backs of the hands or feet. the lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless. aca is also associated with peripheral neuropathy. cause main article: lyme disease microbiology borrelia bacteria, the causative agent of lyme disease, magnified lyme disease is caused by spirochetes, spiral bacteria from the genus borrelia. spirochetes are surrounded by peptidoglycan and flagella, along with an outer membrane similar to gram-negative bacteria. because of their double-membrane envelope, borrelia bacteria are often mistakenly described as gram negative despite the considerable differences in their envelope components from gram-negative bacteria. the lyme-related borrelia species are collectively known as borrelia burgdorferi sensu lato, and show a great deal of genetic diversity. b. burgdorferi sensu lato is a species complex made up of 20 accepted and three proposed genospecies. eight species are known to cause lyme disease: b. mayonii (found in north america), b. burgdorferi sensu stricto, (found in north america and europe), b. afzelii, b. garinii, b. spielmanii, and b. lusitaniae (all found in eurasia). some studies have also proposed that b. valaisiana may sometimes infect humans, but this species does not seem to be important causes of disease. tick life cycle deer tick life cycle ixodes scapularis, the primary vector of lyme disease in eastern north america there are three stages in the life cycle of a tick. larva, nymph, and adult. during the nymph stage, ticks most frequently transmit lyme disease and are usually most active in late spring and early summer in regions where the climate is mild. during the adult stage, lyme disease transmission is less common due to the fact that it is less possible for adult ticks to bite humans and because they tend to be larger in size and therefore can be easily seen and removed. transmission lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among small mammals and birds by ticks that feed on both sets of hosts. hard-bodied ticks of the genus ixodes are the vectors of lyme disease (also the vector for babesia). most infections are caused by ticks in the nymphal stage, because they are very small and thus may feed for long periods of time undetected. nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body. or, the nymphal ticks can be darker. the younger larval ticks are very rarely infected. although deer are the preferred hosts of adult deer ticks, and tick populations are much lower in the absence of deer, ticks generally do not acquire borrelia from deer, instead they obtain them from infected small mammals such as the white-footed mouse, and occasionally birds. areas where lyme is common are expanding. within the tick midgut, the borrelia's outer surface protein a (ospa) binds to the tick receptor for ospa, known as trospa. when the tick feeds, the borrelia downregulates ospa and upregulates ospc, another surface protein. after the bacteria migrate from the midgut to the salivary glands, ospc binds to salp15, a tick salivary protein that appears to have immunosuppressive effects that enhance infection. successful infection of the mammalian host depends on bacterial expression of ospc. tick bites often go unnoticed because of the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. however, transmission is quite rare, with only about 1.2 to 1.4 percent of recognized tick bites resulting in lyme disease. tick ixodes ricinus, developmental stages in europe, the main vector is ixodes ricinus, which is also called the sheep tick or castor bean tick. in china, ixodes persulcatus (the taiga tick) is probably the most important vector. in north america, the black-legged tick or deer tick (ixodes scapularis) is the main vector on the east coast. the lone star tick (amblyomma americanum), which is found throughout the southeastern united states as far west as texas, is unlikely to transmit the lyme disease spirochetes, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of lyme disease. on the west coast of the united states, the main vector is the western black-legged tick (ixodes pacificus). the tendency of this tick species to feed predominantly on host species such as the western fence lizard that are resistant to borrelia infection appears to diminish transmission of lyme disease in the west. transmission can occur across the placenta during pregnancy and as with a number of other spirochetal diseases, adverse pregnancy outcomes are possible with untreated infection; prompt treatment with antibiotics reduces or eliminates this risk. there is no scientific evidence to support lyme disease transmission via blood transfusion, sexual contact, or breast milk. tick-borne co-infections main article: tick-borne disease ticks that transmit b. burgdorferi to humans can also carry and transmit several other microbes, such as babesia microti and anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (hga), respectively. among people with early lyme disease, depending on their location, 2–12% will also have hga and 2–10% will have babesiosis. ticks in certain regions also transmit viruses that cause tick-borne encephalitis and powassan virus disease. co-infections of lyme disease may not require additional treatment, since they may resolve on their own or—as in the case of hga—can be treated with the doxycycline prescribed for lyme. persistent fever or compatible anomalous laboratory findings may be indicative of a co-infection. pathophysiology b. burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joints, peripheral nervous system, and central nervous system. b. burgdorferi does not produce toxins. therefore, many of the signs and symptoms of lyme disease are a consequence of the immune response to spirochete in those tissues. b. burgdorferi is injected into the skin by the bite of an infected ixodes tick. tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. this provides a protective environment where the spirochete can establish infection. the spirochetes multiply and migrate outward within the dermis. the host inflammatory response to the bacteria in the skin causes the characteristic circular em lesion. neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in necessary numbers in the developing em lesion because tick saliva inhibits neutrophil function. this allows the bacteria to survive and eventually spread throughout the body. days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of the disseminated disease. the spread of b. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete. if untreated, the bacteria may persist in the body for months or even years, despite the production of b. burgdorferi antibodies by the immune system. the spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the vlse surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors. in the brain, b. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. the spirochetes may also induce host cells to secrete quinolinic acid, which stimulates the nmda receptor on nerve cells, which may account for the fatigue and malaise observed with lyme encephalopathy. in addition, diffuse white matter pathology during lyme encephalopathy may disrupt gray matter connections, and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. white matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. resolution of mri white matter hyperintensities after antibiotic treatment has been observed. tryptophan, a precursor to serotonin, appears to be reduced within the central nervous system in a number of infectious diseases that affect the brain, including lyme. researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some people with borreliosis. immunological studies exposure to the borrelia bacterium during lyme disease possibly causes a long-lived and damaging inflammatory response, a form of pathogen-induced autoimmune disease. the production of this reaction might be due to a form of molecular mimicry, where borrelia avoids being killed by the immune system by resembling normal parts of the body's tissues. chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. this hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial. diagnosis lyme disease is diagnosed based on symptoms, objective physical findings (such as erythema migrans (em) rash, facial palsy, or arthritis), history of possible exposure to infected ticks, and possibly laboratory tests. people with symptoms of early lyme disease should have a total body skin examination for em rashes and asked whether em-type rashes had manifested within the last 1–2 months. presence of an em rash and recent tick exposure (i.e., being outdoors in a likely tick habitat where lyme is common, within 30 days of the appearance of the rash) are sufficient for lyme diagnosis; no laboratory confirmation is needed or recommended. most people who get infected do not remember a tick or a bite, and the em rash need not look like a bull's eye (most em rashes in the u.s. do not) or be accompanied by any other symptoms. in the u.s., lyme is most common in the new england and mid-atlantic states and parts of wisconsin and minnesota, but it is expanding into other areas. several bordering areas of canada also have high lyme risk. in the absence of an em rash or history of tick exposure, lyme diagnosis depends on laboratory confirmation. the bacteria that cause lyme disease are difficult to observe directly in body tissues and also difficult and too time-consuming to grow in the laboratory. the most widely used tests look instead for presence of antibodies against those bacteria in the blood. a positive antibody test result does not by itself prove active infection but can confirm an infection that is suspected because of symptoms, objective findings, and history of tick exposure in a person. because as many as 5–20% of the normal population have antibodies against lyme, people without history and symptoms suggestive of lyme disease should not be tested for lyme antibodies: a positive result would likely be false, possibly causing unnecessary treatment. in some cases, when history, signs, and symptoms are strongly suggestive of early disseminated lyme disease, empiric treatment may be started and reevaluated as laboratory test results become available. laboratory testing tests for antibodies in the blood by elisa and western blot is the most widely used method for lyme diagnosis. a two-tiered protocol is recommended by the centers for disease control and prevention (cdc): the sensitive elisa test is performed first, and if it is positive or equivocal, then the more specific western blot is run. the immune system takes some time to produce antibodies in quantity. after lyme infection onset, antibodies of types igm and igg usually can first be detected respectively at 2–4 weeks and 4–6 weeks, and peak at 6–8 weeks. when an em rash first appears, detectable antibodies may not be present. therefore, it is recommended that testing not be performed and diagnosis be based on the presence of the em rash. up to 30 days after suspected lyme infection onset, infection can be confirmed by detection of igm or igg antibodies; after that, it is recommended that only igg antibodies be considered. a positive igm and negative igg test result after the first month of infection is generally indicative of a false-positive result. the number of igm antibodies usually collapses 4–6 months after infection, while igg antibodies can remain detectable for years. other tests may be used in neuroborreliosis cases. in europe, neuroborreliosis is usually caused by borrelia garinii and almost always involves lymphocytic