Neuroanatomic Lesion Localization for Busy Vets

What is the neuroanatomic lesion localization for the following case?
Signalment: 4 year old FS DSH
History: Acute onset inability to blink one eye. No history of trauma. She is an indoor only cat. 

To answer this question, of course you must start with a cranial nerve exam. At its most basic level, the cranial nerve examination is a process of elimination. Let's start with the blink reflex. If you touch the medial and lateral canthus, what cranial nerves are you testing? (CN 5 and CN 7) How do you know which nerve is affected? To do this, we try to isolate each cranial nerve in the reflex to see which one misbehaves. How can you isolate these two nerves from each other to see which is the affected nerve? Lets's try a corneal reflex! When done correctly, the cotton swab touches the cornea and the eye retracts into the socket. Doing this tests CN 5 (sensory) and 6 (motor). Voila! If the cat does not blink when you touch the medial or lateral canthus, but DOES retract the globe when you do corneal reflex which nerve is affected? Think you know... scroll (or read!) to the bottom to see the answer. 

But wait! That is only part of the question. We have now localized which cranial nerve is affected but we don't know if this is a central or peripheral nerve lesion localization, right? To look at the brainstem we focus on the nerve pathways running towards and from the forebrain and determine if they're affected. The nerve pathways that are easiest to test are proprioception and motor/tone. Watching the animal walk you may be able to detect a toe drag or delayed placement but ultimately we have to test proprioception through paw replacement testing or my personal favoriate for cats: tactile placing. Similarly, when watching the patient walk you may see a hemiparesis (weakness on one half of the body). Often this is more obvious in the pelvic limb but both ipsilateral limbs can be affected. The last piece to the puzzle is an evaluation of level of mentation. If the animal is obtunded, stuperous or in a coma, we have an effect to the brainstem RAS. If you have 1 or more of these signs, the animal has a brainstem disease. If we DON'T have delayed proprioception, evidence of hemiparesis or a change in mentation, we are more likely to be dealing with a peripheral neuropathy.
Remember:
1) cranial nerve deficit + delayed paw replacement/tactile placing, weakness or decreased mentation = brainstem.
2) cranial nerve deficit without the above = peripheral 

Answer: Cranial nerve 7 is affected. (5 is normal in corneal reflex therefore it is not the problem in the blink reflex either.)

Thanks for reading and have a great week! Do you have a case that is puzzling you? Please reach out - I'd love to help. Did you know I also do onsite or virtual private CE for hospitals? Reach out for more details, if you're interested.

Artificial Intelligence in Neurology

Artificial Intelligence (AI) has really taken off in the last few years and, as such, has driven us as veterinarians to critically evaluate where and how we would like to utilize this new technology. Last year I reported to you about a lecture I listened to at ACVIM about the use of AI for writing radiology reports. It was eye opening, to say the least! Recently (October 2023), a group of mostly veterinary neurologists took on AI in a new way. Abani et al challenged 13 boarded neurologists from Europe and North America to distinguish between AI-generated abstracts and human-generated abstracts. The results are chilling...

Materials and Methods

There were 3 test topics provided in this study. The purpose of providing 3 was to discriminate between "highly familiar" topics and the less familiar topics to see if there was a difference in detection of AI by the reviewers. 
Topic 1: SARS-CoV2 scent detection in dogs (considered low familiarity)
Topic 2: Biomarkers for SRMA (considered high familiarity)
Topic 3: Staining of cannabinoid receptor type 1 (medium familiarity)
An abstract, reference and introduction paragraph were written by humans on these 3 topics. ChatGPT was then used to generate 3 additional abstracts, with references and an introduction paragraph on the 3 topics. It was interesting that the authors noted ChatGPT was prompted as such: " Write an academic abstract with a focus on (subject) in the style of (author characteristics such as position, gender and age) at (University name), for publication in (journal name)." I mean...wow. ChatGPT is able to provide gender, age and position sensitivity. 

Results

• Topic 1 and 3: 4/13 (31%) correctly identified the AI generated abstract when only provided the abstract without references and introduction paper. This increased to 9/13 (69%) when all parts were provided. 

• Topic 2: 7/13 (54%) correctly identified the AI-generated abstract (provided alone), which increased to 10/13 (77%) when all parts were provided. 

Two separate plagiarism detectors were studied in this study as well. All of the original published manuscripts were noted to have 58%-100% similarity to available work which indicated this had been published elsewhere (it had). Test 1, 2, and 3 with the AI-generated papers had similarity indexes of 0-18%. This suggests that the plagiarism detectors could identify what had been previously published (the human-generated papers) and which hadn't (the AI-generated papers). Furthermore, they then evaluated all of the abstracts with an AI-detector. All original manuscripts were noted to have 0% AI-writing. Test 2 was noted to have 100% AI generation, and Tests 1 and 3 were noted to have 0% content written by AI. Gulp. 

Where does this leave us? My heightened sense of anxiety about AI-generated content was further heightened when realizing that many of my well respected, high academic achieving colleagues struggled to distinguish between AI-generated abstracts and human-generated abstracts in an area of our specialty. This further reinforced my commitment to reading the entire paper, whenever possible, before considering the data valid. We were taught to do this in school but alas, with our busy schedules, it can be missed. AI is not all bad, however. It can be quite helpful for correcting grammar, editing, summarizing references or papers and even performing statistics. I would encourage all of us to move through published literature with our eyes fully focused and with awareness of the use of AI in modern veterinary medicine. Except yesterday...hopefully you kept your eyes partially closed and didn't look directly at the sun!! 

I hope you enjoyed this little TidBit. It is a little bit off topic, but I hope you will find it useful, nonetheless. Please know that my TidBit Tuesdays are (to date) fully human-generated, as are my patient reports! Let me know if you have any topics that you'd like me to cover. Have a great week!

Vestibular Epilepsy

Wait, what? Did I read that correctly? Yes, you did! What do you call acute onset, transient vestibular signs? Vestibular paroxysmia (VP)! What do you call it if you have interictal spike and wave forms on EEG (which suggest an epileptic focus)? You guessed it... vestibular epilepsy (VE). 

What is Vestibular Epilepsy?

In human neurology, there is a form of epilepsy in which patients have acute onset vestibular signs (drifting, rolling, nystagmus) that seconds to minutes. If the onset is associated with body position change, it is considered a paroxysmia (VP). However, when an EEG is performed, human patients with vestibular epilepsy will show classic changes consistent with seizures in the temporal and parietal lobes. The big differentiator between paroxysmia and epilepsy is the response to treatment and the presence of changes on EEG. In veterinary patients there are very few studies evaluating this form of epilepsy but clinically perhaps some of you can think of a patient (or two) with similar clinical signs? We see this, albeit rarely!

How To Diagnose Vestibular Epilepsy

Diagnosing VE in veterinary medicine can be challenging. Patients will present with repeated, transient vestibular signs and are normal on examination. Animals with underlying vestibular disease (think central or peripheral vestibular disease) often have a residual positional strabismus, or mild head tilt, or another lingering deficit. Animals with VE do not! (At least not as far as we know...yet.) In a recent study published in JVIM (2024), the authors identified 10 dogs with suspected VE. All 10 dogs were treated with an anticonvulsant drug (or 2). Five of 10 dogs received just levetiracetam, 2 of 10 received Levetiracetam + phenobarbital, and 1 of 10 received levetiracetam and gabapentin or just phenobarbital. Half of the dogs receiving levetiracetam only had resolution of seizures and the other 5 had a sustained reduction. The one dog receiving phenobarbital and levetiracetam had marked improvement after phenobarbital was added, but not before.

What Is The Take Away Message?

1) Be aware of transient vestibular signs - maybe your patient has seizures!?
2) If seizures are suspected, try levetiracetam (22 mg/kg PO q8h standard release; 30 mg/kg PO q12h extended release)
3) The dogs in this study had idiopathic vestibular epilepsy (because the study selected for those cases) but vascular disease (such as transient ischemic attacks; TIA) can cause transient vestibular disease and maybe vestibular epilepsy (according to a different study).   

Not sure what your patient has? Catch a video and set up a consultation! I'm always happy to rule OUT neurologic disease and I am here to help when we rule it IN. Have a great week! I hope those of you celebrating Easter had a nice, relaxing holiday. I look forward to working with you soon!

Cardiac Changes with Idiopathic Epilepsy?

A recent study from Brazil (www.veterinaryworld.org/Vol.17/February-2024/13.pdf) evaluated 10 dogs diagnosed with Tier I level idiopathic epilepsy to determine if changes to the EKG were present. The rationale for doing this study was initiated by the human epileptic syndrome of "sudden death in epilepsy, or SUDEP". SUDEP is a devastating syndrome wherein human patients are found dead after recovery from a recent seizure. This is most traumatic for the parents of pediatric epileptics who may help their child through a seizure, see that they are recovered and then find them deceased a short while later without any signs of additional seizures. The cause of SUDEP is debated however a cardiovascular cause appears most likely. This syndrome is rarely identified and poorly published in veterinary medicine. 

During a seizure, a tremendous release of catecholamines occurs which may stimulate hypertension, as well as intoxicate the cardiac muscle causing poor relaxation and cardiomyopathy. The study reported findings in 10 dogs with epilepsy and compared them to 11 dogs without epilepsy who were apparently healthy on laboratory testing, physical and neurologic examination and without a seizure history. 

Results

The QRS complex was significantly longer in dogs with epilepsy compared to the control group suggesting left ventricular enlargement or left bundle branch block. Additionally, the QT interval was prolonged, and this was attributed to the below reference range ionized calcium concentrations in the epileptic dogs. Interestingly, the control dogs also had lower ionized calcium concentrations so one might question the validity of this test. What do these cardiac changes mean for us? It means that even "well controlled, healthy" epileptic dogs may have occult cardiac damage. Use caution when providing anesthesia to this group and perhaps reach for a preoperative EKG for this population even if their breed or age wouldn't otherwise spur you to do so. Lastly, I found it interesting that the serum glucose concentration was significantly higher in dogs with idiopathic epilepsy compared to the control group. This likely harkens back to the high sympathetic response and catecholamine release mentioned above but another idea crosses my mind as well. Many internet sites still recommend giving glucose or honey to a pet after a seizure, even without evidence of hypoglycemia. Ice cream, popsicles, and honey are frequent additions to post-ictal care in many of our patients. If given prior to the laboratory samples, it could falsely increase the serum glucose concentration. What's the take away here? Don't rule out hypoglycemia as a seizure etiology on a single blood sample. Consider a second one 4-6 hours later, during hospitalization, and note if the glucose drops below the therapeutic range. (Oh, and make sure your clients are advised against giving sugar products postictal. No one needs a sugar rush when you're on a catecholamine rush!)

Thanks for reading! This little article crossed my radar this week and I thought it was good enough to share with all of you! I hope you have a great first full week of Spring (anyone else looking at snow on their forecast??) and I look forward to working with you soon.

Hypothyroidism and Neuropathies

Does hypothyroidism affect the nervous system? You bet! The peripheral nerve is the most common target in the neurologic system. How does a low thyroid hormone affect the peripheral nerve (you might ask)? I'm glad you asked...

Etiology:

1) accumulation of mucinous deposits resulting in nerve entrapment
2) demyelination secondary to Schwann cell defect
3) vascular nerve damage secondary to hypothyroid induced dysfunction of BBB
4) disruption of axonal transport

Signalment:Typically older dogs, however congenital disease does (rarely) happen. NOTE: dogs are not always overweight, heat-seeking or have flaky-hair coats with peripheral neuropathy signs. 

Clinical signs:A polyneuropathy (multiple nerves affected) is most common. This results in paresis without ataxia and reduced to absent peripheral spinal reflexes. Signs may be mild, to start. 
Cranial nerve deficits such as facial nerve paralysis (VII), vestibular dysfunction (VIII), or laryngeal paralysis (X) are common signs of hypothyroidism. Of course, other things can cause damage to these nerves but don't forget to include hypothyroiism on your differential diagnoses list for patients with a peripheral neuropathy. Hypothyroidism may also cause a myopathy and/or megaesophagus.

Diagnostic tests:T4 is a good first step. If abnormal, a full panel is recommended. 

Treatment options:You guessed it...supplementation!

Prognosis:The neuropathy is likely to improve a little or a lot, after several months with therapy if the axonal degeneration is not too severe. I commonly caution owners to be prepeared for perminent deficits and rejoice when that doesn't happen!
Cranial nerve deficits may persist even with appropriate treatment.

Frequency:
Common in older dogs. Remember they don't need to be over0-weight, heat seaking or even sluggish to get a hypothyroid induced peripheral neuropathy. Cats can be hypothyroid too!

May the luck of the Irish be with you this week! Thanks for reading and have a great week! 

How do I use the Menace Response?

Picture this...You are presented with a 4 year old Pug with a history of "bumping into things" recently. You do a complete physical exam, including a fundic exam and neurologic exam (self high five!) and find the following changes:
Mentation: Quiet, alert and responsive
Cranial nerves: Absent menace OS, intact PLR, intact ocular movements, normal remaining cranial nerves
Gait: normal
Postural reactions: absent left pelvic limb, all others normal
Reflex: normal all limbs and cutaneous trunci
Palpation: non painful.

 
First question: Does this patient have neurologic disease? 

Golly, if it didn't this would be a silly TidBit Tuesday, wouldn't it?  It seems odd to ask this question but I feel it is a good habit get into, to ensure you're not trying to make a non-neurologic problem into a neurologic one. Interestingly, a recent report identified 8% of pets referred to a University Neurology service had "pretenders" disease (ex: cruciate rupture that was mistaken for a neurologic condition). 

Second question: What is the neuroanatomic lesion localization?

Start with basic anatomy. In a very simplistic sense, menace uses CN 2 (sensory) and CN 7 (motor) with a pass through the prosencephalon to connect the two CN. This is a complex pathway that we don't fully understand but the true bare basics are CN2, pass through the prosencephalon and CN 7.  Damage to 2, prosencephalon or 7 will result in a menace deficit. Now, expand the anatomy to include the pathways. The left eye uses left CN 2, crosses and uses right prosencephalon and then back to the left CN 7. 
We still don't know if it is CN 2, prosencephalon or CN 7 that is affected, right? Isolate CN 2 from CN 7 by doing PLR. 
PLR = CN 2, midbrain, CN 3. 
Deduction would say that if PLR is normal then CN 2 must be normal too, right?
Now we need to sort out if the menace deficit is due to disease of the prosencephalon or left CN 7. So, isolate CN 7 from CN 2 by looking at the blink reflex.
Blink reflex = CN 5, and 7.
If you tap the medial and lateral canthus and they blink, CN 5 and 7 must be intact! In the case above, we said all cranial nerve tests, other than the menace response, were normal. Therefore, CN 7 must also be normal. 

 
Voila! Neuroanatomic lesion localization is RIGHT prosencephalon!

What about that postural deficit in the left pelvic limb, you ask? 

That pathway goes from the pelvic toes --> up sciatic nerve -->up left spinal cord --> up left brainstem to cross in the midbrain --> ends in right prosencephalon.

This dog has a right prosencephalic lesion (aka right forebrain) giving both a left menace deficit and left pelvic limb deficit. Well done! You now know WHERE the problem is coming from and can build your differential diagnoses list for a focal prosencephalic lesion and/or refer them to a neurologist (instead of an ophthalmologist) for further testing.

Want more? I can do personalized CE at your hospital. We can go through neuroanatomic lesion localization, discuss seizure cases, or any other topic you and your colleagues might find helpful for your practice. Email me for additional details.

Have a great week and stay warm!

Managing Upper Motor Neuron Urinary Retention in Cats

An upper motor neuron bladder means that the sensory information from the bladder cannot be transmitted to the pons and that upper motor neurons from the pons cannot reach the lower motor neurons of the bladder to cause initiation of bladder expression. To cause this, the lesion is usually cranial to S1. Cats are especially difficult to manually express due to their high external sphincter tone.
Let's look at the bladder innervation for just a moment. The detrusor muscle contracts secondary to innervation that comes from the T12-L1 region via the hypogastric nerve. There are two sphincters, both innervated by nerves arriving from the pelvic plexus (S1-S3 region), that help retain urine. The external sphincter is the only one with voluntary control and that is handled by the pudendal nerve. When we say an upper motor neuro bladder (UMN) we are really talking about anything cranial to the pudendal nerve, that is S1, because that is the only nerve with voluntary control. 

We use manual expression in the acute phase of spinal cord injury to avoid separation of the tight junctions of the bladder wall muscles and, therefore, possible permanent injury to the bladder wall. Manual bladder expression works because pressure is exerted onto the urinary bladder which then forces the internal sphincter open, and eventually the external sphincter as well. Due to the high external sphincter tone occasional urinary rupture has occurred when expressing cat urinary bladders. Dogs appear to have less tone and therefore rupture is less common. A recent study (Galluzzi F, De Rensis F, et al Nov 2023) evaluated 34 cats with UMN induced urine retention secondary to acute or chronic spinal cord injury. They divided the cats randomly into two groups: group M underwent manual expression only and group MT underwent manual expression PLUS tactile stimulation of the perigenital region during expression. Tactile stimulation was described as a rapid striping motion of the perigenital region (from prepuce to scrotum or anus to vulva) over a 30 second period. This technique was copied from how female cats will lick their kittens during the first few weeks of life to stimulate urination.(As an aside - In a small study of cats less than 2 weeks of age, urinary retention occurred if this stimulation was not applied.) With this understanding, Galluzzi et al added tactile stimulation to manual expression to see if it improved bladder expression. In the M group, a urinary stream was achieved in half of cats while the MT group obtained a urine stream in 100% of the cats. Additionally, the stream was obtained in significantly less time (3.75 seconds vs 7.8 seconds). This is so simple, and yet make so much sense!

Key Point
Bladder expression for cats with UMN bladder dysfunction could have manual expression PLUS tactile stimulation applied to improve success rates! 

I hope you enjoyed this week's TidBit Tuesday!  Do you have a case you feel would benefit from a neurology consultation? Please reach out or use the online scheduler to schedule a consultation. This has been an emotional week for many veterinarians that I know; please stay safe and know that my phone and email are always available for you if you need to talk. I hope you have a good week. 

What to do with a narrowed disc space?

Narrowed Disc Spaces

It's a Tuesday morning and on your schedule is a 2 year old MC Labrador retriever with a 2 week history of back pain. The neurologic examination is normal. Without any neurologic deficits, remember that the pet hasn't been diagnosed with neurologic disease (yet), so spinal pain can be due to bone, joint, nerve, spinal cord, muscle or meningeal in origin. You elect to take sedated spinal radiographs and send them off to the radiologist. A radiologist will report what they see, which often includes "narrowed disc space(s)" on the report. What do you do with this?

Does a narrowed disc space indicate a disc herniation?
No, sorry. A narrowed disc space could be positional (often), beam angling (often), due to disc degeneration, or disc herniation. Disc degeneration occurs when hydration leaves the annulus fibrosis, thus causing the disc to shrink a little. This is a normal aging process and does not indicate a herniation. Herniation occurs when part of the disc (annulus fibrosis (AF) or nucleus pulposus (NP)) leaves it's normal position. When the NP leaves, we call it a Type I disc herniation. Type I disc herniations are common in chondrodystrophic dogs and about 30% of non-chondrodystrophic dogs. Clinical signs often include calcification of the NP which might be visible on radiographs. Remember, in situ calcification is appropriate and normal for chondrodystrophic and some non-chondrodystrophic dogs and does not indicate herniation. Calcification in the canal suggests that the disc has herniated but does not indicate that the current clinical signs are due to THAT disc herniation. This means we cannot diagnose a type I disc herniation strictly on radiographs. An MRI, CT or myelogram is needed to diagnose a type I disc herniation. 

When the AF displaces, it is called a Type II disc herniation. This is more common in non-chondrodystrophic dogs and is often part of disc associated wobblers and lumbosacral disease. No calcification occurs for this form of herniation therefore it cannot be seen radiographically. A narrowed disc space often (but not always) accompanies a type II disc herniation but is not always radiographically visible. An MRI, CT or myelogram is needed to diagnose a type I disc herniation. 

What about FCE or ANNPE?
Acute noncompressive nucleus pulposus extrusion (ANNPE) or fibrocartilaginous embolism (FCE) are two more forms of disc herniation where in a small amount of disc material leaves its normal location, often under great force. A narrowed disc space can be seen with these types of disc herniation as well but would  NOT be diagnostic for either disease. An MRI is needed to diagnose an FCE or ANNPE. 

What causes of back pain CAN you diagnose on radiographs then??
The most common causes of spinal pain are 2 "D"s, 2 "T"s and an "M" (as I teach it to students). Discospondylitis, disc herniation, trauma, tumor, and meningitis. Of these, only discospondylitis, vertebral neoplasia and fracture/subluxation can be diagnosed on plain radiographs.

The patient above could have discospondylitis on their differential diagnoses list therefore radiographs are absolutely indicated. However, please be cautious reading too much into a "narrowed disc space" and instead look for discospondylitis, vertebral neoplasia or signs of trauma. 

I hope you enjoyed this week's TidBit Tuesday! We're almost into March which, if you're a long-time patron, you know means we're approaching St. Patrick's day. My girls are Irish Dancers and, as such, usually perform in over 30 shows in the month of March. That means this proud mamma has a more limited work schedule due to all of the driving so PLEASE reach out if you cannot find a suitable time on the online scheduler. I may (often can) shift things a bit to accommodate your request! Have a great week and stay safe out there. 

Which Reflexes Should I Do?

Have you ever looked down at the patient, laying calmly and quietly in lateral recumbence, and thought “okay, which reflexes do I do?” There are several choices for each limb, but the most commonly assessed reflexes are as follows:

• Thoracic limb (I was trained by Dr. DeLahunta and was taught to never call this the front limb, but you are welcome to do so!): Biceps, triceps, extensor carpi radialis and withdrawal.

• Pelvic limb (same story as above): patellar reflex, cranial tibialis, gastrocnemius and withdrawal.

Some of these reflexes are harder than others to observe and obtain. The purpose of performing the spinal reflexes is to assess the sensory and motor pathways associated with that specific peripheral nerve and the spinal cord segment. For example, the patella reflex evaluates the femoral nerve and the L4-6 spinal cord segment. A present reflex suggests this pathway is intact. An absent reflex suggests that the peripheral nerve (femoral nerve) and/or the L4-6 spinal cord segments are NOT intact. A recent study (Chiang B, Garia G, et al 2024) evaluated each of these reflexes in 101 dogs and asked 1 neurologist and 1 resident to determine if they were obtained, or not (simple binary question).
Several of the reflexes had high intraobserver agreement, which would suggest that these are both easy to detect and possibly easier to obtain. The reflexes which high intraobserver agreement included the extensor carpi radialis, withdrawal reflexes in both thoracic and pelvic limbs, patellar reflex and cranial tibial reflex. Although all reflexes could (might I say should?) be attempted in the neurologic examination, sometimes we don't have this luxury. From this study, I would suggest that the 4 reflexes mentioned above should be reliably present. If you perform these reflex tests and do not observe a response, it is reasonable to consider them absent or delayed. 

Not sure how to perform these reflexes? I run personalized CE events, including live animal neurologic examination practice, in your clinic. Email me to learn more or to schedule. 
Does neurology make you nervous?? Please reach out to schedule your patient for a neurologic examination or reach me via email with any questions. My job is to help you decide if a patient has neurologic disease, or not, and the way we do this is to utilize the neurologic exam.

Thanks for reading. This article can be found here:DOI: 10.1111/jvim.16999

How Effective is Zonisamide in Cats?

Seizures are a common reason for me to evaluate cats and therefore (I assume) something you encounter frequently. Seizures originate from the forebrain (prosencephalon) and can be secondary to idiopathic epilepsy, structural epilepsy (such as congenital disease, neoplasia, meningoencephalitis, cerebrovascular events, head trauma, and on goes the list), or metabolic seizures (hypoglycemia, thiamine deficiency, etc.).

The mainstay treatment for cats has been phenobarbital for many years and not without good reason. Phenobarbital controls seizures in over 90% of cats, regardless of the etiology, and has predictable clinical side effects. When cats cannot tolerate phenobarbital, or have seizures in excess while on phenobarbital, other antiepileptic drugs (AED) are added; one of those is zonisamide. Very little data has been published to date about zonisamide use in cats. A recent study out of UW (go Bucky) was published recently. I thought it was worth a quick summary, TT style.

How many cats were enrolled in this retrospective, multicenter study? 57

The median age of seizure onset was 7 years (range 0.17-22) and the median age of onset for cats diagnosed with idiopathic epilepsy was 8 years. Note the difference between cats and dogs! Dogs have a lower median age at onset! Importantly, note that 30 cats did not have advanced diagnostics (52%) which means a final diagnosis was not reached and therefore their disease may have affected their response to zonisamide (but we don’t know!).
How did the cats on zonisamide respond to treatment?

• There was a significant decrease in seizures/month AND seizures/day after starting zonisamide. Note: we don’t know how long the seizures were monitored before starting zonisamide.

• 70% of cats responded to zonisamide monotherapy (had less than 1 seizure per 3 months)

• 56% of cats responded to zonisamide as add-on therapy

• Almost 70% of cats diagnosed with idiopathic epilepsy responded to zonisamide but it isn’t clear if these cats were on monotherapy or add-on therapy.

• The median dose was 7.5 mg/kg/day with about 1/3 of the cats receiving the drug once daily and 2/3 receiving it twice daily.

• More cats obtained seizure control on twice daily dosing than once daily dosing but the side effects were more profound on twice daily dosing.

• Side effects were noted in 15/57  cats and they included inappetence (10 cats), sedation, ataxia and vomiting for most reports. The duration of the side effects was up to 4 weeks after starting the medication. This is surprising and warrants further investigation. Anorexia has been the side effect I note more commonly but

• No clinically significant CBC or biochemistry changes were noted on the cats in this study

So what’s the take home message? Would I use zonisamide in a cat? A qualified, yes. Phenobarbital still has a better reported seizure control compared to this cohort of cats on zonisamide. BUT it is worth a try if the cat fails treatment with phenobarbital and the don’t have a history of a sulfa drug reaction (zonisamide is a sulfa derivative). Starting dose should be less than 10 mg/kg daily, and side effects appear dose dependent…but last awhile!

Thanks for reading this week’s, TidBit Tuesday! I hope you learned a little something – I know I did! Keep those consults rolling. Have a great week and stay warm and safe out there.
 
 Reference: https://doi.org/10.1111/jvim.16984

Anesthesia for Pets with Seizures

It’s a Tuesday morning, and on your schedule is a 6 year old Maltese dog with a 3 year history of seizures that appear well controlled on phenobarbital monotherapy. She has a history of 1 seizure every 6-8 months and each seizure is less than 3 minutes in length. No interictal signs noted by the owners and she continues to have a normal neurologic exam. Today, they would like to discuss doing a dental for their dear little dog. What should you consider? How does general anesthesia for a patient with neurologic disease differ from those without?

The Risks of Anesthesia

General anesthesia is not necessarily bad. 😊 The biggest two risks of general anesthesia for dogs or cats with seizures are (1) hypotension and (2) negative effect on the seizure threshold. Let’s talk hypotension.
Your goals are to preserve cerebral blood flow, which is largely controlled by the cereal perfusion pressure, which is largely controlled by the mean arterial blood pressure (MABP). MABP is directly related to intracranial pressure (ICP). Thankfully there is a wide range at which MABP will have little negative effect on ICP. MABP between 50-150 mm HG should result in constant ICP, if other parameters are equal. Hypotension can be caused by some of the medications used (I’m looking at you acepromazine) or caused by CO2 levels. If the PaCO2 levels are above 50, a risk of vasodilation occurs which may decrease MABP. Monitoring CO2 can be quite useful to avoid this. If vasodilation occurs, and consequently decreased MABP, perfusion to the brain can be compromised. Hyperventilation will decrease the PaCO2, result in vasoconstriction and maybe lower the ICP. Some references suggest that PaCO2 should be between 30-35 for “appropriate” cerebral perfusion. Big disclaimer today – I am not an anesthesiologist so specific questions about anesthetic protocols should be directed to your local anesthesiologist! Long-standing, serious, hypotension can affect neuronal membranes and in rare situations could cause neuronal cell membrane damage, or a worsening seizure disorder. Thus, try to keep the PaCO2 in a normal range, and monitor blood pressure for pets with seizures undergoing anesthesia. 
With respect to the seizure threshold, isoflurane, diazepam, midazolam, and possibly propofol are neuronal protective. If you have the luxury of choice, consider using one (or all!) of these medications in your anesthetic protocol. If you have a patient with poorly controlled seizures, administration of IV phenobarbital 20 minutes before starting anesthetic recovery may be useful to add seizure protection during the recovery process. ALWAYS go slow! Give the phenobarbital over 20-30 minutes as a slow infusion to avoid severe cardiovascular or respiratory suppression. This drug is closely related to pentobarbital, our common euthanasia solution. Most patients can receive benzodiazepine medication if active seizures are noted during the recovery process. Paradoxycal hyperactivity following benzodiazepine adminsitration occurs rarely but would be a reason to avoid using the drug in the future if a patient exibited these signs. Patients with significant hepatic disfunction such as those with portosystemic shunts should either avoid benzodiazepine drugs due to inadequate metabolism, or be adiminsered a 25% dose. 

Any anesthetic event, even an uneventful one, can put a patient with a known seizure disorder at risk for seizure breakthrough. This risk persists for at least 24 hours following anesthesia but in rare patients it can be longer. Owners should avoid leaving the pet alone for extended periods of time such as traveling by airplane, boarding the pet or other unobserved time in the first 24 hours after anesthesia. Never withhold chronic anticonvulsant medications prior to anesthesia. Bromide can cause vomiting therefore it should be given with a small meal. Patients receiving bromide (liquid) can receive it rectally if they are anesthetized early in the morning and a small snack with their bromide is not possible. Phenobarbital, levetiracetam and zonisamide can be given on an empty stomach without high risk of GI upset.

This topic was suggested by one of your colleagues - thanks for the suggestion! Do you have a topic you wish I’d cover? Please reach out!  Thanks for reading and have a great day!

Limping - Orthopedic or Neurologic?

Limping is often orthopedic in origin however in some situations limping can be of neurologic origin. Nerve root signature (NRS) sign is observed clinically as a non-weightbearing flexion of one limb, during standing, which may also appear like limping when gaiting. The suspected causes for NRS include vascular compression, inflammation or compression of a nerve root. This is most commonly noted in the thoracic limbs but has been reported in the pelvic limbs also.
In a recent study, a group from NCSU evaluated dogs with cervical disc herniations to see what criteria were present when they had signs of a NRS. This study included 47 dogs. Not surprisingly, all 47 had signs of cervical hyperesthesia with signs like ataxia (n=14), intermittent lameness (n=7), tetraparesis (n=2) and tetraplegia (n=1) being observed less frequently. I personally am not sure how you can identify a dog with a root signature sign if they’re plegic…but apparently, they did! Interestingly (to me) the site of disc herniation was C2-C5 in 20 dogs (43%) and C5-T1 in the other 27 dogs (57%). The nerve roots are supposed to arise from the C6-T2 region which is why it would make the most sense that a NRS sign should involve those nerve roots. Why did the C2-C5 region have NRS signs? Perhaps there was tethering of the nerve roots from "tugging" secondary to a cranially located disc. Perhaps anatomically they had a neve root arise more cranial than typical.
Spinal cord compression was mild in the majority of cases but remember it takes a TON of disc material in the cervical spinal cord to result in compression. Mild spinal cord compression is often surgical because the canal is much more voluminous around the smaller spinal cord (which is different from the thoracolumbar spine). Therefore the canal can contain loads of disc material yet the spinal cord has room to scootch over away from the disc, thus resulting in mild compression. Disc material was almost 3x more likely to be located laterally, within the spinal canal, than medially. Additionally, dogs were 2x more likely to have disc material compressing a nerve root compared to dogs without NRS. The last interesting finding is that 75% of the dogs in this study were over 7 years old. Typical chondrodystrophic disc degeneration with resulting herniation occurs in ages 3-7 year old. Is there a relationship between age, site of disc herniation and NRS or was this coincidental? I’m not sure but felt it was worth of comment.
 
Take away message:
Thoracic limb limping is often orthopedic in origin, however NRS should be considered for cases in which orthopedic disease is not identified. Nerve root signature sign secondary to a cervical disc herniation is more likely to be lateralized and therefore referral for surgical correction is strongly recommended to alleviate the compression to the nerve root.
 
Thanks for reading! Are we through deep winter? I’m not sure but I sure hope you’re staying warm! Please reach out with any questions about root signature sign or other neurologic cases. Have a great week!

Heat Tilt, Turn or Neck Turn...so what?

Does a head tilt help with neurolocalization?
 

A recent study by Nagendran et al (The value of a head turn in neurolocalization, JVIM 2023) described 4 distinct areas of neuroanatomic lesion localization for head turn, head tilt and neck turn and looked at head and body position in each of these localizations. If you see a patient with their head deviated to one side yet parallel to the floor, that would be a head turn. If a patient has their head deviated to one side NOT parallel to the floor, we would consider this a head tilt. The head tilt can be anything from 1-90% from the x axis! If the neck is turned to one direction it would be called torticollis and may be (and often is) associated with either head tilt, head turn, or both. This recent article looked at these three signs, in reference to the neuroanatomic lesion localization, with the goal of trying to sort out the underlying neuropathology (totally cool but not "light reading" and therefore saved for another conversation).
Key Points:

• Forebrain disease – The majority or patients had an ipsilateral head turn, with less than ½ of the dogs demonstrating ipsilateral body/neck turn.

• Brainstem disease – All dogs had an ipsilateral head turn, and 5/9 had an ipsilateral head tilt, with a rare dog demonstrating a neck turn.

• Cerebellar disease – All dogs had an ipsilateral head turn and the majority had a contralateral head tilt with a rare neck/body turn noted showing a contralateral neck/body turn.
  

• Cervical spinal cord disease – all dogs had a contralateral head turn along with a majority (6/7) showing a ontralateral head tilt.

Summary:

• Head turn ONLY – consider forebrain disease

• Head turn with neck turn (ipsilateral) – consider forebrain disease, but the neck turn is an inconsistent finding in many dogs with foreain disease.

• Head turn, neck turn AND head tilt – most likely cervical spinal cord disease but cannot rule out cerebellar disease.

• Head tilt only – likely brainstem disease (or peripheral vestibular disease!)

Take Home Points:
A head tilt, head turn, or neck turn is a useful physical examination finding to point you at neurologic disease however they aren’t discretely localizing on their own. Using the information above, you may be able to support a localization noted in concurrence with your other neurologic findings.

Thanks for reading! I made the difficult decision to increase my consultation fees this year so if you didn’t get an announcement please reach out and I can send you the updated fee schedule. Lastly, it’s winter!! That means sometimes travel can be hazardous and cancelations can happen. I don’t charge if we cancel due to inclement weather and will do my best to work your patient into the schedule as quickly as possible afterwards. I appreciate your business very much and do my best to meet your expectations. Have a great week!

Strokes in Dogs

Strokes are an increasingly common cause of seizures and other intracranial signs in dogs (and cats). Why is the diagnosis becoming more common? My theory is that we are simply performing more MRIs, and therefore making the diagnosis more readily, but it is possible that increasing comorbidities or breed related changes may contribute to the increase in diagnosis.

What is a Stroke?
Stroke, or cerebrovascular disease (CVD) occurs when normal brain fuction is disrupted due to hemorrhage or infarction. CVD is typically due to occlusion of an/multiple intracranial vessels however hemorrhagic strokes can occur in rare cases. Around 50% of dogs will have an underlying predisposing facture such as hyperadrenocorticism, hypothyroidism, protein loosing nephropathy, heartworm disease, heart disease (less common as a cause!) or other "hypercoagulable" diseases. The other 50% do not have any identified predisposing factors and are therefore considered to have had an idiopathic vascular event. 

Clinical presentation

• Acute onset, with progression not typically noted after 24 hours (but it can in rare cases)

• Common in older dogs, less common/rare in younger dogs

• Gait changes (hypermetria, ataxia) and seizures are the two most common presenting complaints leading to a diagnosis of CVD

Diagnosis
The best diagnostic tool for CVD is MRI. Indication of vascular occlusion can be seen immediately but tell-tale signs may resolve if imaging is performed too long after the onset of the clinical signs. 

Treatment
Supportive treatment is often the only treatment needed. Supportive treatment may include anticonvulsant drugs, intensive nursing care if non ambulatory, or rehabilitation if gait abnormalities are identified. A neurology consult may help guide treatment for you and the client.

Outcome
The majority of dogs will improve following CVD but time to improvement and degree of improvement is variable, and based on severity of neurologic impairment, and MRI findings. Recurrence can occur, but is less common. We previously though it was rare, but in one study in Japan (see below) 11 of 50 cases available for follow-up had clinical signs of recurrence of disease after a diagnosis of CVD. A persistent seizure disorder is possible following a CVA. Repeated seizures, without the development of other neurologic signs, could suggest a seizure disorder and NOT progression or regression of disease. 

Other Cool Facts
The Japanese study referenced below noted August and December as months with significantly higher stroke diagnoses, compared to all other months, and October as the lowest month. Interesting!

Thanks for reading. Have a great week and keep those consults rolling! With the onset of winter weather, mobile neurology consultations may become challenging at times. Remember a video consult may suit your needs if I cannot be on site due to inclimate weather! Stay safe and warm out there this week, folks!

Reference: Ozawa T, Miura N, Hasegawa H, et al. Characteristics of and outcome of suspected cerebrovascular disease in dogs: 66 cases. JSAP (2022)' 63, 45-51.

Hypokalemia Myopathy and Positioning Head Tilt in Cats?

I read an interesting article recently about positioning head tilts in cats with hypokalemia myopathy (https://doi.org/10.1177/1098612X231175761) This isn't likely to be something you encounter often in practice, but I hope you will also find it an intesting read nontheless. 

Hypokalemic myopathies are common in cats and often result in signs of weakness including cervical ventroflexion and/or tetraparesis. We can see hypokalemia secondary to renal disease, hyperthyroidism, dietary insufficency, chronic vomiting/diarrhea, and other metabolic causes. The subsequent myopathy occurs due to overpolarization of the muscle sarcolemma resting membrane potential making it resistant to depolarisation. Without depolarization, there is no muscle contraction and we see clinical weakness. 

When the head is turned, the cerebellum (specifically the nodulus and uvula) receive input from the vestibular nuclei, who in turn receive sensory information from the stretch receptors in the cervical muscles, on the whereabouts of the head and neck. This allows the cerebellum to modify the head position so that the head remains paralell to the ground as it is turned. With positioning head tilts, the head tilts to the opposite direction that the head is turning. When looking straight, no head tilt is observed. When turning right, the head tilts slightly to the left, for example.  

This article described 14 cats who had a positioning head tilt obseved on neurologic examintation AND had concurrent hypokalemia. One cat had an MRI and no cerebellar lesions were noted. Does that mean the others didn't? No, of course not. However, when the potassium was normalized the positional head tilt resolved. This would suggest cause and effect but isn't definative. The authors supposed that the muscle firing in the spindle fibers (the very small muscles located in the bigger muscles that convert stretch to neuronal impulse for sensory information) weren't able to depolarize appropriately. This lack of depolarization resulted in an absence of information about the whereabouts of the cervcial muscles (and those attached to the head, specifically) and didn't allow the cerebellum to modify head posture when turning. Pretty cool, huh? Although this is just a therory, I personally think it is pretty slick and clever. 

Take home message:
What do you do with a positioning head tilt in a cat? Look for hypokalemia and if identified, address it! 

Do you know that I'm in charge of my own schedule? I'm not corporate or owned by anyone! So if you cannot find a suitable time on the scheduler please email me! I will do my best to find an earlier time to accommodate a more urgent case. Some of you lovely, considerate, folks have told me that you hate to bother me to ask. If you're one of those, please know you're not a bother. We're both trying to work on behalf of your patient! 
Have a great week. I hope you enjoyed this little TidBit as much as I did. I look forward to working with you soon!

How to Localize a Cranial Nerve

As we sit here at the head of the year, I cannot think of a better time to review the cranial nerves. (Yes, I like cheesy jokes. I have kids. Here's another: what's the best present? See the bottom for the answer.)

First important thing to remember about cranial nerves: all cranial nerves except I and II have cell bodies associated with a specific brainstem segment. You might even argue that CN II localizes to the thalamus, which is an embryological part of the brainstem but...well, then we should have a coffee and get to know each other better!  Let's stick to the idea that CN III-XII have cell bodies in specific brainstem segments, thus making it possible (dare I say easy??)  for us to localize a lesion to either a specific brainstem segment OR the peripheral nerve. 

What are the names of the brainstem segments, again? (Mesencephalon, metencephalon, myelencephalon). Okay, whew! Now that that is over, how do you decide if a deficit is coming from the nerve nucleus in the brainstem OR the peripheral nerve?

Take the following steps:

1. Identify the cranial nerve affected (i.e. facial nerve = CN 7).

2. Identify the segment of brainstem associated with the nucleus of this cranial nerve. Don't remember what cranial nerves are associated with which brainstem segment? Midbrain = CN 3,4; Pons = CN 5, Medulla = CN 6-12

3. Are any ipsilateral long tract deficits (postural reaction deficits, hemiparesis) or mentation changes (obtunded, stupor, coma) present?

   1. If yes, the lesion is in the brainstem segment associated with the cranial nerve (i.e. medulla).

   2. If no, the lesion is affecting the peripheral portion of the affected nerve

Guess what? You can apply these steps to any deficit affecting CN III-XII. Yay!
 
Do you need help performing the neurologic exam? I'd love to help! Looking for the answer to the joke? The answer is: a broken drum! You just cannot beat it. Thanks for reading and Happy New Year!

I am Thankful For You

Thank You and Happy New Year


As we near the end of 2023, I'd like to take this moment to thank you. Thank you for welcoming me into your clinic, for subscribing to the TidBit Tuesday emails, for providing great feedback on cases we've seen together AND on the TidBit Tuesdays that spoke to you, for allowing me to help care for your patients and most importantly, for being the kind, caring and thoughtful vets that you are! It is a pleasure to work with you, see patients with you, consult with you, and learn along with you. I hope you had a good 2023 and that 2024 brings joy, health and happiness to you and those you love. 

Happy New Year! I am excited for 2024 and look forward to working with you soon!

When is Lameness not Orthopedic?

Lameness is typically orthopedic, as we know, but there are times when this isn’t true. How do we know when this is true? To answer this question, I’d love to go through a case with you today.

Signalment: 11 year old FS Labrador

History: She has a 4 week history of right thoracic limb lameness. She is a hunting dog, and signs were noted after a busy weekend in the field. On initial evaluation, mild discomfort was appreciated in her elbow therefore carprofen was started. Clinical signs did not improve; they worsened. She became intermittently non-weightbearing lame in the right limb. All other limbs appeared normal. Additionally, she started helping when laying down or rising from laying. At this point, I stepped into the game. What am I looking for to suggest this might be neurologic in origin?

Neurologic Examination:

Mentation: BAR

Cranial nerves: miosis OD, did not dilate in a dark space. Remaining CN normal.

Gait: Ambulatory, moderate right thoracic limb lameness. When toe touching, the limb was touching on tiptoe only.

Reflexes: Reduced withdrawal distal to the elbow on the right (unable to flex the carpus or elbow completely during withdrawal but able to mechanically flex both joints when I flex them), unable to detect triceps reflex on either side, remainder normal. Absent cutaneous trunci reflex on right, normal on left. Normal reflexes both pelvic limbs.

Postural reactions: Normal paw replacement in left thoracic limb and both pelvic limbs. Unable to assess paw replacement in the right thoracic limb due to non-weightbearing status. Reduced hopping on right thoracic limb compared to left thoracic limb.

Palpation: No spinal pain, normal cervical ROM.

What is the neuroanatomic lesion localization?

The first question is always, is the problem neurologic in origin? She has evidence of reduced reflexes so I would suggest, yes, it is. Essentially, our abnormalities are focused on that right thoracic limb with the addition of miosis OD and absent c. trunci right side.

Reduced withdrawal in the thoracic limb suggests a radial nerve injury/damage. Even though signs are distal to the elbow, the lesion could still be proximal, and neurodegeneration has occurred distally. Is the damage inside the spinal canal (central) or in the peripheral nerves (brachial plexus)? To answer this question, look at the right pelvic limb. Do you see any paw replacement deficits or weakness in the right pelvic limb? These are the long tracts going from the limb to the brain and the must pass right through C6-T2 and C1-C5 as they do so. If the lesion is in the canal, we should see paw replacement deficits in the right pelvic limb. We don’t, so the lesion is more likely in the radial nerves after they have exited from the canal.

What do we do with the miosis? The sympathetic pathway to the eye is as follows: thalamus à brainstem à cervical spinal cord à exit T1-T3 à join vagosympathetic trunk and ascend to the head à ganglion  à go through bulla to jump on CN 5 (trigeminal) à end in the iris for dilation. The radial nerve exits from segments C6-T2, which would cross over with T1-T3 and therefore we could make an argument that the miosis is secondary to involvement of this segment of the radial nerve.

What about the c. trunci? This one is pretty simple to understand once we refresh our memory of anatomy. Cutaneous trunci reflex is a simple spinal cord reflex that uses the dorsal sensory spinal nerves as afferent (sensory), and lateral thoracic nerve as efferent (motor). The lateral thoracic nerve arises from C8-T1. This fits with our assumption of a C6-T2 right sided neuropathy because loss of the lateral thoracic nerve on one side would cause an absent cutaneous trunci reflex.

Neuroanatomic lesion localization: Peripheral C6-T2 neuropathy/radiculopathy.

The differential diagnoses for this case were a lateralized intervertebral disc herniation, neoplasia, much less likely neuritis (infectious or inflammatory) and hypothyroidism. As it turns out this dog was diagnosed via MRI with a mass in the right brachial plexus. The owners elected amputation and it was determined to be a nerve sheath tumor. Why did the signs appear acutely? It’s not completely clear but my guess is that the dog was already decompensated slightly, and the heavy work caused inflammation or maybe even hemorrhage around the mass that resulted in an acute exacerbation.

That’s it for now! Reach out if you have any questions about this case, or any other case! I look forward to working with you soon. Have a great week!

Non-Convulsive Seizures in Dogs

Non-Convulsive Seizures in Dogs and Cats With Cluster Seizures

This week we're going to dig into non-convulsive seizures in dogs a bit before we jump off of the seizure bandwagon and back into other topics in neurology next week. (Sorry to the surgeons that read these!) A recent study out of Germany by Tastensen et al (DOI: 10.1111/jvim.16953) evaluated nonconvulsive seizures in dogs and cats with cluster seizures. A few definitions, first....

Cluster seizures: 2 or more seizures within 24 hours in which pets regain consciousness between seizures. 
Status Epilepticus (SE): Seizures lasting for longer than 5 minutes or 2 or more seizures in which consciousness is not regained. 
Nonconvulsive seizures (NCS): no visible somatic or autonomic manifestation of seizures with evidence on EEG. 
Nonconvulsive status epilepticus (NCSE): no visible somatic or autonomic manifestation of seizures, with evidence on EEG and the seizures are lasting longer than 5 minutes. (yikes!)

This study evaluated 26 dogs and 12 cats with EEG monitoring following cluster seizures and found 11 of the animals (9 dogs, 2 cats) had NCS. Of these 11 dogs and cats, 4 dogs and 2 cats (16%) had NCSE. They found repeated doses of benzodiazepine drugs and levetiracetam did not break the seizures. Only inhalant anesthesia with propofol induction resulted in a return to baseline EEG. 

Six of 11 animals had a decreased level of awareness and a few of them had mild twitching of an ear which could have represented the somatic movement of the seizure. Sadly, this group had a much higher mortality rate (73% NCS; 67% NCSE) than the general population of dogs without NCS or NCSE (27%). Overall, cluster seizures have a higher mortality rate than for dogs or cats without cluster seizures (~40%) as well. None of these patients died as a result of NCSE or NCS however several were euthanized. 

The seizure etiology was more often structural epilepsy (neoplasia, encephalitis, malformation, vascular cause or trauma) and accounted for 22/38 (58%) of the animals in the study. About 18% (7/38) had idiopathic epilepsy, 11% (4/38) had unknown epilepsy and about 18% (7/38) had reactive seizures. Does this mean that dogs and cats with structural epilepsy are more likely to have cluster seizures, or does it mean that the prognosis is inherently poorer for animals with structural epilepsy? If the prognosis is poorer, do clients elect humane euthanasia when in a situation of NCSE more readily, driving up the mortality rate, or does the disease make it harder to treat? Non-convulsive epilepsy is more common in humans with cluster seizures as well, and has a higher mortality rate than people without NCE or NCSE. I don't have the answers to these questions but pose them as a way of critically reviewing the data provided.

Take home message:
If you have a dog or cat with a history of cluster seizures and they are persistently, mentally inappropriate (obtunded, stupor or coma) after stopping the physical appearance of the seizure consider nonconvulsive seizures. Inhalant anesthesia would be recommended however without additional diagnostic testing (such as MRI or spinal tap) it would be unknown if there is high intracranial pressure from the underlying disease which could increase the risk of complication with anesthesia. So what do you do in general practice? If the owner wants a referral for 24 care - start there. If not, consider a bolus of diazepam or midazolam. OR you could monitor for 1-2 hours to determine if the change in behavior is secondary to postictal changes. 

Not sure how to manage a seizure case? Feel free to email or call me or schedule a neurology consult! Please always text or call if it is an emergency; I don't check my email very often during the day.  Have a great rest of your day!

Once Daily Phenobarbital for Cats?

A study by Dr. Mojarradi et al, out of Sweden, was recently published in the Journal of Feline Medicine and Surgery reporting on once daily phenobarbital administration for cats with seizures. The reported half-life of phenobarbital in cats is 43-72 hours which could suggest once daily treatment is possible, however based on pharmacokinetic data twice daily dosing has been the standard of care. This retrospective study questioned if this was necessary. 

This study was a retrospective review of 9 cats up to 3 years from enrollment. They tracked the number of seizures before starting phenobarbital (unfortunately for an unknown amount of time) and compared that to the number of seizures after starting phenobarbital. The cats were required to have 2 or more seizures, separated by at least 24 hours, prior to starting phenobarbital however the frequency and duration of the seizure disorder for each cat isn't known. They do comment that 6/9 cats had 1 or more per month prior to starting phenobarbital. Phenobarbital was started at a mean dose of 1.8 mg/kg PO q24h, the mean serum concentration of phenobarbital was 11 ug/ml (range 6-17) at about 1 month (range 19-54 days). All but 1 cat was seizure-free at that first follow-up. The second and third follow-up appointments, roughly 1 year apart, showed a few more seizures in the time range however overall 8/9 cats were considered to be in seizure remission (no seizures for more than 12 months) at the end of the study. Seizure remission, as defined in this study, was less than 1 seizure every 12 months. If they started at 1 seizure/month, and ended at 1 per year that is a pretty remarkable improvement! So remarkable, I wonder if the phenobarbital is responsible for that shift, or not.
My questions:

• Could such a low serum phenobarbital concentration cause such a dramatic response?

• Could this be the natural regression to the mean (shifts that are unrelated to intervention)?

• Did the retrospective nature of the study include only cats that did well on once daily phenobarbital, otherwise they would have taken twice daily phenobarbital and therefore been excluded from the study? Was this group of cats bound to do well, in other words, and it wasn't due to medication?

Another study by Pakozdy (https://doi.org/10.1177/1098612X12464627) noted that over time, most cats have a natural reduction in seizures while on anticonvulsant drugs. They tracked seizures in cats over a 10 year period and noted that most improved, some were seizure-free and some stopped medication. About 16% of the cats that stopped medication needed to have it restarted due to a return of seizures. 

The data reported in the study from Sweden suggests that we could administer phenobarbital once daily but the results are so remarkable (marked seizure improvement in a short period of time, low serum drug concentrations) that I feel compelled to repeat this study with a different, perhaps large, cohort of cats and make sure this is reliable. My advice: don't switch to once daily just yet!

Thanks for reading! I love managing seizures so please schedule a consult if you have a case that you'd like more assistance with seizure management. I'm happy to help!