Brenda Bishop, VMD
1976 Graduate of the University of Pennsylvania School of Veterinary Medicine.
Brenda Bishop has spent many years researching equine immune mediated diseases.
She has included in this website a practical guide for horse owners as well as a guide
for veterinarians interested in a new thought process for dealing with Equine Shivers.
She answers questions that have gone un-answered for too long.

Brenda Bishop, VMD
"A new scientific truth does not triumph by convincing its opponents and
making them see the light. but rather because its opponents eventually die,
and a new generation grows up that is familiar with it".
Maxwell Planck
The Leptospirosis Horse

Copyright 2012 by Brenda Bishop, VMD.  No portion of this publication may be without
prior written permission of the author.  Portions of this work have previously appeared in
Natural Horse magazine: volume 12 issue 2 (2010) “Demystifying Equine Shivers” by
Brenda Bishop, VMD and volume 5 issue 3 (2003) “Deciphering Equine Fibromyalgia
Syndrome (EFMS)” by Brenda Bishop, VMD.

The most common zoonotic bacterial infection in the world is Leptospirosis.  Due to its
number one status, much is known about its appearance in humans, dogs, cats, cattle,
sheep, pigs and goats.  Comparatively little is known about its existence in horses.  Of
the many different serovars (there are over two hundred known to date) the serovar L.
pomona is associated with two clinical entities in horses: equine recurrent uveitis (ERU)
and spontaneous abortion in mares.  ERU is considered to be an autoimmune problem
by many scientists; leptopirosis is suspected in mares that abort for no apparent reason.  
Both ERU and abortion represent consequences of previous (usually unrecognized)
exposure to one or more Leptospira serovars.  Whether the affected horse had a healthy
immune system or a compromised one at the time of exposure, these horses have won
the initial skirmish (acute infection) but lost the war, eventually suffering loss of one or
both eyes or a fetus.  

Bacteria that have a spiral shape, such as Leptospira and the Lyme disease spirochete
Borrelia, have a predictable course of action once established in their respective hosts.  
They characteristically elicit a biphasic response; the initial acute infection, which may or
may not provoke a fever and general malaise, lasts a short time (days); the second
phase takes weeks or months to manifest.  The symptoms of this second phase are a
reflection of an immune system struggling for control.  When immune system imbalance
goes on long enough, a certain threshold is reached wherein autoimmune conditions
(such as Shivers) can result.  Researchers have found that spirochete infections produce
the same clinical pictures in various animal species and humans, some of whom
develop ‘Persistent Human Leptospirosis’ (PHL).  Horses are thought to be a reservoir in
nature for certain Leptospira serovars; it is known that wild animals shed Leptospira in
their urine which can easily be ingested by grazing livestock.  If in fact some horses
embody a carrier state for the bacteria, these should not be confused with those
individuals whose immune systems are engaged in an ongoing active battle with chronic

The easiest way to envision this second phase is in terms of a prolonged allergic
reaction.  Unlike the initial acute phase which can be life threatening (due to lung, kidney
and/or liver damage), this phase amounts to a progressive complex cascade of events
which leave the affected host with a wide array of complaints.  To further oversimplify the
picture of how specific problems are created, it is helpful to consider the role of mast
cells in the host horse’s body.  An important but poorly understood part of the immune
system, mast cells live abundantly in connective tissues (such as skin and ocular
conjunctiva) and mucosal linings (respiratory, reproductive and gastrointestinal tracts).  
They cluster around nerve endings, the smallest of blood vessels and lymphatics.
Another crucial part of the immune system, plasma cells, circulate freely and produce
antibodies (immunoglobulins) such as IgG, IgM and IgE.  Mast cells have an affinity for
IgE which attaches to their surface.  When leptospiral antigens make contact with this
IgE, the mast cell becomes activated and explodes like a bomb.  Among the many
substances released into the surrounding tissues are histamine, prostaglandins,
cytokines and leukotrienes. These in turn produce constriction of the airways, gastric acid
secretion, spasms of the gastrointestinal tract, itching, irritated nerve endings, swollen
blood vessels and lymphatics, and needless to say inflammatory pain.

Horses in the early stages of persistent leptospiral infections demonstrate chronic
fatigue, occasional toe dragging, itching body parts (mainly the head), depression and
poor appetite.  As time goes on, they might exhibit some of the following: urogenital
discomfort, biting at themselves, transient peripheral lymphadenopathy, cording of the
lymphatics, vasculitis in the hind legs, a mucoid nasal discharge, hyperventilation at rest,
asthma, insulin resistance, difficulty standing up, hind leg gait deficits, anxiety and/or
hallucinogenic behavior.  Both allergic and autoimmune states reflect alterations of the
immune system.  If an allergic response lasts over a long period of time (weeks), IgE
remains abundant and other immunoglobulins eventually enter the fray.  Both Myasthenia
Gravis and Lambert Eaton Myasthenic Syndrome involve antibodies of the IgG class,
acetylcholine receptor antibodies and calcium channel antibodies respectively.  (This is
why a percentage of babies born to mothers with MG or LEMS have ‘neonatal MG’ or
‘neonatal LEMS’ until the antibodies from the mother’s blood disappear within the first
week or two of life.)  Both pre-synaptic (LEMS) Shivers horses and post-synaptic (MG)
Shivers horses already have plenty of IgE; MG is characterized by high levels of mast cell
density in certain tissues and LEMS has been linked to mastocytosis (an excessive
number of mast cells) in humans.  Regardless of which came first, i.e., Leptospirosis or
Shivers, for a Shivers horse dealing with a leptospiral infection, the stage is set for all the
results of mast cell stimulation to escalate in intensity.  Small animal veterinarians have
observed that Leptospirosis vaccination appears to trigger mast cell tumors in some
dogs; there is no approved vaccine for horses.

Even though testing for up to seven serovars of Leptospirosis is available for horses,
results are subject to personal interpretation.  Another diagnostic challenge hinges on
spirochete biology, namely an adaptive ability to morph into ‘round bodies’ (a different
shape) when the local environment changes.  Clarification of spirochete round body
relationships with their vertebrate hosts will be lacking until sorely needed research
regardless of species is accomplished.  As with Fibromyalgia and systemic fungal
infections, not all Leptospirosis horses develop Shivers nor do all Shivers horses have
active Leptospirosis.  If a horse displays signs of massive mast cell stimulation, with or
without the presence of Shivers, Leptospirosis should be high on the list of possible
scenarios.  In the case of a horse with Shivers and a head that simply loves to be rubbed
with a soft towel after exercise, Leptospirosis should be considered.  Oral Doxycycline is
one of the antibiotics of choice for spirochete infections.  It has the added benefit of
having an anti-inflammatory effect on immune mediated neuritis. (Immune mediated
neuritis can manifest as mild itching, stringhalt, Shivers, head shaking, hypersensitivity to
hot and/or cold weather or any number of other syndromes such as EFMS and/or any
combination thereof.)  For a horse with Leptospirosis the dose should be 5 milligrams
per pound twice daily for up to sixty days.  Ideally a blood sample is tested at the start and
again after antibiotic therapy.  Short term benefits can be obtained with antihistamines,
aspirin and/or ibuprofen, however use of these drugs is like closing the barn door after
the horse is out; they have a place but are not practical for long term use.  

With the exception of autoimmune hemolytic anemia, one drug that IS useful for
maintenance of horses with a wide range of immune mediated problems such as
Leptospirosis is Pentosan.  Pentosan polysulfate sodium is gaining popularity in the
treatment of several human diseases, among them Crohn’s disease (an autoimmune
gastrointestinal disorder).  It stabilizes mast cells by inhibiting allergic mast cell
stimulation.  This powerful effect results in reduced histamine release, an effect more
potent than that of hydroxyzine, a drug that merely competes for histamine receptor sites
on target cells and is often prescribed for horses with Cushing’s syndrome.  An example
of symptom overlap that can be addressed with Pentosan is the skin hypersensitivity
common in Fibromyalgia horses.  People with Fibromyalgia have up to four times the
usual number of mast cells just below their skin surface.  Imagine how much discomfort
(itching and burning) such a horse would have upon being groomed with stiff brushes
and/or heavy hands.  Additionally Pentosan lowers intracellular calcium.  An essential
signaling molecule, calcium levels must be maintained in a precise balance, in a ratio of
about twenty thousand times more outside than inside individual cells.  When
intracellular calcium rises, cells die and different neurodegenerative diseases result.  
One of the key regulators of intracellular calcium is the voltage gated calcium channel,
which is dysfunctional in LEMS.  Pentosan’s effects are dose dependent, appear quickly
(24 hours) and last long after it has washed out of the body (weeks).  

The little known herb Butterbur is a perfect therapeutic partner for Pentosan, useful
because it is complementary at worst and synergistic at best.  It is a natural beta blocker,
i.e., it reduces spasms of capillary muscles and lowers blood pressure.  Improved
arterial blood flow results and is probably amplified in the presence of Pentosan which is
heparin like. (It has been shown that Pentosan improves blood supply to subchondral
bone in horses’ joints.)  Butterbur gives dramatic relief to most sufferers of migraine
headaches, one of many human diseases now viewed as ‘calcium channelopathies’.  
That a simple herb could give relief to throbbing blood vessels within the central nervous
system suggests an exciting possibility for controlling spasms in the peripheral nervous
system, an overlapping symptom of Leptospirosis, MG, LEMS and FMS.  While Pentosan
stabilizes mast cells, Butterbur lowers the effects of leukotrienes and prostaglandins
which leak into tissues when mast cells do explode.  Pain relief is the end result.  For a
thousand pound horse a dose of 300 milligrams Butterbur root extract added twice daily
to the feed can be used until results are seen.  Herbs can take weeks to garner
improvement but provide a horse friendly alternative to aspirin or ibuprofen and like
Pentosan can be pulse dosed over the long term.  Horses allergic to daisies,
chrysanthemums or marigolds should not be fed Butterbur, which belongs to the daisy
family.  Both Pentosan and Butterbur, used alone or together, appear to yield impressive
clinical improvement by working at both the central (CNS) and peripheral (PNS) nervous
system levels, a fact which lends excitement to this rapidly expanding field of twenty-first
century research known as ‘autoimmune channelopathies’.