Download Immune-Mediated Myopathies

IN-DEPTH:
MUSCLE DISORDERS
Immune-Mediated Myopathies
Stephanie J. Valberg, DVM, PhD, Diplomate ACVIM
Immune-mediated myopathies in horses can present as signs of acute rhabdomyolysis, multifocal
muscle swelling, and infarction or acute muscle atrophy. Some but not all myopathies are associated
with Streptococcus equi infection. A diagnosis can be made by histopathologic evaluation of the
affected muscle group. Successful treatment requires early recognition and a combination of antibiotic and corticosteroid therapy. Author’s address: Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, 1365 Gortner Avenue, St. Paul, MN
55108; e-mail: [email protected]. © 2006 AAEP.
1.
Introduction
Three distinct myopathies with an apparent immunemediated etiology are currently recognized in horses.
The first myopathy manifests as acute, severe rhabdomyolysis.1 The second presents as focal severe muscle swelling caused by infarction.2 The third
myopathy is characterized by rapid muscle atrophy.3,4
Many but not all of the cases of immune-mediated
myositis seem to be a sequella to infection with Streptococcus equi subspecies equi. S. equi infection
(strangles) typically has a low level of mortality (2.6%);
however, a complication rate of 20.3% has been reported in some outbreaks.5,6 Reported complications
of strangles include purpura hemorrhagica, guttural
pouch empyema, upper respiratory tract obstruction,
bastard strangles, pneumonia, pleuritis, agalactia,
and periorbital abscess. In some horses, a further
complication of S. equi infection is the development of
an immune-mediated myopathy.4 – 6
2.
Acute Rhabdomyolysis Caused by S. equi
Prevalence
There are only a small number of cases discussed in
the literature, and they describe Quarter Horses ⬍7
NOTES
354
2006 Ⲑ Vol. 52 Ⲑ AAEP PROCEEDINGS
yr of age.1,7 This may not reflect the prevalence of
the disease, because many cases may not present to
university hospitals or diagnostic laboratories.
Clinical Signs
Affected horses usually have evidence of submandibular lymphadenopathy and/or guttural pouch empyema caused by S. equi.1 Owners notice that horses
develop a stiff gait that progresses rapidly to markedly firm, swollen, and painful epaxial and gluteal
muscles. Muscle pain becomes severe in spite of
aggressive antimicrobial and anti-inflammatory
treatment. The majority of reported cases became
recumbent, were unable to rise, and developed unrelenting pain that necessitated euthanasia within
24 – 48 h of hospitalization.1
Hematological abnormalities include mature neutrophilia, hyperfibrinogenemia, and marked elevations in creatine kinase (CK; 115,000 –587,000 U/l)
and aspartate aminotransferase (AST) activities
(60 –14,500 U/l).1,7 Titers to the M protein of S.
equi are low in affected horses unless horses are
recently vaccinated for strangles. Titers to another
protein called myosin-binding protein were high in a
small number of horses that were tested.1
IN-DEPTH:
MUSCLE DISORDERS
At post-mortem examination, large, pale areas of
necrotic muscle are evident in hindlimb and lumbar
muscles. The histopathologic lesions are characterized by severe acute myonecrosis with a degree of
macrophage infiltration. Sublumbar muscles often
show the most severe and chronic necrosis that is
indicated by greater macrophage infiltration of
myofibers.1
Pathogenesis
In human medicine, ␤-hemolytic streptococci of
Lancefield groups A, B, C, and G can cause severe
myonecrosis manifested by severe myalgia, muscle
swelling, and sometimes toxic shock.8 Toxic shock
arises as a result of profound non-specific T-cell
stimulation by streptococcal superantigens with the
release of high levels of inflammatory cytokines.9,10
Genes for four superantigens have recently been
identified in S. equi, and it is possible that horses
with S. equi rhabdomyolysis also develop a toxic
shock-like syndrome.11,12 An alternative explanation for rhabdomyolysis may be a bacteremia with
local multiplication and production of exotoxins or
proteases within skeletal muscle. S. equi virulence
factors that may account for muscle necrosis include
an unidentified cytotoxic protein, several proteases,
streptokinase, and streptolysin S.1,5 Although S.
equi has not been cultured in skeletal muscle from
horses with rhabdomyolysis, S. equi bacteria have
been identified in affected muscle using immunofluorescent stains for both Lancefield group C carbohydrate and S. equi M protein.1 There is currently no
evidence that the S. equi involved is an atypical
genetic strain of S. equi.1,13
Treatment
A high mortality rate has been reported in horses
receiving IV penicillin therapy when clinical signs of
strangles and myopathy were well established.1
It is possible that early recognition of the signs of
muscle stiffness in horses with S. equi infections and
prompt aggressive treatment may be required for a
successful outcome. Although streptococcal species
are very susceptible to ␤-lactam antibiotics, a mortality rate of 85% has been reported in human group
A streptococcal myositis despite penicillin treatment.14 An antimicrobial that inhibits protein synthesis, such as rifampin, combined with IV penicillin
might enhance survival rates in horses with S. equi
rhabdomyolysis. In addition, flushing infected guttural pouches and draining abscessed lymph nodes
will diminish the bacterial load. Non-steroidal anti-inflammatories and possibly high doses of shortacting corticosteroids may assist in diminishing the
inflammatory response. Control of unrelenting
pain is a major challenge in horses with severe rhabdomyolysis. Constant-rate infusion of lidocaine,
detomidine, or ketamine may provide better anxiety
and pain relief than periodic injections of tranquilizers.15–17 Horses should be placed in a deeply bedded stall and moved from side to side every 4 h if
Fig. 1. Firm swelling in the adductor muscles of the left hindlimb (arrow) as well as swelling in the biceps femoris and adductor muscles of the right hindlimb (arrow) in a horse with PH.
they are unable to rise. Some horses may benefit
from a sling if they will bear weight on their hindlimbs when assisted to stand.
3.
Infarctive Purpura Hemorrhagic
Prevalence
The occurrence of infarctive purpura hemorrhagica
(PH) in one study was 3 of 53 PH cases reviewed.18
Five other cases of infarctive PH have been described in horses that were either exposed to S. equi
within 3 wk of presentation and/or had markedly
elevated serum enzyme-linked immunosorbent assay (ELISA) M protein titers.2 Although horses
with classic PH usually have a good prognosis, infarctive PH has a high fatality rate.2,7,18
Clinical Signs
The primary presenting complaints for horses with
infarctive PH are painful lameness, muscle stiffness, and/or colic.2 Careful physical examination
reveals classic signs of PH such as petechia and
well-demarcated limb edema. Additionally, horses
with infarctive PH will have focal firm IM swellings
(Fig. 1). Horses with evidence of colic may have
markedly decreased borborygmia and hemorrhagicgastric reflux.
Hematologic abnormalities usually include a leukocytosis characterized by a neutrophilia with a left
shift and toxic change, hyperproteinemia, hypoalbuminemia, and marked elevations in CK (47,000 –
280,000 U/l) and AST (960 –7000 U/l) activities.2,7
If gastrointestinal infarction is present, peritoneal
fluid obtained by abdominocentesis may be normal
or may have an increased total protein, nucleated,
and red blood cell counts.
Ultrasonographic examination of swollen muscle
reveals focal hypoechoic lesions within muscle tisAAEP PROCEEDINGS Ⲑ Vol. 52 Ⲑ 2006
355
IN-DEPTH:
MUSCLE DISORDERS
munosuppressive agents such as cyclophosphamide
and azathioprine.23 One horse with infarctive PH
was successfully treated with penicillin and nonsteroidal anti-inflammatories as well as 3 wk of
dexamethasone (0.1– 0.07 mg/kg) followed by a
10-wk tapering course of oral prednisolone (2 mg/kg
to start).2
4.
Immune-Mediated Polymyositis
Prevalence
Fig. 2. Multifocal areas of hemorrhage in the hindlimb musculature of a horse that was euthanized because of PH.
sue. Biopsies of abnormal muscle show diffuse
acute coagulative necrosis, whereas samples from
palpably normal muscle tissue show no pathological
abnormalities.
Post-mortem findings of horses with infarctive PH
show extensive infarction of the skeletal musculature (Fig. 2), skin, gastrointestinal tract, pancreas,
and lungs and S equi abscessation of a lymph node.
Definitive histopathologic findings include leukocytoclastic vasculitis and acute coagulative necrosis
resembling infarction in numerous tissues.2
Pathogenesis
Infarctive PH resembles Henoch-Schönlein purpura
in humans,19 –21 which is characterized by infarctive
vasculitis of the skin, kidneys, and gastrointestinal
tract caused by IgA immune-complex deposition.
Immune complexes are present in the sera of horses
with PH and seem to be primarily composed of IgM
or IgA and streptococcal M protein.22 Deposition of
complement near immune complexes in vessel walls
may result in cell-membrane destruction, cell death,
and vascular occlusion. The distinctive feature of
infarctive PH in horses is the extensive infarction of
skeletal muscle and consequently marked elevation
in serum CK and AST activity.
Treatment
Early recognition of focal muscle swelling, abdominal discomfort, neutrophilia, hypoalbuminemia, and
marked elevations in CK activity combined with
aggressive antibiotic and corticosteroid treatment
may enhance the likelihood of a successful outcome.2
Treatment of Henoch-Schönlein purpura in humans, including cases with intestinal infarctions,
involves high-dose IV pulse therapy with methylprednisolone (1000 mg/m2 every other day for three
treatments) followed by oral corticosteroids and im356
2006 Ⲑ Vol. 52 Ⲑ AAEP PROCEEDINGS
Immune-mediated polymyositis (IMM) has recently
been reported in horses.3,4,24 In the largest retrospective study, 31 of 1350 horses that received a
muscle biopsy for evaluation of neuromuscular disease were diagnosed with IMM. The breed and age
of all horses identified to date include 32 horses with
Quarter Horse bloodlines and four other breeds including two ponies, one Icelandic horse, and one
Thoroughbred. A bimodal age distribution seems
to occur in affected horses with all horses identified
to date being either ⱕ8 yr of age or ⱖ16 yr of age.4
In approximately one-third of horses with IMM, exposure to S. equi or a respiratory disease seems to be
a triggering factor.
Genetics
IMM in humans is believed to have a non-Mendelian
polygenic pattern of inheritance. The high prevalence of the disorder in Quarter Horses suggests
that there is the potential for a polygenic mode of
inheritance in this breed.
Clinical Signs
The most prominent clinical sign of IMM in Quarter
Horses is rapid onset of muscle atrophy, particularly
affecting the back and croup muscles (Fig. 3), accompanied by stiffness and malaise.3,4,7 Atrophy may
progress to involve 50% of the horse’s muscle mass
within 1 wk and may lead to generalized weakness.
Focal symmetrical atrophy of cervical muscles has
been reported in a pony with IMM.
Hematologic abnormalities are relatively minor in
affected horses and are usually restricted to mild to
moderate elevations in serum CK and AST activity.4
In some cases, serum muscle-enzyme activities are
normal.24
Diagnosis
Muscle tissue obtained from the epaxial and gluteal
muscles contains many of the following abnormalities:
lymphocytic vasculitis, anguloid atrophy, lymphocytic
myofiber infiltration, fiber necrosis with macrophage
infiltration, and regeneration.4,24 Biopsies of semitendinosus or membranosus muscles may show some
evidence of atrophy and vasculitis, but significant inflammatory infiltrates may be absent in these tissues.
The extent of the inflammation that infiltrates into the
epaxial muscles is such that a diagnosis can often be
established from several formalin-fixed Trucut
samples.
IN-DEPTH:
MUSCLE DISORDERS
Horses that are not treated with corticosteroids
may develop extensive muscle atrophy, but in many
cases, muscle mass will gradually recover. Recurrence of atrophy in susceptible horses is common
and may require reintroduction of corticosteroid
therapy. Some horses develop focal residual muscle atrophy.4
References
Fig. 3. Extensive atrophy of the epaxial and gluteal musculature in a Quarter Horse with immune-mediated myositis. (Photo courtesy of Dr. Bonnie Rush).
Pathogenesis
The lymphocytic infiltrate seen in muscle samples
from horses with IMM is distinct from that found in
dogs and humans with immune-mediated polymyositis in that the CD4:CD8 ratio in horses seems
higher.4,25 In contrast to immune-mediated masticatory, muscle myositis that does have a higher
CD4:CD8 ratio, the specific binding of IgG to myofibers seen in the canine masticatory muscle is not a
feature of equine IMM.25,26 The reason why specific muscle groups are affected in horses with IMM
is unclear.
Treatment
Horses with concurrent evidence of streptococcal infection should be treated with antibiotics. It is likely
prudent to avoid IM injections. Administration of
corticosteroids seems to immediately improve signs of
malaise and inappetence, and it prevented further progression of muscle atrophy.3,4 Recommended dosages are dexamethasone (0.05 mg/kg) for 3 days
followed by prednisolone (1 mg/kg for 7–10 days) tapered by 100 mg/wk over 1 mo. Serum CK activity
often normalizes after 7–10 days. Muscle mass will
usually gradually recover over 2–3 mo.
1. Sponseller BT, Valberg SJ, Tennent-Brown BS, et al. Severe acute rhabdomyolysis associated with streptococcus equi
infection in four horses. J Am Vet Med Assoc 2005;227:
1800 –1807.
2. Kaese HJ, Valberg SJ, Hayden DW, et al. Infarctive purpura hemorrhagica in five horses. J Am Vet Med Assoc
2005;226:1893–1898.
3. Valberg SJ. Spinal muscle pathology. Vet Clin North Am
[Equine Pract] 1999;15:87–96.
4. Lewis SS, Valberg SJ. Immune-mediated myositis in 31
horses. J Vet Int Med 2005;19:429.
5. Sweeney CR, Timoney JF, Newton JR, et al. Streptococcus
equi infections in horses: guidelines for treatment, control,
and prevention of strangles. J Vet Int Med 2005;19:123–
134.
6. Sweeney CR, Whitlock RH, Meirs DA, et al. Complications
associated with streptococcus equi infection on a horse farm.
J Am Vet Med Assoc 1987;191:1446 –1448.
7. Valberg SJ, Bullock P, Hogetvedt W, et al. Myopathies associated with streptococcus equi infections in horses, in Proceedings. 42nd Annual American Association of Equine
Practitioners Convention 1996;292–293.
8. Gardam MA, Low DE, Saginur R, et al. Group B streptococcal necrotizing fasciitis and streptococcal toxic shock-like syndrome in adults. Arch Intern Med 1998;158:1704 –1708.
9. Kansal RG, Nizet V, Jeng A, et al. Selective modulation of
superantigen-induced responses by streptococcal cysteine
protease. J Infect Dis 2003;187:398 – 407.
10. Norrby-Teglund A, Thulin P, Gan BS, et al. Evidence for
superantigen involvement in severe group a streptococcal
tissue infections. J Infect Dis 2001;184:853– 860.
11. Artiushin SC, Timoney JF, Sheoran AS, et al. Characterization and immunogenicity of pyrogenic mitogens SePE-H
and SePE-I of streptococcus equi. Microb Pathog 2002;32:
71– 85.
12. Proft T, Webb PD, Handley V, et al. Two novel superantigens found in both group A and group C streptococcus. Infect Immun 2003;71:1361–1369.
13. Al-Ghamdi GM, Kapur V, Ames TR, et al. Use of repetitive
sequence-based polymerase chain reaction for molecular epidemiologic analysis of streptococcus equi subspecies equi.
Am J Vet Res 2000;61:699 –705.
14. Adams EM, Gudmundsson S, Yocum DE, et al. Streptococcal myositis. Arch Intern Med 1985;145:1020 –1023.
15. Cruz AM, Kerr CL, Boure LP, et al. Cardiovascular effects
of insufflation of the abdomen with carbon dioxide in standing horses sedated with detomidine. Am J Vet Res 2004;65:
357–362.
16. Wagner AE, Dunlop CI, Heath RB, et al. Hemodynamic
function during neurectomy in halothane-anesthetized
horses with or without constant dose detomidine infusion.
Vet Surg 1992;21:248 –255.
17. Southwood LL. Postoperative management of the large colon volvulus patient. Vet Clin North Am [Equine Pract]
2004;20:167–197.
18. Pusterla N, Watson JL, Affolter VK, et al. Purpura haemorrhagica in 53 horses. Vet Rec 2003;153:118 –121.
19. Baeza-Herrera C, Atzin-Fuentes JL, Leon-Cruz A, et al.
Henoch-schonlein purpura and intestinal perforation. Cir
Cir 2005;73:389 –391.
20. Trapani S, Micheli A, Grisolia F, et al. Henoch schonlein
purpura in childhood: epidemiological and clinical analysis
AAEP PROCEEDINGS Ⲑ Vol. 52 Ⲑ 2006
357
IN-DEPTH:
MUSCLE DISORDERS
of 150 cases over a 5-year period and review of literature.
Semin Arthritis Rheum 2005;35:143–153.
21. van der Boon F, Groeneweg M. Acute abdominal pain as the
first sign of henoch-schonlein purpura: a hidden diagnosis
in the absence of purpura. Ned Tijdschr Geneeskd 2005;149:
2522–2526.
22. Galan JE, Timoney JF. Immune complexes in purpura
hemorrhagica of the horse contain IgA and M antigen of
streptococcus equi. J Immunol 1985;135:3134 –3137.
23. Wang L, Huang FC, Ko SF, et al. Successful treatment of
mesenteric vasculitis caused by henoch-schonlein purpura
358
2006 Ⲑ Vol. 52 Ⲑ AAEP PROCEEDINGS
with methylprednisolone pulse therapy. Clin Rheumatol
2003;22:140 –142.
24. Barrott MJ, Brooks HW, McGowan CJ. Suspected immunemediated myositis in a pony. Equine Vet Edu 2004; April:
80 – 83.
25. Pumarola M, Moore PF, Shelton GD. Canine inflammatory
myopathy: analysis of cellular infiltrates. Muscle Nerve
2004;29:782–789.
26. Shelton GD, Cardinet GH III, Bandman E. Canine masticatory muscle disorders: a study of 29 cases. Muscle Nerve
1987;10:753–766.