Idiopathic epilepsy is the model to which every dog presented with recurrent seizures is compared. The signalment of the dog and its seizure pattern are the two most important factors toward the establishment of a differential diagnosis. The most important factors in the establishment of a differential diagnosis for recurrent seizures in dogs are the 1. Signalment of the animal and its age at onset of seizures; 2. Seizure pattern (type and frequency); 3. History; and 4. Physical and neurological examination. The most common cause of seizures in dogs is idiopathic epilepsy.
"Idiopathic epilepsy is only epilepsy, with no underlying structural brain lesion or other neurological signs or symptoms. This epilepsy is presumed to be genetic and usually age dependant" (ILEA). Having a good knowledge of the signalment and seizure pattern of the typical idiopathic epileptic dog is necessary since the syndrome is used as point of reference. In idiopathic epilepsy, the seizures are generalized tonic-clonic seizure (convulsion) often preceded by an aura. The frequency progresses gradually with the first few seizures separated in time by weeks to months depending on the breed. The large breeds of dogs often have progressive epilepsy with a tendency to become refractory to treatment. In some of these dogs, cluster seizures occur regularly, as often as every 10 to 30 days. As a rule, if there are more than 2 seizures in the first week of the apparition of the seizures, idiopathic epilepsy should not be assumed and a thorough diagnostic work up performed or advocated. The dog is between 6 months and 5 years of age at onset. The earlier the animal develops seizures within this range, the more severe the epilepsy and the more difficult to control. Although any dog may suffer from idiopathic/genetic epilepsy, there are breeds where it is rare or not documented. In Dobermans, and Sight hounds, another cause should be sought regardless of the seizure pattern and the age of the animal at the onset of seizures. Breeds with severe epilepsy include German Shepherd Dogs, Golden Retrievers, Springer Spaniels, Border Collies, Siberian Huskies. Other breeds frequently affected in Canada are the Sheltie, Welsh Corgi, Nova Scotia Duck Tolling Retriever, Belgian Sheepdog, Cocker Spaniel and Poodle (all sizes).
Other Characteristics of the Idiopathic Epileptic Dog
Physical, neurological and funduscopic examinations: unremarkable
Haematology, biochemical profile, urinalysis: within reference range
Extended data base: cerebrospinal fluid analysis (CSF) and magnetic resonance imaging (MRI) unremarkable
In most idiopathic epileptic dogs, a cerebrospinal fluid (CSF) collection is not essential to pose a diagnosis because the history, signalment of the animal and seizure pattern are quite typical.
DIFFERENTIAL DIAGNOSIS BASED ON DOG'S AGE
A. Most frequent causes of recurrent seizures in the 0-6 months group
1. Epilepsy of the Young Dog (juvenile epilepsy)
Unknown etiology. Likely more than a single cause. The occurrence of seizures may be related to the propensity of the young brain to seize. Animals are 16 weeks old or less at onset. In 25% of these puppies, there is at least one more littermate affected. Generalized tonic-clonic seizures, focal onset with secondary generalization or complex focal seizures. Acute onset. No other clinical signs. The seizures may be frequent, even progressing to status epilepticus (focal or convulsive). No abnormalities in the database except those related to age. The results of the cerebrospinal fluid (CSF) are within reference range or mild changes suggestive of viral infection (self-limited). Phenobarbital 5 mg/kg q12 hours with increases until serum levels are 100-120 umol/L. Measure the phenobarbital serum level every 5 days until desired level is reached. The puppy has a different metabolism for the drug necessitating higher oral dose. After 6 months seizure-free, gradually wean the animal off phenobarbital. The rapidity at which we decrease the phenobarbital depends on the serum levels at the time. If the levels are in the optimal range (100 to 130 umol/L) a minimum of 16 weaning weeks should be allowed. In most cases this author uses 6 to 18 months to wean an animal off antiepileptic treatment. The prognosis is good once the seizures are under control. These puppies grow to be normal dogs, seizure-free and drug-free. The Cocker Spaniel breed seems to be predisposed.
2. Inflammatory Diseases
We distinguish the viral diseases (self-limiting) other than canine distemper, canine distemper, protozoal (Neospora caninum), fungal and rickettsial diseases (Ehrlichia canis), and bacterial.
Slug bait, spoiled dairy products and compost (mycotoxins) because dogs and particularly young dogs have poor eating habits. The seizures are generalized tonic-clonic in nature. Treat as in status epilepticus. Diazepam as an I/V bolus (0.5 to 1 mg/kg) followed with a constant rate infusion (CRI) at the same dose per hour until seizure activity has stopped for four hours. Then gradually wean the animal off over four to six hours.
5. Hypoglycaemia (miniature breeds only)
This is often erroneously listed as a cause of seizures. If seizures are present, there are concomitant marked neurological signs related to the thalamocortex and cerebellum.
7. Hepatic Encephalopathy
This is often erroneously listed as a cause of seizures. Seizures (generalized tonic-clonic as in all metabolic and toxic disorders) are rare with portosystemic shunts. If seizures are present, there are concomitant marked neurological signs related to the thalamocortex preceding and following the seizure. Seizures occur more frequently following surgical correction (24 to 72 hrs).
B. Most frequent causes of recurrent seizures in the 6 months to 5 years old
1. Idiopathic/Genetic Epilepsy
2. Inflammatory Diseases: Encephalitis
A. Infectious diseases
Viral non-Canine Distemper and Canine Distemper
Rickettsial (Ehrlichia and Rocky Mountain Spotted Fever)
Protozoal (Neospora, Toxoplasmosis)
In infectious disease (except for viral non distemper), the infection is frequently systemic with footprint of the disease found on the history, physical examination, and/or blood work.
B. Non infectious diseases
Granulomatous meningoencephalomyelitis (GME) (likely many causes)
Multiple breed specific chronic inflammatory diseases: Yorkshire Terrier, Maltese, Pug
Many other idiopathic causes
3. Thalamocortical Tumours
Most intracranial tumours in dogs are primary. Rarely, hemangiosarcomas lead to metastatic cerebral involvement. The history has a short course (few days to few weeks to occasionally a few months). There are usually behavioural changes that can be subtle.
C. Most frequent causes of recurrent seizures in the dog over 5 years of age
1. Likely Symptomatic Epilepsy (unknown etiology)
2. Inflammatory Diseases
3. Thalamocortical Tumours
4. Encephalopathy (unknown cause) (aging)
5. Beta Cell Tumour
Age-based (<10 months) prognosis in dogs with recurrent seizures
If the neurological examination and database are normal (regardless of the CSF analysis), dogs less than 16 weeks of age at onset of seizures have high probability to become seizure-free and drug-free. This diminishes to 50% when between 16 weeks and 6 months of age at onset, and is guarded if the onset is between six and 10 months of age.
DIAGNOSTIC WORK UP OF A DOG PRESENTED WITH RECURRENT SEIZURES
1. History: Mental Status
2. Consideration of Signalment
3. Documentation of Seizure Pattern (Type & Frequency)
4. Physical, Neurologic and Funduscopic Examinations
5. Minimum Data Base (CBC, chemistry, U/A)
6. +/- MRI, +/- CSF
Comparing the patient to the idiopathic epileptic model, a differential diagnosis is established. The laboratory data is used to confirm a suspicion and not as the focus point. Veterinarians often assume that if the blood work is normal, a diagnosis of idiopathic epilepsy can be posed. In fact the only point that has been confirmed is that the disease is confined to the central nervous system.
The three antiepileptic drugs (AED)s well accepted in the dog today are potassium bromide (KBr), phenobarbital (PB) and the benzodiazepines (diazepam, clorazepate, clonazepam)
Potassium bromide has become the first line AED in the dog. The antiepileptic effect of KBr for the generalized seizures is as strong as phenobarbital. However, since in the past, KBr has been added to the phenobarbital, it may be the combination of both that is effective. Potassium bromide does not seem to cause habituation as phenobarbital does. It is a safe and inexpensive drug. It is excreted unchanged in the urine bypassing the liver. There has been no organ toxicity nor hematologic or biochemical abnormalities reported after many years of use. Chloride is falsely elevated in laboratory because the equipment used for electrolyte measurement does not differentiate chloride from bromide. When added to the Phenobarbital, at serum levels above 20 mmol/L, owners frequently complain of hind limb incoordination, especially in the stairs. It is unavailable as a pharmaceutical product and must be prepared using an industrial grade powder. It is produced with different flavoured (cherry, beef, tuna, etc.) syrups and chewable tablets at concentrations of 100, 200 and 300 mg/ml or /tablet. It is usually a once a day treatment since the half-life is prolonged. However, bromide salt can induce vomiting in some dogs in the hour following administration. In these dogs, we divide the treatment twice daily. Chloride and bromide are halide ions similarly handled by the body. As a consequence, the amount of salt in the diet has a dramatic effect on bromide concentration. The diet must remain unchanged for the bromide levels to remain steady. An increase in the salt content of the diet leads to a decrease in the serum bromide concentration. When one goes down, the other goes up (and vice versa).
Dose: 20 to 40 mg/kg once per day, or divided twice daily. Potassium bromide salt can irritate the stomach causing vomiting in the hour following administration, especially in large dogs since the total dose is greater. Optimal therapeutic serum levels: 17 to 22 mmol/L. If used as monotherapy, levels 20 to 30 mmol/L can be used with minimal side effects. Half-life: 22 to 38 days (varies greatly in relation to the salt in the patient's diet and drinking water). Levels measured at 6 weeks (objective: 8-12 mmol/L; if below, increase the dose, if above, leave at the same dose). Repeat serum levels at 4 to 5 months (objective >17 mmol/L). Dogs tolerate well levels above 25 mmol/L if KBr is used as monotherapy.
Long half-life. Hind limb ataxia frequent with serum levels > 22 mmol/L if used concomitantly with phenobarbital. Polyuria / polydipsia, weight gain, increased incidence for pancreatitis, dietary considerations (salt), industrial grade available only (quality control?), aggression occasionally.
Phenobarbital has become a second line AED after potassium bromide despite its potent antiepileptic effect against partial and generalized seizures. The drug is a strong inducer of the cytochrome P450 system enhancing the body capacity to clear certain substances including phenobarbital itself. With use, the Phenobarbital's half-life shortens leading to progressively lower serum levels despite a regular oral dosing. This may continue for 6 months. There are two serious deterrents to the use of Phenobarbital. First, Phenobarbital is a strong habit-forming drug necessitating regular increments (usually every six to eight weeks) to maintain the antiepileptic effect. The second other important drawback is the hepatotoxicity given dose and time (high dose for a long time). Dogs are likely to develop hepatotoxicity with chronic administration at serum levels above 140umol/L. With adequate monitoring, life-threatening hepatotoxicity is avoidable.
Base line blood work prior to treatment. Initial dose: 2 to 5 mg/kg divided twice daily (> 8 mg/kg to reach optimal therapeutic range). Optimal therapeutic serum levels: 100 to 120 umol/L Half life: 45 to 80 hours. Steady state occurs at five times the half-life. However, phenobarbital is a potent lysosomal inducer enhancing its own metabolism and doing so, leading to a shorter half-life with its use. This is most prevalent in the first few weeks of treatment. Measure the serum levels at four weeks instead of the usual recommended two weeks. Increase the oral dose if needed and re-evaluate the serum levels four weeks later and so on until the optimal range is reached. If the serum levels are higher than anticipated, it is preferable to keep the animal on the same dose to avoid withdrawal seizures. A decrement can be done when another antiepileptic drug has been added and proven effective. To monitor for hepatotoxicity, the serum levels are measured every 6-8 months if the levels are above 120 umol/L and yearly for serum levels within the optimal range. Give the owners the responsibility to tabulate the chemistry data. Tabulate liver enzymes (SAP and ALT), albumin, AED's oral dose and serum AED levels. The liver enzymes are often within reference limits. Frequently, the only sign of impending toxicity is a steadily decreasing albumin concentration although it is still within the reference range. Phenobarbital is highly bound to proteins and as the albumin decreases from poor liver metabolism, there will be a concomitant increase in the serum phenobarbital levels without a concomitant oral dose increase. If there is hypoalbuminemia, the phenobarbital levels increase, adding fuel to the hepatotoxicity.
Half-life shortens with use in the early stage. Habit-forming drug. Hepatotoxicity with chronic use and high serum levels (>120 umol/L). Weight gain, polydipsia/polyuria, lipemia (30%) with increased incidence for pancreatitis, rare idiosyncratic bone marrow suppression observed at onset of treatment that starts with a profound neutropenia. Occasional paradoxical hyperexcitability.
The benzodiazepines (Clonazepam, Clorazepate, Clobazam, Midazolam) are not routinely used for long term management of epilepsy in dogs due to development of refractoriness (by the ninth month of use if not much earlier). Since diazepam is the drug of choice in the treatment of cluster seizures and status epilepticus, the use of benzodiazepine for maintenance therapy may render diazepam ineffective in time of emergency. Rectal diazepam is often used in the in-home emergency measure for dogs that experience cluster seizures. The injectable form is inserted in the rectum (with the use of a teat cannula) at a dose of 0.5 to 1 mg/kg. It is administered at the first sign of seizure activity, and repeated 20 and 40 minutes later even if there are no more seizures, for a total of three treatments within 40 minutes. It often succeeds in aborting the cluster. Clonazepam is used at 0.5 to 2 mg per dog three times daily. The half-life is 6-8 hours. It is often added to potassium bromide and/or phenobarbital. The benzodiazepines are used in the treatment of mainly partial but also generalized seizures that have failed the more conventional drugs. Clorazepate is used similarly. Lately, gabapentin has been used as an add-on AED after KBr and Phenobarbital have failed. The drug is added at a dose of 1800 to 3600 mg/day divided into three doses. There is sedation in the first two weeks of treatment when the drug is used as an add-on. The drug is introduced gradually over a few days to avoid excessive sedation. Levetiracetam is the last AED on the North American market. In our experience, it has been more effective than gabapentin. The biggest deterrent to the use of these drugs is their cost. These drugs are used as an add-on to the actual patient's medication. Phenytoin (Dilantin®), carbamazepine (Tegretol®) and valproic acid (Epival®), the three most commonly used AEDs in humans, are not suitable for use in dogs in reason of their pharmacokinetics. Therapeutic range cannot be reached or maintained.
When to start treatment?
1. At the second generalized seizure even if a few months apart if the animal is less than three years of age at onset
2. More than one generalized seizure per day at first occurrence
3. Convulsive status epilepticus (any cause)
When to stop treatment?
1. Never when a diagnosis of epilepsy has been made or after two years seizure-free
2. After 6 months seizure-free in structural disorders treated successfully
How to stop phenobarbital or potassium bromide?
It should be done very gradually to avoid withdrawal seizures. Evaluate the serum levels before. If the levels are well within therapeutic range (above 90 umol/L), a minimum of 16 weeks is necessary (usually 6 to 18 months). A decrement of 7.5 to 15 mg every three weeks is safe. If the serum levels are below the therapeutic range, few weeks are sufficient (6-8 weeks).
The epilepsy is not controlled despite phenobarbital and potassium bromide?
Consult a veterinary neurologist.