Epileptic seizures are a common cause for veterinary medical consultation. In human medicine, an epileptic seizure has been defined as a transient occurrence of signs, symptoms, or both due to abnormal excessive or synchronous neuronal activity in the brain.1 Such ictal events may originate from disease processes localized to the brain or may reflect the response of a healthy brain to a metabolic or toxic insult. To fulfill the criteria for the diagnosis of epilepsy, an individual must have had at least 1 epileptic seizure, provoked or unprovoked, and the seizure has to be associated with an enduring alteration of the brain that increases the likelihood for future seizures.1 The currently used classification of human epilepsies, which was implemented by the Commission on Classification and Terminology of the International League Against Epilepsy in 1989, distinguishes 3 etiologies of epilepsy: idiopathic, symptomatic, and cryptogenic. Idiopathic epilepsy is diagnosed if no underlying cause other than a possible hereditary predisposition can be identified. Symptomatic epilepsy is the consequence of an identifiable disorder in the CNS. In cryptogenic epilepsy (also called probable symptomatic epilepsy), a hereditary cause is unlikely and an underlying pathological change in the CNS is suspected but cannot be identified.2,3
Multiple studies have provided ample evidence for the existence of hereditary idiopathic epilepsy in various breeds of dogs, including Beagles,4 German Shepherd Dogs,5 Keeshonds,6 Labrador Retrievers,7 Bernese Mountain Dogs,8 Vizslas,9 English Springer Spaniels,10 Irish Wolfhounds,11 Lagotto Romagnolo Dogs,12 Standard Poodles,13 Belgian Groenendaels and Belgian Tervuerens,14 and Border Collies.15 Most dogs with hereditary epilepsy have their first epileptic seizure as young adults, with individual animals infrequently having an onset of seizures at ≥ 7 years of age.10,11,13–16 In dogs that have an onset of epileptic seizures at an advanced age and in which no metabolic or toxic cause can be identified, there is great concern for underlying pathological changes in the CNS; also, an unremarkable neurologic examination between epileptic seizures does not rule out ongoing encephalopathy.17,18 It is generally recommended to pursue a full neurologic workup, including MRI, in these patients.18
The objective of the study reported here was to determine the prevalence and clinical features of cryptogenic epilepsy among dogs with an onset of seizures at ≥ 7 years of age. We sought to characterize this population of dogs with respect to signalment, seizure history, diagnostic findings, response to treatment (ie, number of medications prescribed and frequency of seizures), and survival times and to gain insight into the owners' perception of their dogs' quality of life following diagnosis of cryptogenic epilepsy.
Materials and Methods
Case selection—The diagnostic imaging database of the Veterinary Teaching Hospital, College of Veterinary Medicine, North Carolina State University, was searched for dogs that underwent MRI of the brain at ≥ 7 years of age between December 1, 2003, and June 30, 2011. Medical records of dogs that had MRI of the brain performed at ≥ 7 years of age were screened to identify dogs that developed epileptic seizures at ≥ 7 years of age.
Medical records review—The following information was retrieved from the medical records of each dog with onset of epileptic seizures at ≥ 7 years of age: breed; sex and neuter status; age at time of seizure onset; age at the time of MRI; seizure history prior to MRI, with the most severe seizure pattern (single isolated seizure, cluster seizure, or status epilepticus) and seizure type (focal or generalized) noted; and presence or absence of deficits referable to the brain on neurologic examination at the time of initial evaluation.
Dogs were classified as having either symptomatic or cryptogenic epilepsy. A diagnosis of symptomatic epilepsy was established in dogs in which epileptic seizures were secondary to an encephalopathy identified on MRI or CSF analysis or that had persistent neurologic deficits indicating encephalopathy. If these diagnostic methods did not reveal any clinically important abnormalities and if no persistent neurologic deficits suggestive of encephalopathy were present, a diagnosis of cryptogenic epilepsy was made. Transient neurologic deficits in the postictal period or after initiation of AED treatment did not preclude a diagnosis of cryptogenic epilepsy.
For dogs with a diagnosis of cryptogenic epilepsy, additional information was retrieved from the medical records regarding the following if available: whether glucocorticosteroids were administered prior to MRI; AED treatment at the time of death, loss to follow-up, or completion of the study; findings on general physical examination; findings on neurologic examination and whether abnormalities were transient after a seizure or after initiation of AED treatment; results of a CBC, routine serum biochemical analysis, and urinalysis; serum bile acids concentrations; and results of CSF analysis, infectious disease testing, and MRI of the brain (described in the radiologist's report).
All owners of dogs with cryptogenic epilepsy were contacted via telephone and asked to complete a Web-based questionnaire designed to obtain follow-up information regarding the following aspects: seizure frequency after discharge from the hospital (no more seizures witnessed, typically ≤ 1 seizure/mo, or typically > 1 seizure/mo), current AED treatment, whether a diagnosis had been made later in life explaining the dog's epileptic seizures, date of death, mode of death (spontaneous or euthanasia, related or unrelated to epileptic seizures or AED treatment), and results of a postmortem examination, if performed. If owners did not agree to complete the questionnaire or could not be contacted, as much detailed information as possible was obtained from the referring veterinarian. In the questionnaire, owners were asked to judge their dog's quality of life before and after diagnosis of cryptogenic epilepsy and initiation of AED treatment (on a scale of 1 to 10, where 1 = poor and 10 = excellent). They were also asked to indicate their level of agreement (on a scale of 1 to 5, where 1 = strong agreement and 5 = strong disagreement) with statements that the dog's quality of life did not change after the diagnosis of cryptogenic epilepsy and that benefits of caring for the epileptic dog outweighed the emotional and monetary expenses involved.
For dogs with a diagnosis of symptomatic epilepsy, the nature of underlying CNS pathological changes was recorded (intracranial neoplasia, CNS inflammation, ischemic or hemorrhagic event, degenerative encephalopathy, or encephalopathy of a different or undetermined etiology). A diagnosis was considered definitive if confirmed via CSF analysis in cases of CNS inflammation and histopathologic findings for all disease processes. If a definitive diagnosis was not established, for study purposes a presumptive diagnosis was made on the basis of the radiologist's MRI report, taking results of all other diagnostic modalities into consideration.
Seizure classification—Identification of an episode as an epileptic seizure was made on the basis of the description in the medical records. An event was classified as an epileptic seizure if 3 of the following 4 characteristics were mentioned in connection with the episode: salivation, urination, or defecation; tonic or tonic-clonic posture or movements or rhythmic contractions of facial or appendicular muscles; decreased responsiveness intraictally; and a postictal phase in which abnormal behavior or mental state was noted. If no detailed description of the episode was recorded, events were still considered epileptic seizures if witnessed by the admitting veterinarian or if the term generalized seizure was used. It was assumed that use of this term was based on a description compatible with the criteria for epileptic seizures.
An epileptic seizure was classified as focal if clinical signs were suggestive of involvement of neuronal networks restricted to 1 hemisphere, whereas signs indicating engagement of bilaterally distributed networks resulted in classification of epileptic seizures as generalized. Because of the retrospective study design, no attempt was made to further distinguish between primary or secondary generalized epileptic seizures. Cluster seizures were defined as > 1 epileptic seizure within 24 hours and status epilepticus as seizure activity of ≥ 5 minutes' duration or a series of ≥ 2 seizures without regaining full consciousness between episodes.19
Dogs were only included if, on the basis of history, a toxic etiology was deemed highly unlikely and if a metabolic cause for epileptic seizures was not identified. Furthermore, dogs with unremarkable results of MRI, CSF analysis, and interictal neurologic examination were excluded if only an isolated seizure event was observed for which AED treatment was not initiated. Dogs with a single seizure event were determined to have cryptogenic epilepsy and were included if the dog was treated with an AED following this episode. Dogs were treated with an AED only if this single event was a severe seizure manifestation (cluster seizure or status epilepticus). Because metabolic and toxic causes were ruled out, it was considered likely that these animals had a brain disorder that caused an enduring predisposition to generate epileptic seizures but that treatment with AEDs suppressed further observable seizure activity.
MRI—Imaging was performed with a 1.5-T magnet in all dogs. All dogs were under general anesthesia and placed in sternal recumbency for the procedure; T2-weighted images (sagittal, transverse, and dorsal planes), fluid-attenuation inversion recovery images (transverse plane), proton density–weighted images (transverse plane), and T1-weighted images (transverse and dorsal planes) before and after IV gadolinium administration (0.1 mmol/kg [0.05 mmol/lb]) were obtained. At the discretion of the clinician in charge, further sequences, including gradient-echo, short T1 inversion recovery, and diffusion-weighted images, were obtained. At the time of imaging, all scans were evaluated by 1 of 2 board-certified veterinary radiologists and a written report was generated and became part of the medical record.
CSF analysis—Analysis of a CSF sample (total nucleated cell count, differential cell count, and total protein content) was performed according to standard protocols at the clinical pathology service of the Veterinary Teaching Hospital within 1 hour after sample collection.
Infectious disease testing—Infectious disease testing was performed at the discretion of the attending clinician. Serologic, antigen, or PCR testing was performed at various laboratories for several infectious agents, including canine distemper virus, West Nile virus, Neospora hughesi, Neospora caninum, Toxoplasma gondii, Rickettsia spp, Anaplasma phagocytophilum, Ehrlichia canis, Babesia canis, Borrellia burgdorferi, Bartonella spp, Cryptococcus spp, Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum, and Aspergillus spp.
Statistical analysis—All dogs were grouped according to age at the time of the first observed epileptic seizure (group 1, 7 to 9 years; group 2, 10 to 12 years; and group 3, ≥ 13 years). The percentage of dogs with cryptogenic epilepsy among all dogs that developed epilepsy at ≥ 7 years of age was calculated. The percentage was also determined separately for each of the 3 age groups as well as for the subpopulations of dogs with or without results of a neurologic examination indicating signs of encephalopathy. Sex, age at onset of epileptic seizures, presence of signs indicating an encephalic lesion at the time of initial evaluation, seizure type (focal or generalized), and most severe pattern (single isolated seizures, cluster seizures, or status epilepticus) prior to MRI were compared between dogs with cryptogenic epilepsy and symptomatic epilepsy.
All other statistical evaluations focused on dogs with cryptogenic epilepsy and were performed for dogs in this category as a whole as well as for groups on the basis of age at seizure onset. Results are presented as median and range, and comparisons between groups were performed by means of a Mann-Whitney U test for continuous data and a Fisher exact test (2 categories) or χ2 test (> 2 categories) for categorical data. Survival from the time of the first observed epileptic seizure was assessed by means of Kaplan-Meier curves via the log-rank test. Dogs that were alive at the time of last follow-up or were lost to follow-up were censored from survival analysis. All statistical analysis was performed with commercially available software.a Differences of P ≤ 0.05 were considered significant.
Results
A total of 214 dogs that developed cryptogenic epilepsy or symptomatic epilepsy at ≥ 7 years of age and fulfilled the study inclusion criteria were identified. Follow-up from the time of MRI ranged from 0 to 79 months, with a median of 18 months. Four dogs were lost to follow-up. For 2 of these dogs, no further information was available immediately after discharge; the last follow-up for the 2 remaining dogs was from 2 and 21 months after MRI. Forty-five (21%) dogs had a diagnosis of cryptogenic epilepsy. In 169 (79%) dogs, an underlying CNS disease was identified and a diagnosis of symptomatic epilepsy was made. Distribution of the 2 categories of epilepsy among the 3 age groups was summarized (Table 1). At the time of initial evaluation, neurologic deficits indicative of encephalopathy were detected in 8 of 45 (18%) dogs with cryptogenic epilepsy and 116 of 169 (69%) with symptomatic epilepsy. This difference was significant (P < 0.001). Among dogs without signs of encephalopathy, 37 of 90 (41%) had a diagnosis of cryptogenic epilepsy. Of the 124 dogs with neurologic examination findings that suggested encephalopathy, 8 (6%) were classified as having cryptogenic epilepsy.
Categorization of 214 dogs with cryptogenic or symptomatic epilepsy according to age at the time of seizure onset.
| Age group | No (%) of dogs | ||
|---|---|---|---|
| Cryptogenic epilepsy | Symptomatic epilepsy | Total | |
| 1 | 31 (29) | 75 (71) | 106(50) |
| 2 | 10 (13) | 65 (87) | 75(35) |
| 3 | 4 (12) | 29(88) | 33 (15) |
| Total | 45 (21) | 169(79) | 214 (100) |
All dogs were ≥ 7 years old at first seizure onset. Age groups were assigned as follows: group 1, 7 to 9 years; group 2, 10 to 12 years; and group 3, ≥ 13 years. Percentages reflect the proportion of the total for each row.
One hundred eight dogs were male (16 sexually intact and 92 castrated), and 106 were female (2 sexually intact and 104 spayed). There was no difference in the male-to-female ratio for dogs with cryptogenic epilepsy or symptomatic epilepsy (1.5:1 and 0.9:1, respectively; P = 0.18). Median age at the time of seizure onset for dogs with cryptogenic epilepsy was 9.0 years (range, 7.3 to 16 years) and was significantly (P = 0.003) less than the age at onset of seizures for dogs with symptomatic epilepsy (median, 10.3 years; range, 7 to 18.4 years). A variety of breeds were included in both epilepsy categories. Dogs with cryptogenic epilepsy included ≥ 3 dogs of the following breeds: mixed (n = 8), Beagle (4), Labrador Retriever (4), Siberian Husky (4), Golden Retriever (3), Toy or Miniature Poodle (3), and Rottweiler (3). Siberian Huskies (n = 4) represented 9% of the 45 dogs with cryptogenic epilepsy, whereas this breed comprised only 235 of 34,619 (0.7%) dogs seen at the Veterinary Teaching Hospital during the study period; however, no statistical comparison was performed because of the small number of dogs. Dogs with symptomatic epilepsy included ≥ 5 dogs of the following breeds: Labrador Retriever (n = 20), mixed (19), Golden Retriever (15), Boxer (14), Boston Terrier (10), Chihuahua (6), German Shepherd Dog (6), Miniature Schnauzer (6), and Jack Russell Terrier (5).
The suspected etiology for seizures in dogs with symptomatic epilepsy was intracranial neoplasia (n = 121; 38 confirmed cases), cerebrovascular accident (21), encephalitis (11; 10 confirmed cases), degenerative CNS disease (4), and other or undetermined cause (12). The predominant seizure type was generalized, with only 3 of 45 (7%) dogs with cryptogenic epilepsy and 3 of 169 (2%) with symptomatic epilepsy having focal seizures. Twenty-three (51%) dogs with cryptogenic epilepsy had isolated seizures as the most severe seizure pattern; cluster seizures occurred in 21 (47%), and 1 (2%) had an episode of status epilepticus. Among dogs with symptomatic epilepsy, 68 (40%) had isolated seizures and 87 (52%) had cluster seizures. Status epilepticus occurred in 10 (6%) dogs. The severity of seizures could not be extracted from medical records for the remaining 4 (2%) dogs. Differences in seizure type (P = 0.11) and most severe seizure pattern (P = 0.36) were not significant between dogs with cryptogenic and symptomatic epilepsy.
Dogs with cryptogenic epilepsy underwent MRI 1 to 540 days (median, 30 days) after the first observed epileptic seizure. During this interval, dogs had 1 to > 5 seizure events (median, 2). Two of the 45 dogs with cryptogenic epilepsy received low doses of glucocorticosteroids prior to MRI. One dog received prednisone (0.3 mg/kg [0.14 mg/lb], PO, q 24 h) for treatment of inflammatory bowel disease and an unspecified myelopathy, and the other dog was given prednisone (0.17 mg/kg [0.08 mg/lb], PO, q 24 h) for treatment of hypoadrenocorticism.
None of the dogs with cryptogenic epilepsy had abnormalities identified on general physical examination (n = 45), CBC (45), routine serum biochemical analysis (45), and urinalysis (28) that were considered relevant for epileptogenesis. Serum concentrations of preprandial, postprandial, and pre- and postprandial bile acids were investigated and within normal limits in 3, 2, and 16 dogs, respectively. Abdominal ultrasonography (n = 26), thoracic radiography (43), and MRI of the brain (45) did not identify changes that could be related to the development of epileptic seizures. Findings on MRI of mild senescent brain atrophy (n = 4), a mild caudal occipital malformation without important changes to the neural tissue (1), and mild ventriculomegaly or ventricular asymmetry without signs of obstruction or changes to the surrounding parenchyma (4) as well as changes outside of the cranial vault (5) were considered unimportant for epileptogenesis. Also, no important abnormalities were identified on routine CSF analysis after cerebellomedullary cistern puncture (n = 39). A mild isolated increase in either total nucleated cell count (up to 7 cells/μL [reference range, 0 to 5 cells/μL]; n = 1) or total protein content (up to 40 mg/dL [upper reference limit, 25 mg/dL]; 7) was considered acceptable for a diagnosis of cryptogenic epilepsy. The sample for the dog with increased nucleated cell count was hemodiluted (2,680 RBCs/μL [reference value, 0 RBCs/μL]); the dog had not received glucocorticosteroids and did not have any discernible increase in seizure frequency or develop interictal neurologic deficits during the follow-up period of 32 months. Eight dogs underwent testing for various types of infectious diseases, and all had negative results.
Follow-up information regarding seizure frequency, AEDs, and patient survival was obtained from owners for 34 of 45 (76%) dogs and from the referring veterinarians for the remaining 11 (24%) dogs. At the time of death, loss to follow-up, or completion of the study, 5 (11%) dogs with cryptogenic epilepsy were not receiving any AEDs, 28 (62%) dogs were receiving 1 AED, 11 (24%) were receiving a combination of 2 AEDs, and 1 (2%) was receiving 3 AEDs. Antiepileptic drugs that were prescribed included phenobarbital, potassium bromide, zonisamide, levetiracetam, and gabapentin. Ten (22%) dogs did not have additional seizures after discharge from the Veterinary Teaching Hospital. Three of these dogs were not receiving maintenance AED treatment at the time of death, loss to follow-up, or study completion; 7 dogs were receiving a single AED. Twenty-one (47%) dogs typically had ≤ 1 seizure/mo. Two of these dogs did not receive any AEDs, 10 were receiving 1 AED, and 9 dogs were receiving a combination of 2 AEDs. More than 1 seizure/mo was reported in 6 of 45 (13%) dogs, of which 3, 2, and 1 dog were receiving 1, 2, and 3 AEDs, respectively. No information on seizure frequency following discharge was available for 8 (18%) dogs.
Eleven of 45 (24%) owners did not complete the follow-up questionnaire; information on owners' perception of their dog's quality of life was summarized for the remaining 34 (76%) dogs. On the 1 to 10 scale used to rate their dogs' quality of life (where 1 = poor and 10 = excellent), the median score indicated by all owners who completed the questionnaire was 10 (range, 8 to 10) before a diagnosis of cryptogenic epilepsy was made and AED treatment was initiated. After diagnosis and initiation of AED treatment, the median quality-of-life score was 8 (range, 1 to 10). In response to the statement that their dogs' quality of life did not change after the diagnosis of cryptogenic epilepsy and initiation of AED treatment, the median level of agreement indicated by owners (where 1 = strongly agree and 5 = strongly disagree) was 2 (range, 1 to 5). Fourteen of 34 (41%) owners gave a score of 4 or 5, which was interpreted as perception of a negative impact on the dogs' quality of life. However, in response to the statement that benefits of caring for their epileptic dog outweighed the emotional and monetary expenses involved, the median level of agreement was 1 (range, 1 to 5), and 31 of 34 owners gave scores of 1 or 2.
Twenty of 45 (44%) dogs with cryptogenic epilepsy were alive at the time of study completion, 20 (44%) dogs had died, and survival information was unavailable for the remaining 5 (11%). The median age at death was 12.4 years (range, 9.7 to 16.7), and death in 7 of 20 (35%) dogs was related to epileptic seizures or AED treatment (euthanasia [n = 5] and spontaneous death [2]). Cause of death in the remaining 13 (65%) dogs was unrelated to cryptogenic epilepsy (euthanasia [n = 10] and spontaneous death [3]). Postmortem examination of the CNS was not performed in any of the dogs, and no cause for the epileptic seizures was identified in any case. The overall estimated median survival time from onset of epileptic seizures was 52 months when all deaths were considered events and increased to 83 months when only deaths associated with cryptogenic epilepsy were considered events (Figure 1). There was no significant (P = 0.18) difference in survival time between dogs in which death was related to cryptogenic epilepsy and those that died of other causes.
Kaplan-Meier survival curves from the onset of epileptic seizures for 45 dogs of various breeds with cryptogenic epilepsy. Onset of seizures in all dogs was at ≥ 7 years of age. Dogs that were alive at the time of last follow-up (n = 20) or were lost to follow-up (5) were censored from survival analysis. A—When all deaths were considered events, median survival time was 52 months. B—When deaths unrelated to epileptic seizures or AEDs (n = 13) were censored, median survival time was 83 months. Vertical marks indicate censored data points.
Citation: Journal of the American Veterinary Medical Association 242, 5; 10.2460/javma.242.5.651
Kaplan-Meier survival curves from the onset of epileptic seizures for 45 dogs of various breeds with cryptogenic epilepsy. Onset of seizures in all dogs was at ≥ 7 years of age. Dogs that were alive at the time of last follow-up (n = 20) or were lost to follow-up (5) were censored from survival analysis. A—When all deaths were considered events, median survival time was 52 months. B—When deaths unrelated to epileptic seizures or AEDs (n = 13) were censored, median survival time was 83 months. Vertical marks indicate censored data points.
Citation: Journal of the American Veterinary Medical Association 242, 5; 10.2460/javma.242.5.651
Kaplan-Meier survival curves from the onset of epileptic seizures for 45 dogs of various breeds with cryptogenic epilepsy. Onset of seizures in all dogs was at ≥ 7 years of age. Dogs that were alive at the time of last follow-up (n = 20) or were lost to follow-up (5) were censored from survival analysis. A—When all deaths were considered events, median survival time was 52 months. B—When deaths unrelated to epileptic seizures or AEDs (n = 13) were censored, median survival time was 83 months. Vertical marks indicate censored data points.
Citation: Journal of the American Veterinary Medical Association 242, 5; 10.2460/javma.242.5.651
For comparison among age groups, groups 2 and 3 were combined to account for low numbers of dogs in each group. Results for group 1 (7 to 9 years at the time of seizure onset) and groups 2 and 3 (≥ 10 years at the time of seizure onset) in regard to sex, seizure type, most severe seizure pattern, presence of neurologic deficits indicative of encephalopathy at the time of evaluation, number of AEDs being administered at the time of death, loss to follow-up or study completion, seizure frequency after discharge from the Veterinary Teaching Hospital, and whether death was related to cryptogenic epilepsy did not differ significantly. The median estimated survival time was 55 months for group 1 and 13 months for groups 2 and 3 when all deaths were considered events and 83 months for group 1 and 29 months for groups 2 and 3 when deaths unrelated to cryptogenic epilepsy were censored.
Discussion
When evaluating first-time epileptic seizures in older dogs, there is always a concern that seizures, once an underlying metabolic or toxic cause has been ruled out, are likely secondary to an identifiable underlying pathological process in the CNS.20 In the study reported here, despite the likelihood of symptomatic epilepsy, no underlying disease process could be identified in a substantial proportion of dogs with onset of seizures at ≥ 7 years of age. Information on dogs with cryptogenic epilepsy is lacking in the veterinary literature, and the objective of this study was to evaluate the prevalence and clinical features of cryptogenic epilepsy in dogs, including signalment, seizure history, diagnostic findings, response to treatment (ie, number of medications prescribed and frequency of seizures), and life expectancy. The latter 2 aspects are particularly important for successful client communication in deciding whether a complete diagnostic workup should be performed and in cases where a diagnosis of cryptogenic epilepsy is made.21
The definition of symptomatic epilepsy is straightforward, and a definitive diagnosis can be achieved after a complete neurologic workup; however, classification of canine epilepsy as either idiopathic or cryptogenic is determined via exclusion of identifiable underlying causes for the epileptic seizures. The designation as either idiopathic or cryptogenic epilepsy is somewhat arbitrary at present. For our study, a cutoff age of 7 years was chosen to classify dogs as having cryptogenic rather than idiopathic epilepsy. This decision was made on the basis of the available literature on hereditary epilepsy in various dog breeds, although it should be noted that it is common practice in these studies to use an age of < 7 years at the time of seizure onset as a diagnostic criterion to identify dogs with idiopathic epilepsy. Some of these studies10,11,13,15,16,22 have included few dogs with a seizure onset at 7 years of age or greater. It is possible that some of the dogs with a diagnosis of cryptogenic epilepsy in the present study actually had hereditary idiopathic epilepsy. Alternatively, it is also conceivable that some dogs included in the aforementioned breed-specific epilepsy studies may not have had idiopathic epilepsy. This diagnostic dilemma will not be resolved until methods are available to confirm a hereditary basis for epilepsy in an individual dog.
In the present study, some dogs that had a diagnosis of cryptogenic epilepsy had mild changes detected via MRI and CSF analysis that were considered unimportant for epileptogenesis. The rationale for including dogs with MRI findings of mild generalized brain atrophy in the cryptogenic epilepsy category was that, even though brain atrophy has been associated with canine cognitive dysfunction,23 no evidence in dogs exists that it is the cause for epileptic seizures. Findings of a mild caudal occipital malformation and mild ventriculomegaly or ventricular asymmetry were deemed unimportant because they were characterized by an absence of signal change in the neural parenchyma. In dogs with ventriculomegaly or ventricular asymmetry, evidence of obstruction of the ventricular system was also lacking. These findings likely represented congenital anomalies, and a clinical importance would have likely manifested earlier in life. One dog had a mild increase in the total nucleated cell count of the CSF. Because the sample was hemodiluted and the dog did not have signs of increased seizure activity or neurologic deficits during follow-up and was not administered anti-inflammatory treatment, it was considered likely that the increase in cell count was secondary to hemodilution. The mild increase in total protein content in the CSF of 7 dogs was thought to likely represent a postictal change as described for human patients following epileptic seizures.24 The clinical course of the condition in dogs with elevated total protein concentrations was not supportive of a different underlying cause.
The rationale for classifying dogs with only a single seizure event that were subsequently treated with an AED as epileptic is debatable. An electroencephalographic examination could have been of great help in establishing whether these dogs were truly epileptic with an increased risk for future seizures.12,25,26 Unfortunately, none of the dogs in question underwent electroencephalography at the time of evaluation, and until results of an electroencephalographic examination can be shown to affect the treatment regimen or prognosis for canine patients, it will remain difficult to justify this ancillary test and the associated additional cost.
In 21% (45/214) of dogs in the present study with an onset of seizures at ≥ 7 years of age, no underlying cause could be identified and cryptogenic epilepsy was diagnosed. In dogs that were < 10 years of age when the first epileptic seizure occurred, the proportion was 29% (31/106); it was 13% (14/108) when seizures started at 10 years of age or older. Presence of neurologic deficits indicating an encephalopathy at the time of initial evaluation made an identifiable underlying cause likely; however, in some dogs with cryptogenic epilepsy, transient neurologic signs occurred either postictally or because of recent initiation of AED treatment. Per definition, these signs were transient, but in a clinical situation, waiting for signs to potentially resolve is often not feasible. A considerable proportion (53/90 [59%]) of dogs with an unremarkable neurologic examination during the initial evaluation had an identifiable underlying CNS disease that was considered responsible for symptomatic seizures, which is in agreement with a previous report18 investigating MRI changes in epileptic dogs with unremarkable interictal neurologic examination results. These findings support the common notion that a complete neurologic workup is indicated in any dog with late-onset epileptic seizures, once metabolic and toxic causes have been excluded, irrespective of presence of neurologic deficits.
Breeds of dogs with cryptogenic epilepsy appeared consistent with the overall dog population seen at the Veterinary Teaching 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 the Veterinary Teaching Hospital during the study period (0.7%). This may have been coincidental; alternatively, it may reflect a predisposition for dogs of this breed to develop epilepsy at an advanced age. The breeds comprised by the symptomatic epilepsy group likely reflected a combination of breed popularity and predisposition for development of intracranial neoplasms,27,28 given that this was the most common presumptive and confirmed diagnosis within the group.
There is no consensus on what seizure frequency is acceptable in dogs, and at the Veterinary Teaching Hospital where the study was performed, a frequency of ≤ 1 seizure/mo is generally considered tolerable if these manifest as isolated seizures. However, the owner's perception on this matter largely dictates how aggressively attempts are made to further decrease seizure frequency. In general, the decision to escalate AED treatment is dependent on the owner's idea of an acceptable seizure frequency and a tolerable degree of adverse effects caused by AEDs. Applying our hospital's standard on adequate seizure control to the dogs for which follow-up on seizure frequency was available, good control was achieved in 31 of 37 (84%) patients; still, 14 of the 34 owners who completed the questionnaire indicated that the combination of epileptic seizures and AED treatment had a negative impact on their dog's quality of life. Despite this perceived decrease in quality of life, most (31/34 [91%]) owners agreed that caring for the epileptic pet was worth the emotional and monetary expense. A similar result was found in a study29 of owners' perceptions regarding the long-term care of epileptic dogs, in which most owners stated that they would repeat the decision to care for their epileptic dog. With regard to owner perceptions, it is likely that the owners of dogs with cryptogenic epilepsy in the present study were not representative of the general population of dog owners. The inclusion criteria, which included requirement of a full neurologic workup for dogs, selected for pet owners with a high level of commitment. Also, with a non-response rate of 24%, it is conceivable that there may have been a bias with owners who had a more traumatic experience with their dog's disease being less likely to participate in the survey.
A decreased life expectancy has been reported for dogs with epilepsy.11,21 Although no suitable control population was available to evaluate whether a diagnosis of cryptogenic epilepsy was generally associated with premature death, a median age > 12 years at the time of death suggests that no dramatic shortening of life would be expected for most dogs with this condition. In a subset of dogs (7/20), however, epileptic seizures or adverse effects of AEDs were indicated as the primary reason for the dog's death. With this diverse outcome, it should be stressed that cryptogenic epilepsy is not a single disease entity but likely represents a multitude of different etiologies that result in epileptic seizures and cannot be detected with currently available diagnostic methods or via interictal neurologic examination. In the present study, it is possible that the diagnostic workup for some patients was pursued too early in the course of the disease to detect changes and that repeating the diagnostic tests would have yielded a definitive diagnosis at a later time. On the basis of owners' responses to the questionnaire and available medical records, a reason for development of seizures was not identified in any of the dogs with cryptogenic epilepsy later in life or at the time of death.
ABBREVIATION
| AED | Antiepileptic drug |
GraphPad Prism 4, GraphPad Software Inc, La Jolla, Calif.
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