Seizures

Epilepsy is a group of heterogeneous conditions that share a common feature— chronic, recurring seizures. The terms epilepsy and seizures are not synonymous. A seizure is the clinical manifestation of abnormal electrical activity in the brain. It is a specific event in time. Epilepsy refers to multiple seizures occurring over a long period of time. Although there is no universal agreement on the minimum number of seizures or period of time, a useful clinical definition is two or more seizures over a month or more. Not all seizures are associated with epilepsy. For example, a seizure can be the reaction of a normal brain to a transient insult, such as intoxication or metabolic disorder. This is called a provoked seizure or reactive seizure. If seizures stop when the underlying condition resolves, the patient does not have epilepsy, because the condition is not chronic. On the other hand, if a patient has several seizures over a period of a month or more, and there is no detectable short-term illness responsible for the seizures, then we would say the patient has the condition called epilepsy. Because there are many causes of chronic recurrent seizures, epilepsy is not a specific disease but rather a diverse category of disorders. Epilepsy is broadly divided into idiopathic and symptomatic disorders. Symptomatic epilepsy, also called secondary epilepsy, is when the seizures are caused by an identifiable structural lesion of the brain, such as a tumor. Idiopathic epilepsy, also called primary epilepsy, is chronic recurring seizures with no underlying structural brain lesion or other neurological signs.1,3 Here, the term ‘‘idiopathic’’ means a disorder ‘‘by itself’’ not ‘‘cause unknown.’’ The term idiopathic epilepsy is not applied simply to any patient in whom the cause of the seizures is unknown. Instead, it refers to recognized clinical syndromes with typical clinical features, such as age of onset and lack of other neurological abnormalities. The term ‘‘essential’’ is often used to convey the same meaning, as in essential hypertension. Several other terms are commonly used. The ictus is the seizure itself. Postictal signs are transient clinical abnormalities in brain function that are caused by the ictus and appear when the ictus has ended. Postictal signs typically last a few minutes to hours and can include confusion, blindness, ataxia, and deep sleep.

Im most cases the ictus lasts only a few minutes. Some patients with seizures experience a prodrome, which is long-lasting abnormality occurring hours to days before a before a seizure, such as restlessness or anxiety.An aura is a subjective sensation at the start of a seizure before there are observable signs. The difference between a prodrome and an aura is that prodromes are longer lasting and not associated with abnormal electrical activity in the brain. Human patients describe various sensations during their auras, including dizziness, tingling, and anxiety.9 Common manifestations of auras in animals are hiding, seeking the owner, agitation, or vomiting just before a seizure. In other cases an aura occurs alone, which constitutes a sensory seizure.

DESCRIPTIONS OF SEIZURES

Several classification systems have been developed for human epileptic seizures based on clinical signs, etiology, and electroencephalographic (EEG) information. Applying these schemes to veterinary patients is problematic because not all seizure types in human patients are recognized in animals and EEG data are usually not available for our patients. Therefore, the following descriptive list is offered not as a formal classification but to facilitate communication among clinicians.

Generalized-onset Seizures are those in which the first clinical signs indicate initial involvement of both cerebral hemispheres. Consciousness may be impaired and motor manifestations are bilateral. The most common type of generalized seizure is a generalized tonic-clonic seizure (formerly called grand mal seizures). The first part of the seizure is the tonic phase, during which there is sustained contraction of all muscles. The animal typically loses consciousness and falls to its side in opisthotonus with the limbs extended. Respirations are often irregular or absent and cyanosis is common. Autonomic signs such as salivation, urination, and defecation are common. The tonic phase lasts for a minute or so and then gives way to the clonic phase, during which there is rhythmic contraction of muscles, manifested as paddling or jerking of the limbs and chewing movements. Some animals suffer milder generalized tonic-clonic seizures in which consciousness is maintained.7,8 Another type of generalized seizure is a tonic seizure, in which motor activity consists only of generalized muscle rigidity without a clonic phase. Less common are clonic seizures, in which there is no tonic component; atonic seizures, which consist of a sudden, often brief loss of postural tone causing the patient to fall or drop it’s head; and myoclonic seizures, characterized by brief, shocklike contractions that may be generalized or confined to individual muscle groups.10 There are other causes of myoclonic jerks in animals; that is, not all myoclonic jerks are seizures.

Focal-onset seizures are those in which the initial clinical signs indicate abnormal activity in one region of a cerebral hemisphere. Focal motor seizures consist of abnormal movements of a body part, such as turning the head to one side, rhythmic contractions of a limb or facial muscles, or chewing movement.4,7 Focal sensory seizures cause abnormal sensations such as tingling, pain, or visual hallucinations. An aura that does not evolve into loss of consciousness is a focal sensory seizure. Because the sensations are subjective, it can be difficult to recognize sensory seizures in animals, but ‘‘fly-biting’’ seizures may be a form of sensory seizures with visual hallucinations. Focal autonomic seizures cause predominately autonomic signs, such as vomiting, diarrhea, and apparent abdominal pain. A syndrome characterized by drooling, retching, dysphagia, and painful enlargement of the mandibular salivary glands is likely a form of focal autonomic seizures. Complex focal seizures (formerly called psychomotor seizures) are focal seizures with alterations of awareness. Affected patients may not respond to their owner and often engage in automatisms, which are coordinated, repetitive motor activities such as head pressing, vocalizing, or aimless walking or running.4 Some complex focal seizures are manifested as impaired consciousness and bizarre behavior, such as unprovoked aggression or extreme, irrational fear.15,16 A secondarily generalized seizure usually begins with a focal seizure that evolves into a generalized tonic-clonic seizure. The secondary spread can occur so rapidly that the initial focal component is missed and the seizure is misclassified as a generalized-onset seizure. But with close observation, including videotape review of the seizures, it is apparent that secondarily generalized seizures are common in dogs and cats

Clinical Overview of Canine Idiopathic Epilepsy

The gross structure of the brain in animals with idiopathic epilepsy has no demonstrable pathologic lesion. The prevalence of epilepsy in dogs has been estimated at 1% to 5%.(Holliday et al., 1970, Podell et al., 1995) Although idiopathic epilepsy occurs in a number of species, the most comprehensive studies have been those of humans and dogs. (Holliday et al., 1970, Berendt et al., 2004, Licht et al., 2002, Berendt and Gram, 1999, Podell et al., 1995) In order to establish a diagnosis, affected animals must have a normal neurologic examination and remain normal during the interictal period; however recent work has questioned this dogma (See below). In addition, other systemic and brain abnormalities are not detected with diagnostic tests. Therefore from a clinical perspective, idiopathic epilepsy is a diagnosis of exclusion. The breed, age, and history also provide important clues to an underlying hereditary basis especially if a familial history of seizures exists. 

Most dogs with idiopathic epilepsy suffer their first seizure between 6 months to 6 years of age, although seizures occasionally start before 6 months or as late as 10 years of age.(Berendt and Gram, 1999, Podell et al., 1995, Heynold et al., 1997, Jaggy and Bernardini, 1998)  

The finding of idiopathic seizures without an underlying cause does not necessarily rule in or out a genetic cause. Only careful breeding studies or pedigree analysis can prove a pattern of inheritance. The most common seizure type in dogs with idiopathic epilepsy is a focal seizure with secondary generalization.(Berendt et al., 2004, Licht et al., 2002, Berendt and Gram, 1999, Berendt et al., 2002, Berendt et al., 2008, Licht et al., 2007) However, in some studies, generalized, tonic-clonic seizures were the most commonly observed seizure type.(Dichter, 2009, Heynold et al., 1997) This may suggest the focal aspect of the seizure can be easily missed by the owner. IE seizure phenotypes vary among breeds; IE in some breeds manifests more frequently as focal onset seizures, whereas in others seizures are mostly generalized. The frequency of epileptic dogs suffering cluster seizures (CS) and status epilepticus (SE) also varies. A recent study of 407 idiopathic epileptic dogs documented the frequency of CS to be 41% and the frequency of SE to be 2.5% (Monteiro et al., 2012). In this study, German shepherds and Boxers were over-represented. Within specific breeds the prevalence of CS and SE can be very much higher. A recent study of Australian shepherds showed that eighty percent of the population suffered from SE or CS, very similar to the severe course of IE in other collie breed such as Border collies.(Weissl et al., 2012)

In the past, generalized tonic-clonic seizures were considered the most common type of seizure in dogs with idiopathic epilepsy, and it was even claimed focal-onset seizures were inconstant with a diagnosis of idiopathic epilepsy. However, more recent observations reveal this is clearly not the case and dogs with idiopathic epilepsy can have a variety of focal-onset seizures, including secondarily generalized seizures, and some individuals have more than one type of seizure.(Patterson et al., 2005, Jaggy and Bernardini, 1998, Heynold et al., 1997, Pakozdy et al., 2008, Patterson et al., 2003) The frequency of seizures varies tremendously, ranging from several a day to less than one a year. (Heynold et al., 1997, Podell et al., 1995) Seizures are most common during rest or sleep.(Pakozdy et al., 2008) Even though most seizures appear to occur spontaneously, they may be precipitated by a variety of factors.  In human patients, sleep deprivation, emotional stress, menstruation, missed medication, and concurrent illness are recognized. (Haut et al., 2007) Similar factors are likely important in precipitating seizures in some animals. Reflex seizures are seizures that can be provoked by specific stimuli or events. (Thomas, 2000) The most common trigger in people is flickering light, usually from a television. Other triggers include immersion in hot water, reading, certain sounds, and eating. With reflex seizures, the trigger is specific and the latency between the trigger and seizure is short (seconds to minutes).(Thomas, 2000) Infrequently an owner will describe a consistent temporal association between a specific sound and the onset of a seizure. 

An inherited basis, familial transmission, or a higher incidence has been recognized in many breeds (Table 6.1). Any breed, including mix-breed dogs can be affected. Based on pedigree analysis, a genetic basis for idiopathic epilepsy is suspected in a number of breeds, including the beagle, Belgian tervuren, Keeshond, dachshund, German shepherd, Labrador retriever, golden retriever, Shetland sheepdog, Irish wolfhound, Vizsla, Bernese mountain dog, and English springer spaniel (see section on genetics below).(Patterson et al., 2005, Thomas, 2000, Famula et al., 1997, Hall and Wallace, 1996, Jaggy et al., 1998, Srenk and Jaggy, 1996, Morita et al., 2002, Bielfelt et al., 1971, Casal et al., 2006, Patterson et al., 2003, Kathmann et al., 1999) 

Inter-Ictal Signs

While the majority of canine IE patients are completely normal between seizures and do not display any other clinical signs, others may express mild abnormalities, such as episodic ataxia, between seizures.(Jokinen et al., 2007) Likewise, human IE patients may also display such symptoms between seizures.(Imbrici et al., 2004) In human medicine, an increasing number of studies have identified systemic and neurobehavioral or psychiatric illnesses associated with epilepsy (Austin and Caplan, 2007, Gaitatzis et al., 2004, LaFrance et al., 2008).(Nuyen et al., 2006, Tellez-Zenteno et al., 2005) In fact in people with a history of major depression or anxiety there is an increased risk of unprovoked seizures and epilepsy confirming a bidirectional relationship (Kanner, 2006, Heinrichs and Seyfried, 2006). Neurobehavioral comorbidities have also been reported and studied in a variety of rodent models of epilepsy.(Heinrichs and Seyfried, 2006) In a recent study, neurobehavioral changes were found to be related not only to epilepsy but also to pharmacological response, with pharmacoresistant rats having greater behavior changes.(Gastens et al., 2008) 

A recent veterinary study investigated dogs with idiopathic epilepsy for associated behavioral changes.(Shihab et al., 2011) The aim of the study was to look for behavioral changes associated with the development of epilepsy in dogs. Owners of dog diagnosed with idiopathic epilepsy (n=80) completed a behavioral and seizure questionnaire. Drug-naïve dogs showed an increase in the behavior factors (i) Fear/Anxiety; (ii) Defensive Aggression; and (3) Abnormal Perception. In dogs receiving antiepileptic medication (AEM), there were still increases in Fear/Anxiety and Abnormal Perception, but no longer in Defensive Aggression. Additionally increases in (a) Abnormal Reactivity; (b) Attachment Disorder; (c); Demented Behavior; and (d) Apathetic Behavior were observed. Pharmacoresistant dogs had larger increases in Controlling Aggression, Abnormal Perception, and Demented Behavior than those dogs, which were considered to be drug responders. (Shihab et al., 2011)

Lifespan and Canine Idiopathic Epilepsy

Dogs suffering from idiopathic epilepsy have an increased risk of premature death compared with the general dog population.(Proschowsky et al., 2003, Berendt et al., 2007, Hulsmeyer et al., 2010) This also applies for people with epilepsy for whom the risk of death is highest shortly after onset of seizures.(Neligan et al., 2011, Hauser et al., 1980) The median survival time after the initial  seizure is 2.07 years in Border Collies and 2.3 years in a population of different purebred and mixed-breed dogs.(Hulsmeyer et al., 2010, Proschowsky et al., 2003, Berendt et al., 2007) The life expectancy for Irish Wolfhounds is shortened by almost 2 years in epileptic dogs compared with seizure-free relatives. The same study reported that more than 60% of the total number of deaths in the population were related to epilepsy.(Casal et al., 2006) Factors such as gender, seizure onset, seizure frequency, and seizure control might influence the life span of dogs with epilepsy. In one study, bitches lived longer with epilepsy compared with males, and daily treatment with antiepileptic drugs did not influence the life span of dogs with epilepsy compared with dogs with epilepsy left untreated.(Proschowsky et al., 2003) In Border Collies, seizure onset before the age of 2 years has been shown to significantly decrease survival time.(Hulsmeyer et al., 2010) A recent longitudinal study of survival in Belgian Shepherds with IE revealed that the life span of epileptic dogs was not significantly shortened by the presence of epilepsy.(Gullov et al., 2012) However, epilepsy was the predominant cause of death in the population (19/75 = 25%) and epilepsy-related deaths accounted for 70% (19/27) of all deaths in the group of dogs with epilepsy.(Gullov et al., 2012) Two probable sudden unexpected deaths related to epilepsy occurred in dogs with generalized seizures. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy in humans, with an increased frequency of unexpected deaths up to 24 times compared with unexpected deaths in non-epileptics.(Ficker et al., 1998, Surges et al., 2009) The mechanisms of SUDEP remain elusive, and it seems unlikely that the identification of a single mechanism will explain all incidents, as SUDEP is more likely a result of several predisposing and triggering factors.(Surges et al., 2009, Donner, 2011) Poorly controlled chronic epilepsy with tonic-clonic seizures seems to be the most well-defined risk factor for SUDEP in humans.(Surges et al., 2009, Donner, 2011)

Prevalence of Canine Seizures based on Aetiological Classification

Idiopathic Epilepsy

Various studies have documented the prevalence of idiopathic epilepsy as compared to the other aetiological classifications. A study of dogs less than 1 year of age revealed that idiopathic epilepsy was seen in 75% of cases. (Arrol)  In the same study, symptomatic epilepsy comprised 17%, reactive 7% and cryptogenic less than 2% of the cases. (Table 1).

The prevalence of idiopathic epilepsy in certain breeds of dog has been documented to be much higher than the estimated 0.5 to 5% in the general population; for example, in the Belgian Shepherd Tervueren and Groenendael variants, the prevalence was estimated in one study to be 9.5%, and as high as 33% in one extended Belgian Shepherd family.(Berendt et al., 2008, Berendt et al., 2009) A prevalence of 18.3% was documented in Irish Wolfhounds with IE; recent studies of Petit Basset Griffon Vendeen dogs with IE revealed a prevalence of 8.9%, of Labrador retrievers in Switzerland revealed 6.9% and Danish Labrador retrievers were shown to have 3.1% prevalence.(Casal et al., 2006, Gullov et al., 2011, Berendt et al., 2002, Jaggy et al., 1998)

Cryptogenic Epilepsy

A recent study evaluated 214 client-owned dogs with an onset of epileptic seizures ≥7 years of age.(Schwartz et al., 2013) Forty-five (21%) dogs had a diagnosis of cryptogenic epilepsy, and 169 (79%) had symptomatic epilepsy. In dogs 7 to 9 years and ≥10 years of age at the time of seizure onset, 31 of 106 (29%) and 14 of 108 (13%), respectively, had a diagnosis of cryptogenic epilepsy. Breeds of dogs with cryptogenic epilepsy appeared consistent with the overall dog population seen at the study hospital, with the exception of Siberian Huskies. Even though numbers were small, this breed was apparently overrepresented, compared with the percentage of Siberian Huskies seen at that specific hospital during the study period (0.7%).(Schwartz et al., 2013) This may have been coincidental; alternatively, it may reflect a predisposition for dogs of this breed to develop epilepsy at an advanced age. At the last follow-up time of the study, most (40 [89%]) dogs with cryptogenic epilepsy were receiving ≥1 antiepileptic medication (AEM). Thirty-one of 37 (84%) dogs typically had ≥1 seizure/month following hospital discharge. Death was confirmed in 20 (44%) dogs with cryptogenic epilepsy and was related to seizures or AEMs in 7. Median survival time from onset of seizures was 52 months for all dogs with cryptogenic epilepsy. Median quality-of-life score (scale, 1 [poor] to 10 [excellent]) indicated by 34 owners of dogs with cryptogenic epilepsy was 10 before diagnosis and initiation of AEM treatment and 8 afterward.(Schwartz et al., 2013)

Symptomatic (structural) Epilepsy 

Causes of recurrent epileptic seizures were analyzed in 412 dogs referred to a veterinary hospital in Europe with epilepsy due to an intracranial disorder (i.e., not including reactive seizures) over an 11-year period. (Steinmetz et al., 2013) The causes included head trauma (n=64; 15.5%), brain tumours (n=33; 8%), brain inflammation (n=25; 6%), cortical dysgenesis (n=9; 2%), and several other probable causes (n=17; 4%), including scars (2), hydrocephalus (10), cysts (2), and vascular malformations (3).(Steinmetz et al., 2013) Furthermore, six dogs had a dual pathology (e.g., hydrocephalus and cysts) that most likely caused the symptomatic epilepsy. In the majority (n=258; 63%) of the 412 dogs, a cause could not be unequivocally identified, so these animals were assigned to the idiopathic/cryptogenic group, which was not further separated in this study. In an earlier study on 211 dogs with recurrent seizures referred to a veterinary hospital over a period of 5 years due to intracranial causes, only 3 (1.4%) had a history of head trauma but 18% had brain tumors and 11% had encephalitis.(Pakozdy et al., 2008)

(a) Inflammation. 

Seizures occur in about 13% of dogs with all causes of CNS inflammatory disease based on one large study.(Tipold, 1995) Canine distemper virus (CDV) encephalitis is the most common infectious inflammatory cause of seizures in dogs younger than 1 year of age.(Podell et al., 1995) Seizures often are focal, characterized by “chewing gum” actions, or consist of generalized motor activity.(Tipold, 1995) Similarly, seizures have been reported with post-vaccinal CDV encephalitis in puppies.(Cornwell et al., 1988) These seizures are often progressive and refractory to antiepileptic drug therapy. Identifying the underlying inflammatory disease process is important because the disease continues to progress without appropriate treatment. 

Dogs with non-infectious inflammatory disorders with cerebral cortical involvement frequently clinically manifest seizure activity. Granulomatous meningoencephalomyelitis (GME) is an inflammatory disease of the white matter of the brain. The disseminated form is usually acute and rapidly progressive, whereas the focal form progresses more slowly. Necrotizing meningoencephalitis (NME) is a non-suppurative inflammatory central nervous system (CNS) disease that is common in Pugs, with variants recognised in other breeds such as the Maltese, Chihuahua, Yorkshire Terrier, Pekingese and French Bulldog. In Pugs, NME lesions are most common in the cerebral cortex and subcortical white matter. A recent study including 60 Pug dogs with necropsy confirmed necrotizing meningoencephalitis documented seizure activity in 100%.(Levine et al., 2008)

(b) Intracranial Neoplasia

Epileptic seizures are a well-recognised manifestation of intracranial neoplasia in dogs.(Schwartz et al., 2011, Platt and Haag, 2002, Bagley et al., 1999, Snyder et al., 2006) Not all dogs with brain tumours will develop seizures, hence certain factors must exist that promote epileptogenesis; however, the pathogenesis of tumour-associated seizures is poorly understood.(Shamji et al., 2009, Schaller and Ruegg, 2003, Beaumont and Whittle, 2000) The vast majority of intracranial tumours originate from non-neuronal

cells that lack intrinsic epileptogenic properties with the capability to generate action potentials; therefore, in most instances, seizure development must depend on the tumour’s effects on the adjacent neuronal tissue. Various pathophysiological mechanisms for brain tumour-associated epileptogenesis have been proposed, mainly relating to the peri-tumoural area. Proposed epileptogenic factors include: local cerebral ischaemia; morphological changes causing isolation and denervation of cerebral cortical areas; neuronal, axonal and synaptic plasticity; perturbation in balance of neurotransmitters and their respective receptors; ionic changes and alterations in pH; triggering of a peri-tumoural immune response and modified intercellular communication

of surrounding glial cells.(Beaumont and Whittle, 2000, Schaller and Ruegg, 2003) Generation of seizure activity likely results from interplay of these factors and additionally depends on the patients’ susceptibility to seizure development. The causal relationship between intracranial neoplasia in dogs and seizure activity has frequently been reported but studies identifying risk factors for seizure development are lacking.(Snyder et al., 2006, Bagley et al., 1999, Bagley and Gavin, 1998) To identify clinical risk factors for seizures in dogs with intracranial neoplasia, a recent cross-sectional retrospective study was performed on 68 dogs with histopathologically confirmed primary or secondary intracranial neoplasia, complete clinical history and magnetic resonance imaging of the brain was conducted.(Schwartz et al., 2011) Prevalence of findings was compared between dogs with and without seizures. Forty-two dogs had tumour-related seizures and the remaining 26 were seizure-free. Tumour types included meningioma (23 dogs with and 5 without seizures), glioma (9 dogs with and 6 without seizures), choroid plexus tumour (2 dogs without seizures), neuroblastoma (1 dog with seizures) and metastatic/invasive tumours including lymphoma (9 dogs with and 13 without seizures). On the basis of multi-variable logistic regression analysis, risk factors for seizures associated with intracranial neoplasia were magnetic resonance imaging findings consistent with the presence of neoplastic tissue in frontal lobe, marked gadolinium enhancement and magnetic resonance imaging findings of subfalcine and/or subtentorial herniation. The proportion of dogs with seizure activity was highest among individuals with meningiomas followed by gliomas, and metastatic/ invasive tumours, however, there was no significant relationship between tumour type and seizure development. A true difference may have remained undetected due to the limited number of dogs that fulfilled the inclusion criteria.(Schwartz et al., 2011)

In human beings, the occurrence of tumour-associated seizures is highly dependent on tumour type. Seizure frequency is highest in dysembryoblastic neuroepithelial tumours (DNETs) and also oligodendrogliomas and astrocytomas are reported to cause seizures in more than half of the patients. Among these, especially slow-growing, low-grade gliomas are associated with seizure development.(Shamji et al., 2009, Beaumont and Whittle, 2000, van Breemen et al., 2007) A single study on canine brain tumours could detect such an increased likelihood of seizures in a certain tumour type. Dogs with oligodendrogliomas were identified to more likely present with seizures when compared to dogs with other primary brain tumours. (Snyder et al., 2006) The proportion of dogs with seizures was highest when the temporal, frontal or parietal lobes or the olfactory bulb contained neoplastic tissue, similarly reported previously.(Bagley et al., 1999) This is in accordance with the human literature that found highest occurrence rates when these regions were affected whereas involvement of the occipital lobe was less commonly associated with epileptogenesis.(Mahaley and Dudka, 1981, Lieu and Howng, 2000, Lynam et al., 2007, Liigant et al., 2001) Dogs with primary or secondary intracranial neoplasia are at risk of seizures, particularly those with tumours that affect the frontal lobe, enhance markedly with gadolinium, or cause subfalcine and/or subtentorial herniation. Two thirds of the dogs included in this case series developed epileptic seizures as a clinical sign of intracranial neoplasia and in three quarters of these dogs a seizure was the first clinical sign noted by the owners. These figures emphasise the high prevalence of tumour-associated epilepsy and the importance of intracranial neoplasia as a potential underlying cause for seizures. Other studies have found a lower prevalence of seizures in dogs with intracranial neoplasia. Snyder and others (2006) found 51% to show seizure activity, whereas 45% of dogs presented by Bagley and others (1999) displayed tumour-associated seizures.(Bagley et al., 1999, Snyder et al., 2006)  

A human study found all tumour-associated seizures to start focally of which half subsequently experienced generalization.(Liigant et al., 2001) A similar situation could be expected in canine patients, nevertheless, focal seizures may remain undetected in many instances. In the presented study, seizure severity in more than half of the dogs with tumour-associated seizures had progressed to cluster seizures at the time of MR imaging. 

(c) Head Trauma

Traumatic brain injury (TBI) is a major cause of epilepsy in people.(Lowenstein, 2009) Epidemiologic human studies have found that posttraumatic epilepsy (PTE) accounts for approximately 20% of symptomatic epilepsy in the general population, and 5% of all patients seen at specialized epilepsy centers.(Agrawal et al., 2006) The main, critical determinant of the development of PTE is the severity of the head injury.(Lowenstein, 2009) Key risk factors include skull fracture, intracranial haematoma, and a depressed level of consciousness at the time of admission to the emergency department. In addition, the occurrence of seizures within the first week after TBI also appears to be a risk factor for subsequent development of epilepsy.(Lowenstein, 2009)

The mechanisms underlying development of PTE are not completely understood (D'Ambrosio and Perucca, 2004, Pitkanen et al., 2009) Furthermore, there is a lack of reliable biomarkers that allow predicting which patients develop epilepsy after TBI (Lowenstein, 2009). There is often a delay of months to years in the emergence of epilepsy after the initial injury.

Of the 236 dogs with head injury in a large retrospective epidemiological study of dogs with epilepsy, 44 (18.6%) exhibited early and/or late seizures.(Steinmetz et al., 2013) Observed seizure types were partial and generalized tonic–clonic; convulsive status epilepticus or cluster seizures were observed in four dogs. Age at head injury in these 44 dogs was 3.69 years (range 0.16– 15 years). Twenty-five dogs were female, 13 male, four male-neutered, and two spayed; the proportion of female dogs was significantly higher than the proportion of male animals. The predominant cause of head injury in these 44 dogs was a car accident (n = 20), followed by punches (9), falls (8), horse kicks (4), and bites (3), respectively.  Of the 198 dogs that did not die immediately after or within 1 week following head injury, 13 dogs (6.6%) developed late recurrent seizures, indicating development of epilepsy. The average latency between head injury and onset of epilepsy was 1 year.  Most dogs (86%) with head injury had closed injury, but 14% had open injury with broken skull and, in nine dogs, penetrating injury. Open injury was associated significantly more often with seizures (early or late) than closed injury. Furthermore, 14.3% of the dogs with open injury developed epilepsy compared to 5.3% of the dogs with closed injury, which, however, was not statistical. The average latency between head injury and onset of epilepsy was similar in dogs with closed and open head injuries. In dogs with penetrating injury, 44% showed early seizures after the injury, but none of the dogs developed epilepsy, which may be secondary to the fact that only seven dogs survived the first week after head injury. 

A separate study evaluated 259 dogs admitted with head trauma over a ten year period at The Ohio State University Veterinary Medical Center.(Friedenberg et al., 2012) Overall, 3.5% of dogs with head trauma developed in-hospital seizures, and 6.8% of  dogs with head trauma for which follow-up information was available developed seizures  after hospital discharge, compared with an epilepsy rate of 1.4% in the authors’ hospital. Dogs that developed in-hospital seizures were significantly more likely to have been hit by a car or experienced acceleration-deceleration injury. Additionally, 10% of dogs with traumatic brain injury had in-hospital seizures. No visit or patient characteristics were significantly associated with the development of out-of-hospital seizures.(Friedenberg et al., 2012)

(d) Vascular Disease

Stroke is increasingly identified as the underlying cause of acute neurological disease in dogs by magnetic resonance imaging (MRI) or computed tomography (CT).(Garosi et al., 2006, Goncalves et al., 2011, Garosi, 2010, Platt et al., 2006, Garosi and McConnell, 2005, Garosi et al., 2005, Platt and Garosi, 2003) A stroke can be caused by either a haemorrhage in the brain, i.e. haemorrhagic stroke, or by thromboembolic occlusion of a cerebral artery causing ischaemic stroke.(Wessmann et al., 2009) In dogs, the majority of strokes appear to be ischaemic. (Wessmann et al., 2009) The typical clinical picture in dogs with ischaemic stroke is characterised by acute neurological deficits, varying according to the site and the extension of the lesion.(Garosi et al., 2006, Garosi, 2010, Goncalves et al., 2011) Neurological signs include altered mentation, hemi- or tetra-paresis, circling, cranial nerve deficits, and vestibular signs. Deterioration can be seen within the first 24 h of the insult due to progressive oedema, but should generally not be expected beyond this time frame. (Wessmann et al., 2009) Seizures have been described in dogs with strokes but in general their frequency of occurrence seems low.

Twenty seven dogs confirmed clinically to have experienced ischaemic stoke were evaluated for clinical topographic similarities with the human disease.(Gredal et al., 2013) Seizures were reported as part of the acute symptomatology in 15 dogs (56%). Five of these were only reported with seizures in the acute phase, whereas seven developed chronic epilepsy after the stroke event. Four of 5 dogs (Paul et al., 2010), 1 of 16 dogs (Goncalves et al., 2011), 1 of 22 (Garosi et al., 2006), and 0 of 6 dogs (Rossmeisl et al., 2007) with ischemic stroke affecting the prosencephalon exhibited seizures at presentation; several dogs had seizure activity on follow up examination however. In humans, seizures have been reported to be the initial manifestation of stroke in 4-43% of patients depending on whether the cause is ischemic or hemorrhagic.(Giroud et al., 1994) Most humans that develop seizures following acute ischemic events do so within 1 month of diagnosis.

Reactive Seizures

Apart from epilepsy, seizures may represent a natural response of the normal brain to metabolic disturbances or intoxication. (Brauer et al., 2011, Engel and Starkman, 1994, Podell et al., 1995) A study of 608 dogs with recurrent epileptic seizures, documented 196 dogs (32%), which exhibited such “reactive” seizures, compared to 154 dogs (25%) with symptomatic epilepsy and 258 dogs (42%) with idiopathic/cryptogenic epilepsy.(Steinmetz et al., 2013) An earlier study identified 29 dogs with reactive seizures out of a group of 240 (12%) with recurrent seizures.(Pakozdy et al., 2008)

A recent study evaluated a total of 877 dogs, which had seizure disorders and were presented to a university hospital in Europe over a 4-year period. (Brauer et al., 2011). A metabolic or toxic disorder (Fig.xx) was found in 96/877 (11%) of dogs with seizures. The majority of the 96 dogs had generalised seizures with loss of consciousness (49%, 47/96). Thirty-nine dogs (41%, 39/96) were presented in status epilepticus. Thirty-one dogs (32%, 31/96) were found to be hypoglycaemic. Electrolyte disorders were responsible for seizures in 10 dogs (10%, 10/96). Hepatic encephalopathy with concurrent seizures occurred in nine dogs (9%, 9/96). Hypothyroidism was the suspected cause in three dogs (3%, 3/96). Uraemic encephalopathy (2%, 2/96), presumptive hypoxia (2%, 2/96) and hyperglycaemia (2%, 2/96) were less frequent causes of seizures. Intoxication was the most frequent diagnosis (39%, 37/96). Metaldehyde (19%, 7/37) and organophosphate or carbamate poisoning (16%, 6/37) were the most frequent intoxications.(Brauer et al., 2011)

Breed

Based on pedigree analysis, a genetic basis for idiopathic epilepsy is suspected in a number of breeds, including the beagle, Belgian tervuren, Keeshond, dachshund, German shepherd, Labrador retriever, golden retriever, Shetland sheepdog, Irish wolfhound, Vizsla, Bernese mountain dog, horaks laborhounds, cocker spaniels, wire haired fox terriers, boxers, dachshunds, toy poodles, Irish setters, miniature schnauzers, Siberian huskys, St Bernards, Bernese mountain dogs and English springer spaniels. (Patterson et al., 2005, Thomas, 2000, Famula et al., 1997, Hall and Wallace, 1996, Jaggy et al., 1998, Srenk and Jaggy, 1996, Morita et al., 2002, Bielfelt et al., 1971, Casal et al., 2006, Patterson et al., 2003, Kathmann et al., 1999) 

A UK based study was recently reported which evaluated the epidemiology of idiopathic epilepsy.(Short et al., 2011) The diagnosis of idiopathic epilepsy was based on three or more generalised/focal or myoclonic seizures more than 24 hours apart. Dogs were excluded from the study if they suffered from acquired epilepsy or reactive epilepsy, if they had had fewer than three seizures in total, and if less than 12 months had passed since the start of seizures and a brain MRI had not been performed; 1260 dogs satisfied the inclusion criteria which comprised 79 pedigree breeds and a group of crossbreeds. Four breeds and cross breed dogs combined to represent more than 50% of the total cases; the Labrador retriever (11%), Border collie (10.5%), Staffordshire bull terrier (5.2%) and the cross breeds (20.5%). The study did recognize that the Labrador and German shepherd dog are popular breeds in the UK, with an excess of 40,000 and 20,000 dogs being registered with the UK Kennel Club, respectively, on a yearly basis; hence, a larger proportion of these breeds would be expected to have epilepsy due to their overall popularity.(Short et al., 2011) The border collie and Staffordshire bull terrier, however, have lower annual registration figures, with 3000 and 10,000 dogs, respectively, registered annually. The proportion of epileptic dogs in this series was similar for the labrador (11 per cent) and the border collie (10.5 per cent), and for the German shepherd dog (6.5 per cent) and the Staffordshire bull terrier (5.2 per cent), despite the difference in annual registration figures, suggesting that the border collie and Staffordshire bull terrier are at a greater risk of developing epilepsy.(Short et al., 2011)

Another recent UK based epidemiological study evaluated dogs with epilepsy of unknown origin (EUO) which was diagnosed based on a history of more than two seizures in the absence of other medical problems and a history of seizures for more than one year, or four or more separate repeat antiepileptic drug prescriptions (in the absence of evidence of their use for any purpose other than seizure control).(Kearsley-Fleet et al., 2013) The study included 87,317 dogs presenting to veterinarians in the UK over a 14 month time period. Twenty percent were crossbreds. The most common pure dog breeds were the labrador retriever (9.8 per cent), Staffordshire bull terrier (7.8 per cent), Parsons (Jack) Russell terrier (7.1 per cent) and cocker spaniel (4.0 per cent). The most common breed groups were the terrier group (22.2 per cent), gundogs (21.4 per cent), toy group (10.7 per cent) and pastoral (8.5 per cent). Of purebreds, 20.2 per cent and 27.4 per cent were small and large-sized, respectively, and 44.2 per cent and 7.4 per cent were short and long-haired. Many (42.6 per cent) of the dogs were solid coat-colour; 11.6 per cent were black and 11.4 per cent were red-golden, while 37.4 per cent of dogs were two-tone in colour and 19.9 per cent were multicoloured.(Kearsley-Fleet et al., 2013)

Individual breeds also appeared at increased odds of EUO, though purebred dogs (as a group) versus crossbred dogs were not statistically significant in the univariable analysis. Heavier dogs were statistically significantly associated with presence of EUO, as were short coat length and certain coat colours in purebred dogs. In the multivariable analysis, sex, breed and age at consultation were statistically significantly associated with presence of EUO. Among specific breeds, the border terrier had 2.70 and the German shepherd dog 1.90 times the odds of EUO compared with crossbred dogs. The West Highland white terrier had reduced odds of 0.23 of EUO compared with crossbred dogs(Kearsley-Fleet et al., 2013). 

Gender 

The Kearsley and others study (2013) found that in EUO, 48% of all dogs were female, and 53.0% were neutered.(Kearsley-Fleet et al., 2013) Univariate risk factor analysis identified that males, and neutered dogs appeared at increased odds of EUO. Male dogs had 1.72 times the odds of EUO compared with females. However, there was no evidence of an association between neuter status and EUO.

Short and others (2011) investigated the gender and neuter status of a cohort of idiopathic epileptic dogs (n=1188) and compared this data to randomly chosen non-epileptic dogs requiring veterinary attention (n=2040).(Short et al., 2011) The epileptic group contained 63 per cent male dogs, compared with 51 per cent of the non-epileptic population (P=0.001), and 57 per cent of the epileptic dogs were neutered, compared with 45 per cent of the non-epileptic population (P=0.001). When considering sex and neuter status, 49 per cent of the male epileptic cases were neutered compared with 30 per cent of the non- epileptic dogs (P=0.001) and 69 per cent of the female epileptic cases were neutered compared with 61 per cent of the non- epileptic dogs (P=0.01). The over-representation of males in the epileptic cohort is in agreement with other studies conducted on the Bernese mountain dog, and the Irish wolfhound, although the latter study only showed a male bias before the age of 30 months.(Casal et al., 2006, Kathmann et al., 1999) The age of neutering and the age of onset of epilepsy were not available for the dogs in the Short and others study. A study of 49 idiopathic epileptic Border collies revealed that affected dogs were equally distributed between males (24 males; 12 neutered) and females (25 females; 18 neutered).(Hulsmeyer et al., 2010) Of 15 dogs neutered after seizure onset, only 1 owner (7%; 1/15) reported mild improvement in seizure frequency, whereas 13 dogs (86%; 13/15) exhibited no positive trends, and in 1 dog (7%; 1/15) the seizure frequency increased. Four dogs (neutered before seizure onset) experienced their 1st seizure at the time of neutering (2 dogs experienced seizures on the same day and 2 dogs did so within 1 week after neutering).(Hulsmeyer et al., 2010) A study of Danish Labrador retrievers also found there to be no evidence for a gender predisposition, nor could any effect of neutering be identified.(Berendt et al., 2002)

Age

Short and others (2011) investigated the age of a cohort of idiopathic epileptic dogs (n=1188) and compared this data to randomly chosen non-epileptic dogs requiring veterinary attention (n=2040) and the distributions were similar; however, the age of onset of the seizure activity was not available.(Short et al., 2011) The Kearsley and others study (2013) found that in EUO, dogs aged between 3.01 years and 6.00 years had 0.58 times the odds of EUO compared with dogs aged 10.01 years or older.(Kearsley-Fleet et al., 2013)

In a study of epilepsy in dogs less than a year of age, the mean age at first seizure for the idiopathic group was 6.8 months (median seven) for the symptomatic group, 7.5 months (median 7.5), the reactive group, four months (median 3.25) and the probable symptomatic group (cryptogenic), 3.3 months (median 3.5).(Arrol et al., 2012) Overall, there was no association between seizure aetiology and age at which the first seizure occurred.(Arrol et al., 2012) 

Multiple studies have evaluated age of onset of idiopathic epilepsy in specific breeds. Jaggy and others (1998) investigated idiopathic epilepsy in Labrador retrievers finding that the mean age at first seizure of all epileptic dogs was 30.6 months with 31.9 months for males and 28.8 months for females.(Jaggy et al., 1998) In contrast, mean age at first seizure of affected dogs from two healthy parental animals and from an epileptic and healthy parental animal was 35.1 and 22.1 months, respectively. Forty-one per cent of animals manifested the first seizure between one and three years of age, 25 percent within the first year and 34 per cent at over three years.(Jaggy et al., 1998) Labrador retrievers were also investigated as part of a separate epidemiological study; the age at the first observed seizure ranged between five and 91 months.(Heynold et al., 1997) Approximately two-thirds of the dogs were between one and three years old, with an average of 34 months for males and 28 months for females.(Heynold et al., 1997) At first presentation, the dogs were between 10 and 125 months of age (mean, 46). In a study of 49 Border collies with idiopathic epilepsy, Age at seizure onset was between 1 and 5 years in 36 dogs (74%), <1 year in 9 dogs (18%), and >5 years of age in 4 dogs (8%).(Hulsmeyer et al., 2010) Median age at seizure onset was 2.37 years regardless of gender and reproductive status. A large study involving 146 Irish wolfhounds with idiopathic epilepsy found that the incidence of females with onset of seizures between 3 and 4 years of age was low, with 82% of first observed seizures occurring before 3 years of age.(Casal et al., 2006) The age of onset for males ranged from 6–107 months. Only 67% of males experienced their first seizure before the age of 3 years, whereas the onset of seizures occurred by 4 years of age in 83% of all male dogs.(Casal et al., 2006) Overall, significantly more dogs had their first seizure before 3 years of life than after 3 years. Significantly more males than females had their first seizure in the 37- to 42- month and the 43- to 48-month periods.(Casal et al., 2006)

Neurological Examination & Canine Seizure Disorders

A normal neurological examination in the interictal period is one of the criteria used to identify idiopathic epilepsy. However, while the majority of canine IE patients are completely normal between seizures and do not display any other clinical signs, others may express mild abnormalities, such as episodic ataxia, between seizures.(Jokinen et al., 2007) Likewise, human IE patients may also display such symptoms between seizures.(Imbrici et al., 2004) In human medicine, an increasing number of studies have identified systemic and neurobehavioral or psychiatric illnesses associated with epilepsy (Austin and Caplan, 2007, Gaitatzis et al., 2004, LaFrance et al., 2008).(Nuyen et al., 2006, Tellez-Zenteno et al., 2005) In fact in people with a history of major depression or anxiety there is an increased risk of unprovoked seizures and epilepsy confirming a bidirectional relationship (Kanner, 2006, Heinrichs and Seyfried, 2006). Neurobehavioral comorbidities have also been reported and studied in a variety of rodent models of epilepsy.(Heinrichs and Seyfried, 2006) In a recent study, neurobehavioral changes were found to be related not only to epilepsy but also to pharmacological response, with pharmacoresistant rats having greater behavior changes.(Gastens et al., 2008) 

A recent veterinary study investigated dogs with idiopathic epilepsy for associated behavioral changes.(Shihab et al., 2011) The aim of the study was to look for behavioral changes associated with the development of epilepsy in dogs. Owners of dog diagnosed with idiopathic epilepsy (n=80) completed a behavioral and seizure questionnaire. Drug-naïve dogs showed an increase in the behavior factors (i) Fear/Anxiety; (ii) Defensive Aggression; and (3) Abnormal Perception. In dogs receiving antiepileptic medication (AEM), there were still increases in Fear/Anxiety and Abnormal Perception, but no longer in Defensive Aggression. Additionally increases in (a) Abnormal Reactivity; (b) Attachment Disorder; (c); Demented Behavior; and (d) Apathetic Behavior were observed. Pharmacoresistant dogs had larger increases in Controlling Aggression, Abnormal Perception, and Demented Behavior than those dogs, which were considered to be drug responders. (Shihab et al., 2011)

A study conducted by Smith and others (2008) investigated how many dogs with seizures and a normal neurological examination had abnormal MRI findings.(Smith et al., 2008) This study found that in dogs under six years of age, an underlying cause was identified on MRI in only 2.2 per cent of dogs, whereas this number increased to 26.7 per cent of dogs over the age of six years. The study looking at dogs whose first seizure occurred below the age of one year demonstrated that 5.3 per cent perceived to be clinically normal by neurological examination and blood results had an underlying cause identified with MRI and CSF analyses.(Arrol et al., 2012) This result should help guide general practitioners when considering whether referral is indicated, especially in cases where financial constraints may be an issue.

In a study on dogs with epilepsy, which were less than 1 year of age, 74 per cent (17of 23) of the symptomatic dogs were found to have an abnormal neurological examination.(Arrol et al., 2012) The odds ratio for dogs with a symptomatic aetiology having an abnormal neurological examination compared with the other groups combined was 76.5 (P=0.001). Six dogs with a normal neurological examination had an underlying cause identified with MRI and CSF analyses.

Prognosis of Canine Seizure Disorders

Previous studies have shown that the life span of dogs with epilepsy have an increased risk of premature death compared with the general dog population.(Proschowsky et al., 2003, Berendt et al., 2007, Hulsmeyer et al., 2010) This also applies for people with epilepsy for whom the risk of death is highest shortly after onset of seizures.(Neligan et al., 2011, Hauser et al., 1980) The median survival time after index seizure is 2.07 years in Border Collies and 2.3 years in a population of different purebred and mixed-breed dogs.(Hulsmeyer et al., 2010, Proschowsky et al., 2003, Berendt et al., 2007) The life expectancy for Irish Wolfhounds is shortened by almost 2 years in epileptic dogs compared with seizure-free relatives. The same study reported that more than 60% of the total number of deaths in the population were related to epilepsy.(Casal et al., 2006) 

The survival analysis in a study of epilepsy in juvenile dogs (< 1year old) gave a mean survival time of 7.1 years, which is substantially longer than that previously mentioned.(Arrol et al., 2012) From this data the authors speculated that dogs with a younger age of seizure onset are easier to control with AEDs or have a less severe epilepsy course and thus are less likely to be euthanased. The IE group in this study had a similar outcome with a mean survival time of 6.1 years.

Factors such as gender, seizure onset, seizure frequency, and seizure control might influence the life span of dogs with epilepsy. In the study of dogs with epilepsy which were less than 1 year of age, univariate analysis revealed that there was no significant association between age at first seizure and survival (P=0.25), nor was there an association among sex (P=0.50), neutered status (P=0.40), breed (P=0.27), whether the animal had experienced status epilepticus (P=0.50), or presented primarily with focal (P=0.17) or generalised seizures (P=0.117).(Arrol et al., 2012) There was, however, a significant association between aetiology and survival (P=0.01). The mean survival of dogs with idiopathic disease was 2255 days, compared to those with symptomatic disease which was 1855 days, reactive seizures which was 2744 days (Fig xx 1). There was also an association between cluster seizures and survival; the mean survival of those with cluster seizures was 2372 days, while those without cluster seizures had a median of 3061 days (P=0.022). Finally, the number of AEMs the animal was receiving before investigation was also found to be associated with survival (P=0.002). Dogs that had received no AEMs before investigation had a mean survival of 3287 days whereas those medicated with one AEM had a mean survival of 1575 days and those with two or more AEMs had a mean survival of 2169 days (Fig xx 2).  

In another study, bitches lived longer with epilepsy compared with males, and daily treatment with antiepileptic drugs did not influence the life span of dogs with epilepsy compared with dogs with epilepsy left untreated.(Proschowsky et al., 2003) In Border Collies, seizure onset before the age of 2 years has been shown to significantly decrease survival time.(Hulsmeyer et al., 2010) A recent longitudinal study of survival in Belgian Shepherds with IE revealed that the life span of epileptic dogs was not significantly shortened by the presence of epilepsy.(Gullov et al., 2012) However, epilepsy was the predominant cause of death in the population (19/75 = 25%) and epilepsy-related deaths accounted for 70% (19/27) of all deaths in the group of dogs with epilepsy.(Gullov et al., 2012) Two probable sudden unexpected deaths related to epilepsy occurred in dogs with generalized seizures. 

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy in humans, with an increased frequency of unexpected deaths up to 24 times compared with unexpected deaths in non-epileptics.(Ficker et al., 1998, Surges et al., 2009) The mechanisms of SUDEP remain elusive, and it seems unlikely that the identification of a single mechanism will explain all incidents, as SUDEP is more likely a result of several predisposing and triggering factors.(Surges et al., 2009, Donner, 2011) Poorly controlled chronic epilepsy with tonic-clonic seizures seems to be the most well-defined risk factor for SUDEP in humans.(Surges et al., 2009, Donner, 2011)

Diagnostic testing

CSF analysis can play an important role in the diagnostic investigation of the underlying causes of repeated seizures. However, in dogs with a normal inter-ictal neurological examination and MRI scan, it rarely reveals significant abnormalities, and the risk of performing a CSF tap may outweigh the potential diagnostic gain.