Spice was spending nearly all her time lying down. The 16-year-old Paint mare didn't appear to be weak or in pain---she could readily scramble to her feet when she wanted to. But she simply wouldn't stay on her feet. For almost a month, she'd get up just two or three times a day to eat, drink, defecate and urinate, then she'd lie down again.
Several veterinarians came out to see Spice that April in 2008, but they found no obvious reasons for her peculiar behavior. She was current on her vaccinations, she wasn't lame and her vital signs were normal.
Spice's veterinarian was baffled and recommended a consultation with nearby Colorado State University. But the mare's owner was afraid that the ride would be too difficult for her or that she would go down in the trailer. So Lutz Goehring, DVM, PhD, a faculty member with the veterinary teaching hospital, made a farm call.
Goehring found Spice lying calmly in sternal recumbency, propped up on her chest and looking as if she just decided to take a brief afternoon nap. "I was thinking I'd find a horse who looked ill or in distress, but she was happy, and it was obvious she had been really well cared for in the time she was down," he says. "Her owner had bedded her on deep sand in a large roofed area. She looked like a mare who just happened to be lying down and resting."
Spice also seemed normal as she got up, which she did with just a bit of encouragement. "She had no problem at all standing up. She was very coordinated and strong, with normal reflexes," Goehring says. But, he adds, once the mare was on her feet, "we did notice something very unusual."
As she stood Spice's muscles became stiff and tense. "You could actually see the muscles contracting under the skin," says Goehring. When she was asked to walk she moved in short, rigid steps. When she stood still, her hind and forelimbs were drawn closer together than normal, giving her the appearance she was standing on a large circus ball. These were all important, but somewhat contradictory, clues.
Process of elimination
Goehring worked through a number of potential diagnoses:
? Tying up (recurrent exertional rhabdomyolysis) causes severe, painful cramping of the large muscles, usually after exercise. When you see muscles contracting as Spice's were, "you naturally think of tying up," Goehring says, "but all of her muscles were affected, not just the hindquarters as you'd?expect." Also, horses who are tying up?are usually in obvious pain, with profuse sweating and rapid breathing; Spice was not. "To be certain, we also tested her urine and blood and did?not see any of the proteins you'd find?associated with the muscle damage of tying up," he adds.
? Hyperkalemic periodic paralysis (HYPP) is an inherited muscle disorder of Quarter Horses and related breeds that causes muscle tremors, weakness and recumbency. But Spice's pedigree did not include any horses known to carry HYPP, nor did she display the characteristic weakness and collapse.
? Tetanus is a rigid paralytic disease caused when the anaerobic bacterium Clostridium tetani, which normally lives in soil and feces, enters a puncture wound. Tetanus can cause stiffness throughout the body, but Spice was current in her vaccinations against this disease, and she was not displaying any other classic signs of the condition, including the protrusion of the nictitating membrane across the eye.
? Botulism is a paralytic condition that occurs when a horse ingests food or water contaminated with toxins produced by the bacterium Clostridium botulinum. Horses with early stages of botulism often lie down for long periods as the associated paralysis develops. But botulism usually affects the muscles of the head and mouth first. Spice was eating and drinking normally.
? Laminitis, the inflammation of the sensitive soft tissues that connect the coffin bone to the interior of the hoof wall in the foot, can cause horses to stand with an unusual "base-narrow" stance like Spice was showing. But laminitis is extremely painful, yet the mare did not react at all to sole pressure from hoof testers, and radiographs of all four hooves showed no coffin bone rotation.
? Fractures to the pelvis or lower spine can leave a horse reluctant to walk, even if he doesn't appear to be obviously lame. Goehring ruled out an injury like that in Spice with a rectal exam.
? Neurological diseases, such as equine protozoal myeloencephalitis (EPM) or West Nile encephalitis, can cause a variety of signs, including stiffness, recumbency, weakness and incoordination. To investigate this possibility Goehring performed a full neurological workup on Spice, checking the muscle tone in her tail and asking her to walk forward, backward and in small circles. "In neurological disease, you see some incoordination or asymmetry," he says. "But we didn't see any of that. She was moving stiffly but was not weak or clumsy."
Having exhausted the possibilities for physical exams, Goehring gathered blood samples to follow up with laboratory tests, and he suggested transporting the mare to the University clinic so he could take spinal fluid samples and a muscle biopsy. But Spice's owner was still concerned about the toll the trip might take on her mare and opted to pursue only tests that could be done on the farm---especially since Goehring didn't yet have a particular diagnosis in mind.
Working on the assumption that some type of muscle pain was keeping the mare off her feet, Goehring prescribed a course of phenylbutazone and the muscle relaxant methocarbamol, and he asked Spice's owner to provide him with frequent updates on the mare's condition up until his next scheduled visit, in two weeks. By then, he hoped, the results of the blood tests would have shed more light on the cause of Spice's trouble.
One last shot
Spice was getting worse when Goehring returned. Instead of lying on her chest, the mare was now spending most of her time stretched out flat on her side, and she was eating and drinking while down. She was also getting up less often, as little as only once a day to defecate and urinate before stretching out again on her opposite side.
The standard blood work had revealed nothing abnormal, and the tests were also negative for antibodies to the West Nile virus as well as Sarcocystis neurona, the organism responsible for EPM. Spice's protein and enzyme levels were normal, indicating there was no muscle damage or malfunction, nor did her blood show any sign of inflammation or infection.
Goehring encouraged Spice to rise then spent a few minutes just watching her. He noticed the same pattern he'd seen on his first visit: "She'd walk around for a few minutes, and then you'd notice muscle contractions and a tightening of all her muscles. Then she would lie down in a very coordinated way. She didn't seem upset or uncomfortable; it was almost as if she got tired, and lying down was her way to cope with the increased muscle contractions and what I assume was associated fatigue and soreness from it."
The problem had to originate in either her muscles or her nerves---but given that the phenylbutazone and muscle relaxant had had no effect, a neurological explanation now seemed more likely. "If the problem wasn't with the muscles, it had to be the nerves that control them," says Goehring.
Yet Spice's signs didn't fit into any known neurological pathology. "A traumatic neurological event or a disease process generally affects neurons at one specific location in the nervous system, so you'll see a horse lose control of his hindquarters or one side of his body. But every muscle on this mare seemed to be involved equally," says Goehring. "Toxins can also affect a horse's nervous system, but they tend to target a particular type of neuron and are progressive; eventually you'll see seizures and other more serious problems."
That left one area of possibility: an immune-related disease affecting only a specific portion of the central nervous system. "In immune-mediated diseases, the horse's own body will attack a very specific target group of cells or structures," says Goehring. "It was possible, we thought, that such a scenario could give us the strange presentation we were seeing. At the time, we had no idea what that specific process might be, but it was really our last shot."
A one-in-a-million diagnosis
To test that hypothesis, Goehring recommended a course of injectable corticosteroids. "Steroids will suppress the body's immune system, which?can be a bad thing unless it's the?immune system itself that is harming the body," he explains. If Spice's?condition was an immune-mediated neuropathy, the steroids would lead?to improvement.
Goehring was headed to a conference, so a colleague oversaw the treatment, starting with a relatively high dose followed by smaller subsequent doses that tapered off over the course of a week. "At the conference, I discussed this case with several prominent equine neurologists and told them what I was going to try," he says. "They were interested but maybe a little skeptical. So it was nice when I was able to share the text I got two days later that the treatment was working---the mare was up and moving more."
Indeed, Spice showed a dramatic improvement: By the end of the week she was standing about 75 percent of the time. That success led Goehring to search the literature for a possible explanation.
He found one disease in human medicine that seemed to fit Spice's case: Moersch-Woltmann syndrome, also called "stiff person syndrome" (SPS). People with SPS experience fluctuating muscle rigidity, particularly in their trunk and limbs. The first symptom is usually stiffness in the back that can come and go, often triggered by loud noises or stressful events.
Over weeks or months, the disease progresses until the painful spasms become increasingly frequent and involve the entire body, to the point of immobilizing the person for hours. Patients typically have a halting, stiff gait because the muscles never fully relax between spasms. They also report being exhausted by the episodes. SPS is extremely rare---the exact frequency is unknown but it may affect as few as one in a million people. The condition typically develops between the ages of 30 and 50, although babies may be born with it.
SPS was first named in 1956, and in the 1980s, researchers linked the disease with an autoimmune dysfunction after they discovered that the majority of affected individuals were producing high levels of antibodies to an enzyme called glutamic acid decarboxylase (GAD)---that is, their bodies were attacking and destroying this critical enzyme in large numbers. GAD is essential for the production of an amino acid called gamma-aminobutyric acid (GABA). GABA acts as an inhibitory neurotransmitter, meaning it slows down the activity of nerve cells.
"When a horse or person moves, certain muscles have to relax in order for others to contract," explains Goehring. "For instance, when the biceps [on the front of the upper arm] contracts, the triceps [on the back of the upper arm] must relax [in order to raise the arm]. GABA helps make this happen by blocking nerve impulses."
In people with SPS, the destruction of GAD, and the subsequent reduction in GABA, causes nerve cells to fire too often and too easily. And so, for example, the biceps and triceps muscles might struggle to contract simultaneously---a situation that produces the characteristic limb stiffness and muscle spasms.
Could horses experience an equine version of SPS? Goehring found one paper published in 2000 that described a Belgian Warmblood who had shown periodic stiffness similar to Spice's and who had elevated antibodies to GAD, just as in SPS. The authors of the paper dubbed their observations "stiff horse syndrome."
To see whether Spice might have stiff horse syndrome, Goehring had her blood tested for antibodies to GAD, along with a sample from a normal, healthy mare for comparison. Spice's blood had a significantly higher amount of the antibodies. This result wasn't a definitive diagnosis, but it did strongly suggest that the mare might have this rare condition.
Exploring unknown ground
Even though there was little precedent for treating Spice, her owner decided she wanted to try. The mare was kept on the corticosteroids for another month, during which time she gradually improved to her normal self. She was then weaned from the medication, after which she continued to remain on her feet as much as any normal horse. Continuing blood tests showed the mare's GAD antibodies decreasing over the course of treatment.
"This made me more certain that she had some form of stiff horse syndrome," says Goehring. "It seemed that we had interrupted the immune system enough for the assault on GAD to end, allowing GABA to be produced and regulate muscle activity."
Goehring hypothesized that the muscle contractions Spice had been experiencing were simply exhausting the mare, which caused her to lie down more than normal. "What we were seeing wasn't an inability to stand," he says, "but an all-over soreness and tiredness that made her not want to."
Months passed with no further developments, until the following spring, when the mare began lying down more than normal again. "I wasn't surprised," says Goehring, "because once the immune system returns to full function, it's going to start attacking antibodies again. The question is just how quickly and to what extent."
At that time, Goehring adds, "we looked into officially testing for GAD to quantify just how badly she might be affected, but new testing methods for human samples appeared to not work in horses." Instead, he started Spice on another course of corticosteroids and, as before, the mare improved dramatically within a few days.
This pattern continued for four years: Every eight to 12 months Spice would begin to spend more time lying down, and a course of corticosteroids would get her back on her feet. To reduce the risk of adverse side effects, Goehring gave Spice the lowest amount necessary to see an improvement. But the mare never showed any other signs of illness or trouble until she died after an unrelated colic earlier this year.
Although stiff horse syndrome is undoubtedly quite rare, Goehring says he suspects it may occasionally go undiagnosed: "I'm certain there are horses out there with this right now, but no one knows. Personally, I see maybe one or two cases a year that come in as an orthopedic problem. The horses aren't lame; they just have a generalized stiffness that gets worse with work. They have normal muscle enzyme activity, and when you put them through diagnostics like scintigraphy and radiographs you can't find?a problem, and they don't have any?other obvious illness. In these cases I add stiff horse syndrome to the list of considerations and suggest corticosteroid treatments."
Unfortunately, he says, many owners are doubtful and reluctant to pursue that suggestion: "It's as if they don't believe me. But if they try it and the horse improves, we're that much closer to an answer. And if we can do it before the horse goes down, even better."
Goehring adds that Spice's case shows that this condition, although chronic, can potentially be managed long-term with corticosteroids and attentive care: "This mare was watched closely by her owner, who learned what the signs of trouble?were and then knew how to care for her. She's really the reason this mare did so well."