The Nuts and Bolts of Anticonvulsant Drug Monitoring

The following information is contained in these two tables:
1. What drugs can I run therapeutic drug monitoring levels?
2. Where do I submit samples?
3. When do I draw blood for sampling?
4. What is the standard reference interval?
5. What is MY (i.e. Dr. Heidi Barnes Heller's) recommended reference range
6. How should I collect this sample? Note - all samples for therapeutic drug monitoring should be spun and separated into a plain red top tube. Do not use serum separator tubes! Plasma can be used for some samples also. Please separate the plasma into a plain red top tube as well.
7. What time of the day should I collect the sample?
*** The format became a little messy with the mailer so email me directly if you want a printable PDF of these tables.

What is not contained in these tables?
How do I use this information obtained from a drug serum concentration?? Stay tuned for that in a separate TidBit Tuesday! :)

As always, please stay safe, and mentally and physically healthy out there. I love working with you and look forward to continuing to do so.

Please note that I am performing consults through December 25th and then I will be modifying my schedule through January 16th because of my concern for increasing COVID numbers following the holidays. As many of you know, I have an at risk kiddo so I am super-duper cautious. If you need a consult between December 25th and January 16th please email me to discuss options.

Happy Hanukkah to those of you also celebrating!

20% of dogs receiving AEDs have dermatologic reactions??

Up to 20% of dogs taking AEDs may have a drug reaction that manifests as a dermatologic reaction.

Wow! That number is higher than I remember from residency; what's your experience?? I dug into this statistic this week after consulting on a case about a possible dermatologic drug reaction in a dog receiving an anti-epileptic drug (AED).

What signs are seen?

During a prospective study, 15 dogs (of 137 dogs) were identified as having a dermatologic condition after starting an AED. However, three may have had signs before starting the AED. All 15 were treated with phenobarbital!

9 dogs were seen by a dermatologist and the following signs were documented:

• Extensive erosions or epidermal necrosis leading to skin detachment (4 dogs)

• Papules, pustules, erythema, crusty lesions (8 dogs)

• Pruritus and/or alopecia (3 dogs)

How do they *know* it is related to the drug?

They utilized an index based assessment, which is used for drugs in which withdrawal or drug challenges may be unethical (AEDs!). The index is called the Naranjo intext. I'm not terribly familiar with the nuances of using this index, so forgive my lack of a more detailed explanation. When they applied this, they considered 6 dogs to have probable cutaneous drug reactions, possible drug reactions in 8 dogs and doubtful in 1 dog. We all know these indexes can be wrong, but those numbers sound pretty compelling, and concerning.

How was it managed?

The AED therapy was withdrawn in 7 cases and 5 subsequently resolved completely with 2 weeks. Another dog had partial improvement after withdrawal of the drug and the rest received supportive or directed treatment such as anti-inflammatory, antimicrobial topicals, ant parasitic agents, or systemic prednisolone. All dogs had resolution of signs with the above treatments, but improvement wasn't complete and appeared temporary.

Key Point: Do a thorough physical examination on your patients before starting any AED and document new dermatologic changes if they arise. Can they still be coincidental? Yes. But, maybe we're are missing some that are not.

Do you need help with an epileptic patient? I am especially fond of helping with seizure management so I'd love to help! Call, text or email. Please note that I respond to emails at night (most days) so if you have an urgent question please call or text.

*Reference: Koch T, Mueller BD, et al. Cutaneous adverse drug reactions in dogs treated with antiepileptic drugs. Frontiers in Veterinary Science 2016: 3: 1-10.

Meningitis...Encephalitis...?

Canine Meningitis...Encephalitis...Meningoencephalitis... oh bother...

Canine Meningitis...Encephalitis...Meningoencephalitis... oh bother...

Canine meningoencephalitis is a general term, used to collectively describe inflammation in the brain and meninges of dogs. Although infectious meningoencephalitis can occur, the majority of dogs have a non-infectious, inflammatory disease.

Remember the term GME? Well, that is only ONE type of non-infectious inflammatory meningoencephalitis! Note: to call it GME we need histopathology. Not surprisingly, many clients do not opt for brain biopsies so we cannot confirm if it is GME, or NME or NLE or another histologic subtype of inflammatory brain disease antemortem. That won't do!

IF I CANNOT CALL IT GME IN A LIVE PATIENT, WHAT DO I CALL IT?

We call the collection of non-infectious, inflammatory brain diseases Meningoencephalitis of Unknown Etiology (MUE). Or, if you're British it's MUA (aetiology). Or, sometimes its called MUO (origin). Shoot, we're back to alphabet soup again. 😒 When we settle on a term, I'll let you know, but for now the literature typically refers to non-infectious, inflammatory brain disease as MUE. (Not GME)

CLINICAL SIGNS
* Any age, breed or body condition. (cats too!)
* Chronic or acute progression of signs (I've diagnosed it in dogs with clinical signs for 6 months, and those with a 24 hour history of signs).
* Multifocal or focal neuroanatomic lesion localization.
* Unless the dog has SRMA (one form of non-infectious inflammatory brain disease), fever is NOT a common clinical sign.

DIAGNOSIS
MUE is a clinical diagnosis which must be supported by diagnostic investigation. Without diagnostic investigation the word presumptive is recommended, or simply include MUE in the listed differential diagnoses in the medical record.

* Magnetic resonance imaging (MRI) focused to the area of neuroanatomic lesion localization
* Cerebrospinal fluid (CSF) analysis
* Negative geographically specific infectious disease testing
We cannot diagnose MUE with blood work, or on neurologic examination alone. (Sorry)

Extra tidbit - GME is not caused by vaccination or population density according to a recently completed study!*

TREATMENT
Standard treatment is immunosuppressive glucocorticoid therapy (1 mg/kg twice daily prednisone or prednisone equivalent dose) because of the ease of administration for owners, good penetration through the blood brain barrier and comparatively low cost. A slow taper over months is recommended, however some animals require medication for life. If glucocorticoid therapy is intolerable to dog or owner, other protocols could be considered.

PROGNOSIS
Survival to 3 months is the most reliable predictor of long-term survival.

What do I tell clients? Start treatment, and repeat a CSF tap at 1 month. If the pet is doing well, CSF tap is normal or normalizing, keep going. If all is going well by 3 months, consider repeating another CSF tap and continue to monitor life-long for relapse of clinical signs. The prognosis is based on the old saying, " if the dog is doing well, it's likely to do well." Sigh...just a sign that we have a lot more work to do sorting out this disease.

As a small business, I sincerely appreciate your business and your willingness to continue to support mobile neurology. I am the only mobile veterinary neurologist in Wisconsin and Illinois and, I appreciate your support!

Stay Safe, and Happy December Everyone!

*Barnes Heller HL, Granick M, Pinkerton M, Keuler NS. Case-control study of risk factors for granulomatous meningoencephalomyelitis in dogs. JAVMA 2019:254(7):7-10.

Tetanus and Animals

Tetanus and Animals

I saw a case of suspected tetanus this week in a cat so I thought we could take this opportunity to review this rare, but important, neurologic disease.

Tetanus is cased by the release of tetanus toxin by the Clostridium tetani bacterium. Once the toxin is produced in the wound, it travels via retrograde transportation from the peripheral nerve to the central nervous system where it attacks the real target: the inhibitory interneurons that regulate motor activity. So (you might ask), what is the lesion localization for tetanus? It is a CNS disease at the level of the spinal cord and brain NOT (as one might assume) a peripheral neuromuscular lesion localization!

Signs

The interneurons are focused on regulating muscle tone therefore a disruption of their function results spasticity. Remember, spasticity can occur in all skeletal muscles therefore diaphragm and intercostal muscles can be affected, resulting in respiratory paralysis. The spasticity can be stimulated by noise, touch and light. The incubation period for cats is 5-10 days with a longer suspected incubation period in dogs. According to a recent report about tetanus toxin, strychine intoxication is the only condition that exactly mimics the disease, however other myopathic diseases such as hypocalcemia can be included in the differential diagnoses in the early stages.

Treatment

Debridement of the wound(s) and antibiotics such as penicillin G and metronidazole are recommended to treat the infection but have no effect on the already-formed toxin circulating the body. Therefore, supportive nursing care is critical until a plateau in signs becomes evident. After this point, if the dog or cat can eat, drink, and void voluntarily, supportive care can be continued at home. Tetanus antitoxin is available for cases in which an early diagnosis is obtained however this has limited use in dogs and cats.

Prognosis

Recovery is expected for animals with appropriate supportive care. If respiratory paralysis occurs, ventilatory support may be needed, resulting in added expense and risk of secondary infections. However, a full recovery can be expected for dogs and cats affected by tetanus toxin with appropriate treatment and time.

A special shout out to the vets successfully managing this recent case. Keep it up and way to go!

Happy Thanksgiving! Stay safe, and keep those consults rolling.

Recent open access reference if you are interested: Popoff MR. Tetanus in animals. J Vet Diagn Invest. 2020 Mar;32(2):184-191. doi: 10.1177/1040638720906814. Epub 2020 Feb 18.

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.

Midazolam vs. Diazepam...Which Drug is Better for At-Home Cluster Care?

Midazolam vs. Diazepam for At Home Seizure Care

History of Cluster Buster Protocols

In 1995 Dr. Michael Podell championed the idea of at-home, rectal diazepam use for canine cluster seizures. In that study, dogs that received rectal diazepam had fewer  cluster seizures compared to those that didn't receive the drug. Since then, at home cluster care has become standard practice for many veterinarians. 
According to human literature, benzodiazepine drugs (midazolam, diazepam and lorazepam) are the "best" first line anticonvulsant drugs to stop status epilepticus. As is typical, we simply adopted this idea in veterinary medicine without data to support it's use. But...the benzodiazepine drugs do show improved seizure cessation so...they probably help in some manner. 

Which Benzodiazepine is Better?

Here is where the science gets a bit muddy. We've compared rectal diazepam to intranasal midazolam and intranasal midazolam was superior. We've compared intranasal midazolam to intravenous midazolam and intranasal midazolam stopped seizures faster. However, all of these studies involved few animals and ethically we cannot have a group of untreated animals to determine true efficacy. 

What are the current recommendations?

At this time, intranasal midazolam at a dose of 0.2 mg/kg up to 3 times in 24 hours is my recommendation for dogs with a cluster or status epilepticus history. Do your best to use a nasal atomizer because this has been shown to be the superior technique compared to nasal-drop application.  (I have found them at Midwest Vet:https://www.midwestvetsupply.com/products). Essentially nasal drop technique requires the client to drip the midazolam intranasal slowly during the active seizure while also avoiding getting bitten. The atomizer looks like a marshmallow that is attached to the end of the syringe and the client is then able to press the atomizer against the nare and dispense the dose in one "push". Not clear on this technique? Please ask me, I am happy to clarify! I do not have a financial incentive or disclosure for this product, or Midwest Vet Supply. :)

Hope you enjoyed the glorious weather a bit last week. I will be closed Friday October 16th, Saturday the 17th and Tuesday the 20th as we celebrate a collection of birthdays in my family. (Including mine!) 

Have a good week! 

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! 

Tick Paralysis and Dogs

Tick Paralysis and Dogs

The ticks are still here but owners may have stopped applying topical treatments. So fall is the time to be on the look out for Tick Paralyses (okay, really anytime but now isn't a BAD time to be aware)!

What causes Tick Paralysis?

Salivary transfer from a Dermacentor (in America) and Ixodes (in Australia, for my Australian readers) will result in neuromuscular blockade. How it actually works is really pretty ingenious. (Skip this next part if you're in a hurry.) At the presynaptic terminal, acetylcholine packets must be released into the neuromuscular junction so they can then bind to the post synaptic (muscle) membrane receptors. The acetylcholine binds to the presynaptic membrane using specific proteins as well as calcium. The saliva from one of the aforementioned types of ticks will interfere with acetylcholine release at the presynaptic terminal by binding calcium. Amazing, really.  

What are the common clinical signs?

If you cannot release acetylcholine from the presynaptic membrane at the neuromuscular junction, what can you do? 

Exactly, nothing. 

Therefore clinical signs are an ascending pelvic to thoracic limb flaccid paralysis. No reflexes, no motor, no paw replacement, nada. These signs begin 5-9 days after exposure to the tick saliva. Cranial nerves are RARELY affected. This is important because botulism more commonly affects cranial nerves and this can be one way to try to differentiate between these two diseases. 

How do you make the diagnosis?

1. Find the tick.
2. Remove the tick.
2.5 (Apply Frontline/Bravecto/other)
3. Clinical improvement should begin 24-48 hours after tick removal.
No specific testing is available to confirm the diagnosis. 

I once had to find a tick on an Old English Sheepdog waaaay back in the year 2000. Topical tick treatment wasn't as prevalent then as it is now, so our solution was to shave the dog. We found the tick between the dog's toes. (Insert eye rolling here!!) In 2020, I suggest applying Frontline/Bravecto (your choice of topical flea treatment) first then perform a non-invasive tick hunt and monitoring for clinical improvement. If ineffective after 48 hours you can either commence a thorough tick hunt, or search for other causes of flaccid paralysis. (Or, call me for a neurology consultation!)

How do you manage patients flaccid paralysis?

Flaccid paralysis means that the animal does not have reflexes, or voluntary motor. As such, these animals may be at risk of respiratory failure due to loss of intercostal muscle function. Therefore CO2 monitoring, respiratory watch and ventilatory support if needed can be very important in the early stages of disease. Due to the rapid recovery, most patients do not need long-term intensive nursing care or physical therapy. 

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! 

Metronidazole and Vestibular Signs

Today is the first day of Fall 2020!
In honor of this awesome season, I thought we'd talk about another type of fall...vestibular disease! :) 

How Does Metronidazole Cause Vestibular Signs?

It is not 100% certain, but it appears that modulation of GABA at the level of the cerebellum is involved. Stay with me...!! GABA is an inhibitory neurotransmitter and there is LOADS of GABA in the cerebellum because it is a largely inhibitory part of the brain. (I like to think of the cerebellum as my mother. As a mother, my job is to "modulate" the activity of my children so they don't get hurt! When you take a step, I tell you how far, how wide, etc. so that you don't trip on a stair. See my point?) Okay, so if the cerebellum is inhibitory to movement, and you remove inhibition, movement gets exaggerated. (Hypermetria, intention tremors, truncal sway!) The cerebellum helps to keep balance in check as well via various mechanisms. Getting back to metronidazole, if we inhibit GABA, then actions become more exaggerated. 

Signs of Metronidazole Toxicity

DOG: Signs of cerebellovestibular disease including head tilt, nystagmus, positional strabismus, truncal sway, hypermetria, intention tremor. 
CAT: Okay, cat's don't play by the rules. They show forebrain signs such as seizures, blindness and mentation changes. Let's not talk about cats today, okay?

Diagnosis of Metronidazole Toxicity

This is both an easy one, and a hard one. There isn't a specific "test" used to make the diagnosis. However, with a history of ANY DOSE of metronidazole within the last 12 hours, one might consider metronidazole toxicity. I have seen several dogs that received metronidazole historically without trouble and developed signs of toxicity on subsequent dosing. I also have seen signs of toxicity at the first dosing sequence at standard doses. It is more likely at higher doses (60 mg/kg/day) but do not exclude the possibility at lower doses. 

Treatment for Metronidazole Toxicity

Stop metronidazole administration! Additionally, you can administer diazepam at 0.1-0.5 mg/kg PO q8hr for several days. Why diazepam? I'm glad you asked! Diazepam is a GABA agonist, therefore it confers more inhibition to the cerebellum. Dogs receiving oral diazepam recovered in 1.5 days compared to untreated dogs that recovered in 11 days. (Evans J, et al. JVIM 2003; 17(3):304-310.) I routinely prescribe diazepam for pets with suspected metronidazole toxicity as a result of this study. 

Whew it has been busy lately!! 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! 

Can the neurologic examination predict disease?

Age, the Neurologic Examination and Prediction of Disease

Age isn't a disease, right? But, disease is associated with age. The older pet, is more likely to have structural disease (i.e. idiopathic epilepsy vs CNS neoplasia), compared to the younger pet. But, none of us want to diagnose a terminal disease in an older patient simply because the patient is older!

How can the Neurologic Examination Help Vets with Old Patients?

Can we look at two of the most commonly performed tests on the neurologic examination and determine the sensitivity and specificity for the detection of a forebrain lesion? Actually, yes we can.  The menace response and paw replacement (previously called conscious proprioception) testing both assess the forebrain and are some of the most commonly performed parts of the neurologic examination. Here is what a recent group from Australia found:

Menace response
Sensitivity: 72%
Specificity: 47%
Odds ratio:  2.26

Proprioception
Sensitivity: 54%
Specificity: 72%
Odds ratio: 3.08
If age is then factored into the analysis, dogs greater than or equal to 6 years of age are more likely to have a forebrain disease detected if they have a menace or proprioceptive deficit. 

As a "field" neurologist (without a pocket MRI...yet) this tells me that I should encourage diagnostic imaging in patients with menace deficits and proprioceptive deficits. The chances (or Odds) of a patient having underlying forebrain disease is higher if they have these deficits than if they don't. Seems intuitive, but proprioceptive testing isn't as sensitive as assessing the menace response so by all means don't forget to do that on an older patient! :)

Hope this little study was insightful for you too.
Chan MK, Jull P. Accuracy of selected neurological clinical tests in diagnosing MRI-detectable forebrain lesion in dogs [published online ahead of print, 2020 Jul 15]. Aust Vet J. 2020;10.

Keep those consults coming! I'm continuing to answer email consults in the evenings but do my best to be available during working hours should you have a questions and wish to call or text me. On site consultation is available Monday through Saturday at variable times throughout the week.

Have a good week! 

C Reactive Protein and Discospondylitis

C-Reactive Protein and Discospondylitis

What is C-Reactive Protein (CRP)?

It is an acute phase protein that has been used in other inflammatory conditions such as SRMA, IMPA or inflammatory bowel disease to support or monitor the clinical response to treatment. 

Is it elevated with Discospondylitis?

Short answer: yes.
Long answer: It was elevated in most dogs in a recent study that were diagnosed with bacterial discospondylitis, but not all. In 8 dogs they measured it again 4-6 weeks into antibiotic treatment and it was normal in all 8 dogs. 

What can we do with this information in practice?

When faced with a patient with discospondylitis you can use CRP to support the radiographic evidence of discospondylitis. I would NOT suggest using this as a disease monitoring tool for dogs with discospondylitis because, as the authors point out, the intervertebral disc is a very immune privileged area of the body therefore infection could persist that is not reflected in the CRP. One of the dogs, in the study quoted above,  with normal CRP, had a recurrence of signs after stopping antibiotics. This suggests that CRP may not be a good long-term monitoring tool. 

That's all for this week! Have a safe, happy week and keep those consults coming! 

Nye G, Liebel FX, Harcourt-Brown T. C-reactive protein in dogs with suspected bacterial diskospondylitis: 16 cases (2010-2019). Vet Rec Open. 2020;7(1):e000386. Published 2020 Jul 20. doi:10.1136/vetreco-2019-000386

Neuroanatomic Lesion Localization Practice Case

Lesion Localization and Case Building Practice

Lesion localization is one of those things that can be lost, if not practiced. Don't lose it! You're welcome! :)

Maria, is a 13 year old FS Lab
History: Presented to me with a 24 hour history of acute onset difficulty walking. 

Neurologic examination:
Mentation: BAR
Cranial nerves: right head tilt, rotary nystagmus, remainder normal.
Gait: Moderate vestibular ataxia, falling right. No hypermetria or intention tremors noted. 
Postural reactions: absent right thoracic and right pelvic limbs, normal other limbs
Spinal reflexes: Normal all limbs, normal c. trunci and perineal
Palpation: non painful, normal cervical ROM

You know what you've got to do now, right?

What is the Neuroanatomic Lesion Localization?

There are several ways to go through lesion localization.

OPTION 1:
I like to make lists. Start by listing all of the abnormalities and ALL possible locations that could result in an abnormal finding. For example:
1) Right head tilt - peripheral CN 8 (right), medulla (right), cerebellum (right or left)
2) Rotary nystagmus - same as above
3) Vestibular ataxia - same as above
4) Reduced paw replacement right side - right C6-T2, right C-C5, right medulla, right pons, right or left midbrain, left prosencephalon.

Now, we start to eliminate some things. How do to differentiate peripheral vs. brainstem vs cerebellar disease? Well, for starters any animal with cerebellar disease is expected to have hypermetria and/or intention tremors and Maria did not. We can cross out cerebellar disease. What else? Animals with brainstem disease should have a) change in mentation and/or b)ipsilateral  paw replacement deficits and/or c) hemiparesis. Maria has paw replacement deficits ipsilateral to the head tilt so she most likely has brainstem disease. 

OPTION 2:
The other way to work through this is to identify the cranial nerve affected on the exam (in this case, cranial nerve 8), identify the brainstem segment associated with this cranial nerve (in this case, medulla) and then ask yourself if you can identify a,b, or c from above. If not, it is peripheral and if so, it is brainstem. 

Differential Diagnoses

Brain stem vestibular disease in an elderly dog without an important prior medical history would suggest the following differential diagnoses:
Degenerative: none
Anomalous: none
Metabolic: Hypothyroidism
Neoplastic/nutritional: Neoplasia of the brainstem
Infectious/inflammatory/idiopathic: meningoencephalitis (infectious or inflammatory)
Trauma: no supportive history
Vascular: Cerebrovascular accident (stroke)

Diagnostic plan

CBC, serum biochemistry, T4, blood pressure, urinalysis. (Screen for causes of stroke and hypothyroidism). Brain MRI +/- CSF tap. 

Final diagnosis: Cerebrovascular disease! She was lucky. We didn't find any underlying cause of disease therefore this was considered idiopathic vascular disease. She showed gradual improvement with the addition of meclizine over 3-4 days with a residual head tilt after 7 days. The head tilt is expected to be permanent but isn't always the case. 

How did you do? The neurologic examination, when done thoroughly, can be your best diagnostic tool for patients with neurologic disease! Keep practicing. 

I hope you are well, and taking care of yourself. If you have a dog or cat with neurologic disease please reach out - I'd love to help. 

Happy September 1st!

The Five Types of Disc Herniation

The Five Types of Disc Herniation (that we know of!)

1. Dystrophic calcification secondary to chondroid degeneration of nucleus pulposus (NP), called a Hanson Type I. This causes mechanical stress on the outer annulus fibrosus (AF), leading to rupture of individual collagenous strands of AF and eventually full failure.

2. Fibrous degeneration occurs when fibers of disc split leading to accumulation of tissue fluid and plasma between them. Over time the mechanical pressure exerted by NP causes thickening of the AF dorsally, causing protrusion. (Hanson Type II).

3. ANNPE (Acute noncompressive nucleus pulposus extrusion) - this is normal NP that is exploded into the canal, usually during activity. Also called a traumatic disc herniation.

4. AHNPE (Acute hydrated nucleus pulposus extrusion) – An apparently normally hydrated NP that is compressive and often located ventral to the cord, often in the neck.

   1. Significantly more neuro deficits and less signs of cervical pain with AHNPE compared to other causes of cervical myelopathy.

5. FCE (Fibrocartilaginous embolism): a piece of NP that becomes dislodged and finds its way into the vasculature surrounding the spinal cord. This can be into venous or arterial blood vessels. The end result is an acute shift in blood flow at the level of the spinal cord.

Match the clinical sign with the type of disc herniation

A. Chronic, progressive ataxia progressing to paresis
B. Acute, non-progressive unilateral weakness affecting one leg, or one side (hemiparesis)
C. Acute, progressive, painful ataxia progressing to paresis in a chondrodystrophic dog
D. Acute non-progressive ataxia and paresis affecting both sides of the body (paraparesis or tetraparesis)
E. Acute, rapidly progressive tetraparesis and ataxia of all four limbs with minimal cervical pain

If you answered...
Type I: C
Type II: A
ANNPE: D
AHNPE: E
FCE: B

you are correct!

Based on the clinical picture, it can be very difficult to distinguish Type I from ANNPE, and AHNPE. Typically, type I is painful (but not always), and the other two are minimally to non-painful. 

Which of these require surgery?

Any disc herniation that results in compression of the spinal cord with associated clinical signs could be considered for surgical correction. This statement would then suggest that Type I, Type II and AHNPE could be surgically corrected. Therefore, any patient with signs of a progressive or painful myelopathy should be evaluated for diagnostic imaging (typically MRI) for possible surgical intervention whenever possible.

Bonus question:
Can you name two diseases that are commonly diagnosed instead of a type I or type II disc herniation? Scroll to the bottom for the answer!

Change is coming! Starting in September I will have new fees, and new availability.  I am happy to accommodate outside of these hours whenever possible so please reach out if you cannot find a suitable time using the online scheduler. ( https://barnesveterinaryservices.com/ )

New Hours (Starting September 8th)
Monday 11a-1p, 4-5p
Tuesday 3-4p
Wednesday 11a-1p, 2-4p
Thursday 2-4p
Friday 12-1p
Saturday 9-11a

Bonus Question Answer
 Meningoencephalomyelitis (a.k.a meningitis), and neoplasia. Keep these two on your differential diagnoses list when you suspect a disc herniation!!

CBD oil and Canine Epilepsy

What is the Effect of CBD oil on Canine Seizures?

Yes, I'm opening a proverbial can of worms today! As a neurologist, vets often ask me if CBD can be used as an anti-epileptic drug (AED). As a practicing veterinarian in Wisconsin I say I cannot recommend or prescribe CBD containing products.

As a neurologist, I add the following…

In June 2019 a study was published that attempted to answer the question:
“What effect does CBD oil have on seizure control?”1
 According to the authors:

• CBD is metabolized through the cytochrome system in the liver in humans, and probably dogs. The ALP increased in all dogs receiving CBD oil in that study. What is the clinical significance? Unknown, currently.

• There was no difference in seizure response between the CBD group or the placebo group (Response = dogs that had a 50% or greater reduction in seizures during the 12-week observation period.) Do we need a different dose? Different formulation? Or did it simply not work for this group of dogs?

• Drugs that are metabolized through the liver (e.g. phenobarbital, zonisamide) may be affected by CBD. This means that the adverse clinical effects could be more pronounced in dogs concurrently receiving these drugs.

• What adverse clinical effects does CBD have? We don't know yet. Several dogs in the CBD group developed ataxia, however they were concurrently on other anti-epileptic drugs. Was the ataxia due to CBD, or because of increased serum concentrations of concurrent AED?

So, although my response to clients remains that I don’t recommend it. My reasoning includes all of the reasons listed above in addition to the recommendations by the government officials in Wisconsin.

What if a client wants to give it anyway? As a veterinarian, I would thoroughly document the discussion, and then recommend monitoring at least liver values (ideally the entire biochemistry panel) every 4-6 months while the pet receives the product. It may be that CBD is the magical seizure potion we are searching for to help our drug-resistant seizure patients. However, history would tell us that the newest “catch all” tonic is typically not as universally perfect as we wish it to be. Be educated, be careful, and be observant when we walk into this yet uncharted territory of CBD oil and seizures.

1. McGrath S. et al Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. JAVMA 2019; 254(11): 1301-1308.

 Are you working with a patient with seizures and need some expert help? I'd love to! Please reach out via email, telephone or schedule an appointment online.

Microbiome and Epilepsy

Microbiotia-Gut-Brain axis...say what?

There has been growing evidence in human, and veterinary, medicine to suggest that what is in the gut can influence brain development, function and even the course of disease. Many clients have a firm belief that food plays a role in a dog's epilepsy however it has been less clear to me what this role may be. Is it the gluten in the diet (as with some Border Terriers)? Or, is it the microbiome? Maybe both? Maybe neither?

Lactobacilli and the Influence on the Brain

Research suggests that Lactobacillus sp. can play a role on brain function in humans through it's anti-inflammatory properties and perhaps through the production of GABA, an inhibitory neurotransmitter. What about dogs with epilepsy? Dr. Karen Munana investigated Lactobacilli in fecal samples of dogs with epilepsy and compared them to fecal samples of dogs without epilepsy. (See reference below)

No difference in absolute ore relative numbers of Lactobacillus species were found in drug-free epileptic dogs compared to healthy dogs. Furthermore, Lactobacilli were not killed in culture when exposed to phenobarbital, potassium bromide, zonisamide and levetiracetam. 

For now, this means we don't see a difference in this important bacterial species. This DOESN'T mean that we may not find a difference in the future, and it DOES NOT mean that gut health isn't linked to canine epilepsy. I will keep my ear to the ground on this one and keep you posted on any breaking news on GI health-brain health linking.

Stay safe, stay healthy, and keep me posted on how I can help you, help your patients with neurologic disease!

*Muñana KR, Jacob ME, Callahan BJ. Evaluation of fecal Lactobacillus populations in dogs with idiopathic epilepsy: a pilot study. Anim Microbiome. 2020;2(1):19. 

Cognitive Dysfunction Syndrome in Cats

What is Cognitive Dysfunction in Cats?

Sixteen 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 learn more about aging in cats, it has become a more widely recognized disease by yours truly, as well as many of you in practice. 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 referred to cognitive dysfunction can also be associated with other age-related illnesses (e.g. osteoarthritis, structural intracranial disease such as neoplasia, or cardiovascular disease). 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, recently published in the Veterinary Clinics of North America by Dr. Miele and associates that echos 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...you see 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 disease. This may include complete blood count, full biochemistry panel including thyroid screening, urinalysis, chest radiographs, blood pressure assessment, brain MRI and possibly 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 specifically evaluating 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 do you see in practice? What have you used (successfully, or not) for treatment? Please reach out - I want to hear your perspective!

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.