Hormones and seizures

There are anecdotal reports of the successful use of proligestone and delmadinone injection to control mild canine epilepsy in both sexes. The usual reports of usage of these drugs are for dogs that have had several brief seizures over a couple of years, but perhaps not of sufficient frequency to justify daily phenobarbitone administration. In these reports the datasheet recommended dose has been given every 6 months. However, it is obviously difficult to monitor the benefit of treatment in any animal where seizures are only occurring a few times a year. Proligesterone is a synthetic progestagen (the only natural progestagen being progesterone). All progestagens have antioestrogenic and antigonadotropic properties. Delmadinone is an antiandrogen with a greater antigonatropic effect than progesterone. So is there any rationale for these treatments?

The effect of sex hormones on epilepsy has been well-documented in man and experimental animals. In animal models oestrogen has been shown to have proconvulsant effects whilst progesterone has anticonvulsant properties. Infusion of oestrogen can lower the seizure threshold – with increased effect in animals with an existing cortical lesion.

Some anticonvulsant drugs may suppress seizures by enhancing activity of GABAergic systems. Enhancement of the effects of GABA should increase seizure threshold. Progesterone's anticonvulsant and neuroprotective effects may be due to the steroid's actions on GABAA-benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors, as many progesterone metabolites have a greater effect in vitro on benzodiazepine binding and chloride flux than progesterone, but poor affinity for progestin receptors (Frye CA 1995). Progesterone may have further effects through another action in inhibition of glutamergic activity. Of course in the real world where patients may be exposed to multipharmacy we should also consider that some of the responses reports may be related to the effect of sex hormones on concentrations of anticonvulsant drugs.

Catamenial epilepsy (associated with the menstrual cycle) is recognised to affect one in three epileptic women (Foldvary-Schaefer & Falcone 2003). In general there is an increase in seizure frequency immediately before or during menses but three distinct patterns of catamenial epilepsy have been described: perimenstrual, periovulatory, and luteal. Increased seizure frequency prior to the menses correlates with decreased progesterone concentrations, and high oestrogen levels before ovulation are associated with increased seizure frequency. If sex hormone secretion during the menstrual cycle influences seizure patterns in women it is likely that similar effects should be demonstrable in domestic pets. Although many therapies have been proposed for catamenial epilepsy, including acetazolamide, cyclical use of benzodiazepines or conventional antiepileptic drugs (AEDs), and hormonal therapy (including medoxyprogesterone acetate), there is not a strong evidence-base for the effectiveness of these treatments.

It is clear that there is scope for further research into the hormonal influence on seizures in domestic pets. The ability to address multiple factors affecting the severity and frequency of seizures may provide a mechanism for better control of seizures in some animals.

Dietary manipulation
In man there is increasing interest in dietary manipulation to assist in the management of epilepsy. Recent studies have investigated the use of a ketogenic diet (high fat and low protein/ carbohydrate), as an alternative therapy for children with refractory epilepsy. Seven out of ten patients treated in one trial (Ginzberg and others, 2004) experienced over 50% seizure reduction while on the diet. However, total seizure control was not attained in any patient. In another study (Francois et al) the ketogenic diet improved seizure control in 12/29 cases.

Naturally there has also been interest in the role of diet in the management of canine epilepsy. A variety of diets have been suggested to be efficacious in control of canine seizures including a simple reduced protein diet and the use of a ketogenic diet as in man (low CHO, low protein and high fat). Whilst there may be some published evidence for the use of these diets in man care should be taken in extrapolating this information to animals. Metabolism of food is very different in man and animals and it should be remembered that the levels of ketosis easily induced in man cannot be induced in dogs by dietary manipulation. In addition it appears that the ketogenic diet is most efficacious in children with specific types of epilepsy so findings cannot be extrapolated to all human epileptics, let alone across species.

Many advocates of dietary change in the management of canine epilepsy argue that the perceived benefits come from the avoidance of toxins or allergens in specialised diets rather than a low protein content. Others argue that it is in fact dietary deficiencies or the grain content of commercial diets that triggers epilepsy and therefore advocate BARF (bones and raw food) diets in its control. Whilst there are many anecdotal reports of the value of reduced protein or hypoallergenic diets in epileptic dogs there does not appear to be any controlled study or peer-reviewed literature to support these claims.

Acupuncture
There are a number of published studies showing some benefits of acupuncture as an adjunctive treatment for epilepsy in man and animals. The reports of successful use in dogs have been sporadic (Van Niekerk J, 1988; van Neikerk and Eckersley, 1988; Janssesns, 1993; Panzert and Chrisman, 1994.).

In 1993 Janssens reported the use of ear acupuncture in the treatment of eleven dogs with longstanding epilepsy. The summary of the results looks encouraging. However, of the 4 dogs reported to be seizure free for between 13 and 24 months after treatment one was seizure free on anticonvulsant therapy before treatment, and although the 3 others had reduced seizure frequency after treatment, seizure interval in one was sufficiently long for this effect to be a coincidence. Improvement (defined as reduced dose of medication or reduced seizure frequency) was reported in 3 other dogs, a further 2 possibly showed less severe signs and in 2 there was no response. The author concluded that the results were encouraging and should be tested in a larger group of patients.

A new canine auricular acupuncture point for the treatment for epilepsy was studied by Panzert and Chrisman in 1994. The new acupoint was used with a previously reported canine auricular acupoint (van Neikerk and Eckersley, 1988) for the treatment of epilepsy in five dogs. This study reported testimonial evidence only but concluded that “the technique is worthy of scientific investigation, and controlled research is proposed”. Since that time the work does not appear to have continued (at least follow-up results are not reported).

Permanent acupuncture has been advocated as an adjunct to conventional therapies for the management of epilepsy in man. This involves the implantation of gold beads at sites of acupuncture points, under anaesthesia. Some extreme claims are made for this treatment in dogs ‘up to 60% of epileptic dogs are cured’ with little supportive published data.

In one published study from the Veterinary Hospital of the University of Pennsylvania (Klide and others, 1987) five epileptic dogs, unresponsive to high levels of antiepileptic medication were treated at the acupuncture clinic. Small gold implants were placed subcutaneously over the calvaria to provide constant stimulation at specific acupuncture points. All five dogs showed a change in seizure patterns following gold implant placement. Two dogs had decreases in seizure frequency (with their medication continued unchanged), but reverted to their previous seizure pattern approximately five months after treatment. Three dogs continued to have decreased numbers of seizures and were maintained on decreased levels of anticonvulsants.

The data from these reports is difficult to interpret due to the lack of a comparable control population. It would however seem that, provided it is used as an adjunctive to conventional therapy under veterinary control, acupuncture may offer a safe alternative to other unlicensed treatments.

Vagal nerve stimulation
A novel idea in the management of human epilepsy is the use of vagal nerve stimulation (VNS). The vagal nerve is unique among peripheral nerves of the body in that its nuclei begin in the brainstem. It is not known how VNS achieves an anti-epileptic effect. One theory is that the stimulation scrambles some of the synchronous discharges of the brain associated with seizure activity. Periodic scrambling of the discharges may prevent the recruitment phase needed to begin a seizure.

VNS has not been shown to be more effective than any anticonvulsant in man - its advantage lies in its lack of central nervous system side-effects (sedation and ataxia). However, it has its own transient, side-effects of neck pain and voice change. When effective, VNS permits dose reduction, or elimination, of anticonvulsant drugs, and also seems to shorten the duration of seizures and recovery time. Some human patients do well with this treatment but it is not possible to predict which will benefit.

Investigation of this technique in dogs has been sketchy. Digital ocular compression (to stimulate the vagal nerve) has been shown to be effective in some canine epileptics. One study of seven dogs with epilepsy (Speciale and Stahlbrodt, 1999) showed ocular compression to be efficacious for aborting seizures in 3 dogs. Seizure onset was prevented in 2 other dogs.

In 2002 Munana and co-workers took 10 dogs with poorly controlled seizures and surgically implanted a programmable pacemaker-like device delivering intermittent stimulation to the vagus. Dogs were randomly assigned to two 13-week test periods, 1 with nerve stimulation and 1 without nerve stimulation. No significant difference in seizure frequency, duration, or severity was detected between overall 13-week treatment and control periods. However, during the final 4 weeks of the treatment period, a significant decrease (34.4%) in mean seizure frequency was detected, compared with the control period.

Effect of gender and neutering
A slight predilection for epilepsy in males has been documented in several studies. However, Berendt et al (2002) failed to show a significant difference in risk between genders, nor could they detect any effect of neutering in a study of Danish Labradors.

There is some experimental data on the effect of sex steroid hormones on brain cell excitability and seizures and oestrogen, is consistently found to increase susceptibility to seizures. There are anecdotal reports of the successful use of proligestone and delmadinone injection to control mild canine epilepsy in both sexes. The usual reports of usage of these drugs are for dogs that have had several brief seizures over a couple of years, but perhaps not of sufficient frequency to justify daily phenobarbitone administration. In these reports the datasheet recommended dose has been given every 6 months. However, it is obviously difficult to monitor the benefit of treatment in any animal where seizures are only occurring a few times a year.

Neutering female dogs (particularly those showing increased seizure activity associated with the reproductive cycle) may be beneficial. In contrast, androgens (male sex hormones) appear to have little effect. However it is clear that there is scope for further research into the hormonal influence on seizures in domestic pets.

Homeopathy
As with all conditions there are anecdotal reports of successful management of canine epilepsy with homeopathy. However, little controlled work has been done on this therapy.

Surgical treatment
There are only a few papers on surgical treatment for seizures in canine epilepsy (if surgical management of space occupying lesions is excluded). In man surgical removal of seizure foci in the brain has been an acceptable form of treatment for over 50 years. Computed tomography- guided stereotactic procedures have been used for brain biopsy in dogs and similar procedures might be applicable for identifiable epileptic foci in the future.

Effect of Thyroid abnormalities
Thyroid testing should be considered in any dog with recurrent seizures. Although the relationship between hypothyroidism and recurrent seizures is unclear, thyroid testing is relatively inexpensive and carries little risk to the patient. Interpretation of these tests should be made with caution if the animal is already receiving antiepileptic medication since several recent studies have demonstrated that phenobarbitone therapy causes falsely low values on some thyroid tests (Geiger and others, 2000).

References

Foldvary-Schaefer N, Falcone T (2003) Catamenial epilepsy: pathophysiology, diagnosis, and management. Neurology. Sep 1; 61 (6 Suppl 2): S2-15. - PubMed -

Frye C A (1995) The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res. Oct 23; 696 (1-2): 113-20. - PubMed -

Ginzberg M, Watemberg N, Levi A, Gabai A, Nissenkorn A, Blumkin L, Vinkler C, Lev D, Lerman-Sagie T. (2004) Ketogenic diet as antiepileptic therapy: a description of the clinical experience and the multidisciplinary approach at the metabolic-neurogenetic clinic at the Wolfson Medical Center Harefuah. 143(3), 177-81, 248, 247.

Francois LL, Manel V, Rousselle C, David M. (2003) Ketogenic regime as anti-epileptic treatment: its use in 29 epileptic children Arch Pediatr. 10(4):300-6.

Berendt M, Gredal H, Pedersen LG, Alban L, Alving J. (2002) A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors. JVIM 16(3),262-8.

Munana KR, Vitec SM, Tarver WB et al. (2002) Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs. JAVMA 221, 977-983. - PubMed -

Gieger TL, Hosgood G, Taboada J, Wolfsheimer KJ, Mueller PB (2000) Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. JVIM.14(3), 277-81.

Speciale J, Stahlbrodt JE. (1999) Use of ocular compression to induce vagal stimulation and aid in controlling seizures in seven dogs. JAVMA 214,663-665. - PubMed -

Panzer RB, Chrisman CL. (1994) An auricular acupuncture treatment for idiopathic canine epilepsy: a preliminary report. Am J Chin Med. 22(1), 11-7.

Janssens LAA (1993) Ear acupuncture for treatment of epilepsy in dogs. Progress in Veterinary Neurology 4 (3), 89-94.

van Niekerk J, Eckersley N (1988) The use of acupuncture in canine epilepsy. J S Afr Vet Assoc. 59(1):5

Klide A M, Farnbach G C, Gallagher S M (1987) Acupuncture therapy for the treatment of intractable, idiopathic epilepsy in five dogs. Acupunct Electrother Res.12(1), 71-4.