Therapy

Seizures can generally all be treated the same way. The goals of treatment are to reduce the frequency and severity of seizures; it is very unlikely that seizures will be completely eliminated with medication, and this is a crit­ical concept to transmit to the owners.

In the emergency scenario, injectable diaz­epam or midazolam are the treatment of choice. An injection of 0.5mg/kg IV should stop an active seizure. If IV access is not available, 1-2mg∕kg of diazepam can be given rectally or intranasally to stop the current seizure. Diazepam will only exert anticonvulsant effects for about 15 min­utes - long enough to place an IV catheter and get preliminary blood work such as a packed cell volume, total solids, and a blood glucose measurement. During this time, someone should get a brief history from the owners to begin to determine the underlying cause of the seizures to help direct treat­ment. For example, there is no reason to start a known diabetic, hypoglycemic cat on phenobarbital if it has been inadvertently over dosed with glargine. Conversely, a geri­atric dog who has had multiple seizures over the last few months is likely going to require initiation of a maintenance anti-seizure medication.

Cluster seizures and status epilepticus are emergency situations. Prolonged seizure activity can lead to neuronal damage, hyper­thermia, disseminated intravascular coagula­tion (DIC), and death.

Boluses of diazepam can be repeated as needed, but if repeat dosing (more than two or three times) is necessary, a long-term maintenance anti-seizure medication should be considered. There are multiple long-term therapeutic options for seizure control. Traditionally, long-term treatment is consid­ered effective if there is at least a 50% reduc­tion in the number of seizures during a given time.

Box 8.2

Medical intervention with anticonvulsants is meant to prevent a crisis scenario from occurring. Treatment of seizure disorders is a balance between seizure control and the side-effects of the medications.

Phenobarbital (PB) is generally dosed at ≥2.2 mg/kg PO BID in the dog as mainte­nance therapy and it must be dosed at the same amount twice daily. It can be loaded at 16-20 mg/kg IV once to be followed by main­tenance dosing 12 hours later. This loading dose should be reduced in geriatric or com­promised patients by 25-50% so as to not induce marked sedation and paresis. Serum phenobarbital levels should be kept between 20 and 30 ug/mL; a serum level over 30 ug/ mL will not confer better seizure control and will make a hepatopathy more likely. Cats often require a lower dose of PB to reach therapeutic levels. PB is metabolized by the liver and induces its own metabolism and the inducible insoenzyme of alkaline phos­phatase (ALP), so ALP levels are expected to go up in dogs on phenobarbital. Hepatotoxicity due to phenobarbital is asso­ciated with chronically high serum levels, generally over 40 ug/mL for over 6 months. In those cases, alanine aminotransaminase (ALT) is generally higher than ALP. For ther­apeutic drug monitoring, sampling is not time-sensitive. It is recommended to check a serum biochemical profile and a serum drug level every 6 months. Phenobarbital will also interfere with thyroid hormone testing; dogs will show a low total T4 and fT4, but will not be truly hypothyroid. Once an animal is on PB, thyroid testing is not recommended as the results cannot be reliably interpreted.

Levetiracetam (Keppra) is a newer anti­seizure medication that is safe for use in dogs and cats. It is dosed starting at 20 mg/kg TID for the regular formulation and starting at 30 mg/kg PO BID for the extended release formulation. Extended release tablets can not be split! Levetiracetam is available in inject­able parenteral, liquid, and tablet formula­tions.

Zonisamide is a sulfonamide anti-seizure medication that is safe for use in dogs and cats. It is generally dosed at 5 mg/kg PO BID, but must be increased to 10 mg/kg PO BID in dogs concurrently receiving phenobarbital. Zonisamide comes in 25 mg, 50 mg, and 100 mg capsules and can be compounded into a suspension. Similar to the sulfonamide antibiotics, it is hepatically metabolized and can induce hepatopathies. There are also scattered reports of suspected idiosyncratic reactions including hepatopathies and dermatologic disorders associated with zon- isamide administration. Rare, unpublished reports of neutropenia exist, but more common side effects include sedation, ataxia, vomiting, and inappetance.

Bromide is a halide salt that is an effective anti-seizure medication in the dog; it has recently been shown that it is not as effective nor as well tolerated as phenobarbital. It is not recommended for use in the cat due to life-threatening respiratory side effects and poor efficacy. It is typically dosed at 40mg/ kg/day, and it is sometimes possible to use a lower dose of 20-30 mg/kg/day when com­bined with phenobarbital. The target thera­peutic seerum range is from 1-3mg/mL. Bromide doses can be given SID or divided in half and administered BID to reduce gastro- intenstinal upset. Bromide is not metabo­lized and is excreted unchanged by the kidneys; avoidance is recommended in ani­mals with renal dysfunction.

Drugs Not Recommended for Maintenance Use

Diazepam is not an effective long-term anti­seizure medication in the dog and cat. In the cat, oral diazepam can cause an idiosyncratic hepatic necrosis and is therefore not recom­mended. Dogs develop tolerance to oral diaz­epam as early as 5 days after maintenance therapy, and it is then no longer effective. Gabapentin is a poor anticonvulsant and so not generally recommended for primary sei­zure control. Phenytoin is no longer used as it is not truly effective in the dog. Primidone is also no longer used as it is predominantly metabolized to phenobarbital, which has a longer half-life.

Absolute Indications for

Anti-seizure Medications

Absolute indications for anti-seizure medi­cations include cluster seizures, structural intracranial disease, an abnormal neurologic examination, and aggression pre- or post­seizure. Another very important indication for medication is a progressively shortening interictal interval - if seizures are getting closer together, then anti-seizure medica­tions are highly recommended.

Drug Selection: Which Drug and When

When choosing an anti-seizure medication, it is important to consider how quickly you need seizure control, for how long you will need it, comorbid conditions and, if it's a maintenance medication, the owners' limitations for medi­cation administration frequency.

Levetiracetam provides seizure control immediately if given IV and within 24 hours if started at maintenance orally. Phenobarbital provides seizure control within minutes if loaded IV and levels become therapeutic in about one week and stable by 10-14 days if started at maintenance doses. Zonisamide becomes effective after 3-5 days and reaches steady state by 7-10 days. Bromide can reach therapeutic levels within hours if NaBr is loaded IV or within a week if KBr is loaded PO, though it may not be effective for up to a month at maintenance doses and will not reach steady state for 3 months.

No one anticonvulsant is definitively better than another, but the positive and negative effects and interactions of each drug may affect how attractive an individual drug is for a specific case. Both phenobarbital and zon- isamide are metabolized by the liver and so both should be avoided in patients with sig­nificant hepatopathies.

Bromide is very slow to effect, so it is not recommended for short-term seizure control within 2 months. It is also very sensitive to diet, so it is not a good choice in families with small children that throw food on the floor, or dogs that swim in salt water.

In geriatric dogs with significant degenera­tive joint disease and compromised mobility, it is advisable to avoid sedation.

Rescue/Relapse Therapies

If a dog or cat is known to have single sei­zures, there is no need for a rescue therapy at home. Giving additional medications in that scenario can prolong recovery and is not likely to have any benefit. Animals that are known to have clusters of seizures are differ­ent. Depending on the pattern of seizures, a rescue therapy at home may be indicated. If the seizures are minutes apart, and the ani­mal does not recover enough to be able to swallow, then rectal diazepam is likely the best option. This presents multiple difficul­ties: it is a controlled drug with the potential for abuse and it is most rapidly absorbed when given in its liquid state (the injectable form). This requires the owner to draw up the diazepam into a syringe, remove the needle, then place a tomcat catheter or simi­lar device to allow placement of the drug into the rectum - many owners are overwhelmed by this. Diazepam should not be left in clear plastic containers (like syringes) as it is light sensitive and will gradually be adsorbed by the plastic and lose efficacy. Suppositories are not recommended in this scenario as they, by definition, must melt and work slowly. A different option is to use leveti­racetam at home. In the scenario described above, the injectable form of levetiracetam can be administered IM or per rectum for seizure control. If the patient recovers enough between seizures in a cluster to be able to swallow, then oral levetiracetam can be administered with the aim of breaking the cycle of the cluster seizures.

Medical intervention with anticonvulsants is meant to prevent a crisis scenario from occurring. More definitive treatments, such as surgery or radiation, may or may not be an option for intracranial tumors. In this sce­nario, consultation with a veterinary neurol­ogist is strongly recommended. Watchful monitoring is not often recommended in a dog or cat with seizures unless they are single seizures that are very far apart (months) chronologically.

Quality of Life

Quality of life is a major concern when man­aging a patient with a seizure disorder. It can be very difficult to balance seizure control with side effects from the medications. When side effects begin to compromise quality of life, or when seizure frequency increases despite changes in medication protocols, then the goals need to be reevaluated.

Patient

One of the more objective measurements for patient quality of life is seizure frequency. It is helpful to have owners keep track of sei­zure episodes so that therapy and progres­sion of disease can be objectively measured. This can also help the owners objectively see when a seizure disorder is progressing despite treatment. Another consideration is ease of medication administration.

Client

There are many client considerations to think about. With a seizure disorder, medication regime is at the top of the list. Some seizure disorders will progress despite treatment and may require multiple anticonvulsant drugs to be used at once to attain adequate seizure control. An animal on multiple anti-seizure medications will have to be administered many pills multiple times of day; this is not practical or feasible for some working owners. Daily schedule adjustments play into end-of- life decisions for some families. Some owners cannot emotionally handle their pet having a seizure; in this case, there is nothing we can do to reliably prevent all seizures from happen­ing. Financial limitations often come into play in managing a pet with a seizure disorder as there is significant cost associated with multi­ple anti-seizure medications and the recom­mended monitoring and blood work.

Medical management of seizures associated with brain tumors will only help for a certain amount of time, though that time is variable. Here, anti-seizure medication therapy is meant to prevent a crisis, though progression is inevitable. Some cats with meningiomas can live years with anticonvulsants and short courses of prednisone (as needed), while oth­ers will be so severely affected that a decision for intervention versus euthanasia has to be made more precipitously. Although we do not have extensive data on the natural course of disease with meningiomas or gliomas in dogs, survival times with medical management can vary significantly based on tumor type, loca­tion within the brain, and growth rate of the tumor.