Seizures in Dogs and Cats

By Sean Sanders

Seizures in Dogs and Cats offers a practical, complete resource for the veterinary management of seizures in dog and cat patients.  The book is carefully designed for ease of use in the clinical setting, presenting clinically oriented information on the etiology, diagnosis, and management of seizures.  Each chapter begins with key points, then presents greater detail, making the book equally useful for fast access during the exam and for further reference.

The book begins with chapters on the history, biology, and classification of seizures, then covers diagnosis, medical and surgical treatment, emergencies, and complementary medicine.  Unique chapters cover client communications and potential future directions of the field.  Seizures in Dogs and Cats puts all the information needed to manage seizures in the veterinary clinic at your fingertips.

• Language: English
• Publisher: Wiley
• Release date: Apr 29, 2015
• ISBN: 9781118689653

Book preview

1

Historical perspectives

Prehistoric and ancient observation

The first ancient humans who witnessed an animal having a seizure were probably as wide eyed, surprised and scared as people are today. That first observed seizure likely corresponds to the beginning of the human/animal relationship. The very first human/animal relationship originated at a point in our history where we as a species started to feed off the leftover scraps of organized packs of wild dogs. Thus began a relationship with canines, most likely around the time we decided to supplement our diet with more than what Mother Nature would provide. We became hunter-gatherers rather than just gatherers. At some point in human history, we started to spend more time observing animals in their natural environment, learning from them (e.g., how they hunted, social interactions, etc.) as opposed to just killing them for food (Figure 1.1). Considering the fact that dogs were the earliest cohabitants of humans, early domesticated dogs were perhaps the first animals (other than our own species) humans witnessed to have a seizure. Ancient humans were well on their way toward higher cognitive abilities, which allowed them to associate the characteristics of a convulsing wolf/dog as comparable to those of a human exhibiting similar signs. Considering the genetic predisposition to have seizures in both species, epileptic seizures secondary to brain injury may have been observed as commonly as spontaneous seizures. Traumatic brain injury to either a human or a dog would probably account for some of the first observed occurrences of seizures. Seizures and epilepsy have undoubtedly been part of our species from the very bottom of the evolutionary tree. Historically, epileptic seizures are one of the oldest described afflictions of humans. As early man would recognize a cut on their finger as similar to a cut on an animal’s digit, so too would they recognize the similarities in symptoms associated with a convulsion, fit, or seizure between humans, dogs, and cats.

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Figure 1.1 Some of the first observations by humans of canines having seizures may have occurred while watching wild dogs hunt. While the incidence of epileptic seizures in dogs is similar to humans, seizures secondary to head trauma were most likely witnessed during these early observations.

Photograph of original painting by Heinrich Harder (1858–1935) Aurochs Fighting Wolves (~1920). Public domain.

It is estimated that the natural occurrence of seizures in dogs is similar to that of humans, whereas in cats and other species, seizures are considered significantly less common (Berendt et al., 2004; Schriefl et al., 2008). Observation of the first cat having a seizure would most likely to have occurred following head trauma inflicted on a wild cat by another animal or man or with the domestication of cats, as opposed to natural observation, since they are less common. The earliest recorded history of animal observation dates to approximately 35,000–40,000 bp (before present), when the Neanderthals painted images of animals on cave walls in what is now modern-day France (Figure 1.2). The earliest recorded history of animal/human cohabitation dates back to Cro-Magnon humans (early Homo sapiens) at round 20,000–15,000 bp, when humans started to dabble in agriculture and the domestication of animals, which naturally came with it. It is suspected, however, that humans and animals coexisted together thousands of years prior to 15,000–20,000 bp. The discovery of a child’s footprint along with that of a large dog in the Chauvet Cave of southern France suggests humans and dogs (wolf/dogs) coexisted as early as 26,000 bp (Garcia, 2005). Humans and dogs began hunting together around 12,000 bp. This time also coincides with the development of early civilizations further strengthened by the domestication of livestock, namely, sheep and goats (Wilkinson, 1992).

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Figure 1.2 Earliest discovered cave paintings of animals, ca. 30,000–32,000 bp (before present). Facsimile reproduction of the Wall of Lions depicting lions hunting bison. Chauvet Cave Complex, Pont d’Arc Valley, Ardèche Southern France. Public domain.

The domestication of cats is thought to follow dogs by several thousand years. The earliest evidence of cats living among humans dates to about 5300 years ago in ancient China.

With the development of a relationship centered on cohabitation, humans were now applying their knowledge of self to other species. The earliest development of medicine would have little distinction between that practiced on other humans or that practiced on animals. The origins of comparative medicine likely began with animal sacrifice, as those doing the sacrificing were the earliest vivisectionists and often local healers. Humans would easily be able to make the connection between similar medical conditions such as a vomiting dog being very comparable to a vomiting human. Unless a medical condition was the result of a known trauma, most afflictions were thought to be due to a combination of mystical or magical sources. Demonic possession by many cultures was the foundation of early medicine although this was shadowed by the development of religious explanations for disease. The application of medical knowledge between species was in parallel and often applied to each species by the same medical (often religious) practitioner. Our understanding of prehistoric medicine is deduced from the first recorded history on the planet.

Early civilization

While we do not think of epilepsy today as a disease per se, historically, it was regarded as one of the earliest recognized afflictions of humans. It has been described in ancient Mesopotamian, Babylonian, Indian, Egyptian, and Chinese civilizations. The earliest description of epilepsy in human beings dates back to about 6000 years ago (4000 bp) in a Babylonian text describing epileptic psychoses. The magico-mystical or magico-religious notion that seizures (and most disease in general) occurred through possession of an individual by spirits or punishment of an individual by the gods for evil doing arose in ancient Mesopotamia. The earliest written recorded history of human observation of animals dates roughly to 3500–3000 bp. This corresponds with the earliest known written history of mankind, which comes from the foundation of civilization located in ancient Mesopotamia between the Tigris and Euphrates river valleys of modern-day Iraq.

Further descriptions of the condition were made around 1000 bp within a Babylonian text on diagnostic medicine known as the Sakikku (meaning all diseases) (Reynolds and Kinnier Wilson, 2008). The Mesopotamian word antašubbû is commonly referred to as the falling disease or the hand of sin, which was brought about by the god of the moon and the notion that it was a manifestation of the possession by evil spirits (i.e., lunatic) (Labat, 1951). The Ayurvedic medical texts describe the oldest know medical system, developed in ancient India between 4500 and 1500 bp, and within the Charaka Samhita, dated at around 450 bp, is a description of a condition labeled as apasmara (meaning loss of consciousness) (Magiorkinis and Diamantis, 2011). In contrast to other civilizations, the ancient people of present-day India did not think of disease from a magico-religious stance; rather, they believed that the cause of seizures was due to physiological and physiochemical disorders of the body. Rather than praying to the gods or visiting temples, they took a more practical and proto-scientific approach to treatment of the condition through altering etiological factors, diet changes, and lifestyle changes, which allowed those afflicted with the condition to have better management of their seizures (Manyam, 1992).

References to rabies in animals can be found as early as 2000 bp in the Codex of Eshnunna. These collections of laws inscribed on two cuneiform tablets are similar to the Laws of Hammurabi, which are also of early Mesopotamian origin. These laws specifically refer to the penalties one might face if a rabid dog that they owned was to bite a person. Certainly, we can infer that if rabies was being observed in dogs, seizures were being observed in dogs.

With specific reference to animal disease, the earliest written description may come from the veterinary papyrus of Kahun (Figure 1.3). This document produced in ancient Egypt at around 1900 bp contains the oldest known veterinary writings outside of the Ayurvedic texts. Within the Kahun papyrus is a specific passage, which could be (note: extreme emphasis on could be) interpreted as the description of a dog having a seizure or collapse:

…if when it courses (?) scenting (?) the ground, it falls down, it should be said mysterious prostration as to it. When the incantations have been said I should thrust my hand within its hemu, a henu of water at my side. When the hand of a man reaches to wash the bone of its back, the man should wash his hand in this henu of water each time that the hand becomes gummed (?) until thou hast drawn forth the heat-dried blood, or anything else or the hesa (?). Thou wilt know that he is cured on the coming of the hesa.

Of course, much can be said about the interpretation of the passage; however, similar behaviors observed in humans would have been applied to those observed in animals, especially the animals for which humans spent the majority of their time with. There is no ancient Egyptian word for veterinarian; therefore, it is presumed that ancient Egyptian physicians treated both humans and animals (Gordon and Schwabe, 2004).

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Figure 1.3 (a) Egyptian depictions of various domesticated dogs. (b) The veterinary papyrus of Kahun was produced during the Middle Kingdom of Egypt ca. 1825 bp. Flinders Petrie discovered the fragments in ad 1889. With thanks to the Petrie Museum of Egyptian Archaeology, UCL.

Copyright: Petrie Museum of Egyptian Archaeology, University College London UC32037.

Shalihotra (c. 2350 bp), one of the earliest Ayurvedic veterinary practitioners, focused on the anatomy, physiology, surgery, and diseases of horses and elephants in the Shalihotra Samhita text (Singh and Chauhan, 2001). An important distinction should be made. Even at this time in ancient India, similar to ancient Egypt, those who provided medical service to animals and humans were the same individuals. The division between the practice of veterinary medicine and human medicine is fairly vague, and its definition was dependent on where one lived and in which specific culture they belonged to. For the most part up to the Renaissance, there was no division between the medical treatment of humans and animals. Because many afflictions were thought to be due to possession of the body by evil spirits or the punishment from angry gods, mystics or members of the religious orders often performed the treatments. Medicines (loosely speaking) used to treat humans and animals were often identical or very similar.

In the late 6th century bp, a switch started to occur from the traditional mythological and theological explanation of the world more to one grounded on pure reason. The birthplace of natural science and philosophy (from a Western sense) was the city of Miletus, at the time a Greek city and now on the Aegean coast of modern-day Turkey. Here, what came to be known as the Milesian philosophy started as an attempt to explain the physical universe through observation, reason, and the beginning of the ancient scientific method. Hippocrates (ca. 400 bp) was the first to link epilepsy to the brain and the potential for a hereditary basis of the disease. He also noted that the prognosis associated with epileptic seizures was worse the earlier it was seen in life and could often be brought on by head injuries. Additionally, we can attribute the term grand mal to Hippocrates who called epilepsy, the great sickness. Dioscorides (ad 40–90) was one of the first documented to prescribe medications based on observed properties of certain herbal remedies to help with epileptic seizures. He used mugwort (Artemisia vulgaris) or ragweed to treat epileptic seizures (Chapter 9). The first classification scheme of the epilepsies is attributed to Galen (ad 131–201) who derived the system of idiopathic (primary disorder of the brain), secondary epilepsy due to abnormalities of cardiac flow to the brain and a third type due to a disorder of another part of the body that is secondarily transmitted to the brain.

The Middle Ages

Just when it looked like that humans were starting to get a head start on science, the Dark Ages came at the fall of the Roman Empire, and the figurative pause button was pressed on science. In Medieval times (ca. ad 6th century to 13th century), mysticism, religious fanaticism, and dogmatism were the common themes in all aspects of life and science. Humans went from treating epilepsy with empirical results derived from herbs to exorcism and trephination to rid the body of demonic possession. How animals who experienced seizures in these times were treated is unknown; however, because it was thought that animals could be possessed by demons, we would assume that the same sorcerer, magician, priest, or alchemist would be called upon to cure the animal of seizures (if the animal was considered valuable enough). Diseases such as rabies and the plague were present in many civilizations, and to a significant degree, the value of animals was more related to their ability to provide food, fiber, and work as opposed to companionship. People were having a hard time taking care of themselves, let alone their animals. Farriers, around the time of the beginning of the Middle Ages, were the first professionals to focus their attention on the health of animals. Toward the end of the Middle Ages and the beginning of the Renaissance, farriers in London were organized with the goal of providing better care to horses. This organization is thought to be the beginning of modern veterinary medicine.

The Renaissance

The Renaissance marked the beginning of the end of the notion epileptic seizures were brought on by demonic possession, evil spirits, or bad luck. Advances in anatomy, physiology, and pathophysiology led to the connection between symptomology correlated with pathophysiology and anatomy. Additionally, a distinction began to arise between the medical treatment of humans and animals. Gaston de Foix wrote about the sickness and care of dogs in Livre de la Chasse (translated to Book of the Hunt) between ad 1387 and AD 1390. He described many common maladies of dogs and how to treat them, including mange, broken bones, neovascularization of the cornea, and the various forms of rabies (Figure 1.4). His description of disease and its treatment in dogs is rational and based chiefly on observation utilizing common remedies at the time, such as valerian and other herbs (Chapter 9). Of special note is the lack of superstition or any reference to a magico-religious cause for disease. It is also apparent that Gaston de Foix cared deeply for the dogs he wrote about. The original book was copied many times over by other authors claiming the work to be their own or referring to it heavily. Edward of Norwich, the second Duke of York, translated the book and added some of his own comments in The Master of Game between 1406 and 1413 (Baillie-Grohman and Baillie-Grohman, 2005). In his descriptions of the various forms of rabies, he refers to a form that does not result in the death of the dog nor does the dog run about biting man and other beast. In this form of madness, referred to as running madness, the dog will show many of the same signs as a dog with rabies with the exception of biting other animals or humans and eventual death. The dog will run about howling and crying in a form of madness … go up or down without any form of abiding. This phrase means that there are no lasting or enduring features of the condition as one would expect with transient epileptic seizures.

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Figure 1.4 Veterinary medicine in the Renaissance. An illumination from Livre de la Chasse (Book of the Hunt) circa 1390 by Gaston III Phœbus, Count de Foix. Photographic credit: The Pierpont Morgan Library, New York.

Copyright: The Pierpont Morgan Library, New York. MS M 1044, fol. 31v. Bequest of Clara S. Peck, 1983.

Charles Drélincourt (1633–1694) was the first recorded experimenter to induce seizures in a dog by placing a needle into the dog’s fourth ventricle (Temkin, 1971). Experimentation on animals was extremely common during the transition from the Renaissance to the Enlightenment and was one of the driving forces toward the age of reason and the beginning of the modern biological sciences.

The Enlightenment

Claude Bourgelat (1712–1779) founded the first veterinary college in 1761 at Lyon, France, in response to a rinderpest outbreak in cattle. Undoubtedly, convulsions in animals, still referred to as falling sickness, were addressed similar to the means of his predecessors. However, scientists such as Felice Fontana (1730–1803) were beginning to conduct electrical experiments on tissues such as nerves, muscles, and the brain of animals. Fontana demonstrated that convulsions could be generated through direct pressure and electrical stimulation on the brain of frogs in 1757 (Marchand and Hofff, 1955). The Veterinary College of London was founded in 1791 as a way for farriers to gain better knowledge regarding the care or horses. For the most part, the science revolving around convulsions was attempting to distinguish epilepsy as a true medical condition as opposed to that which afflicted the insane and in many instances was still considered contagious.

Dr. Benjamin Rush (1746–1836), a Philadelphia physician and one of the signers of the Declaration of Independence, addressed a class of medical students at the University of Pennsylvania in 1799. In his speech entitled On the Duty and Advantages of Studying the Diseases of Domestic Animals, Rush encouraged the young soon-to-be physicians to embrace his studies and labors the means of lessening the miseries of domestic animals (Figure 1.5). Rush was inspired from a study abroad at Edinburgh University on the advances of veterinary medicine in Europe especially when compared to the abysmal practice he witnessed in the fledgling democracy. Rush was instrumental in creating one of the first veterinary colleges in the USA.

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Figure 1.5 In 1799, physician, Benjamin Rush addressed a group of young medical students imploring them to use their talents to lessen the miseries of domestic animals. Rush was instrumental in developing one of the first Veterinary Teaching Colleges in the USA.

The vast majority of investigation looking to a physiological cause for seizures continued to be propagated through animal experimentation, primarily in dogs and cats. Numerous investigators observed convulsions induced through bloodletting, although even at the time of Hippocrates, it was noticed that animals would convulse when slaughtered (Eadie, 2009). Much like the ancient Egyptians who noted convulsions with head trauma and paralysis with spinal trauma in animals, early observers of symptomology had no physiological basis to connect the clinical signs to a pathophysiological mechanism for the behavior. The experimentation, which fostered the connection between symptomology and pathophysiological mechanisms, is a hallmark of the Enlightenment. Charles-Édouard Brown-Séquard (1817–1894) observed convulsive-like behavior when the spinal cord was transected in animals (Brown-Séquard, 1857). While he was the first to describe the anatomy and function of the spinal cord, he advocated trephination and cauterization of the larynx with silver nitrate for the treatment of epilepsy. Much of his work focused on the reflex epilepsies, which could be induced in animals following hemitransection of the spinal cord. He noted that if the face or neck were scratched, the nonparalyzed side of the animal would involuntarily convulse. He suspected that there was a degree of dyscognition; however, it was later speculated that he was inducing an exaggerated scratch reflex. His contemporaries were of the general agreement that a lack of unconsciousness during the convulsions did not fit with standard epilepsy experiments, and therefore, it was not a good model for the study of convulsions in animals. To this day, there is no good explanation for Brown-Séquard’s observation of spinal epilepsy (Eadie, 2009).

In 1857, Edward Sieveking introduced the use of potassium bromide for the treatment of epileptic seizures, which was further supported by Charles Locock (Locock, 1857). However, it was not until 1861 when Samuel Wilks provided solid evidence as to the efficacy of potassium bromide, catapulting it into popularity for the treatment of epileptic seizures (Wilks, 1861). This instance was the beginning of modern pharmacology for the treatment of epilepsy. Potassium bromide is still, to this day, widely used to treat epileptic seizures in dogs. Pietro Albertoni (1848–1933) performed some of the earliest experiments looking at the effects of various drugs and medications in their ability to prevent experimentally induced seizures in animals in the late 1800s (Albertoni, 1882). Albertoni demonstrated that single doses or continued high doses of potassium bromide reduced the excitability of the cerebral cortex and prevented convulsions with electrical stimulation of the cortex in dogs. Expanding on this finding, he showed that when using ethyl ether or chloral hydrate, in doses leaving dogs awake, electrically induced seizures were prevented. Up to this point, epileptic seizure remedies may have been classified as spiritual (e.g., amulets, prayer, and exorcism), botanical based (e.g., skullcap, valerian, mistletoe, etc.), chemical (i.e., sulfur, silver nitrate, mercury, etc.), alterations to the physical form (e.g., bleeding, trephination, cauterization, castration, induced vomiting, etc.), and therapies derived from fauna (e.g., seal genitals, tortoise blood, crocodile feces, etc.). Undoubtedly, a lack of perceived benefits led to an early philosophy of therapeutic nihilism whereby the intrinsic lack of benefit of anything led to the practice of doing no harm as many of the concoctions had undesirable side effects. Interestingly, we still use this common philosophical practice today.

The modern era

The modern era in the history of epilepsy begins in the late 19th century with the discovery of potassium bromide, more refined animal experimentation, and a distinct correlation between seizure semiology and pathology. One of the most influential neurologists ever was John Hughlings Jackson (1835–1911). The discovery that organic disease (brain tumors, pus, or head trauma) was often present in humans and animals on necropsy further solidified the notion that seizures were not a disease but rather a sign of brain dysfunction. Granted, even the ancients were able to make the association between head trauma and seizures. While their ability to recognize symptomology was impressive, they did not have the underlying knowledge of pathophysiology from which to link the two. Jackson, through observation, was able to draw many conclusions including the notion that epileptic seizures originated from the cerebral cortex gray matter (Jackson, 1873). Eduard Hitzig (1838–1907) and Gustav Fritsch (1838–1927) performed some of the earliest experiments in dogs when they applied electrical current to portions of the dog’s cerebral cortex in order to elicit muscular contractions. Following the cessation of cerebral stimulation, Hitzig and Fritsch noted that the convulsions spread to affect both sides of the dog’s body with extensor rigidity and dilated pupils (Eadie, 2009). John Hughlings Jackson was able to bring together both symptomology and physiology in a more complete pathophysiological model of epilepsy (Jackson, 1869, 1873). Jackson came to the conclusion that epilepsy was not one disease but many different etiologies, which brought about epileptic convulsions based on the area of gray matter that was discharged (Engel, 2013). Jackson was aided greatly by the experiments of his friend and colleague Sir David Ferrier (1843–1928) who used electricity to stimulate areas of the brain of dogs, cats, and rabbits to provide an early understanding of the somatotopical organization of the brain (Ferrier, 1873) (Figure 1.6). His experiments on animals validated the semiology of what Jackson observed in humans with epileptic seizures and in Jackson’s words were the starting point for a comparative physiology of the convulsions (Jackson, 1873). Luigi Luciani (1842–1991) performed cerebral resections in dogs and demonstrated that removal of portions of the cerebrum could result in convulsions. Surprisingly, some dogs survived his surgeries and would go on to continue to have convulsions. Luciani’s work further validated the cortical origin of epileptic seizures (Manni and Petrosini, 1997). Charles Horsley, a neurosurgeon—aided by the observations of Jackson, a neurologist, and Ferrier, an electrophysiologist—applied his colleagues’ observations to attempt to cure epilepsy by the removal of brain tissue suspected to be epileptogenic in a man who suffered from focal motor seizures secondary to a depressed skull fracture. The surgery performed in 1886 was successful, resulting in a seizure-free patient (Horsley, 1886).

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Figure 1.6 Experimental electrical stimulation points and associated movements in the dog and cat brain as described by Sir David Ferrier in 1890. From Ferrier (1890).

At about the same time, Jackson and Ferrier were formulating the beginning of our modern understanding of the functional brain, veterinary medicine in the USA was getting its formal start. Dr. James Law (1838–1921), of Cornell University, published The Farmer’s Veterinary Adviser in 1876. In this document, epilepsy was also referred to as falling sickness. It was associated with distemper, teething in the young animal, and parasitic infection. A reference was made to reflex seizures elicited in guinea pigs by Brown-Séquard by tickling the neck and how a similar condition may be observed in humans. A description of the symptoms was followed by treatment recommendations consisting of removal of possible inciting causes, such as verminous infestations, restriction of diet, and more exercise for excitable animals (Law, 1876). Epileptic seizures were treated with injections of chloral hydrate or inhalation of chloroform or ether. Convulsions and fits of young dogs and cats were considered separately from epilepsy but still under the category and chapter concerning disease of the nervous system. Interestingly, treatment did not include potassium bromide but rather removal of the offending cause (worms or other irritating matters), good feeding, air, exercise, lodging, and tonics made of bitters and iron. By the ninth edition (1889), salts of bromide were advised as treatments for excitability of the nervous system along with the aforementioned tonics of bitters, chloral hydrate, chloroform, and ether.

The 20th century

Advances in anatomy, physiology, and pathophysiology of the nervous system continued into the early 20th century. Thousands of years of experimental research on dogs, cats, and other animals built a foundation for our understanding of the brain and epilepsy. The development of the electroencephalograph (EEG) in the same year as phenobarbital (1912) provided a noninvasive way both to continue to study the electrical activity of the brain and treat seizures with the first effective drug since the introduction of potassium bromide over 50 years prior. The first EEG recording of a mammal (a dog) and published photograph of an EEG were made by Vladimir Pravdich-Neminsky in 1912, at that time referred to as the electrocerebrogram (Niedermeyer et al., 2011). It would be another 12 years before the first human EEG was created by Hans Berger in 1924 who is credited with inventing the electroencephalograph (sorry Vladimir…).

In 1912, a sleep-deprived resident psychiatrist, Alfred Haupmann, gave phenobarbital (then marketed as a hypnotic) to the epileptic patients within the ward that he presided over, so that he might get a better night’s sleep. Not only did the patients sleep throughout the night, but he also discovered that they had fewer seizures during the day. Haupmann published his serendipitous finding, and phenobarbital went on to become the most widely used anticonvulsant to this day (Brodie, 2010). A cat model of experimentally induced seizures was used to screen a group of potential anticonvulsant drugs with presumably less sedative effects compared to phenobarbital. Putnam and Merritt reported a detailed description of the cat electrocution apparatus in a 1937 Science article (Putnam and Merritt, 1937). In the report, the authors state, The method appears to involve no undue cruelty, and indeed is similar to that used for executing stray animals by some animal protective societies (Figure 1.7). One year later, Merritt and Putnam (1938) published the results describing the anticonvulsive effects of phenytoin. Prior to the discovery of the anticonvulsive effects of phenytoin, potassium bromide and phenobarbital were the most advanced pharmacological agents used to treat epileptic seizures. The ketogenic diet developed by Dr. Russell Wilder of the Mayo Clinic in 1921 was also used to a lesser degree (Wheless, 2008). Cerebral cortical resection was performed in a small number of cases to treat (and often cure) epilepsy. Following the discovery of phenytoin, the ketogenic diet fell out of favor, and a strong push was made to actively pursue other pharmacological-based therapies.

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Figure 1.7 The cat electrocution apparatus utilized by Putnam and Merritt to test potential antiseizure drugs. Thousands of years of experimentation on animals helped greatly to expand human understanding and treatment of epilepsy.

From Putnam, T.J. and Merritt, H.H. 1937. Experimental Determination of the Anticonvulsant Properties of Some Phenyl Derivatives. Science. 85(2213). 525–526.

In the People’s Home Stock Book by veterinarian W.C. Fair, published in 1919, there is little mentioned of the contemporary anticonvulsants used by humans to treat animals (Figure 1.8). There is no mention of epilepsy in dogs, other than convulsions associated with distemper. Cats on the other hand have a treatment section on Fits–Convulsions and Epilepsy. It was noted that epilepsy in cats differed from fits and convulsions in that there was no delirium associated with convulsions (similar to focal motor seizures of cats we identify today). Cats were treated with a cathartic of either buckthorn syrup or castor oil and wrapped in a hot blanket or dropped in warm water (all but the head). It was also recommended to give two grains of bromide of potash four times a day (Fair, 1919). For epilepsy, cats were given laudanum (tincture of opium) or chloral hydrate, syrup of buckthorn (to move the bowels), and it was recommended to feed a highly digestible diet and exercise the animal. In the human medicine section of the same book (The People’s Home Library, Book One), epilepsy was under the category Falling Fits and treated with bromide of potassium. Oxide of zinc and stramonium ointment (herbal remedy derived from Jimson weed) were also recommended as a treatment for the falling sickness.

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Figure 1.8 Even in the early 20th century, contemporary treatment of seizures in dogs and cats did not rely on the most advanced drugs at the time, such as potassium bromide and phenobarbital. Rather, emphasis was placed on numerous different treatments including herbal remedies, good diet, and exercise.

From The People’s Home Library: A Library of Three Practical Books. 1919. The R.C. Barnum Company. Cleveland, OH.

Advances in the treatment of epilepsy for dogs and cats primarily, and to this day, rely on pharmacology similar to humans. Although there is a significant difference between the species, there are limitations in regard to the use of various antiseizure medications in dogs and cats. In the 1960s, carbamazepine and the benzodiazepines were introduced. Benzodiazepines found significant use in veterinary medicine, especially for the control of status epilepticus. Disposition limitations and toxic effects of certain human drugs prevent their current use in dogs and cats; however, despite this, the pharmacological success in treating seizures of dogs and cats is similar (if not slightly better) than humans. Phenobarbital and potassium bromide continue to be the most commonly prescribed antiseizure medications in dogs, and for cats, phenobarbital is by far the most widely used antiseizure drug.

A more direct focus on the advancement of diagnosis and treatment of disease of the nervous system of dogs and cats was developed following World War II. Veterinarians such as J.T. McGrath, A.C. Palmer, B.F. Hoerlein, John Lorenz, and Alexander de Lahunta gave special attention to the nervous system of dogs and cats. Their research, textbooks, and education of thousands of veterinarians significantly advanced the field of veterinary neurology and opened the door for many others to follow in their footsteps.

Advances in experimental techniques and a general pejorative view on animal experimentation shifted the bulk of animal research to rodent models in the late 1970s. The discovery of the patch clamp technique for the study of electrophysiology by Erwin Neher and Bert Sakmann opened a whole new era of science for not only studying the underlying pathophysiology of epileptic seizures but also the underlying mechanisms of how many drugs worked to suppress seizure activity. In the early 1970s, Dr. Terrell Holliday contributed significantly to the understanding of the canine EEG associated with paroxysmal central nervous system disorders. The contributions of Dr. Wolfgang Löscher and Dr. Dawn Boothe continue to advance our understanding of canine and feline anticonvulsants and have prevented an incalculable amount of toxic reactions of dogs and cats to common drugs used to treat seizures in humans. Dr. Michael Podell continues to pave the way through sharing his experiences with the clinical application of new antiseizure medications.

One of the most significant advances to the diagnosis of the causes of epilepsy was in the form of advanced imaging of the brain. J.M. Cobb described the technique of pneumoencephalography in the dog in 1960. While performed decades earlier in humans, this radiographic technique allowed for the first time the visualization of structures of the brain in a minimally invasive way (compared to vivisection) (Cobb, 1960). The 1980s brought computed tomography (CT) into clinical use for imaging the canine and feline brain. In the 1990s, magnetic resonance imaging (MRI) of companion animal brains was introduced, which opened the door to the brain. MRI quickly became the gold standard of imaging the brain and today is used clinically in almost all veterinary schools and even more veterinary private practices by specialist veterinary neurologists.

Six thousand years later

At the beginning of the 21st century, we find that the diagnostic tests and treatment modalities for seizures in dogs and cats are in step with those employed for humans just as they were 6000 years ago. Certain limitations continue. While there is no lack of sophistication or desire to investigate the causes of seizures in dogs and cats, those limitations, discussed in further chapters, are slowly being overcome. Epilepsy is one of the oldest afflictions documented in human history, and it is interesting that references to dogs and cats having seizures are for the most part absent. Comparative medicine receives little mention in the historical perspectives of human epilepsy other than the use of animals in experiments to further the advancement of our understanding of epilepsy, as it affects humans. Perhaps this is due to the notion that our predecessors found little difference between species and therefore have no need to compare them. While dogs and cats certainly have never suffered from the psychosocial stigma of epilepsy (as far as we can tell), they have undoubtedly suffered in other ways, particularly through a lack of understanding of epileptic seizures as it applies to them. We are lucky to be surrounded by investigators who continue to make important advances in the study of veterinary and human epilepsy. The applied knowledge of these researchers in a clinical setting is the duty and obligation of the practicing veterinarian.

References

Albertoni, P. 1882. Untersuchungen Uber Die Wirkungeiniger Arzneimittel Auf Die Erregbarkeit Des Grosshirnsnebst Beitragen Zur Therapie Der Epilepsie. Naunyn-Schmiedeberg’s Archives of Pharmacology. 15:249–288.

Baillie-Grohman, W.A. and Baillie-Grohman, F. eds. 2005. The Master of Game: The Oldest English Book on Hunting. Philadelphia: University of Pennsylvania Press.

Berendt, M., Gredal, H., and Alving, J. 2004. Characteristics and Phenomenology of Epileptic Partial Seizures in Dogs: Similarities with Human Seizure Semiology. Epilepsy Research. 61(1–3):167–173.

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2

The biology of seizures

Introduction

When most people think of seizures, they tend to think of chaotic brain activity. In fact, epileptic seizures are often just the opposite. Normally, neurons fire singularly or in short bursts. If we look at a normal animal’s electroencephalogram (EEG) during slow-wave sleep, it is easy to recognize there is a distinct pattern to the electrical activity being recorded from the cortex; however, in the event of an epileptic seizure, synchronous activity predominates (Figure 2.1).

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Figure 2.1 Above is an EEG of a dog with a typical slow-wave sleep pattern, a normal EEG. Courtesy of D. Colette Williams, PhD, University of California, Davis.

A seizure occurs when neurons, which have a natural tendency to want to fire, form oscillating or reverberating hypersynchronous discharges. The summation of several neurons discharging at one time creates an environment where a local abnormality may influence nearby neurons to spontaneously fire, leading to the further discharge of more neurons at even more distant sites from the point of epileptogenesis. Certain areas of the brain, such as the thalamus, possess natural pacemaker activity. Thalamic neurons contain a specific variety of voltage-gated ion channels, which allow for the generation of rhythmic self-sustaining action potentials without any external influence. As these electrical signals propagate throughout the brain, they travel within normal anatomic conductive pathways (e.g., corona radiata, internal capsule, etc.), eventually reaching areas such as the motor cortex, resulting in the manifestation of, in several cases, a generalized motor seizure, or the limbic structures of the brain where focal motor or psychomotor epileptic seizures are more likely to manifest.

An epileptic seizure is a sudden, involuntary, synchronous discharge of brain neurons. Epileptic seizures are sometimes referred to as arrests, convulsions, spasms, attacks, fits, or an ictus. The outward manifestation of a seizure is dependent on which area of the brain it originates in or propagates to. Epilepsy is a term specifically referring to chronic, recurrent seizures or the propensity for an individual to have more than one seizure (Blume et al., 2001).

Because chronic seizures (epilepsy) affect as much as 5% of the canine population, most clinical veterinarians will be presented with numerous cases of dogs with a history of seizures every year (Kay, 1989; Podell et al., 1995). Epileptic seizures are much less common in cats; however, the same approach to a patient having epileptic seizures can be made for cats, as well as dogs. The incidence of epileptic seizures within the canine population is significantly greater than that of humans (about 1% of the population) (Lehnertz et al., 2007). Epilepsy is the most common neurological condition a veterinarian will be presented with. The first step the clinician should take in evaluating an animal whose owners are complaining of epileptic seizures is to figure out if the animal is indeed having epileptic seizures. Other conditions commonly mistaken for epileptic seizures may include:

Syncope/cardiac disease (collapse)

Vestibular disease

Myasthenia gravis

Cervical pain

Tremor syndromes

Behavioral abnormalities

Periodic weakness

Narcolepsy/cataplexy

Technically, the term seizure could mean any medical condition resulting in a sudden cessation of normal activity. In the context of our discussion, we will assume the term seizure is in reference to an epileptic seizure. It is very important before proceeding with an extensive diagnostic workup to determine if the animal is experiencing a true seizure or a seizure-like event. There is no etiological significance to a seizure. An epileptic seizure simply represents a sign or symptom of brain dysfunction. In a sense, a seizure is the brain’s way of limping. A limp only tells you there is a problem with the leg but not what the problem is. Similarly, a seizure only tells the clinician there is a problem with the brain but not what the problem might be. The brain is a fundamentally excitatory organ, and it is in the animal’s best interest, for survivability, to be able to take in as much information from its environment as possible but at the same time be able to focus on a refined amount of information. In a simplistic manner, it helps to think of the brain as a car waiting at a stoplight with the driver having their foot on the gas and the brake at the same time—ready to go at a moment’s notice but being held back until necessary.

Following a volley of information, the brain will discharge its various responses. Those responses, when considered in aggregate form, will produce a behavior. A basal level of excitation can be seen in several areas of the nervous system. For instance, the activation of antigravity muscles when an animal is falling will result in an excitation of extensor muscles on the side the animal is falling to, in order to prevent contact with the ground. The brain is in a constant balance between inhibition and excitation. Neurons want to fire, and it is up to a fine balance between the inhibitory and excitatory components of the central nervous system to keep neuronal activation and synchronization in check. If isolated from their surroundings, neurons will fire spontaneously (Roberts, 1984). When the neuron is placed in an environment such as the brain, its firing potential is controlled by other nearby neurons and components of the extracellular environment. The primary means of quieting the brain or holding activation in check is through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), synthesized from the amino acid glutamine.

Generally speaking, the epileptic properties of a specific area of the brain are determined by hyperexcitability and synchronization. Many theories have been postulated as to the generation of epileptic seizures; why some areas of the brain have epileptogenic properties. One of the earliest theories was a lack of inhibition, leading to a hyperexcitable environment. Another theory supports the notion that seizures are secondary to a regional area of unusual concentrations of strong or dense excitatory interconnections. With either theory, there is an excess of gas in the brain and not enough brakes.

Most of the mechanisms thought to contribute to the generation of epileptic seizures are centered around the idea of either alterations in the inhibitory/excitatory homeostasis of the brain, changes in transmembrane ion concentrations, alterations in neuronal homeostasis, alterations in the function of neurotransmitters, factors that cause a large group of neurons to fire spontaneously, and alterations in either glucose or oxygen metabolism (see Table 2.1). In the end, many factors are involved in the generation and propagation of seizures. There is no one single cause of epileptic seizures just like there is no one single cause for a limp. Therapies are directed at the prevention of seizures, not necessarily the cause (with the exception of surgery, see Chapter 10). With an increased understanding of the basic pathophysiology of seizures, more targeted therapies toward the cause of seizures, as opposed to the suppression of seizures, will be possible.

Table 2.1 Mechanisms leading to abnormal neuronal discharge.

The neuron

The neuron is the primary functional information processing unit of the brain. Collections of neurons and glial cells form aggregates, which allow for the generation of specific brain-derived behaviors such as simple reflexes to complex cognition. Each singular element is essential for overall brain function. The neuron is a highly specialized cell, which has the natural ability to create a communicating signal in the form of an action potential. A detailed description underlying neurophysiology is beyond the scope of this book; however, an elementary description of the neuron may help in understanding how various elements of the nervous system come together to either suppress or potentiate epileptic activity. Neurons come in several different forms, created for a specialized function relating to the area of the brain the neuron resides. Neurons create synaptic connections with other neurons. This is the second aspect of neural communication. There are approximately 86 billion neurons in the human brain (Herculano-Houzel, 2012). Added to another 85 billion, nonneuronal cells in the brain combine to form approximately 1 trillion synapses/mm³. The dog brain is estimated to have significantly less neurons than the human brain. The cat brain has more neurons than the dog brain. The brain is more than a computer and more than a machine; and it is a physical connection between matter and energy. The brain, a collection of biological tissues, is able to create action and thought. This amazing organ is responsible for generating the greatest works of art, scientific theories, and complex emotions. An infinite number of neural connections are possible, resulting in an incomprehensible amount of diversity. It is no wonder things occasionally go wrong. In fact, when considering all of the potential for mistakes, it is amazing the brain actually works so well.

Most neurons are comprised of a cell body, dendrites, and an axon. The dendrites are highly branched extensions of the cell body, which radiate outward, creating a large surface area for contact or synapses with other neurons. Think of a large tree with multiple branches and subbranches intermixed with similar trees. A significant variety of specialized dendritic forms exist in the nervous system (Figure 2.2). The axon leaves the cell body at the axon hillock. The axon hillock is the point of the neuronal cell body where the summated change in membrane potential results in the propagation of the action potential. The action potential is a self-generating electrical wave. The action potential spreads through the axon as an orthodromic (i.e., one way) impulse in an anterograde (i.e., away from) manner from the cell body. The axon is often covered by segments of myelin. The segmental nature of this covering allows for saltatory conduction. Saltatory conduction is a mechanism of action potential propagation where the electrical charge jumps from one unmyelinated (i.e., nodes of Ranvier) segment to another. Think of it in this way: would it be faster to walk from point A to point B or to skip (note: the answer is skip) (Figure 2.3)? Once the action potential reaches the terminus of the axon, the signal (information) encoded by the action potential opens ion channels, which then trigger the events leading to synaptic vesicles, containing neurotransmitter, to dock with the cell membrane and release their contents into the extracellular space. The neurotransmitter diffuses across the synaptic junction where it then comes into contact with receptors on the surface membrane of another neuron. The neuron releasing the neurotransmitter is referred to as the presynaptic cell, and the neuron receiving the neurotransmitter is referred to as the postsynaptic cell. The connection between the two neurons is the synapse (Figure 2.4). Transmitted signals may be inhibitory or excitatory. This is an example of a chemical synapse because neurotransmitters are released.

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Figure 2.2 The brain contains a wide variety of morphologically different neurons, each with its own form to follow function. Neurons may be inhibitory or excitatory. They may have a local environmental influence or send their axonal projections over great distances to affect remote areas of the brain or spinal cord.

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Figure 2.3 Anatomy of a typical neuron. The action potential is generated at the axon hillock due to the presence of a large number of sodium ion channels. Once the membrane depolarizes, the electrical charge propagates down the axon toward the synapse through a process known as saltatory conduction. The electrical signal, in the form of positively charged sodium ions, passes through the axon, held inside the axon by the myelin sheath, which prevents the ions from leaking out (inset). At the node of Ranvier, sodium ions leak out and are then exchanged for potassium ions and pumped back into the axon, and the process begins again, propagating toward the synaptic connection.

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Figure 2.4 Example of a typical chemical synapse. The axon terminates near the postsynaptic neuron creating a synaptic cleft. The neurotransmitter packaged in synaptic vesicles is released into the synaptic cleft and diffuses to junctional folds, where it binds to chemical receptors, causing these ligand-gated ion channels to open, allowing ions to pass through, resulting in either hyperpolarization of the postsynaptic membrane (inhibition) or depolarization (excitation).

Electricity 101

Electrical potential or voltage (V) is the force exerted on a charged particle (i.e., ion). It is the difference between the cathode (positive) and anode (negative). The greater the difference, the more force is applied to the ion, which makes it move toward its opposite charge. Opposite charges attract each other and like charges repel one another. The flow of these ions is referred to as current (I). If the ions are prevented from flowing toward their opposite charge, they are meeting resistance (R). If they move toward their opposite charge, they have conductance (g). The greater the conductance (or lower the resistance), the higher the current. This relationship is known as Ohm’s law and can be expressed as

In this simple equation, if conductance is zero (no movement of ions), no current will flow even if there is a high potential (voltage). In the model of a cell membrane, ion channels allow ions to move back and forth across the membrane (Figure 2.5). The ion channels reduce the resistance (or increase the conductance), which allows current to flow. By opening or closing ion channels, the potential of the cell membrane will change. The presence of other oppositely charged ions or proteins will also create electrical potential (i.e., a draw of the opposite charged ion across the membrane).

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Figure 2.5 A membrane separates two compartments. Ion channels permeable to chloride and sodium ions are present allowing the free flow of those ions across the membrane. The movement of ions is referred to as current measured in volts. Calcium ions are also present, but there is no way for them to move across the membrane. Therefore, there is high resistance to calcium ions (or no conductance). Similarly, the chloride and sodium ions have high conductance and low resistance. The calcium ions provide an electrical gradient for the oppositely charged chloride ions to move toward, while the negatively charged proteins on the opposite of the membrane will attract the sodium ions.

How a neuron fires

An understanding of what makes neurons fire can be very helpful in not only explaining why a seizure may occur but also why certain medications help prevent seizures and why excessive activity of the brain (in the form of seizures) can lead to brain damage. A single neuron is an amazing, highly evolved and complex structure, which by itself has the propensity to generate a signal (i.e., action potential). The neuronal membrane and its associated ion pumps and ion channels are the structures responsible for this characteristic. This structure allows certain ions to be pumped and concentrated on one side of the membrane and others to diffuse across the membrane along a concentration gradient. When a difference of charge exists on opposite sides of the membrane, a potential is present, measured as voltage. However, the ability to generate a signal must be coupled with interconnections involving other neurons in order to form circuits. These circuits, when considered as an aggregate, create a system (e.g., visual, auditory, olfactory, motor, etc.) responsible for a certain behavior, reflex, or sensation. Communication depends on an element to generate a message (i.e., signal), transmission of the message (i.e., wires or axons), and receipt of the message (i.e., postsynaptic neuron). Billions of neurons making an infinite number of connections and subsequent circuits create the most complex structure known to humans, the brain. These micro- and macrocircuits are responsible for the behavior of the brain. This may be a simple two- to three-neuron circuit, which allows for a reflex or memory, to a collection of macrocircuits, which allow for cognition.

A neuron is activated through a highly evolved and specialized electrical gradient. A well-balanced flux of ions across the neuronal cell membrane is responsible for the electrical gradient, which makes up the resting membrane potential (Figure 2.6). To create a membrane potential, we need ions (charged molecules like sodium, potassium, and calcium) on each side of a cell membrane. The movement of those ions is highly regulated. In addition, charged proteins help to maintain the potential. The resting membrane potential is the difference in voltage between the inside of the cell and the outside of the cell. The flow of ions across the membrane is variable through conductance and resistance. The easier it is for an ion to move through a membrane, the higher its conductance and the lower its resistance. When a neuron is quiet, the inside of the cell is electrically negative (hyperpolarized) and the outside is positive. This potential is maintained through an active process using adenosine triphosphate (ATP) to pump ions in and out of the cell and through a passive process whereby ions continuously leak down their concentration gradient. Think of this potential similar to a windup toy. You use energy to turn a crank, which coils up a spring. The spring stores that energy as a potential to do work. When you reach a certain point or threshold, the energy is released as the behavior of the toy (like a jack in the box). When the membrane potential of a neuron reaches threshold, there is an all-or-none firing of the neuron.

c2-fig-0006

Figure 2.6 The typical neuronal membrane is comprised of many elements that allow for a voltage potential. Chloride, calcium, and sodium ions are concentrated outside of the cell, while potassium is concentrated inside the cell. Potassium ion channels allow free movement of potassium across the membrane. Negatively, charged proteins confined to the interior of the cell draw potassium ions into the cell. The sodium/potassium ATPase pump pumps sodium and potassium against their concentration gradients.

Potassium and negatively charged proteins are concentrated inside the cell, whereas sodium, calcium, and chloride are concentrated outside of the cell. Potassium ions readily cross the membrane when the cell is at rest. The driving force to attract the positively charged potassium ions is the negatively charged proteins inside the cell. The proteins cannot cross the cell membrane; however, the potassium ions can (i.e., they have high conductance). This attraction of opposites creates an ionic concentration gradient. Sodium, chloride, and calcium are concentrated outside of the cell. Their conductance through the membrane is very low (and conversely resistance is high). The concentration gradients arise through the actions of ion pumps located in the cellular membrane and the continual leaking of ions through the cellular membrane. The two most important ion pumps are the sodium/potassium pump and the calcium pump. In the presence of intracellular sodium, the enzyme pump hydrolyzes ATP, and the energy released exchanges three intracellular sodium ions for two extracellular potassium ions. The purpose of this very important pump is to concentrate sodium outside of the cell and concentrate potassium inside the cell (Figure 2.7). These processes lead to a resting membrane potential of the inside of a typical neuron at –65 mV. For a neuron to fire, the membrane potential must reach a threshold (the point where the switch is automatically flipped). The action potential is an all-or-none phenomenon. It cannot be graded. The neuron either fires an impulse or is at rest. This potential is primarily due to the conductance of sodium and potassium ions.

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Figure 2.7 The sodium/potassium ATPase pump is an enzyme that hydrolyzes ATP in the presence of intercellular sodium (a). The conformation of the pump changes (b). releasing sodium to the extracellular environment in exchange for two extracellular potassium ions (c). When the potassium ions bind, another conformation change occurs, releasing potassium to the intracellular environment. The inorganic phosphate ion is released, which allows it to combine with ADP in order to form ATP, and the cycle occurs again (d). The action of this pump ensures that sodium is concentrated outside the cell and potassium inside the cell. The pump uses ATP energy to work against the concentration gradient of the ions.

Voltage-gated ion channels are transmembrane proteins that allow specific ions to pass through the cell membrane while excluding others. These proteins form pores in the cell membrane. The pores open or close based on the electrical potential of the cell membrane; thus, they are