The refractory seizure (Sz) patient: The diagnostic and therapeutic approach (Proceedings)

Refractory epileptic defined

There are varied opinions about this definition but for this discussion we will define a patient as refractory when: 1) an anticonvulsant (AC) has been used as monotherapy, the high end of the "therapeutic" blood level has been achieved for the AC and the patient continues to have the same or an increased number of seizures (szs) 2) a patient that has developed side effects from an AC that now precludes its use or 3) the patient that has been well controlled for months or years and recently has had a significant increase in sz frequency.

What is your approach with this type of patient? Do you just give more of the same AC? Do you perform any diagnostics? Do you change or add another AC? Which one would you add or change to? These and many other questions have to be answered depending upon the specific situation.

What about diagnostics? My clinical philosophy is that all refractory sz patients should have at least a CBC, Chem panel, UA, Bile acids, and a blood level determined for the specific AC that is being used. It is only with this basic information that one can begin to make logical decisions. The client must understand that this information is needed before major changes can be undertaken with regard to AC therapy.

For example, in author's opinion, any sz patient that has been well-controlled for years, regardless of the AC used, and then becomes poorly controlled while retaining a therapeutic blood level for the AC in use, deserves an aggressive work-up to investigate the possibility that the patient has not now acquired a new problem that may also cause seizures (e.g. brain tumor, insulinoma, hepatic dz, etc.) This may include blood tests mentioned in the previous paragraph, imaging procedures (CAT scan, MRI), insulin/glucose levels, CSF taps, etc. Certainly, the specific patient and situation will dictate how in depth the diagnostic approach would be.

If the above diagnostics are normal and we are strictly dealing with a "poorly controlled" sz patient what are our therapeutic options? And what is a logical/organized approach? Since each patient is a single entity, I will address the above questions using the more common clinical scenarios we are faced with each day, and give a step-by-step approach for each.

Scenario I

On phenobarbital (PB) or primidone (PM) monotherapy (BID therapy) and poor control:

Step 1 – Must measure a phenobarbital blood level. If the level is below 30μg/ml, then increase dose to attain a 40μg/ml level using the following formula:

If a blood level of 40 μg/ml is reached and the animal is still poorly controlled, then step 2 can be tried before abandoning monotherapy. (Remember that it takes 11-14 days to attain steady state levels with PB and PM therefore, recheck the blood level after that time has elapsed).

Step 2 - Switch to TID therapy with PB or add potassium bromide (KBR) to PB (see Step 3). If TID therapy with PB is used, use the same dose each treatment as the BID dose for the first few weeks, and then try to decrease dose. Usually a dose of 18-30 mg/kg/day divided TID is as much as most dogs will tolerate without continued drowsiness or ataxia.

Step 3 -Add KBR: Begin with 30 mg/kg/day SID or divided BID, and if dog becomes sedated drop PB dose by 20%. Thereafter, every 2 weeks ↑ the KBR dose by 10 mg/kg/day, until a dose of 50 mg/kg/day is reached. The goal for KBR is to attain a blood level of 1.0-1.5 mg/ml, before decreasing the PB. Once this level is attained, PB can be further decreased. The ultimate goal is to attain levels in the range of 10-25 μl/ml and 1.5-2.5 mg/ml for PB, and KBR, respectively. Patient response will dictate whether the low or high end of the range is needed. Realize each patient can be different, and that some dogs may tolerate a higher blood level of KBR in combination with PB, therefore, if there are no signs of toxicity at 2.5 mg/ml of KBR, the dose of KBR can continue to be increased if needed.

Scenario II

Patient is on PB or PM (in therapeutic range), sz frequency is increasing rapidly, and therefore, therapeutic levels of KBR are needed faster than in scenario I. In this instance, one can use a loading dose of 600 mg/kg of BR. This should achieve a serum level of 1.0-1.5 mg/ml. This dose is given as 120 mg/kg/day for 5 days to decrease the risk of vomiting and induction of severe sedation. If sedation is severe, then stop the loading and go to maintenance dose. Once the loading dose is finished, go to the beginning maintenance dose of 30-40 mg/kg/day. It is helpful to perform a KBR serum level after loading to see if you have reached the 1.0-1.5 mg/ml target level. Tapering of PB is then done as in Scenario I.

Scenario III

Patient is on PB or PM and has now developed evidence of hepatotoxicity necessitating stopping PB or PM. This is one of the more difficult situations. This author believes that the PB or PM should be stopped immediately since the hepatotoxicity may not always be simply dose related and any dose of PB or PM could continue to be detrimental to liver function.

Step 1 – Stop PB or PM completely and obtain a PB blood level. This will help with decisions on KBR maintenance dose.

Step 2 – Immediately start loading dose of KBR (600 mg/kg), divide QID over next 24 hours or over the 5 day period as above.

Step 3 – Begin maintenance dose of KBR at 30 mg/kg/day and increase to 40-50 mg/kg/day over a 4-week period. Perform KBR level at beginning of maintenance dose.

Note: If PB level in Step 1 is high (≥ 30 μg/ml) then KBR will certainly cause depression, and a lower starting maintenance dose may be needed. Remember, these patients have liver dz, and the blood levels of PB may remain higher for a longer period of time due to slower metabolism of the PB. This is why the initial PB level in Step 1 can aid in making decisions about the initial maintenance dose of KBR.

Step 4 – Perform KBR blood level in 4 weeks after maintenance Rx. Goal is to attain a KBR level of 2.0 mg – 3.0 mg/ml. (Since this is monotherapy) Note: Steady state levels are not attained for 8-9 weeks with KBR, but these initial blood levels can give one some guidance.

Scenario IV

Patient is on KBR as monotherapy, maintenance/steady state blood levels are in therapeutic range, and sz frequency has not changed and better control is still needed.

Step 1 – Begin PB at 1 mg/kg twice daily.

Step 2 – Perform blood PB level in 2 weeks.

Step 3 – Goal is to improve sz control with the smallest dose of PB possible. When used in conjunction with KBR a beneficial response may be seen when the PB blood level is 5-10 μg/ml. This level would not be effective if PB was used as monotherapy.

Scenario V

Patient is on PB and KBR (both in therapeutic range) and sz activity is unchanged (see Step 2) or a patient that is experiencing intolerable side effects of this combination therapy. (See Step 1)

Step 1 – For the patient with intolerable side effects. Perform blood levels for PB and KBR and decrease dosage of whichever AC is in the high end of the therapeutic range.

Step 2 – Add on Felbatol, Lamictal, Keppra, Neurontin, or Zonegran. These are some of the somewhat newer anticonvulsants used in people and therefore there have not been large scale studies of their use in dogs but some studies have shown them to be potentially effective as add-on therapy and/or monotherapy in some cases.

One must remember that once you have reached this point with a seizure patient the cost of treatment rises dramatically since the newer ACs are very pricey. Again good client education is important.

Additional Therapy Which May Be Helpful In The Seizure Patient Include:

1. Taurine –

- 500 mg BID in cat

- 400 mg/40lbs BID in dog

2. Vitamin B6 – daily requirements

3. Co-Enzyme Q 10

These medications "may" help decrease sz activity. Although there are no well-controlled studies with regard to their effectiveness, these drugs cause no harm, and therefore have no contraindications.

Management of the cluster sz patient

Definition: This is the patient that based upon historical information is known to consistently have multiple szs in a 24-72 hour period.

What can be done in an attempt to decrease the number of szs during this 24-72 hr period? These are the alternatives the author has used and, at times, found to be effective in managing the cluster sz patient.

1. Use clorazepate 0.5 – 2 mg/kg BID to TID. Begin immediately after the 1st sz and continue on a BID-TID regimen for the next 48-96 hrs and then stop. This is used in addition to the AC maintenance therapy the animal is already on. Note: the clorazepate is not to be used as maintenance therapy; it is only used to help during the time of sz activity.

2. Rectal administration of diazepam (DZ): Have owner administer diazepam (2 mg/kg/dose) rectally via a plastic teat cannula and syringe. This can be done 3-4 times over a 24-hour period. Rectal DZ should not be used and the owner instructed to seek veterinary attention if 1) the animal has had 4 or more szs during a 24 hour period 2) animal is excessively depressed or 3) there is rectal bleeding. The rectal DZ is given immediately after the 1st sz, and then, if needed, 2-3 more times over the remainder of the next 24 hours. Further rectal DZ is only given if other szs occur during the next 24 hours. Note: Recently there has been a report of a dog developing a rectal abscess and tear secondary to this administration method. Although this appears to be unusual, the owner should be shown how to perform this procedure.

In addition, this same dose of DZ may be effective if administered by the intranasal route. Absorption has been shown to occur by this route too.

Drug options

A - Compounding Pharmacies for KBR: Mortar and Pestle (Des Moines, IA, 1-800-279-7054); Island Pharmacy (Woodruff, WI, 1-800-328-7060; Professional Compounding Center of Baltimore, 1-800-673-8277)

B - Dr. Allen Sisson (Angell Memorial Animal Hospital, Boston, MA)

C- Dr. Michael Podell

D- Note, if there are parentheses next to a price the generic cost is in the