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We’ve been reading a lot about amyotrophic lateral sclerosis (ALS) lately.  One thing is abundantly clear and that is there will be no single treatment to cure this disease.  There are inherited forms of ALS, fALS, and then there are sporadic cases, sALS. Our take on the overall picture of ALS is that no matter the inciting event at some point there is a final common pathway…that is inflammation.

Dogs get late onset fALS.  We suspect horses get fALS as well.  Is someone looking for it?  It would be very rare and most likely, with no treatment options, the horse would be euthanized before a clinician would think of ALS. Horses get subclinical inflammation presenting as a peripheral neuropathy.  After some time passes the neuromuscular disease progresses to the lower motor neurons (polyneuritis equi) and then it affects the upper motor neurons if the horse lives long enough. Diagnosis is the big issue here, to recognize a case of equine ALS.

The sporadic form of ALS seems more insidious…the sub-clinical pathways probably take a long time to surface into clinical disease.  The dysregulated systems that are forefront in human fALS are being targeted with specific small molecules-it is unlikely they will target sALS patients.  Even after years of failed attempts to find the cure for ALS the approach is the same: one path-one drug. New molecules come along, and so far they failed, even if they showed promise in mice that develop ALS.

The newest platform is skipping the animal step and moving right into people with promising drugs or small molecules. The entry criteria for the studies using novel small molecules targeting fALS are not available to sALS.  The treatments are super expensive. These approaches will never translate into an equine therapy.

Back to our hypothesis that it will take multiple drugs to combat presumptive equine ALS (eALS).  And this is a huge problem.  If one decided on a cocktail that was effective, the licensing process for the therapy would be impossible to get through FDA.  The effectiveness trial is mind boggling…we are suggesting the cocktail may involve 5 drugs at a minimum. The safety trial alone would cost at least a million dollars, our one-drug safety trial was nearly a half-million alone.

How does one start to evaluate therapeutic cocktails for a rare disease such as ALS?   Initially an animal model of the disease is necessary.  And a non-subjective test to evaluate if the disease is present in the animal.  And then one needs to identify the drugs that could be beneficial based on a firm understanding of the disease process. After all this is complete, it would be possible to approach FDA.

After our experiences with a simple and direct treatment using two well known drugs with specific actions for a specific disease with a defined and useful animal model, we can absolutely say the task for licensing a putative five drug ALS cocktail is insurmountable.

Ah, but a man’s reach should exceed his grasp, Or what’s a heaven for? (Robert Browning)

We have an approach that just may be doable.  And that is finding single therapies that hit multiple targets.  Our idea will rest upon finding a useful diagnostic test to ascertain effectiveness.  We aren’t afraid to try our approach in ALS models and compare the results to multiple drugs that target dysfunctional ALS pathways. Of course, testing multiple drugs together is a huge step that is outside the box thinking.  Out of the box thinking is what it will take to tackle ALS.

Our reach is big.  We’ll let you know how it goes.

cyst microscopic cropSarcocystosis is one of the most frequent infections of animals, the organisms are found in the muscles and the central nervous system! There are, perhaps, 196 species of Sarcocystis, yet the complete life cycle is only known for 26 of them. Sarcocystis require a prey-predator, 2 host, relationship to survive. Each host supports different stages of the life cycle. Hosts vary for each species of Sarcocystis.  Intermediate hosts support several species of Sarcocystis, each species use different definitive hosts.

People get sarcocystosis, two species use people as the definitive host.  Humans also serve as intermediate (or aberrant hosts) for several other species. Raw beef can infect you with S. hominis and raw pork can give you S. suihominis. Gastrointestinal symptoms are present when Sarcocystis cause disease in people  definitively hosting the parasite. Muscle pain is reported in people that serve Sarcocystis as an intermediate host. Most of the time people are asymptomatic with muscular sarcocystosis. People can get sick from an enterotoxin associated with Sarcocystis that infect horse muscles. if horse meat is uncooked.

Horses get sarcocystosis from dogs, the organism causing infections is S. equicanis (bertrami). In the US the horse-infecting organism is named S. fayeri. Donkeys harbor S. asinus, but experiments may show that this is actually S. fayeri. The visible difference in equicanis (bertrami) and fayeri is the thickness of cyst walls in muscles observed under the microscope. Our picture above is fayeri,  a thick-walled sarcocyst.  S. bertrami forms a thin-walled cyst. Dogs shed infective betrami organisms 8-10 days after eating infected muscle tissue. Horses eat the organisms from dog feces-contaminated feed.  It takes two to three weeks before signs appear in horses.  Signs include fever, neurological signs, apathy, and inappetence  a couple of months after infection. Muscle enzymes can be elevated in infected horses and increased enzymes can be measured in blood samples.

Sarcocystis fayeri cysts are found in skeletal muscles and the heart.  Ten and 25 days after infection (two waves of organisms are released from the gut) the developing parasites are found in arteries of the heart, brain, and kidney.  Muscle cysts (sarcocysts) are first seen at 55 days .  And by 77 days the muscle tissue can infect dogs to start the cycle again. We are taught that S. fayeri is only mildly pathogenic, horses develop anemia and fever after infections and some horses may have a stiff gait. More virulent isolates can cause inflammation of muscles and, in one case, the horse developed autoimmune anemia.  People that eat raw horse meat can get food poisoning, this is due to a toxin associated with the cysts.  A fetus can be infected by S. fayeri by crossing the placenta, so foals can be born with mature cysts in their muscles.

Malnourished horses show clinical muscle inflammation (myositis) and muscle atrophy that can be associated with S. fayeri. Muscle cysts are usually unassociated with clinical signs or muscle inflammation, leading to conclusions that fayeri infections are benign. Most clinicians agree S. fayeri isn’t an issue in horses.  However, there are some researchers that think S. fayeri should be considered in horses with neuromuscular disease. Scientists at UC Davis examined muscle tissues from horses with and without a history of neuromuscular disease.  They found an association, but not statistical significance, between disease and cysts.  More horses with neuromuscular disease had S. fayeri cysts when compared to the number of cysts found in horses that died from other causes.

We decided to look at the problem a different way.  While UC Davis looked at cysts, we chose to look for S. fayeri antitoxin in the serum of horses. An advantage to antitoxin analysis is that the test is performed in the live horse.  We found that 24% of normal horses had antitoxin in their serum. We also found that S. neurona antibodies were more often associated with neuromuscular disease in horses  than S. fayeri antitoxin (antibodies against the toxin released from cysts). That said, horses were more often infected with both species of Sarcocystis, not just one strain.

Horses infected with S. neurona and S. fayeri were more likely to show disease. We looked at inflammation using CRP (C-reactive protein) and found that CRP was detected in horses with and without apparent disease. We did find that significantly more horses with neuromuscular disease had an elevated CRP when compared to normal horses (p= .0135).  However, the data we needed to link the UC Davis study and ours was missing.  We needed to show  the relationship of antitoxin found in horses (our test) with sarcocysts found on histopathological slides (the gold-standard test for fayeri-sarcocystosis).

We examined three tissues (muscle tissue from the heart, esophagus, and skeletal muscle) from thirty-two horses (that’s a big number in horse studies) and measured the presence of antitoxin.  Our results confirmed that our serum test was almost the same as the results you would get if a full post-mortem exam was conducted. Also, in our study the infected horses were asymptomatic.

The conclusions thus far are that S. fayeri can be detected pre-mortem and should be considered in horses with signs of sarcocystosis or neuromuscular disease that has no other cause.  Also, horses with neuromuscular disease are more likely to have an elevated CRP.  In our S. fayeri study horses did have elevated CRP values but the inflammation was associated with other gastrointestinal parasites, not EMS (equine muscular sarcocystosis).

Why are we still interested in S. fayeri? Certainly our results support the strain of S. fayeri  infecting our 32 horses was non-virulent and support the view of most clinicians that S. fayeri may not be an issue in most horses, just some of them.

For us, it’s about the toxin.  The toxin is an actin-depolymerizing factor (ADF).  Another Apicomplexan, Toxoplasma gondii, has a very similar ADF. The TG-ADF can protect lab animals against T. gondii infections. Interestingly, some animals with lethal S. neurona infections also were infected with T. gondii. The difference between protection (mice) versus no-ADF protection (sea otters) could be stage of infection (with TG), ,strain-virulence, or something we didn't think of yet.

Can S. fayeri-ADF protect against S. neurona infections in horses? Is ADF species specific? Is ADF a virulence factor or even a survival factor for the organism? Are there cyst-producing S. fayeri organisms that don't produce ADF? Does S. neurona produce an ADF? And, can a S. neurona be incorporated into a fayeri sarcocyst? These are all questions to be answered by experiment.

Here is our opinion. It is worth monitoring S. fayeri infection in horses. It is worth considering S. fayeri infection as a cause of neuromuscular disease in horses showing weakness, muscle atrophy, and inflammation for which there is no other explanation. The disease EMS should be considered in old and debilitated horses.  Sarcocystis fayeri should be considered in horses with chronic inflammation. When  horses showing weakness do not have antibodies against S. neurona, EMS should be considered. Horses that provide meat that is fed to dogs should be monitored for S. fayeri.

If you have questions about S. fayeri, give us a call.


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.

decision

One study is intended to treat horses with lingering or recurring syndrome after EPM treatment.  We call the syndrome PTEDSpost-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.

 

20150924_1503271531-e1493401997820-169x300This horse has muscle atrophy.  The cause can be one of any number of three letter acronyms.  Acronyms for equine neurological diseases can be very confusing.  You probably understand EPM and PNE--equine protozoal myeloencephalitis and polyneuritis equi. Have you heard of EDM and EMD--equine degenerative myeloencephalopathy and equine motor neuron disease?  What are their causes and what are the signs your horse may have when afflicted with one of these mysterious conditions?  And of paramount importance-can they be treated?

We  provided exhaustive reviews of EPM and our guide to understanding polyneuritis equi.  If you missed them you can catch up at amazon.com.  Just search for Siobhan Ellison and the available books pop up.

The cause of equine degenerative myeloencephalopathy remains a mystery.  EDM damages multiple areas of the spinal cord resulting in muscle and locomotion disorders. Quite some time ago, EDM was the second most common diagnosis of spinal cord disease at Cornell University. There are a few folks that believe EDM has a genetic basis. In young horses EDM and EMD can occur together. The signs occur early on and will stabilize (not continue to get worse) when the horse is 4 or so, but signs won’t improve either. Another disease that is recognized in young horses is Wobblers, or cervical vertebral malformation, CVM.  The neuromuscular disease and an uncoordinated gait in CVM is due to physical restriction of the spinal cord in the spinal canal. CVM is recognized when young horses are started under saddle, although the condition was  present before that. As the horse grows and matures CVM gets worse. The important point is that these conditions are recognized in young horses.

Equine motor neuron disease is also a degenerative disease of the spinal cord.  EMD affects multiple areas of the nervous system.  Most signs in the horse are based on muscle weakness and loss of innervation to the muscles used in locomotion. Perhaps the stiff gait and low head carriage help differentiate EMD from EPM, EDM, CVM, and PNE. Remember Lyme disease (Borreliosis) also produces a stiff-gaited horse. The vector for Lyme disease is a tick and the disease is found more commonly in the Eastern US. EMD is induced experimentally by feeding a diet deficient in Vitamin E for a little over 3 years. Treating EMD with natural Vitamin E in the early stages can improve the outcome of the disease.  Grazing on good quality pasture is the best natural source of vitamin E for horses.

Based on what is known, Vitamin E supplementation can help with early onset EMD, but don’t expect vitamin E to help with EDM. Perhaps you can remember which one is treatable…EMD is “E to Medicate” and EDM is “E doesn’t Medicate”.  These are mnemonics that work for me. Sadly, some horses can develop more than one of these conditions at the same time. When horses have multiple diseases it will take a planned approach to rule in or rule out the cause of the signs. The first step is listing the clinical signs. Testing is an important part of ferreting out a diagnosis. Testing can include serum analysis for Vitamin E, muscle biopsy, and additional serum tests for infectious disease like protozoa or Borrelia.  Medicating and watching for a change in signs often leads to an expensive misdiagnosis.  Here is a comparative list of signs that can be observed in horses with EPM, EMD, and EDM. Your veterinarian can help you determine the proper approach to obtain a diagnosis and select an appropriate therapy.

EPM EMD EDM Wobblers PNE
Shifts weight on rear legs X
Difficulty standing X X X
Lays down a lot X
Muscle fasciculations/trembling X X X
Stiff gait X X X
Low head carriage X
Muscle atrophy X X X X
Weight loss X X X
Ataxia-symmetric X X X
Wide based stance X X X
Proprioceptive deficits X X X X
Diagnosed by post-mortem exam X X X
Weakness X X X X
Abnormal behavior X X X
Lameness X
Difficulty swallowing X X
Seizures X
 

 

 

 

 

 

What’s myelin and why is it important?

For this we need some background.

When we think of the nervous system, we generally think of two parts, first there’s the brain, called the Central Nervous System, CNS. Then there is the part that passes information to and from the brain. We call this the Peripheral Nervous System, PNS.

Nerve impulses from the body are passed along nerves by shifting chemicals. It is a slow process. Some nerves are fine with slow impulses, the nerves that cause your intestines to move food along, for instance. Then there are the nerves that must pass information very quickly.

clip_image002Imagine placing a hand on a hot stove. It wouldn’t do for the information to take a long time to get to the brain then a long time for the brain to communicate to the muscles to move the hand. The quicker the better. To do that, the fast nerves have a method to move the impulses quickly down a nerve. What happens is that the nerve is insulated with a sheath, this allows the impulse to rapidly skip down the nerve jumping long distances across the insulated portions. This insulation is called a myelin sheath.

If the myelin sheath doesn’t work properly, the nerve impulses don’t go quickly. This makes the myelin sheath extremely important. To coordinate complicated actions such as walking, running, and chewing, for examples, muscle groups need to work in complex coordinated patterns. Each muscle or set of muscles needs to contract in the proper sequence and exactly on cue. Any interruption or delay has severe consequences.

Animals and people have these important rapid transit nerves. Unfortunately, this myelin sheath can be damaged. Generally, it is the body’s own defense system that attacks this myelin sheath. It’s the same defense system that helps you conquer disease, and ward off infections. The body has a way of defining what is part of the body, named “self”, and what doesn’t belong, “non-self” which includes invading bacteria, virus, or protozoa. The body routinely attacks any “non-self” invaders and destroys them.

This “self” identification system is usually perfect. Not always, though. If the body misidentifies something that should be “self” as “non-self”, the body attacks the “non-self” with all the resources it has available. In general, it’s the immune system that is called into action. There’s also the inflammatory system which works hand in hand with the immune system to destroy invaders.

So how can this happen?

The body breaks down the invaders into small pieces. The body identifies each of these pieces, classifies them as “non-self” and produces antibodies against these pieces. This way the body can wipe out the invaders by attaching antibodies at many places. Think of an antibody like a hook. Each antibody is very specific and only attaches to the piece that it is meant to attack. The body produces a sea of these antibody hooks. If the target piece exists, the antibody hooks automatically attach and the rest of the immune system uses these hooks to help destroy the invaders.

Now suppose the system that determines “self” and “non-self” gets mixed up- or even duped. Suppose an invader doesn’t get classified as “non-self”. The body will not recognize it as an invader and will not attack it. Some bacteria will take advantage of this, they’ll coat themselves with materials that the body doesn’t recognize as foreign. Parasites disguise themselves by changing the way they present themselves, varying the expression of genes. Sometimes parasites are masters of disguise and hijack “self”-proteins in order to manipulate the immune system. The result is that if the body misinterprets what should be “self” as “non-self”, those antibody hooks will attach to normal tissue and the immune system will attack it.

This can happen with the myelin. There are several ways it can happen. Once it does happen, the immune system will break down the myelin sheaths. When that happens, myelin fragments are released into the blood stream. We test the blood for antibodies against myelin to see if those fragments are present. If they are present, we know that there is a problem.

Suppose one has a horse and that horse develops a coordination problem. Suppose it doesn’t walk well, it staggers and falls. If we test the blood and find the myelin fragments, that goes a very long way toward telling us why the horse has a problem and what to do about it.

If myelin is attacked by the immune system, all the myelin is attacked. We won’t generally see a single problem, we’ll see an array of signs-diffuse over the body. We call this array of signs “polyneuritis”. “Poly” means many, neuritis means the nerves are affected. If we’re talking about a horse, we tack on the word “equi” so we know we’re talking about the horse.