What is Cognitive Dysfunction in Cats?

Almost twenty years ago when I left my residency and started out as a newly minted neurologist, feline cognitive dysfunction syndrome (CDS) was not on my radar. That has changed. As we learned more about aging in cats, CDS has become a more recognized disease by yours truly, as well as many others. If you're like me and need a Tidbit-Tuesday style refresher...read on!

What is cognitive dysfunction syndrome?
Cognitive dysfunction syndrome (CDS) is a term used to describe deterioration of mental capabilities associated with age.  Clinical signs of cognitive dysfunction can also be associated with other age-related illnesses (e.g. osteoarthritis, structural intracranial disease such as neoplasia, or cardiovascular disease) which makes it difficult to diagnose. See table 1 for an outline of behavior changes seen in cats with CDS.
The underlying etiology of CDS is yet unknown. Causes such as oxidative stress/damage, neurodegeneration  and vascular changes are among the leading hypothesis for human and canine CDS, and therefore suspected to be similar in feline CDS.  Deposits of extracellular B-amyloid and intracellular accumulation of microtubule-associated protein tau have been seen in human patients with cognitive dysfunction. Similarly,  B-amyloid deposits and increased tau have been detected in aged cats with cognitive decline, however the significance remains unclear. 

What are the clinical signs of cognitive dysfunction in cats?
There is a handy article, published in the Veterinary Clinics of North America in 2020 by Dr. Miele and associates that echoes what others have been reporting in a very concise little table. (See reference at bottom) I have replicated this table, with a few modifications, here. Note: There are other signs such as decreased appetite or thirst, that don't usually drive an owner or veterinarian to seek consultation from a neurologist so I haven't included them here. 

Table 1: Clinical behavioral changes associated with CDS in cats.Increased vocalization, especially at nightAltered social interaction and relationships, either with other or other pet. Altered sleep/wake patterHouse soilingSpatial Disorientation or confusion (i.e. forgetting the location of the litter box)Temporal disorientation (i.e. forgetting if they have been fed)Altered activity (i.e. aimless wandering)AnxietyLearning and memory dysfunction

How is CDS in cats diagnosed?
Oh, this is as tangled of a web as the tau proteins we chase. (A little CDS humor here...the tau proteins can cause the "tangles" seen in human CDS!). Currently, the diagnosis is made by ruling out structural brain disease and systemic causes for diseases that mimic CDS. This may include complete blood count, full biochemistry panel including thyroid screening, urinalysis, chest radiographs, blood pressure assessment, brain MRI and possibly a spinal tap. Imaging changes associated with canine CDS include increased depth of the sulci, dilation of ventricles secondary to neuronal loss (called ex vacuo hydrocephalus) and a measurably small interthalamic adhesion. Exclude everything else, and it's probably CDS.

How can we help these cats age easier?
Currently, there are no proven treatments for feline CDS.  The addition of antioxidants (B vitamins, vitamin C, other) as well as fish oil were evaluated for use in cats in one study and showed promise. The use of S-adenosyl-L-methionine (SAMe) has been recommended for cats based on a study that identified improved performance on cognitive testing. This study only found significant improvement in cognitive function testing in the least affected cats. In addition to medical management, environmental management with ready access to food, water, litter box and areas of comfort (beds, hiding spots) is recommended. Environmental stimulation with low impact toys, or bird feeders in which the cat can choose to ignore any activity if they do not feel inclined to engage, are recommended. Finally, focused veterinary visits can be important for cat owners to feel supported through the aging process. Focus your exam to specifically evaluate body weight, urine production (to assess for signs of dehydration), behavior changes and mobility.This may help detect signs earlier in the course of disease and to identify concurrent morbidity that may contribute to, or be confused with, cognitive dysfunction.

Did I forget anything? Most of you treat and see this more than I do. What have you used (successfully, or not) for treatment? 

Reference:
Miele A, Sordo L, Gunn-Moore DA. Feline Aging: Promoting Physiologic and Emotional Well-Being. Vet Clin North Am - Small Anim Pract. 2020;50(4):719-748. 

Feline Hyperesthesia Syndrome

What is it?

Appropriately termed a ‘mystery disease’, feline hyperesthesia syndrome (FHS) has an unknown etiology to date. Clinical signs often include skin rippling over the dorsum, tail chasing and self-trauma, sudden jumping and running for no obvious reason and occasionally vocalization during episodes. Interestingly most cats are young (less than 1 year of age). The etiology has been proposed to be behavioral (due to the lack of identifiable organic disease), seizure disorder (due to the paroxysmal type clinical signs and directed motor activity), or a collection of multiple factors including behavioral and environmental.

How is it Diagnosed?

Obtaining a diagnosis is complex because as of yet, we don’t understand the etiology. <Groan> Therefore, as a neurologist I attempt to rule out organic CNS disease. This includes MRI, spinal tap, sometimes muscle biopsies and electrodiagnostic evaluation for peripheral neuropathy/myopathy. A recent retrospective study evaluated 7 cats with this clinical picture and did not identify any neurologic cause in these cats.1 Treatment with gabapentin, meloxicam, antibiotics, phenobarbital, prednisolone, and topiramate were tried in multiple cats. Clinical improvement was noted in 6 of 7 cats using gabapentin alone (2 cats), gabapentin, cyclosporine, and amitriptyline (1 cat), gabapentin, prednisolone, phenobarbital (1 cat) or gabapentin, topiramate and meloxicam (1 cat). Treatment in my practice consists of anticonvulsants to rule out/in epileptic activity, followed by pain management with gabapentin.  Referral to a behaviorist, dermatologist and/or internist is often made as well because of the complex and unknown nature of this mystery disease.

That's it for this week. Short and sweet because, honestly, I thought you could use a little less to read during summer!

Have a terrific week. Keep those consults coming! We've worked through some really interesting cases lately.

Brain Herniation in Cats

Brain herniation is diagnosed when one part of the brain shifts to another part of the cranial vault. The four most common types of herniation include: 1) Midline falx herniation (from left to right side of the forebrain), 2) caudal transtentorial herniation (cerebrum herniations under the tentori cerebelli onto the cerebellum and brainstem, 3) rostral transtentorial herniation (cerebellum herniates rostrally into forebain and 4) foramen magnum herniation (cerebellum exits out the foramen magnum). Brain herniation may be acute, secondary to a sudden shift in intracranial pressure or gradual secondary to a chronic or slow rising intracranial pressure.

The most common cause of acute herniation is trauma, resulting in cytotoxic and vasogenic edema or hemorrhage with a subsequent sudden increase in intracranial pressure. Brain tumors account for the majority of cases with a gradual increase in intracranial pressure.

The Cushing's Reflex, identified by Dr. Harvey Cushing, describes a reflexive bradycardia and hypertension with a reduced level of consciousness, induced by increased intracranial pressure. Increased pressure can result in poor cerebral perfusion, and ultimately brain herniation. 
A recent article evaluated cats with brain herniation noted on MRI to cats with intracranial disease WITHOUT brain herniation for signs of the Cushing's Reflex, and other clinical factors that might predict the presence of herniation. They evaluated: age, weight, heart rate, respiratory rate, temperature, blood pressure, level of mentation, Glasgow Coma Scale gait assessment and brainstem reflexes. Can you guess what they found?

There was no significant difference in any of these factors between the two groups except as related to level of consciousness and age. Cats with brain herniation were significantly older, and had a reduced level of consciousness compared to cats with intracranial disease without evidence of herniation. Wow!

Why didn't we see a Cushing's Reflex? Well, one option is that the majority of cats were diagnosed with intracranial neoplasia which we know is a slow growing process. This may have provided ample time for compensatory mechanisms so that a significant difference couldn't be determined in this study. Another option is that clinical evidence of brain herniation is simply less obvious or prevalent in cats. One prior study of cats with normal brains found incidental herniation in up to 40% of the cats! 

What's the take away? Cats with brain herniation may present very similarly to cats without brain herniation . Therefore, any cat with an intracranial neuroanatomic lesion localization undergoing general anesthesia should be managed as if they have increased intracranial pressures. Do not administer anesthetic drugs that are known to markedly increased or decrease blood pressure as this may negatively affect the cerebral perfusion pressure. When in doubt, assume they have increased intracranial pressure. 

Thanks for reading! This week is the 4H Dane County Fair so if you need me I'll be watching horse shows and eating cotton candy! Feel free to text or email anytime, however my live consult availability is very limited due to my kid's show schedules. Have a great week!

Levetiracetam use in Cats

We all know cats are not small dogs, so how does levetiracetam (leh-vuh-tr-A-suh-tam) differ between species?

Metabolism
The mechanism of action (modification of the SV2A receptor) is the same for cats and dogs. This mechanism of action (MOA) is unique to levetiracetam and different that the MOA for phenobarbital. 

Formulations
There are two formulations available 1) standard release (SRL) and 2) extended release (XRL). The dosage of 20 mg/kg PO q8h for the SRL formulation, comes from pharmacokinetic analysis of this drug in a cohort of healthy cats. A therapeutic range has not yet been developed for cats therefore if seizure control is poor, the dosage is often increased until signs of toxicity are noted and then reduced to the highest effective dose with minimal side effects. When doing that, the prescriber is using the individual animal as a guide for toxicity rather than an established therapeutic range. Reported side effects include hypersalivation (mild, transient), inappetence and mild lethargy. There are very few efficacy studies for cats, however in 2008, a single study reported a greater than 50% reduction in seizures  in 7 of 10 cats when levetiracetam was added to phenobarbital. Liquid formulations are readily available through compounding pharmacies and can be used interchangeably with the 250 mg size tablets. Use caution when prescribing the liquid formulation to ensure it does not have xylitol as an added ingredient. 

Extended release levetiracetam is available in 500 mg and 750 mg size tablets. Historically, this has limited its use in cats. In 2017, I decided it was high time we changed that thinking so we evaluated the pharmacokinetics of a single dose of 500 mg XRL in healthy cats and found that it was well tolerated with minimal side effects. Furthermore, we identified that a reduce dosing interval from q8hr (SRL) to q24h when using XRL was appropriate for cats! The serum levetiracetam concentrations were really high therefore we subsequently evaluated the use of levetiracetam over 10 days to monitor for drug accumulation. Thankfully, none was identified! No efficacy studies have been performed using 500 mg PO XRL q24h in cats, to date, however I do recommend this dosage for cats, when levetiracetam is needed and q8h dosing isn't an option.

The story doesn't end there! Medicating cats is such a terrible thing to do to a cat (and horrifying for some owners) that I then explored the idea of transdermal levetiracetam (TD).The dosage of 20 mg/kg transdermal q8h resulted in serum concentrations similar to those of the oral route with minimal side effects. We have not evaluated TD levetiracetam long-term so efficacy remains unknown. Do I use TD levetiracetam? Yes. I ensure that the clients know that this is cutting edge research and therefore long-term efficacy studies have not been performed; purely that it is well tolerated. 

That's all for now! Please reach out with any suggested topics and stay tuned for a super fun neurology CE event coming this summer. Shhhh...it's still in the planning stages! 

Have a great week!

Phenobarbital and Cats

It comes as no surprise that I'm a super fan of phenobarbital for seizure control in cats. My research at the University of Wisconsin started with the development of a novel transdermal phenobarbital product, and it ended (so far) with a novel oral formulation (not published yet). Phenobarbital works WELL and for many cats but, alas it isn't perfect.

Misconception vs. TRUTH

1) Phenobarbital causes elevated ALP enzymes in cats.....IT DOES NOT. There was one study that reported a few elevations but NONE of the 77 cats in a recent study, nor any of the cats in a prior study my resident and I conducted had elevated ALP enzymes. Elevated ALP is a dog thing!

2) Phenobarbital does not have observable side effects....FALSE! Side effects occur in 46.7%of cats (Marsh et al). Sedation and ataxia were the most common side effects, but not the only ones.
Here are the side effects (called Type A adverse events), and percent of cats affected, as reported in Marsh's study:
a. Sedation 89%
b. Ataxia 53%
c. Polyphagia 22%
d. Polydipsia 6%
e. Polyuria 6%
f. Anorexia 6%
** Perhaps the last 4 are only notable to the observant owner, or in single cat households. Also of note, side effects in cats are reported less often compared with dogs.
Type B adverse events were extremely rare in the recent study, as well as in my experience. Bone marrow suppression did occur in 1 cat (as can be seen with dogs) and it resolved with removal of the phenobarbital. Lymphadenopathy has been linked to phenobarbital use as well.

3) Phenobarbital side effects happen randomly...FALSE! They are dose dependent and predictable. Higher serum concentrations (above 35 ug/ml) result in a higher odds ratio of developing a side effect. Additionally, 20 of the 36 cats in the study by Marsh had transient signs. The majority of side effects only occured in the first 4 weeks of treatment. This is a terrific point to make when discussing the use of this drug with clients.

What is the Take Away Message?

1) Start phenobarbital at a dosage targeted to reach 20-30 ug/ml. This typically means about 3 mg/kg (or a bit less) q12h.The goal is seizure control without concerning side effects.

2) Counsel clients that side effects occur in about 1/2 of cats, and of those, the majority occur within the first 4 weeks of administration AND resolve without any dose adjustments. If side effects are present beyond 4 weeks, consider a dose reduction.

Happy Rosh Hashana to those celebrating and happy first day of Fall (a few days late)!

Keep those consults coming; I look forward to seeing you soon.

*Marsh O, Corsini G, Van Dijk J, Gutierrez-Quintana R, De Risio L. Prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats. Journal of Feline Medicine and Surgery. June 2020. doi:10.1177/1098612X20924925

*Finnerty K, Barnes Heller H, Mercier M, et al. Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004 -2013). JAVMA 2014: 244(2):195-199.

Feline Orofacial Pain Syndrome

This is a little bit out of my wheelhouse, but it has come across my radar recently on a few cases so I thought I'd share with you what I know about FOPS.

What is it?

This is not a seizure, we don't think, and shouldn't be confused with orofacial seizures in cats. FOPS is a behavioral disorder in cats with evidence of oral discomfort and occasionally tongue, lip or gum mutilation. There is some suspicion that this is a neuropathy, or neuropathic pain disorder arising from the trigeminal nerve or the ganglion processing from CN V.

How does it present?

This disease is more common in Burmese cats, but can be seen in any breed at any age. Signs are often linked to dental work, tooth eruption or oral surgery. According to data from one study (link below), the median age was 7 years at first onset of signs, with the majority of cats having repeated or ongoing signs.

Can it be diagnosed?

It is a diagnosis of exclusion. Rule out underlying dental disease, oral pain, or diet-related causes for automatisms of the mouth following eating or other activities. Unfortunately no confirmatory test exists at this time.

How is it treated?

Not well.... oh wait, that is not what you mean, is it? Sadly, it is the truth. What treatments have been tried?

• Dental procedures: 35/53 cats improved following a dental procedure but it was not sustained in 9 cats.

• NSAIDS: 18 cats received NSAIDS of some variety. This was effective in 6 cats

• Corticosteroids: 7/17 cats had relief with steroid use.

• Antibiotics: 2/12 cats attained improvement with antibiotics (unknown type, dose)

• Combination treatment (anti-inflammatory and antibiotic): 9/21 this was effective

• Opioids: 4/14 these were effective

• Phenobarbital: 14/14 cats, effective (this was combined with a dental 2 cats)

• Diazepam oral: 13/14 cats this was effective (combined with a dental in 1 cat)

• Gabapentin: only used in 1 cat and was effective (my experience has been that this is not effective)

• Chlorpheniramine: 2/4 cats it was effective

Take Home Message

It is very important to read the numbers regarding treatment carefully. This data is reporting a subjective response to treatment, with variable doses and types of drugs within one class, in a small group of cats. This data is suggestive of efficacy with phenobarbital or diazepam use but other treatment choices may be effective. These medications are proposed to be effective because of their anti-allodynic effect, not anticonvulsant effects. Human patients with neuropathic pain that is reported to be burning in sensation find phenobarbital particularly effective. Remember that oral diazepam can cause idiosyncratic hepatic necrosis and therefore should be used with caution in cats.

Have a great week, and thanks for reading!

My hours are changing December 20-January 30th. Please reach out via email or text if you cannot find a suitable time for a consult as I may have some flexibility outside of posted times.

Link to an article for additional information:https://doi.org/10.1016%2Fj.jfms.2010.03.005

Audiogenic Reflex Seizures, Anyone?

As I write this, the fireworks are blazing in my neighborhood and there is a general sense of noise in the nation. How can noise relate to seizures?

What are they?

Feline audiogenic reflex seizures (FARS) start in cats late in life (> 10 years of age) and are triggered by a sound or sounds. The seizure phenotype (appearance) has a myoclonic component, but may also have absence or generalized seizures, as well.

What causes FARS?
Any noise, but usually a high frequency sound such as clinking a spoon in a tea cup triggers the seizures. Some cats will have spontaneous seizures in addition to FARS and others will purely have FARS. If you are seeing an older cat with new onset seizures, consider having the client keep a "sound diary" for a few weeks to see if there is a correlation.

Why bother identifying this...you're going to tell me to give phenobarbital!
Au contraire mon frere! A sentinel study was published in 2017 by Lowrie, et al (https://doi.org/10.1177%2F1098612X15622806) that showed a marked improvement in cats on levetiracetam in a randomized, controlled, open-label study with phenobarbital. 100% of the cats in the levetiracetam group obtained seizure control compared to 3% in the phenobarbital group. So you're correct that I typically prefer phenobarbital for feline seizures...except for FARS!

What causes FARS?

Interestingly, the majority of cats diagnosed with FARS in the published studies have had idiopathic epilepsy with a small portion showing progressive signs suggestive of active forebrain disease (neoplasia, meningoencephalitis).

That's it for today, folks! I hope you have a safe, fun week and stay cool during this hot weather!

BREAKING NEWS: Phenobarbital causes side effects in cats!

Phenobarbital and Cats

It comes as no surprise that I'm a super fan of phenobarbital for seizure control in cats. My research at the University of Wisconsin started with the development of a novel transdermal phenobarbital product, and it ended (so far) with a novel oral formulation (not published yet). Phenobarbital works WELL and for many cats. But, it still has some misconceptions which I'll enumerate below.

Misconception.... TRUTH

1) Phenobarbital causes elevated ALP enzymes in cats.....IT DOES NOT. There was one study that reported a few elevations but NONE of the 77 cats in a recent study, nor any of the cats in a prior study my resident and I conducted had elevated ALP enzymes. Elevated ALP is a dog thing!

2) Phenobarbital does not have observable side effects....FALSE! Side effects occur in 46.7%of cats (Marsh et al). Sedation and ataxia were the most common side effects, but not the only ones.
Here are the side effects (called Type A adverse events), and percent of cats affected, as reported in Marsh's study:
a. Sedation 89%
b. Ataxia 53%
c.Polyphagia 22%
d. Polydipsia 6%
e. Polyuria 6%
f. Anorexia 6%
** Perhaps the last 4 are only notable to the observant owner, or in single cat households. Also of note, side effects in cats are reported less often compared with dogs.
Type B adverse events were extremely rare in the recent study, as well as in my experience. Bone marrow suppression did occur in 1 cat (as can be seen with dogs) and it resolved with removal of the phenobarbital. Lymphadenopathy has been linked to phenobarbital use as well.

3) Phenobarbital side effects happen randomly...FALSE! They are dose dependent and predictable. Higher serum concentrations (above 35 ug/ml) result in a higher odds ratio of developing a side effect. Additionally, 20 of the 36 cats in the study by Marsh had transient signs. The majority of side effects only occured in the first 4 weeks of treatment. This is a terrific point to make when discussing the use of this drug with clients.

What is the Take Away Message?

1) Start phenobarbital at a dosage targeted to reach 20-30 ug/ml. This typically means about 3 mg/kg (or a bit less) q12h.The goal is seizure control without concerning side effects.

2) Counsel clients that side effects occur in about 1/2 of cats, and of those, the majority occur within the first 4 weeks of administration AND resolve without any dose adjustments. If side effects are present beyond 4 weeks, consider a dose reduction.

Thanks for your business, especially in these unusual times. I truly enjoy working with you, and your staff. Please stay safe, stay healthy, and keep those consults coming!

*Marsh O, Corsini G, Van Dijk J, Gutierrez-Quintana R, De Risio L. Prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats. Journal of Feline Medicine and Surgery. June 2020. doi:10.1177/1098612X20924925

*Finnerty K, Barnes Heller H, Mercier M, et al. Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004 -2013). JAVMA 2014: 244(2):195-199.

Do Cats Have Seizures?

Do Cats Have Seizures?

You might be thinking "Has she lost her mind? Of course cats have seizures!" Naturally, we know this to be true (or half of my research is for nothing...eek!) A recent article published in the Journal of Veterinary Internal Medicine looked at a population of cats in the UK in the year 2013 to answer some  questions about feline epilepsy. I have bulleted them below for ease of reading however this is an open access article so feel free to pull the entire article if you would like to know more!

The study aims: "To estimate the prevalence of recurrent seizure disorders (RSD) and epilepsy in the wider cat population under primary veterinary care int he UK and to evaluate demographic risk factors for their occurrence. A secondary aim was to explore risk factors associated with the diagnosis of epilepsy among the subset of cats."

• 1-year prevalence (2013) for recurrent seizure disorders (not called epilepsy): 0.16%

• 1-year prevalence for epilepsy: 0.04%

* Note these are lower than the listed prevalence for referral institutions (and mobile veterinary neurologists) for the obvious reason that referral hospitals have a different caseload!

Diagnosing epilepsy in cats is not defined, as it is in dogs, by the International Veterinary Epilepsy Task Force (IVETF). Many neurologists, myself included, extrapolate from the IVETF recommendations but also realize the limitations in data for cats.
The IVETF recommendations for dogs to diagnose epilepsy (Tier 1 - aka without diagnostic testing) are:

• two or more seizures, at least 24 hours apart

• Age 6 months - 6 years old

• Normal (unremarkable) neurologic examination inter-ictal

• No clinical abnormalities on CBC, serum biochemisry, urinalysis

A diagnosis of epilepsy was made in this study in 24.89% of the cats with recurrent seizure disorders. There was a disturbing sentence that I quote "It is conceivable that general veterinary practitioners may feel reluctant to formally diagnose epilepsy or idiopathic epilepsy in cats because of a combination of factors, including their limited confidence in performing a complete neurological examination in cats, the longstanding traditional belief that cats do not commonly have idiopathic epilepsy, and a believe that access to advanced imaging is essential to exclude other causes."  This sentence is the reason I chose this article for our TidBit Tuesday this week. First, if you're not diagnosing a cat with epilepsy (and presumable starting appropriate care or recommending appropriate testing) because of a lack of confidence in the exam, know that you are not alone! Please call me for a neurologic examination with your feline patient - I too understand the limitations of cats in assisting with their own health care. (To put it mildly.) Let's not let a lack of confidence in the examination block us from doing what is right by the pet. Secondly, idiopathic epilepsy does occur and in this study it was almost 1/4 of the cases of recurrent seizures (if they diagnosed it correctly, of course). It has been reported that up to 12% of cats can have a normal neurologic examination and have structural disease, but that shouldn't stop us from attempting appropriate treatment. Please, let's remove this thought from our practices. Finally, you do NOT need access to advanced imaging to make a presumptive diagnosis of idiopathic epilepsy. The Tier I recommendations were designed expressly to meet the needs of making this diagnosis (in dogs) without MRI or spinal tap. Whew...okay, back on track. 

Following multivariate analysis, the only variable that stood out as a risk factor for a diagnosis of epilepsy was age. Cats 3-6 years of age had a 3.32 times higher odds of developing epilepsy then cats less than 3 years of age.

Insurance was also a risk factor but that doesn't apply to the majority of the pets that I interact with so I have left that portion of the study out. Breed and sex were not associated risk factors. 

*O'Neill, DG, Phillipps, SA, Egan, JR, Brodbelt, D, Church, DB, Volk, HA. Epidemiology of recurrent seizure disorders and epilepsy in cats under primary veterinary care in the United Kingdom. J Vet Intern Med. 2020; 1– 13. https://doi.org/10.1111/jvim.15881

I hope you are doing well and staying safe. I appreciate what you do to help clients and their pets. Let me know how I can help you manage your patients with neurologic disease.

On site consultation is available Monday through Saturday at variable times throughout the week. Email consults are completed in evenings. 

Have a good week!