Dazzled By Science Part Five: Case Reports and Case Series
Last time we talked about data “mining,” database research from a wide variety of sources, including university veterinary medical records and canine genome databases. Data mining would not have been feasible without the rapid development of supercomputers capable of rapidly analyzing thousands of pieces of data. Now we are going to talk about something on the opposite end of the spectrum – case reports and case series; after that, we will cover reviews and mention consensus statements.
A case report or case study is a detailed review of an unusual (generally not previously reported) clinical case, surgical technique, necropsy, laboratory, or histopathology finding. One of the goals is to alert other veterinarians to “be on the lookout” for this unique or unusual occurrence. Case series is basically the report of two or more similar unusual cases. The case report describes what happened to an individual animal; it is not a study per se but a description of something that might be considered “weird” or peculiar. Since publishing case reports in reputable journals requires peer and editorial review, it can take some time from the identification of the unusual finding to publication.
In some cases, social media and veterinary websites, like the Drost Project (https://visgar.vetmed.ufl.edu), can provide rapid pictorial dissemination of unusual cases. However, rapid dissemination of (mis)information on social and news media platforms can generate excessive worry or stress, as was seen with the unusual “Parvovirus-like” disease of dogs in northern Michigan (AAHA.org). After thousands of posts, calls, and news articles, it turns out the “mystery disease” was “regular” Parvovirus. In this case, the in-clinic parvo tests were false negative (test results indicating that an individual does not have a disease when they actually have it). Clinicians may be less likely to prepare and submit a case report if they can easily provide the information on veterinary social media sites.
Harris et al. reported a novel treatment for an amphetamine overdose in a dog. The dog, a 4-year-old, female-spayed, mixed breed, had ingested an unknown quantity of a human ADHD medication. In the US, poison control centers have information about the toxic and lethal doses of most drugs and compounds (on a mg/kg basis) and provide treatment and prognosis information (https://www.petpoisonhelpline.com). This dog presented to the ER for acute ingestion of approximately 12.3 mg/kg of extended-release amphetamine/ dextroamphetamine. In dogs, the lethal oral dose for amphetamines ranges from 9 to 27 mg/kg. Amphetamine overdose stimulates the central nervous system and cardiovascular, respiratory, and gastrointestinal systems resulting in agitation, tremors, seizures, tachycardia (increased heart rate), hypertension, panting, vomiting, and hypersalivation. Treatment usually involves decontamination and supportive care. These veterinarians added “intralipid” (Intralipid emulsion), an intravenous lipid (fat) compound that has been previously used in the treatment of drug overdose. Although the mechanism of action is unclear, it is “thought” to provide a “lipid sink” for lipophilic drugs. The authors also measured amphetamine concentration before and after intralipid infusion. The concentration of amphetamine decreased, and the dog improved and was discharged less than 24 hours after admission. This is the first reported case of the use of intralipid for an amphetamine overdose in a dog and could provide guidance for veterinarians faced with an amphetamine overdose.
Abnormal behavior, including human aggression, was described in three dogs with 
presumed idiopathic epilepsy treated with the antiseizure medication zonisamide. This is an unusual case report (which could actually be called a “case series”), and I am not sure of the ethics of adding back a drug that is “presumed” to cause an adverse behavioral change in a pet dog. In case 1, an 11-year-old dog with a three-year history of epilepsy treated with zonisamide, presented for increasing frequency of seizures. The dose of zonisamide was gradually increased to achieve more control over the seizures. As the dose increased, new abnormal behaviors (abrupt barking during sleep without obvious external stimuli, standing, and biting tail) developed. The cause of increased seizures and new abnormal behavior includes a brain tumor; however advanced brain imaging ruled this out. The owners and the authors believed there was an association between the drug and the abnormal behavior, however, the owners declined to reintroduce zonisamide. Case two, a 6-year-old dog, was referred for aggression toward female family members, especially a sleeping child. The dog had a 3-year history of epilepsy treated with zonisamide. Although the seizures were poorly controlled, with an abundance of caution, zonisamide was abruptly discontinued. Additional antiseizure medications were ineffective, and zonisamide was again administered. The authors state: “The severity and frequency of the episodic aggression showed proportional relationship with the dose of zonisamide.” In case three a 10-year-old dog was referred for new onset of seizures and treated with zonisamide. Abnormal behavior (insomnia, agitation, constant attention-seeking behavior through the night, restlessness, and excessive reaction to the external stimuli) was noted, which decreased with decreased drug dose. After the discontinuation of the drug the behaviors disappeared but recurred with the reintroduction of the drug, which was done “to confirm the direct association of abnormal behavior and zonisamide.” I must admit as a veterinarian, scientist, and person with dogs I am bothered by their ethics statement: “Ethical review and approval was not required for the animal study because this case report describes a medical condition of client-owned dogs without serious iatrogenic consequence. Written informed consent was obtained from the owners for the participation of their animals in this study.” Furthermore, these cases describe dogs on multiple drugs, with varied behavioral signs, and at best, “an association” between behavior and the antiseizure medication. This could simply represent regression to the mean.
Videos of the abnormal behavior for cases one and two are available here: https://www.frontiersin.org/articles/10.3389/fvets.2021.763822/full#supplementary-material
Laitis et al. published an interesting retrospective case series looking at the relationship between awake bruxism (clenching or grinding the teeth) and forebrain lesions. Although awake bruxism has been considered a stereotypy in horses, a sign of stress in sheep, and an indicator of pain in dogs, there is little evidence for these etiologies, and awake bruxism has not been thoroughly examined in veterinary medicine. In this observational retrospective single-center case series, they identified four dogs that met the criteria for awake bruxism. In addition to awake bruxism, the dogs presented with a variety of mostly vague clinical and physical signs. All four dogs had advanced imaging that showed evidence of a lesion in the forebrain that affected the diencephalon (thalamus and hypothalamus). Although awake bruxism is not a common clinical finding in the dog, this case series suggests that advanced brain imaging should be considered to rule out forebrain disease.
Now let’s change directions a bit and talk about reviews or review articles. Most often review articles are requested by the journal, although they can be suggested by individual researchers to the journal editor. Reviews can also result from a single-topic conference or meeting. In general, reviews are written by an expert or experts in a specific field, sometimes a senior faculty member and a graduate student or post-doctoral fellow. Just as “Dazzled by science” includes my biases, all reviews include the biases of the authors. It is worth looking at the references to identify how many references come from the authors’ group or laboratory. If most references are from the author’s research group, the interpretation of the data is likely more biased that when a wide variety of researchers are referenced. Sometimes you need to read reviews with a healthy dose of skepticism. If you are unfamiliar with the topic, you may miss that some references and “anecdotes” involve single cases and that the review “overinterprets” the data. If you read something that “doesn’t seem right” or is at odds with “what you thought you knew,” take a look at the references or contact one of your science nerdy friends. Sometimes you can get a hint from the title of the reference; if the review says “XYZ drug” is known to cause aggression in dogs, yet the title of the article is “Aggressive behavior in one dog after treatment with XYZ drug” – one would be justified to be skeptical of other statements made in the review.
The review of sleep disorders in dogs (Mondino et al.) provides a clear review of the physiology and neurobiology of normal sleep, sleep-wake cycles, wakefulness, and sleep-promoting systems. It also includes colored graphics designed to show sleep-related abnormalities in the dog. References are primarily but not exclusively review articles or research studies from the human literature. Now granted, we know that there are many similarities between the human and canine brains, but we also know that sleep in dogs has been little studied. So when discussing rapid eye movement (REM) sleep disorder in dogs, the authors state “those motor behaviors are considered to be enactments of dreams,” however the cited references are a review in humans and a study of REM sleep in six human patients with Parkinson’s disease. Does this mean that the motor movements associated with REM sleep disorder in dogs is not related to dreaming – no, we tend to assume that what humans experience is what dogs experience (and other sentient animals), but that isn’t always true. I would have been happier if they had said, “Studies in humans suggest that motor behaviors in dogs with REM sleep disorder are considered to be enactments of dreams.” Despite that criticism, this is a good review of sleep disorders in dogs with citations from both the canine and human literature.
Meneses et al. from Overall’s group reviewed the literature on canine separation anxiety (SA). This is a thorough and well-referenced review that critically evaluates the literature. They provide definitions, epidemiological data, diagnosis, and factors that may (according to the current literature) play a causal lot causative role in the development of SA. From peer-reviewed studies, they identified seven areas that may be related to the development of SA: developmental, acquisition, environmental, owner-related, behavioral, genetic, and general. A review of these areas produced 20 putative factors that may convey an increased risk for the development of SA. However, all factors were correlational, not causative. For example, There is no evidence that “spoiling dogs” causes SA. “Spoiling” has been proposed as an impetus for the development of SA, particularly when hyper attachment (characterized as “pet owner has an excessive emotional connection and praises or overindulgences their pet through various activities, such as allowing their pet to follow them, sleep on the bed or in the bedroom, sit on the furniture with them or on their lap, receive gratuitous treats or attention, and receive attention when initiated by the pet rather than to receive attention when initiated by only the owner” is a characteristic of SA. Age at acquisition and early age trauma deserve additional investigation regarding their role in the development of SA. There is some evidence that genetic polymorphisms may increase the risk for the development of SA for some breeds. Canine temperament and personality have not been sufficiently or consistently examined to identify their role in the development of SA. This is an excellent review of the literature investigating separation anxiety in dogs.
Consensus Statements are generally guidelines based in science or evidence-based medicine that deal with a specific disease, condition, or treatment. In general, experts are gathered by veterinary organizations: including the American College of Veterinary Internal Medical, American Heartworm Association, Veterinary Emergency and Critical Care Society, and the American College of Veterinary Emergency and Critical Care, American Animal Hospital Association. The current scientific evidence is evaluated and assigned a “scientific merit” score based on the available evidence. Consensus statements provide the veterinary community with up-to-date information on the pathophysiology, diagnosis, and treatment of clinically important animal diseases. In general they are written by a group of experts, reviewed by additional experts, and published in an open access. Consensus statements provide definitions, criterion for diagnosis, management and treatment protocols, and level of evidence for recommendations. College of Veterinary Internal Medicine consensus statements can be found here: https://onlinelibrary.wiley.com/page/journal/19391676/homepage/free_reviews_and_consensus_statements.htm
In previous articles of “Dazzled by science” we have discussed different types of research and how to evaluate a scientific publication critically. This time we covered publications that are peer-reviewed but not researched based. Next time we’ll take a wide turn to delve into medications – who approves them? What does approval mean? What does extra-label use mean? Is extra-label use legal?? etc. etc. – it is going to be a wild ride – stay tuned.
Sources
Harris S, McMichael MA, Harmon R, Boothe D. Case Report: Successful intravenous lipid emulsion therapy for canine amphetamine toxicosis. Front. Vet. Sci. 9:938021, 2022. doi: 10.3389/fvets.2022.938021
Kanazono S, Ukai M, Hiramoto A. Abnormal behavior episodes associated with zonisamide in three dogs: a case report. Front. Vet. Sci. 8:763822, 2021. doi: 10.3389/fvets.2021.763822
Liatiis T, Madden M, Marioni-Henry K. Bruxism in awake dogs as a clinical sign of forebrain disease: 4 cases. J Vet Intern Med. 36:2132–2141, 2022.
Mondino A, Delucchi L, Moeser A, Cerdá-González S, Vanini G. Sleep Disorders in dogs: a pathophysiological and clinical review. Top Companion Anim Med. 43:100516, 2021. doi: 10.1016/j.tcam.2021.100516.
Meneses T, Robinson J, Rose J, Vernick J, Overall K L. Review of epidemiological, pathological, genetic, and epigenetic factors that may contribute to the development of separation anxiety in dogs, J Am Vet Med Assn, 259, 1118-1129, 2021.
