Come mothers and fathers throughout the land
And don't criticize what you can't understand
Your sons and your daughters are beyond your command
Your old road is rapidly agin'
Please get out of the new one If you can't lend your hand
For the times they are a-changin'
(Bob Dylan, recipient of a Nobel prize literature)
We find Bob Dylan’s words particularly inspiring. No doubt the diagnosis and treatment of neurological disease is in flux. A new road to understanding! We welcome questions about our work and opinions from those that have experience with our work. Published studies support that inflammation is a significant cause of clinical signs related to neurological disease in humans and animals. Equine protozoal myeloencephalitis (EPM) is not the only cause of neurological signs in horses! A horse with an abnormal neurological exam may be difficult to diagnose. Often as not an exam may be abnormal after EPM treatment. We are trying to do something about that by putting our research into practice.
Our FDA concurred studies have open enrollment. Each protocol is designed to treat clinical signs of inflammation associated with neurological disease in a specific target population. The differences between the studies may be subtle and the purpose of this blog is to help you parse the difference in the study protocols to select the most appropriate course of action.
One study is intended to treat horses with lingering or recurring syndrome after EPM treatment. We call the syndrome PTEDS…post-treatment EPM disease syndrome. The name is similar to that given by CDC (Center of Disease Control and Prevention) for post-treatment Lyme disease syndrome (PTLDS). The short explanation is that after treating Lyme disease, or in our case EPM, there can be residual inflammation. The inflammatory syndrome may look like the original disease, but clinical signs are unresponsive to antimicrobials. After years of frustration with “chronic Lyme disease” it is generally recognized that PTLDS is the culprit. The term “chronic Lyme disease” is no longer supported by the experts. Also, CDC reports that studies have not shown that people who received prolonged courses of antibiotics do better in the long run than people treated with placebo for PTLDS (formerly “chronic Lyme disease”). Furthermore, long-term antibiotic or alternative treatments for Lyme disease have been associated with serious complications.
To enroll in study 219-FE-1.1 the horse must have been properly diagnosed and then treated with a full course (per label instructions) of a licensed anti-protozoal drug. The treatment must be within 90 days of enrollment into the study. If the horse was treated with compounded medication the horse may not enroll. If the horse received additional medication with the anti-protozoal, the horse may not enroll. Some additional medications that negate eligibility are DMSO or steroids. Horses that got double-dosed, extra doses, or longer duration over the label instructions would also be excluded.
The FDA standard for a proper EPM diagnosis starts with a neurologic exam. Additional testing includes cervical radiographs that are normal (for the age and breed of the animal) and the IFAT serum:CSF ratio value (that is published) and supports protozoal infection as the etiology. The CSF cytology must fall within parameters that support protozoal infection. The vitamin E level had to be normal, the serum EHV-1 and West Nile Virus test needed to be negative (or consistent with a vaccine titer). The 219-FE-1.1 selects a study population that is “properly diagnosed and treated” followed by treatment failure or relapse within 90 days of treatment.
If a horse continues to show clinical signs of EPM or the signs resolved, and then reappeared (relapsed), then the horse is eligible for enrollment. The clinical signs need to be demonstrative (that means scored by the veterinarian with a gait analysis between 2-4). We have a gait analysis score sheet that can help determine the level of clinical signs. For this study, the neurological deficit must be obvious at normal gaits or postures and the signs are exacerbated with manipulation (this would be a GAS of 2). Horses that have very prominent deficits and give the impression they may fall (GAS 3), or profound deficits with frequent stumbling or tripping and may fall with manipulation (GAS 4) are eligible. Horses that fall are a GAS 4. Horses that are down and unable to get up are not eligible. This is a placebo controlled study. The animal has 2 out of 3 chances of receiving the study medication and not the placebo. Although horses can be removed from the study at any time, a minimum of 5 days may be needed to see an effect from the study medication.
If the horse did not have a diagnosis of EPM the study 219-FE-3.7 is more appropriate. When is EPM not likely to be the cause of clinical signs? If there are no antibodies to S. neurona in the serum. This study does not have a requirement for CSF fluid analysis or a previous history of testing CSF to enroll. Study 219-Fe-3.7 includes a study population that is likely to have PNE. If the horse is seronegative for Sarcocystis neurona confirmed using IFAT or ELISA tests, it is generally accepted by the experts that EPM isn’t the cause of clinical signs. Other causes of neurological disease are ruled out by history (no trauma), negative osteoarthropathy (this can be ruled out by endoscopic exam). There are other factors that are supportive that PNE is a likely diagnosis—no history of recent respiratory illness or history of a recent fever. The acceptable Clinical Score is between 2-4 for the study.
You may wonder why a gait assessment isn’t used to enter 219-FE-3.7. It is because the six published cases of PNE were diagnosed by observing signs that were not related to gait. Horses with PNE show skin hypersensitivity and then lose sensation. Horses show some other signs, familiar to veterinarians, that differentiate a PNE horse from an EPM horse. The gait shown by a PNE horse becomes weak later in the disease process. Unfortunately, the six published cases were all untreatable and most had gait deficits. It is our goal to identify and treat these horses before they become untreatable.
The scoring system for a horse with PNE is a little different than the system used for EPM. If the signs are mild and do not interfere with the intended use of the horse, the Clinical Score is 1. These signs are too minimal for a veterinarian to fully evaluate a treatment response; even if an owner is locked in on the aberrant signs, this case would not qualify for the study. A horse that has moderate signs of PNE are found by a neurological examination and interfere with the intended use, or are the signs are so severe that they compromise the intended use and euthanasia may be considered. These are horses that should consider entering this study. All study animals will receive study medication. As in all field studies, horses can be removed from the study at any time. A minimum of 5 days may be needed to see an effect from the medication.
We believe that inflammation is associated with parasitic protozoa and inflammation is most likely responsible for the clinical signs of disease—this concept is probably widely accepted by equine veterinarians. However, we diverge from the old road and address the inflammatory response in an EPM treatment. We don’t understand why this is a controversial issue or why it has been overlooked by pharmaceutical development companies.
It is not kosher to just add anti-inflammatory agents to anti-protozoal drugs because there are unintended consequences from mixing drugs. That is why FDA requires studies, review processes and a path for licensing treatments. That is our goal: giving the equine community a licensed EPM medication. To that end, the Study 092-SE-1 is a placebo controlled study—the placebo is Protazil. This type of study is called a non-inferiority study because the animal is treated and the response to the treatment is compared between groups of treated animals. The proper diagnosis of EPM is required for entry into this study, starting with a neurologic exam. Additional testing includes cervical radiographs that are normal (for the age and breed of the animal) and the IFAT serum:CSF ratio consistent with a diagnosis of EPM. The CSF cytology analysis must show that the analysis is consistent with a diagnosis of EPM. The serum vitamin E level had to be normal and the serum EHV-1 and West Nile Virus tests need to be negative (or consistent with a vaccine titer).
If you have a horse that may qualify for a study we are running give us a call. We promise not to sing.