(Marco Albore e Francesca Calissi)
Loxoscelism is a condition produced by the bite of the recluse spiders (genus Loxosceles). It is the only proven cause of arachnogenic necrosis in humans.
A small percentage of the spider species in the world are medically important with the majority causing systemic injury. Spiders of the genus Loxosceles cause necrotic dermatologic injury through a unique enzyme, sphingomyelinase D, found only in one other spider genus and several Bacteria.
Although all Loxosceles species tested so far have the dermonecrotic sphingomyelinase D enzyme, most Loxosceles spider species have yet to be shown to be medically important.
Loxoscelism
Distribution of Loxosceles
Loxosceles spiders are predominantly found in the temperate and tropical regions of the Americas, Africa, and Europe: in Italy Loxosceles together with Latrodectus are the most dangerous spiders. There are approximately 100 species of Loxosceles spiders; 80% occurring in the Western Hemisphere.
There are three widespread species routinely reported to cause dermonecrosis: Loxosceles laeta (throughout much of South America), L intermedia (Brazil, Argentina) and L gaucho (Brazil).
L laeta possibly being the most toxic.
In the rest of the world, Loxosceles species are not as well represented.
In general (Microhabitats occupied by Loxosceles intermedia and Loxosceles laeta - Araneae: Sicariidae- in Curitiba, Paraná, Brazil., 2005), Loxosceles spiders are nocturnal, preferring to hide during the day in crevices and other places of refuge. In natural environments, they are found under rocks or in burrows of other animals where they make a small retreat web of flocculent silk. In human habitats (Prevalence of Loxosceles laeta in houses in central Chile., 1970), they are often found behind furniture, in basements, in attics, in cupboards, and other places where they can squeeze into a small cavity.
Bites occur when the spider is pressed against flesh, typically while dressing or by a sleeping human rolling over on the spider at night. In heavily infested areas therefore, clothing and shoes should be shaken before dressing, and worn items such as garden clothing or sports equipment in storage should be rigorously inspected or stored in spiderexcluding containers. The risk of bites by Loxosceles spiders is, nonetheless, not as common as often purported as people can live with dozens to thousands of Loxosceles spiders without a medical incident.
Identification of Loxosceles spiders
Many medical publications definitively state that Loxosceles spiders can easily be identified "(Identifying and Misidentifying the Brown Recluse Spider., 2007) by a violin or fiddle pattern on the dorsal surface of the cephalothorax. Although this is true in principle, lack of expertise causes nonarachnologists (including physicians) to mistake many varied darkened forms on spider bodies as violin patterns.
A more useful diagnostic feature is that Loxosceles spiders have six eyes arranged in
nontouching pairs in a U-shaped pattern. Most spiders have eight eyes and can be excluded as this medically important group. One must be aware, however, that the eye pattern is not totally exclusive.
Loxosceles toxin
Loxosceles bites can cause necrosis in humans, guinea pigs, and rabbits,28 but not in mice and rats, thereby showing differential mammalian toxicity due to unknown reason. Research has recently characterized the nature and composition of the toxins causing the necrosis.
Spiders may vary the amount of venom injected depending on the prey type. It is possible therefore that spiders have the capability to give varied amounts of venom in defensive biting and, accordingly, vary the severity of the bite injury.
Venoms are a mixture (Variations in Loxosceles spider venom composition and toxicity contribute to the severity of envenomation., 2005) of proteins with similar electrophoretic profiles in the region of low molecular mass proteins (20-40 kD). The toxins in both L intermedia and L laeta seem to be equivalent. One 30- to 35-kD protein, a nonproteolytic sphingomyelinase , is endowed with all biological properties ascribed to whole L laeta venom and sphingomyelinases from L intermedia including dermonecrotic and platelet aggregation and complement- dependent hemolytic activities.
Investigators (Identification of high molecular weight serine-proteases in Loxosceles intermedia (brown spider) venom., 2000) have also described broad enzymatic activities in tissue from Loxosceles venom. These activities include:
* hyaluronidase
* alkaline phosphatase
* esterase
* ATPase
* sphingomyelinase D(Sphingomyelinase D activity of brown recluse spider (Loxosceles reclusa) venom as studied by 31P-NMR: effects on the time-course of sphingomyelin hydrolysis., 1998)
Sphingomyelin phosphodiesterase D is an enzyme with system name sphingomyelin ceramide-phosphohydrolase. This enzyme catalyses the following chemical reaction
sphingomyelin + H2O \rightleftharpoons ceramide phosphate + choline
Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation, proliferation, and programmed cell death (PCD) of cells.
One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. Apoptosis, or Type I programmed cell death, is essential for the maintenance of normal cellular homeostasis and is an important physiological response to many forms of cellular stress. Ceramide accumulation has been found following treatment of cells with a number of apoptotic agents including ionizing radiation, UV light, TNF-alpha, and chemotherapeutic agents. However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive.
- but not phosphodiesterase, phospholipase A or C, or collagenase.
It is possible that Loxosceles spider venom may have proteinase proenzyme activity. After treatment with trypsin, spider venom from extracted apparatus contains two serine proteases.In addition, there are two metalloproteinases recently characterized. Venom therefore may have intrinsic venom metalloproteinase activity in addition to that occurring through victim metalloproteinase activation.
Loxosceles intermedia spider envenomation induces cleavage of an endogenous metalloproteinase, resulting in cleavage of glycophorins from the erythrocyte surface and facilitating complement-mediated lysis. This activation is mediated by the alternative pathway.
Loxosceles spider gastric contents contain proteases (Detection and characterization of metalloproteinases with gelatinolytic, fibronectinolytic and fibrinogenolytic activities in brown spider (Loxosceles intermedia) venom., 1998) capable of cleaving native collagen, gelatin, fibrinogen, fibronectin, fibrin, and elastin.
Clostridium perfringens (Isolation and identification of Clostridium perfringens in the venom and fangs of Loxosceles intermedia (brown spider): enhancement of the dermonecrotic lesion in loxoscelism., 2002) can be isolated in the venom and fangs of L intermedia.
Pathophysiology
In milder cases, Loxosceles bites may simply cause a very mild urticarial reaction. In the more severe cases, the initial bite is painless, but this is followed over 2 to 8 hours by sharp, penetrating pain that progressively changes into a burning sensation. There may be two small puncta at the bite site. The bite area pales and the area immediately surrounding the bite becomes red and edematous, with mild to severe pain secondary to vasospasm and ischemia. A blister may form, and over the several days after the bite, there is typically a blue violet color, hard, stellate, sunken center. There is anesthesia of the center.
Spread may occur gravitationally. Sloughing follows. Healing by second intent takes 6 to 8 weeks.
Initially, experimental injection of venom results in vessel instability, cytoplasmic endothelial cell vacuolization, and blebs. There is loss of adhesion of the endothelial cells to their extracellular substrate as well as each other. During the first 4 hours, there appear edema, hemorrhage, vessel wall degeneration, plasma exudation thrombosis, neutrophil accumulation in and around blood vessels with intensive diapedesis, dermal collection of polymorphonuclear (PMN) leukocytes, and subcutaneous and muscular edema. Over the next 5 days (Histopathological findings in rabbits after experimental acute exposure to the Loxosceles intermedia (brown spider) venom., 2002), there is massive neutrophilic infiltration into the dermis and subcutaneous muscle, with vessel destruction, thrombosis, hemorrhage, myonecrosis, and coagulative necrosis.
Venom sphingomyelinase degrades the sphingomyelin component of the red blood cell membranes causing hemolysis. The hemolysis as well as the accumulation of PMN leukocytes appears to be related to the activation of circulating complement. Venom sphingomyelinase can induce hemolysis in vitro without complement (BOUND COMPLEMENT AND IMMUNOLOGIC INJURY OF BLOOD VESSELS., 1965) L reclusa sphingomyelinase D also stimulates serum amyloid (Serum amyloid P component: its role in platelet activation stimulated by sphingomyelinase D purified from the venom of the brown recluse spider (Loxosceles reclusa)., 1990), but not C-reactive protein (Platelet activation stimulated by the toxin of the brown recluse spider requires serum amyloid P component, not C-reactive protein., 1989), to activate platelets, leading to thrombocytopenia.
The platelet activation is via an adenosine 5V-diphosphate release mechanism and is inhibited by indomethacin. Tumor necrosis factor (Loxosceles spider venom induces metalloproteinase mediated cleavage of MCP/CD46 and MHCI and induces protection against C-mediated lysis., 2002) is induced.
Diagnosis
The standard for diagnosis of spider bites is collecting and properly identifying the biting spider responsible for the cutaneous findings.
One emerging condition that is commonly misdiagnosed as loxoscelism in particular, and as generic spider bites in general, is methicillin-resistant Staphylococcus aureus infection. This misdiagnosis is made in both nosocomial and community-acquired settings.
(It’s Not a Spider Bite, It’s Community-Acquired Methicillin-Resistant Staphylococcus aureus., 2004)
Laboratory diagnosis
The diagnosis of loxoscelism remains a clinical judgment dependent on proof of a Loxosceles spider bite. There is at least one potential venom test that has been developed and tested experimentally, using an ELISA (A new assay for the detection of Loxosceles species (brown recluse) spider venom., 2002). The authors detected venom from rabbit test subjects up to 7 days after injection. Venom was recoverable from plucked hair and skin aspirates, but the greatest yield was with biopsy specimens. There is currently no commercially available assay for humans.
Therapy
The proper treatment of loxoscelism remains controversial. Reported therapies include hyperbaric oxygen, dapsone,antihistamines including cyproheptadine, antibiotics, dextran, glucocorticosteroids, vasodilators, heparin, nitroglycerin, electric shock, curettage, surgical excision, and antivenin. It seems reasonable at minimum to provide routine first aid: elevation, immobilization, application of ice, local wound care, and tetanus prophylaxis.
- Corticosteroids: Dapsone has been recommended for over two decades, based on the prominent role of PMN leukocytes in the pathophysiology of the injury. Dapsone inhibits the PMN myeloperoxidase-hydrogen peroxide-halide generation of oxygen intermediates, as well as inhibiting chemotaxis.Despite the common usage of dapsone, no prospective human study supports dapsone as an effective treatment for Loxosceles envenomations in humans.Most patients have a 1- to 2-g drop in hemoglobin during therapy. Systemic or intralesional glucocorticosteroids are also commonly given. These may have less benefit on ulcer formation than to ameliorate the general systemic effects, including the reactive erythema.
(Treating Spider Bites: Is Dapsone an Option?, 2005)
- Hyperbaric oxygen: Several authors have advocated hyperbaric oxygen for the treatment of Loxosceles bites. Maynor et al (Brown recluse spider envenomation: a prospective trial of hyperbaric oxygen therapy., 1997) treated 14 patients with hyperbaric oxygen in an uncontrolled study and reported benefit. The rationale was that hyperbaric oxygen would inactivate the sulfhydryl-containing sphingomyelinase D (Effect of hyperbaric oxygen on sphingomyelinase D activity of brown recluse spider (Loxosceles reclusa) venom as studied by 31P nuclear magnetic resonance spectroscopy., 1997) in Loxosceles venom by oxidizing sulfhydryl bonds. Also, hyperbaric oxygen increases tissue oxygen tension and causes PMN sequestration in the lungs, removing them from circulation.
- Electric shock: The idea behind treating Loxosceles bites with electric shock arose after reported successes using electric stun guns for field therapy of insect stings and poisonous snakebites. Osborn reported 147 cases (Treatment of venomous bite by high voltage direct current., 1990) of confirmed and suspected spider bites treated with high-voltage direct current (Electic Shock on Venomous Bites & Stings., 2012). Sixteen patients had positive identification of L reclusa. Treatment involved 40 to 50 kVd s_1 delivered for 1 to 2 seconds per shock pulse. Two pulses were delivered through the center of the lesion, then four or more around the perimeter using a handheld stun gun. Therapy was given from 2 hours to 5 weeks after the bites. Improvement was reported by the patient or seen by the author in every case.
Conclusions
Loxosceles spiders are the only important cause of skin necrosis from spider bites. Loxosceles spiders are common in much of the tropical and temperate world. Considering how prevalent they are, human bites from Loxosceles spiders are uncommon. When bites occur, they are usually mild, but they can occasionally cause ulceration and rarely systemic symptoms. Other more common diseases mimic spider bites, and, therefore, unless the culprit Loxosceles spider is caught in the act, practitioners must be willing to challenge the diagnosis of Loxosceles bite. There is no evidence-based effective therapy (Therapy of brown spider envenomation: a controlled trial of hyperbaric oxygen, dapsone, and cyproheptadine., 1995) for loxoscelism at the present time.
Clinics in Dermatology (2006) 24, 213–221
Loxoscelism
David L. Swanson, MDa,*, Richard S. Vetter, MSb
aDepartment of Dermatology, Mayo Clinic, Scottsdale, AZ 85259, USA
bDepartment of Entomology, University of California Riverside, Riverside, CA 92521, USA
