management of status epilepticus and cluster seizure activity. In the cat, the longer t ½ and lower development of tolerance allows for the use of DZ as a maintenance AED at 0.5-1.0 mg/kg q 12 h. However, a potentially life threatening hepatic necrosis along with other more common side effects including ataxia, sedation, increased appetite and behaviour changes need to be considered when using DZ in this species. Hepatic enzymes should be closely monitored in the cat starting 4 to 5 days after the onset of therapy monitoring for hepatic necrosis. Clonazepam (0.1-0.5 mg/kg PO q 8 h) and clorazepate (1-3 mg/kg PO q 12 h) are occasionally used as add-on AEDs in the dog but their use is limited by rapid drug tolerance. Clonazepam can be used in the cat as a maintenance or add-on AED at a dose of 1/8 of 0.5 mg tablet PO q 8-12 h. Withdrawal seizures can occur with benzodiazepines so drug withdrawal should occur slowly.
Refractory Seizure Patient
When the seizure patient is refractory to phenobarbital and/or Br, therapy becomes more complicated with increased cost, greater potential for adverse effects and drug interactions and often increased dosing frequencies.
Levetiracetam: Levetiracetam is a piracetam analog that is approved for partial onset seizures with and without generalization in man. It is primarily renally excreted with minimal hepatic metabolism in the dog and has a low potential for drug interactions. Based on the t ½ of 3-8 h, dosing every 8 h is usually is required. It appears to be relatively safe in the dog and cat with initial reports suggesting a significant improvement in seizure control. It can be added to the phenobarbital and/or Br therapy but hopefully to ultimately decrease the PB dose. The suggested dose of levetiracetam is 20 mg/kg q 8h often starting at q 12 h. Based on cost, it is beneficial to use lowest dose required for seizure control.
Zonisamide: Zonisamide is a sulfonamide derivative that is used for partial onset seizures in man. Zonisamide is suitable for q 12 h dosing in the dog based on the t ½ of 15-20 h. It is 80% excreted in the urine with minimal hepatic metabolism and low potential for drug interactions based on low protein binding. Side effects appear to be mild in the dog, including sedation and ataxia. Suggested dosage is 4-10 mg/kg q 12 h. Cost may be a factor especially in large dogs.
Gabapentin: Gabapentin is used for partial and generalized seizures in man. In the dog q 6-8 h dosing is required because of short t ½ of 2-4 h. Gabapentin is both renally excreted and undergoes hepatic metabolism (30-40 %). Gabapentin has a low potential for drug interactions based on its lack of protein binding. Gabapentin is well tolerated with sedation reported as an uncommon adverse effect. Suggested dose is 8-20 mg/kg q 6-8h. Gabapentin may prove more useful in the management of neuropathic pain and the scratching of cavalier spaniels with Chiari-like malformation. Gabapentin has been suggested for treatment of feline hyperesthesia syndrome with suggested doses including 50 mg/cat q 24 h with gradual increase to q 12h then q 8h if required, or 5-10 mg/kg q 12h.
Felbamate: Felbamate is a dicarbamate compound used in man for partial onset seizures. It has occasionally been associated with severe hepatotoxicity and aplastic anemia in man. It is primarily renally excreted in dogs with some hepatic metabolism. Suggested starting dose of felbamate is 15-20 mg/kg q 8 h. The adverse effects of felbamate include occasional blood dyscrasias such as thrombocytopenia and leucopenia and hepatic disease so routine CBC and serum chemistries should be evaluated q 2-6 months.
Acupuncture, diet management, vagal nerve stimulation, homeopathy.
References are available upon request.