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| {{DiseaseDisorder infobox | | |||
| Name = Lyme disease | | |||
| ICD10 = {{ICD10|A|69|2|a|65}} | | |||
| ICD9 = {{ICD9|088.81}} | | |||
| ICDO = | | |||
| Image = Adult_deer_tick.jpg| | |||
| Caption = Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed. | | |||
| = | | |||
| MedlinePlus = 001319 | | |||
| eMedicineSubj = med | | |||
| eMedicineTopic = 1346| | |||
| DiseasesDB = 1531 | | |||
| }} | |||
| '''Lyme disease''' (Borreliosis) is a ] ] with a ] from the species complex '']'', which is most often acquired from the bite of an infected '']'', or black-legged, ], also known as a ]. The deer tick is not the only carrier of this disease. The deer tick is frequently mistaken for a ] which is more common and larger in size. ''Borrelia burgdorferi'' ] is the predominant cause of Lyme disease in the U.S.; Lyme disease in Europe is more often caused by ''Borrelia afzelii'' or ''Borrelia garinii''. | |||
| The disease varies widely in its presentation, which may include a rash and flu-like symptoms in its initial stage, followed by the possibility of musculoskeletal, ], ], ] and ] manifestations. In most cases of Lyme disease, symptoms can be eliminated with ], especially if treatment is begun early in the course of illness. | |||
| A percentage of patients with Lyme disease have symptoms that last months to years after treatment with ]. These symptoms can include muscle and joint pains, arthritis, stiff neck, cognitive defects, neurological complaints or fatigue. The cause of these continuing symptoms is not yet known. There is some evidence that they may result from an ] type of response, in which a person’s immune system continues to respond even after the infection has been cleared, as well as | |||
| ] with the ]. | |||
| Delayed or inadequate treatment may often lead to "late stage" Lyme disease that is disabling and difficult to treat. Amid great ] over diagnosis, testing and treatment, two different standards of care for Lyme disease have emerged.<!-- | |||
| --><ref name="Johnson-a">{{cite web | last = Johnson | first = Lorraine | title = Lyme disease: two standards of care | publisher = International Lyme and Associated Diseases Society | date = 2005-02 | url = http://www.ilads.org/insurance.html | accessdate = 2006-11-17 }}</ref><!-- | |||
| --><ref name="Johnson-b">{{cite journal | author = Johnson L, Stricker R | title = Treatment of Lyme disease: a medicolegal assessment. | journal = Expert Rev Anti Infect Ther | volume = 2 | issue = 4 | pages = 533-57 | year = 2004 | id = PMID 15482219}}</ref> | |||
| ==History== | |||
| The first record of a condition associated with Lyme disease dates back to 1883 in ], former ], where a physician named ] described a degenerative ] now known as ]. | |||
| In a 1909 meeting of the Swedish Society of Dermatology, ] presented research about an expanding, ring like lesion he had observed. Afzelius published his work 12 years later and speculated that the rash came from the bite of an ''Ixodes'' tick, meningitic symptoms and signs in a number of cases and that both sexes were affected. This rash is now known as ] (EM), the skin rash found in early stage Lyme disease.<ref>B. Lipschütz: Zur Kenntnis der "Erythema chronicum migrans". Acta dermato-venereologica, Stockholm, 1931, 12: 100–102.</ref> | |||
| In the 1920s, French physicians Garin and Bujadoux described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, and they postulated the symptoms were due to a spirochetal infection. In the 1940s, German neurologist ] described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions. | |||
| In 1948 ]-like structures were observed in skin specimens by Swedish dermatologist Carl Lennhoff.<ref>Lenhoff, Carl "Spirochetes in aetiologically obscure diseases" Acta Dermato-Venreol. 1948;28 295-324</ref>In the 1950s relations between tick bite, lymphocytoma, EM and Bannwarth's syndrome are seen throughout Europe leading to the use of ] for treatment.<ref>Bianchi GE. Dermatologica. 1950;100(4-6):270-3. PMID 15421023</ref><ref>Hellerstrom S. Erythema chronicum migrans Afzelius with meningitis. Acta Derm Venereol. 1951;31(2):227-34. PMID 14829184</ref><ref>Hollstrüm E. Successful treatment of erythema migrans Afzelius Acta Derm Venereol (Stockh). 1951;31:235-43 PMID 14829185</ref><ref>Paschoud JM. Dermatologica. 1954 Apr-Jun;108(4-6):435-7. PMID 13190934</ref><ref>Schwank R. Cesk Dermatol. 1955 Oct;30(5):278-85. PMID 13284811</ref><ref>Paschoud JM. | |||
| Hautarzt. 1958 Jul;9(7):311-5. PMID 13574656</ref> | |||
| Interest in ] in the U.S. began with the first report of tick-borne ] (''Borrelia hermsii'') in 1915, following the recognition of five human patients in Colorado.<ref>Meador CN. "Five cases of relapsing fever originating in Colorado, with positive blood findings in two". Colorado Medicine 1915;12:365-9.</ref> | |||
| In 1970 a physician in Wisconsin named Rudolph Scrimenti reports the first case of EM in U.S. and treats it with penicillin based on European literature.<ref>Scrimenti RJ. Erythema chronicum migrans. Arch Dermatol. 1970 Jul;102(1):104-5. PMID 5497158</ref> | |||
| The full ] now known as Lyme disease was not recognized until a cluster of cases originally thought to be ] was identified in three towns in southeastern ] in 1975, including the towns ] and ], which gave the disease its popular name.<ref>Steere AC. "Lyme borreliosis in 2005, 30 years after initial observations in Lyme Connecticut.Wien Klin Wochenschr". 2006 Nov;118(21-22):625-33</ref>This was investigated by ], and others from ]. The recognition that the patients in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe.<ref name=Sternbach>{{cite journal | author = Sternbach G, Dibble C | title = Willy Burgdorfer: Lyme disease. | journal = J Emerg Med | volume = 14 | issue = 5 | pages = 631-4 | year = 1996| id = PMID 8933327}}</ref> | |||
| Before 1976, elements of ''Borrelia burgdorferi'' sensu lato infection were called or known as Tickborne meningopolyneuritis, Garin-Bujadoux syndrome, Bannworth syndrome, Afzelius syndrome, ] or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease,<ref>Mast WE, Burrows WM. Erythema chronicum migrans and "lyme arthritis". | |||
| JAMA. 1976 Nov 22;236(21):2392. PMID 989847</ref><ref>Steere AC, Malawista SE, Snydman DR, Shope RE, Andiman WA, Ross MR, Steele FM. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities. | |||
| Arthritis Rheum. 1977 Jan-Feb;20(1):7-17. PMID 836338</ref>Lyme borreliosis or simply borreliosis. | |||
| In 1980 Steere, et al, began to test ] regimens in adult patients with Lyme disease.<ref>Steere AC, Malawista SE, Newman JH, Spieler PN, Bartenhagen NH. Antibiotic therapy in Lyme disease. | |||
| Ann Intern Med. 1980 Jul;93(1):1-8. PMID 6967272</ref><ref>Steere AC, Hutchinson GJ, Rahn DW, Sigal LH, Craft JE, DeSanna ET, et al. Treatment of the early manifestations of Lyme disease Ann Intern Med. 1983;99:22-6. PMID 6407378</ref> | |||
| In 1982 a novel ] was cultured from the mid-gut of '']'' ticks in ], New York, and subsequently from patients with Lyme disease. The infecting agent was then identified by ] at the ], and soon after isolated by ], a scientist at the ], who specialized in the study of spirochete microorganisms. The spirochete was named '']'' in his honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with ]. | |||
| After identification of the Lyme disease agent, ''Borrelia burgdorferi'', antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including ], ], ], intravenous and intramuscular penicillin and intravenous ].<ref>Johnson SE, Klein GC, Schmid GP, Feeley JC. Susceptibility of the Lyme disease spirochete to seven antimicrobial agents. Yale J Biol Med. 1984 Jul-Aug;57(4):549-53.PMID 6516457</ref><ref>Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. | |||
| Ann Intern Med. 1983 Dec;99(6):767-72. PMID 6316826</ref><ref>Steere AC, Green J, Schoen RT, Taylor E, Hutchinson GJ, Rahn DW, Malawista SE. Successful parenteral penicillin therapy of established Lyme arthritis. N Engl J Med. 1985 Apr 4;312(14):869-74.PMID 3883177</ref> <ref>Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ. New chemotherapeutic approaches in the treatment of Lyme borreliosis. | |||
| Ann N Y Acad Sci. 1988;539:352-61.PMID 3056203</ref><ref>Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis Lancet. 1990;336:1404-6. PMID: 1978873</ref> | |||
| After the isolation of the spirochete from the mid-gut of ''Ixodes'' ticks, how ticks actually transmitted this new pathogen was the subject of much discussion. The hypothesis that Lyme disease spirochetes were transmitted via the salivary gland route of ''Ixodes'' ticks was confirmed when spirochetes were actually identified in tick saliva in 1987.<ref>Ribeiro JMC, Mather TN, Piesman J, Spielman A. Dissemination and salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae). J Med Entomol 1987;24:201-5.</ref> | |||
| ==Microbiology== | |||
| {{main|Lyme disease microbiology}} | |||
| ] | |||
| Lyme disease is caused by ] ] from the ] '']'', which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. The ''Borrelia'' ] known to cause Lyme disease are collectively known as '']'' sensu lato, and have been found to have greater ] than previously estimated.<!-- | |||
| --><ref name="Bunikis-a">{{cite journal | author=Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG | title=Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents ''Borrelia burgdorferi'' in North America and ''Borrelia afzelii'' in Europe | journal=Microbiology | year=2004 | pages=1741-55 | volume=150 | issue=Pt 6 | id=PMID 15184561 | url=http://mic.sgmjournals.org/cgi/reprint/150/6/1741.pdf | format=PDF}}</ref> | |||
| Until recently it was thought that only three genospecies caused Lyme disease: ''B. burgdorferi'' sensu stricto (predominant in ], but also in ]), ''B. afzelii'', and ''B. garinii'' (both predominant in ]). However, newly discovered genospecies have also been found to cause disease in humans. | |||
| ''Borrelia'' is a ] bacterium. | |||
| ==Transmission== | |||
| ===By ticks=== | |||
| Hard-bodied ('']'') ticks are the primary Lyme disease ]. There have also been reports of lyme disease from cats and kittens. In Europe, '']'' (known commonly as the sheep tick, castor bean tick, or European castor bean tick) is the transmitter. In North America, '']'' (black-legged tick or deer tick) has been identified as the key to the disease's spread on the east coast, while on the west coast the primary vector is '']'' (Western black-legged tick). It is important to note that the majority of infections are caused by ticks in the nymph stage, as adult ticks do not become infected through feeding. | |||
| Another possible vector is '']'' (Lone Star tick),<!-- | |||
| --><ref name="Clark">{{cite journal | author=Clark K | title=''Borrelia'' species in host-seeking ticks and small mammals in northern Florida. | journal=J Clin Microbiol | volume=42 | issue=11 | pages=5076-86 | year=2004 | id=PMID 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF}}</ref> | |||
| which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well. | |||
| It is believed that the longer the duration of tick attachment, the greater the risk of disease transmission; typically, for the spirochete to be transferred, the tick must be attached for a minimum of 24 hours, although only the first part of this statement can be said to be strictly correct. (See ].) | |||
| Unfortunately only about 20% of persons infected with Lyme disease by the deer tick are aware of having had any tick bite,<!-- | |||
| --><ref name="Wormser">{{cite journal | author=Wormser G, Masters E, Nowakowski J, McKenna D, Holmgren D, Ma K, Ihde L, Cavaliere L, Nadelman R | title=Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions. | journal=Clin Infect Dis | volume=41 | issue=7 | pages=958-65 | year=2005 | id=PMID 16142659}}</ref> making early detection difficult in the absence of a rash. Tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick ] that prevent the host from feeling any itch or pain from the bite. | |||
| New research suggests that transmission can occur within a few hours of tick attachment, and that the rate of transmission by infected ticks may be much higher than previously assumed.{{Fact|date=March 2007}} | |||
| ===Congenital=== | |||
| Lyme disease can be transmitted from an infected mother to fetus through the ] during pregnancy, possibly resulting in ].<!-- | |||
| --><ref name="MacDonald">{{cite journal | author=MacDonald AB | title=Gestational Lyme borreliosis. Implications for the fetus | journal=Rheum Dis Clin North Am | year=1989 | pages=657-77 | volume=15 | issue=4 | id=PMID 2685924 | url=http://www.molecularalzheimer.org/files/Gestational_Lyme_Borreliosis_-_Annotated_1989.pdf | format=]}}</ref><!-- | |||
| --><ref name="Schlesinger">{{cite journal | author=Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman MT | title=Maternal-fetal transmission of the Lyme disease spirochete, ''Borrelia burgdorferi'' | journal=Ann Intern Med | year=1985 | pages=67-8 | volume=103 | issue=1 | id=PMID 4003991}}</ref> | |||
| The risk of transmission is minimized if the mother receives prompt antibiotic treatment. Antibiotics that can be given to pregnant women with Lyme disease include amoxicillin, ], or penicillin (oral or intramuscular).<ref></ref> | |||
| ===Other=== | |||
| There is at least one case report of transmission by a ].<!-- | |||
| --><ref name="Luger">{{cite journal | author=Luger S | title=Lyme disease transmitted by a biting fly. | journal=N Engl J Med | volume=322 | issue=24 | pages=1752 | year=1990 | id=PMID 2342543 | url=http://cassia.org/library/N_Engl_J_Med_1990_Jun_14,322(24),1752.htm | format=html}}</ref><!-- | |||
| --> Lyme spirochetes have been found in biting flies as well as ].<!-- | |||
| --><ref name="Magnarelli">{{cite journal | author=Magnarelli L, Anderson J | title=Ticks and biting insects infected with the etiologic agent of Lyme disease, ''Borrelia burgdorferi''. | journal=J Clin Microbiol | volume=26 | issue=8 | pages=1482-6 | year=1988 | id=PMID 3170711 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=266646&blobtype=pdf | format=PDF}}</ref> Some researchers believe biting insects do not feed long enough to transmit the infection, while others including ''Borrelia burgdorferi'' discoverer ] believe more research is needed.<!-- | |||
| --><ref name="Burgdorfer">{{cite conference | author=Burgdorfer W | title=Increased evidence of mosquito/spirochete associations. | booktitle=11th International Scientific Conference on Lyme Disease, 1998 | year=1998 | url=http://www.lyme.org/conferences/98_abstract.html | format=html}}</ref> ] has been anecdotally reported; Lyme spirochetes have been found in semen<!-- | |||
| --><ref name="Bach">{{cite conference | author=Bach G | title=Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients. | booktitle=14th International Scientific Conference on Lyme Disease, 2001 | year=2001 | url=http://www.anapsid.org/lyme/bach.html | format=html}}</ref> | |||
| and breast milk,<!-- | |||
| --><ref name="Schmidt">{{cite journal | author=Schmidt B, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A | title=Detection of ''Borrelia burgdorferi'' DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. | journal=Diagn Microbiol Infect Dis | volume=21 | issue=3 | pages=121-8 | year=1995 | id=PMID 7648832}}</ref> however sexual transmission of the spirochete by these routes is not known to occur.<ref name=Steere_2003>{{cite web | author = Steere AC | title = Lyme Disease: Questions and Answers |publisher = Massachusetts General Hospital / Harvard Medical School | url = http://www.mgh.harvard.edu/medicine/rheu/Q&ALYME.pdf | date = 2003-02-01 | accessdate = 2007-03-22}}</ref> | |||
| ==Ecology== | |||
| Urbanization and other anthropogenic factors can be implicated in the spread of the Lyme disease into the human population. In many areas, expansion of suburban neighborhoods has led to the gradual deforestation of surrounding wooded areas and increasing "border" contact between humans and tick-dense areas. Human expansion has also resulted in a gradual reduction of the predators that normally hunt deer as well as mice, chipmunks and other small rodents -- the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission to Lyme residents has greatly increased.<!-- | |||
| --><ref name="LoGiudice">{{cite journal | author = LoGiudice K, Ostfeld R, Schmidt K, Keesing F | title = The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk. | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 2 | pages = 567-71 | year = 2003 | id = PMID 12525705}}</ref><!-- | |||
| --><ref name="Patz">{{cite journal | author = Patz J, Daszak P, Tabor G, Aguirre A, Pearl M, Epstein J, Wolfe N, Kilpatrick A, Foufopoulos J, Molyneux D, Bradley D | title = Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence. | journal = Environ Health Perspect | volume = 112 | issue = 10 | pages = 1092-8 | year = 2004 | id = PMID 15238283}}</ref> | |||
| Researchers are also investigating possible links between ] and the spread of vector-borne diseases including Lyme disease.<ref name="Khasnis">{{cite journal | author = Khasnis A, Nettleman M | title = Global warming and infectious disease. | journal = Arch Med Res | volume = 36 | issue = 6 | pages = 689-96 | year = | id = PMID 16216650}}</ref> | |||
| The deer tick (''Ixodes scapularis'', the primary vector in the northeastern U.S.) has a two-year life cycle, first progressing from larva to nymph, and then from nymph to adult. The tick feeds only once at each stage. In the fall, large acorn forests attract deer as well as mice, chipmunks and other small rodents infected with ''B. burgdorferi''. During the following spring, the ticks lay their eggs. The rodent population then "booms." Tick eggs hatch into larvae, which feed on the rodents; thus the larvae acquire infection from the rodents. (Note: At this stage, it is proposed that tick infestation may be controlled using acaricides (]). | |||
| Adult ticks may also transmit disease to humans. After feeding, female adult ticks lay their eggs on the ground, and the cycle is complete. On the west coast, Lyme disease is spread by the western black-legged tick (''Ixodes pacificus''), which has a different life cycle. | |||
| The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests that eliminating deer from smaller areas (less than 2.5 ] or 6.2 ]) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".<ref name="Perkins">{{cite journal | author = Perkins S, Cattadori I, Tagliapietra V, Rizzoli A, Hudson P | title = Localized deer absence leads to tick amplification. | journal = Ecology | volume = 87 | issue = 8 | pages = 1981-6 | year = 2006 | id = PMID 16937637}}</ref> | |||
| ==Epidemiology== | |||
| Lyme disease is the most common ] in ] and ], and one of the fastest-growing ] in the ]. Of cases reported to the United States ] (CDC), the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.<ref> CDC - Reported Cases of Lyme Disease by Year, United States, 1991-2005.</ref> | |||
| Although Lyme disease has now been reported in 49 of 50 states in the U.S, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). Charts and tables for Lyme disease statistics in the U.S. can be found at the . | |||
| The number of reported cases of the disease have been increasing, as are endemic regions in North America. For example, it had previously been thought that ''Borrelia burgdorferi'' sensu lato couldn't be maintained in an enzootic cycle in ] because it was assumed the large lizard population would dilute the prevalence of ''Borrelia burgdorferi'' in local tick populations, but this has since been proven false as lizards are now known carriers of ticks in North America, Europe and North Africa. Indeed, the ] of ''Borrelia'' has been detected in lizards, indicating that they can be infected.<ref>Swanson KI, Norris DE. Detection of ''Borrelia burgdorferi'' DNA in Lizards from Southern Maryland. Vector Borne Zoonotic Dis. 2007 Spring;7(1):42-9</ref> | |||
| Whereas ''Borrelia burgdorferi'' is most associated with deer tick and the white tailed mouse, ''Borrelia afzelii'' is most frequently detected in rodent-feeding vector ticks, ''Borrelia garinii'' and ''Borrelia valaisiana'' appear to be associated with birds. Both rodents and birds are competent reservoir hosts for ''Borrelia burgdorferi'' sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association. | |||
| In ], cases of ''Borrelia burgdorferi'' sensu lato infected ticks are found predominantly in ], ], ], ], ], ] and ], but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at . | |||
| ''Borrelia burgdorferi'' sensu lato infested ticks are being found more frequently in ], as well as in Northwest ] and far eastern ].<ref>Li M, Masuzawa T, Takada N, Ishiguro F, Fujita H, Iwaki A, Wang H, Wang J, Kawabata M, Yanagihara Y. "Lyme disease ''Borrelia'' species in northeastern China resemble those isolated from far eastern Russia and Japan". Appl Environ Microbiol 1998 Jul;64(7):2705-9</ref><ref>Masuzawa T. "Terrestrial distribution of the Lyme borreliosis agent ''Borrelia burgdorferi'' sensu lato in East Asia".Jpn J Infect Dis. 2004 Dec;57(6):229-35</ref> ''Borrelia'' has been isolated in Mongolia as well.<ref>Walder G, Lkhamsuren E, Shagdar A, Bataa J, Batmunkh T, Orth D, Heinz FX, Danichova GA, Khasnatinov MA, Wurzner R, Dierich MP."Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia."Int J Med Microbiol. 2006 May;296 Suppl 40:69-75.</ref> | |||
| In ] tick-borne disease recognition and occurrence is rising. Ticks carrying ''Borrelia burgdorferi'' sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of ''Borrelia'' has not yet been defined.<ref>Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH."Description of Lyme disease-like syndrome in Brazil: is it a new tick-borne disease or Lyme disease variation?" Braz J Med Biol Res. 2007 Apr;40(4):443-56.</ref> The first reported case of Lyme disease in Brazil was made in 1993 in ].<ref>Yoshinari NH, Oyafuso LK, Monteiro FG, de Barros PJ, da Cruz FC, Ferreira LG, Bonasser F, Baggio D, Cossermelli W."Lyme disease. Report of a case observed in Brazil" Rev Hosp Clin Fac Med Sao Paulo. 1993 Jul-Aug;48(4):170-4.</ref> ''Borrelia burgdorferi'' sensu stricto antigens in patients have been identified in Colombia and in Bolivia. | |||
| In Northern Africa ''Borrelia burgdorferi'' sensu lato has been identified in ], ], ] and ].<ref>Bouattour A, Ghorbel A, Chabchoub A, Postic D. "Lyme borreliosis situation in North Africa" Arch Inst Pasteur Tunis. 2004;81(1-4):13-20</ref><ref>Dsouli N, Younsi-Kabachii H, Postic D, Nouira S, Gern L, Bouattour A. "Reservoir role of lizard ''Psammodromus algirus'' in transmission cycle of ''Borrelia burgdorferi'' sensu lato (Spirochaetaceae) in Tunisia." J Med Entomol. 2006 Jul;43(4):737-42.</ref><ref>Helmy N. "Seasonal abundance of ''Ornithodoros (O.) savignyi'' and prevalence of infection with ''Borrelia'' spirochetes in Egypt". J Egypt Soc Parasitol. 2000 Aug;30(2):607-19.</ref> | |||
| In Western and sub-Saharan Africa, tick-borne ] was first identified by the British physicians Joseph Dutton and John Todd in 1905. ''Borrelia'' in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that Lyme disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.<ref>Fivaz BH, Petney TN. "Lyme disease--a new disease in southern Africa?" | |||
| J S Afr Vet Assoc. 1989 Sep;60(3):155-8.</ref> In East Africa, two cases of Lyme disease have been reported in Kenya.<ref>Jowi JO, Gathua SN. Lyme disease: report of two cases. East Afr Med J. 2005 May;82(5):267-9. | |||
| PMID 16119758</ref> | |||
| In ] there is no definitive evidence for the existence of ''B. burgdorferi'' or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.<ref>Piesman J, Stone BF. Vector competence of the Australian paralysis tick, ''Ixodes holocyclus'', for the Lyme disease spirochete ''Borrelia burgdorferi''. Int J Parasitol. 1991 Feb;21(1):109-11.PMID 2040556</ref> Cases of neuroborreliosis have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial. | |||
| To date, data shows that ] temperate regions are most endemic for Lyme disease.<ref>Grubhoffer L, Golovchenko M, Vancova M, Zacharovova-Slavickova K, Rudenko N, Oliver JH Jr. Lyme borreliosis: insights into tick-/host-borrelia relations. Folia Parasitol (Praha). 2005 Nov;52(4):279-94. Review. PMID 16405291</ref><ref>Higgins R. Emerging or re-emerging bacterial zoonotic diseases: bartonellosis, leptospirosis, Lyme borreliosis, plague. Rev Sci Tech. 2004 Aug;23(2):569-81.PMID 15702720</ref> | |||
| ==Prevention== | |||
| The best prevention involves avoiding areas in which ticks are found; this can reduce the probability of contracting Lyme disease. Other good prevention practices include wearing clothing that covers the entire body when in a wooded area; using mosquito/tick repellent; after exposure to wooded areas, checking all parts of the body (including hair) for ticks. | |||
| For clothing, you should wear long-sleeve shirts and pants that are tucked into socks or boots. One should also wear light-colored clothing so that you can see the tick on you before it attaches itself. | |||
| ===Vaccination=== | |||
| A ] against a North American strain of the spirochetal bacteria was available between 1998 and 2002 by ] (GSK) called Lymerix and was based on the outer surface protein A (Osp-A) of ''Borrelia''. Osp-A causes creation of antibodies from the body's immune system to attack that protein. When taking it off the market, GSK cited poor sales, need for frequent boosters, the high price of the vaccine, and exclusion of children. Some people believe that the actual reason was that the vaccine was neither safe nor effective. A group of patients who took Lymerix developed arthritis, muscle pain and other troubling symptoms after vaccination. ] litigation against GSK followed. Cassidy v. SmithKline Beecham, No. 99-10423 (Ct. Common Pleas, PA state court) (common settlement case).<ref name="LymeInfo-Vaccine">Safety/Efficacy concerns re: Lyme vaccine: LYMErix ''LymeInfo.net''</ref> | |||
| It was later learned that patients with the genetic ] HLA-DR4 were susceptible to T-cell cross-reactivity between ]s of OspA and lymphocyte function-associated antigen in these patients causing an autoimmune reaction.<ref> Willett TA, Meyer AL, Brown EL, Huber BT. "An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope". Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1303-8.</ref> | |||
| New vaccines are being researched using outer surface protein C (Osp-C) and ] as methods of immunization.<ref>Earnhart CG, Marconi RT. "OspC phylogenetic analyses support the feasibility of a broadly protective polyvalent chimeric Lyme disease vaccine". Clin Vaccine Immunol. 2007 Mar 14</ref><ref> Pozsgay V, Kubler-Kielb J."Synthesis of an experimental glycolipoprotein vaccine against Lyme disease". | |||
| Carbohydr Res. 2007 Feb 26;342(3-4):621-6</ref> | |||
| ===Removal of ticks=== | |||
| There are many urban legends about the proper and effective method to remove a tick. One legend states that something hot (cigarette; burnt match) should be applied to the back of the tick, which causes the tick to remove its head from the victim. It further states that ticks "screw" their heads into their victims; therefore, one must "unscrew" the head. These legends are incorrect and potentially dangerous because if a tick is disturbed it may regurgitate its stomach contents into the host including the agents of tick borne disease if the tick is infected. | |||
| Proper removal of a tick: use a pair of tweezers, grab the head of the tick near the mouth, and pull it straight out, no turning or twisting. The area should then be disinfected with rubbing alcohol or hydrogen peroxide. If the head is not completely removed, local infection of the person/animal bitten may result, and a doctor should be consulted (or a veterinarian if the tick was removed from a pet). It is important not to handle the tick with bare hands or let it crawl on you because simply touching a tick that has RMSF (]) may transmit that infection.<ref> American Family Physician. August 15, 2002.</ref> | |||
| An alternate method that does not risk squeezing the tick's thorax (causing regurgitation of bodily fluids into the wound) uses 18 inches of sewing thread. The thread is tied in a simple overhand knot that is tightened slowly around the tick's head. If both ends of the thread are pressed against the skin while gently pulling, the knot will tighten around the tick's head. Slowly pulling the ends of the thread will then dislodge the tick from the bite site with a reduced chance of leaving the head attached. This method also works with fine weight fishing line. | |||
| ==Symptoms== | |||
| ===Acute (early) symptoms=== | |||
| The ] from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (a couple of days), or much longer (months to years). Symptoms most often occur from May through September because the nymphal stage of the tick is responsible for most cases.<ref></ref> Asymptomatic infection exists, but is uncommon.<ref name="pmid12905137">[http://dermatology.jwatch.org/cgi/content/long/2003/1028/6 Steere AC et al. Asymptomatic infection with ''Borrelia burgdorferi''. Clin Infect Dis 2003 Aug 15; 37:528-32. PMID 12905137</ref> Early symptoms of Lyme disease may be heterogeneous and nonspecific and include: | |||
| ] | |||
| *Rash | |||
| Patients may have an expanding rash, ] (EM), at the site of the tick bite. Most patients with EM do not recall a deer tick bite. The characteristic "bull's-eye" rash with central clearing is not the most common form; homogeneously red rashes are more frequent.<!-- | |||
| --><ref name="pmid11900494">{{cite journal | author=Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC | title=Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans | journal=Ann Intern Med | year=2002 | pages=421-8 | volume=136 | issue=6 | id=PMID 11900494 | url=http://www.annals.org/cgi/reprint/136/6/421.pdf | format=PDF}}</ref><!-- | |||
| --><ref name="pmid11982300">{{cite journal | author=Edlow JA | title=Erythema migrans | journal=Med Clin North Am | year=2002 | pages=239-60 | volume=86 | issue=2 | id=PMID 11982300}}</ref><!-- | |||
| --> | |||
| The rash is classically 5 to 6.8 cm in diameter appearing as an annular homogenous erythema (59%), central erythema (30%), central clearing (9%), or central purpura (2%).<ref name="pmid17113969">Feder HM Jr, Abeles M, Bernstein M, Whitaker-Worth D, Grant-Kels JM. | |||
| Diagnosis, treatment, and prognosis of erythema migrans and Lyme arthritis. Clin Dermatol. 2006 Nov-Dec;24(6):509-20. | |||
| PMID 17113969</ref> EM may be less than 5 cm in ].<ref name="pmid16484816"> Weber K, Wilske B. "Mini erythema migrans--a sign of early Lyme borreliosis". Dermatology. 2006;212(2):113-6 PMID 16484816</ref> Multiple painless EM rashes may occur, indicating disseminated infection. | |||
| The true ] of the rash is disputed, with estimates ranging from less than 50%<!-- | |||
| --><ref name="pmid11982305">{{cite journal | author=Donta ST | title=Late and chronic Lyme disease | journal=Med Clin North Am | year=2002 | pages=341-9, vii | volume=86 | issue=2 | id=PMID 11982305 | url=http://www.immunesupport.com/library/print.cfm?ID=3579&t=CFIDS_FM}}</ref><!-- | |||
| --><ref name="pmid15581390">{{cite journal | author=Cameron D, Gaito A, Narris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Scherrer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R; ILADS Working Group | title=Evidence-based guidelines for the management of Lyme disease | journal=Expert Rev Anti Infect Ther | year=2004 | pages=S1-13 | volume=2 | issue=(1 Suppl) | id=PMID 15581390 | url=http://www.ilads.org/files/ILADS_Guidelines.pdf | format=PDF}}</ref><!-- | |||
| --> to over 80% of those infected.<ref>[http://www.cdc.gov/ncidod/dvbid/lyme/ld_LymeDiseaseRashPhotos.htm CDC Lyme Disease Erythema Migrans Disease Retrieved May 13 2007</ref> | |||
| Because of the "bull's-eye" description to describe the Lyme disease rash, the condition commonly called ] is sometimes confused with Lyme disease. | |||
| *] | |||
| *] or ] | |||
| *] | |||
| *]<ref name="pmid6859726">{{cite journal |author=Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW, Sigal LH, Spieler PN, Stenn KS, Malawista SE |title=The early clinical manifestations of Lyme disease |journal=Ann. Intern. Med. |volume=99 |issue=1 |pages=76-82 |year=1983 |pmid=6859726 |doi=}}</ref> | |||
| *] and ] | |||
| *Cardiac. 10% of patients may have cardiac manifestations including ] and ].<ref name="pmid2682955">{{cite journal |author=Ciesielski CA, Markowitz LE, Horsley R, Hightower AW, Russell H, Broome CV |title=Lyme disease surveillance in the United States, 1983-1986 |journal=Rev. Infect. Dis. |volume=11 Suppl 6 |issue= |pages=S1435-41 |year=1989 |pmid=2682955 |doi=}}</ref> | |||
| * Neurologic symptoms (neuroborreliosis) may occur in 18% <ref name="pmid2682955">.</ref>. Bannwarth's syndrome is the triad of lymphocytic meningitis, cranial nerve palsy, and radiculoneuritis. The most common cranial palsy is the 7th cranial nerve (]) in the form of ]. | |||
| *]{{Fact|article|date=May 2007}} | |||
| *] and intestinal pain may also occur{{Fact|article|date=May 2007}} | |||
| ===Late stage symptoms=== | |||
| Lyme disease in its tertiary form can have a multitude of symptoms. The symptoms appear heterogeneous in the infected population, which may be due to innate immunity or ''Borrelia'' sub-species bacterium. The late symptoms of Lyme disease can appear months after initial infection and often progress in cumulative fashion over time. Neuro-psychiatric symptoms often develop much later in disease sequence, much like tertiary ]. | |||
| Physical: | |||
| *] | |||
| *] | |||
| *] with or without frank ] | |||
| *] | |||
| *] | |||
| *] | |||
| *] (too-rapid heartbeat) | |||
| *] disorders | |||
| *] suppression | |||
| *] disorder | |||
| Neurological (can effect ] or ] components): | |||
| *] | |||
| *] or ] | |||
| *] | |||
| *] or ] | |||
| *] problems (eg. ], ] or ]), ], or ] | |||
| *] (severe sensitivity to sound & vibration) | |||
| *] (balance disorder may be mediated by CNS or inner/middle ear) and other ] symptoms<ref>Rosenhall U, Hanner P, Kaijser B. "''Borrelia'' infection and vertigo."Acta Otolaryngol. 1988 Jul-Aug;106(1-2):111-6.</ref><ref>Moscatello AL, Worden DL, Nadelman RB, Wormser G, Lucente F."Otolaryngologic aspects of Lyme disease." Laryngoscope. 1991 Jun;101(6 Pt 1):592-5. </ref> | |||
| *] | |||
| *] | |||
| *] | |||
| Neuropsychiatric: | |||
| *], ] | |||
| *] | |||
| *short-term ] | |||
| *] | |||
| *]s | |||
| *] | |||
| *] impairment (]) | |||
| *] (rare) including diagnosis of ] and ]<ref> | |||
| Fallon BA, Nields JA. "Lyme disease: a neuropsychiatric illness". Am J Psychiatry. 1994 Nov;151(11):1571-83.</ref><ref>Hess A, Buchmann J, Zettl UK, Henschel S, Schlaefke D, Grau G, Benecke R."Abstract ''Borrelia burgdorferi'' central nervous system infection presenting as an organic schizophrenia-like disorder". Biol Psychiatry. 1999 Mar 15;45(6):795.</ref> | |||
| ==Diagnosis== | |||
| The most reliable method of diagnosing Lyme disease is a clinical exam by an experienced practitioner, taking into account symptoms, history, and possible exposure to ticks in an ] area. Clinicians who diagnose strictly based on the ] are in error, as the ] explicitly states that this definition is intended for ] purposes only, and is "not intended to be used in clinical diagnosis."<ref name="CDC LD Definition">{{cite web | title=Lyme Disease (''Borrelia burgdorferi''): 1996 Case Definition | work=CDC Case Definitions for Infectious Conditions under Public Health Surveillance | url=http://www.cdc.gov/epo/dphsi/casedef/lyme_disease_current.htm | accessdate=2006-03-15}}</ref><ref name="CDC Testimony">{{cite web | title=CDC Testimony before the Connecticut Department of Health and Attorney General's Office | work=CDC's Lyme Prevention and Control Activities | url=http://www.hhs.gov/asl/testify/t040129.html | accessdate=2006-03-15}}</ref> | |||
| The ], which does not occur in all cases, is considered sufficient to make a diagnosis of Lyme disease and prompt treatment without further testing. In fact because of the undisputed high rate of false negatives during the early stage of the disease (before a sufficient antibody response has been established), it is recommended that tests not be performed when a patient has an ].<ref name="Edlow" /><ref name="Brown">{{cite journal | author=Brown SL, Hansen SL, Langone JJ | title=Role of serology in the diagnosis of Lyme disease | journal=JAMA | year=1999 | pages=62-6 | volume=282 | issue=1 | id=PMID 10404913}}</ref><ref name="Hofmann">{{cite journal | author=Hofmann H | title=Lyme borreliosis--problems of serological diagnosis | journal=Infection | year=1996 | pages=470-2 | volume=24 | issue=6 | id=PMID 9007597}}</ref> | |||
| ===Serology=== | |||
| The ] laboratory tests most widely available and employed are the ] and ]. In the two-tiered protocol recommended by the ] according to their ], the ] is performed first, and if it is positive or equivocal, a ] is then performed to support the diagnosis. The reliability of testing in diagnosis remains controversial (see ]).<!-- | |||
| --> However studies show the Western blot IgM has a ] of 94-96% for patients with symptoms suggestive of Lyme disease with infection by ''Borrelia burgoferi''.<ref name="Engstrom">{{cite journal | author=Engstrom SM, Shoop E, Johnson RC | title=Immunoblot interpretation criteria for serodiagnosis of early Lyme disease | journal=J Clin Microbiol | year=1995 | pages=419-27 | volume=33 | issue=2 | id=PMID 7714202 | url=http://jcm.asm.org/cgi/reprint/33/2/419.pdf | format=PDF}}</ref><ref name="Sivak">{{cite journal | author=Sivak SL, Aguero-Rosenfeld ME, Nowakowski J, Nadelman RB, Wormser GP | title=Accuracy of IgM immunoblotting to confirm the clinical diagnosis of early Lyme disease | journal=Arch Intern Med | year=1996 | pages=2105-9 | volume=156 | issue=18 | id=PMID 8862103}}</ref> | |||
| ] test results have been widely reported in both early and late disease. False Negatives can take place for a broad spectrum of reasons, including cross reaction of other infections such as<ref name="Gossens">{{cite journal | author=Goossens HA, Nohlmans MK, van den Bogaard AE | title=Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis | journal=Infection | year=1999 | pages=231 | volume=27 | issue=3 | id=PMID 10378140}}</ref><!-- | |||
| --><ref name="Berardi">{{cite journal | author=Berardi VP, Weeks KE, Steere AC | title=Serodiagnosis of early Lyme disease: analysis of IgM and IgG antibody responses by using an antibody-capture enzyme immunoassay | journal=J Infect Dis | year=1988 | pages=754-60 | volume=158 | issue=4 | id=PMID 3049839}}</ref><!-- | |||
| --> cytomegalovirus.<ref name="Gossens" /><!-- | |||
| --> and herpes simplex type virus 2.<!-- | |||
| --><ref name="Strasfeld">{{cite journal | author=Strasfeld L, Romanzi L, Seder RH, Berardi VP | title=False-positive serological test results for Lyme disease in a patient with acute herpes simplex virus type 2 infection | journal=Clin Infect Dis | year=2005 | pages=1826-7 | volume=41 | issue=12 | id=PMID 16288417}}</ref><!-- | |||
| --><ref name="Lawrence"/><!-- | |||
| --><ref name="Coyle">{{cite journal | author=Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ | title=Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease | journal=Neurology | year=1995 | pages=2010-5 | volume=45 | issue=11 | id=PMID 7501150}}</ref><!-- | |||
| --><ref name="Paul">{{cite journal | author=Paul A | title= | journal=MMW Mortschr Med | year=2001 | pages=17 | volume=143 | issue=6 | id=PMID 11247357}}</ref><!-- | |||
| --><ref name="Pikelj">{{cite journal | author=Pikelj F, Strle F, Mozina M | title=Seronegative Lyme disease and transitory atrioventricular block | journal=Ann Intern Med | year=1989 | pages=90 | volume=111 | issue=1 | id=PMID 11247357}}</ref><!-- | |||
| --><ref name="Oksi">{{cite journal | author=Oksi J, Uksila J, Marjamaki M, Nikoskelainen J, Viljanen MK | title=Antibodies against whole sonicated ''Borrelia burgdorferi'' spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis | journal=J Clin Microbiol | year=1995 | pages=2260-4 | volume=33 | issue=9 | id=PMID 7494012 | url=http://jcm.asm.org/cgi/reprint/33/9/2260.pdf | format=PDF}}</ref> | |||
| ] (PCR) tests for Lyme disease may also be available to the patient. A PCR test attempts to detect the genetic material (]) of the Lyme disease spirochete, whereas the Western blot and ELISA tests look for antibodies to the organism. PCR tests are rarely susceptible to ] results but can often show ] results. PCR reliability is still questioned. The low number of spirochetes in tissue samples and body fluids is one of the reasons why it is difficult to demonstrate ''Borrelia burgdorferi'' active infection by PCR, especially in the late stage of the disease. | |||
| With the exception of PCR testing, currently there is no practical means for detection of the presence of the organism, as serologic studies only test for ] of ''Borrelia''. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to ''Borrelia'' antigens indicate disease, but lower titers can be misleading. The IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.<ref> N Burdash and J Fernandes "Lyme borreliosis: detecting the great imitator" Journal of the American Osteopathic Association, Vol 91, Issue 6, 573-573. 1991.</ref> | |||
| Western blot, ELISA and PCR can be performed by either blood test via ] or ] (CSF) via ]. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive, reportedly CSF yields positive results in only 10-30% of patients cultured. The diagnosis of neurologic infection by ''Borrelia'' should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.<ref>Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ. "Detection of ''Borrelia burgdorferi''-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease". Neurology. 1995 Nov;45(11):2010-5</ref>A negative result obtained by these methods can never exclude Lyme disease. However, a positive result can confirm the diagnosis or treatment failure independently of results of antibody tests. | |||
| New tests being studied for commercial use for ''Borrelia'' infection hold more promise for unequivocal testing than the the standard commercial laboratory tests now available. These include Lymphocyte transformation tests, aka LTT-MELISA(R),<ref>Diagn Microbiol Infect Dis. 2007 Jan;57(1):27-34, “A novel lymphocyte transformation test (LTT-MELISA®) for Lyme borreliosis.”, Valentine-Thon E, Ilsemann K, Sandkamp M.</ref> and focus floating microscopy (FFM). New research indicates ] ] may also be a possible marker for neuroborreliosis.<ref>Rupprecht TA, Koedel U, Angele B, Fingerle V, Pfister HW. "Cytokine CXCL13--a possible early CSF marker for neuroborreliosis" Nervenarzt. 2006 Apr;77(4):470-3. German.</ref><ref>Cadavid D. The mammalian host response to borrelia infection. | |||
| Wien Klin Wochenschr. 2006 Nov;118(21-22):653-8. PMID 17160603</ref><ref>Narayan K, Dail D, Li L, Cadavid D, Amrute S, Fitzgerald-Bocarsly P, Pachner AR. The nervous system as ectopic germinal center: CXCL13 and IgG in lyme neuroborreliosis. | |||
| Ann Neurol. 2005 Jun;57(6):813-23. PMID 15929033</ref> | |||
| Skin ] can be used to confirm infection of ''Borrelia'' but it usually reserved for research work and not used in the clinical setting. | |||
| ===Imaging=== | |||
| ] imaging is often used to look for ] ] indicative of Lyme encephalitis in the patient. SPECT is not a diagnostic tool in and of itself, but it a useful method of determining brain function. | |||
| In Lyme patients cerebral hypoperfusion of frontal ] and ] structures is usually found.<ref>Logigian EL, Johnson KA, Kijewski MF, Kaplan RF, Becker JA, Jones KJ, Garada BM, Holman BL, Steere AC. "Reversible cerebral hypoperfusion in Lyme encephalopathy". Neurology. 1997 Dec;49(6):1661-70</ref> In about 70% of chronic Lyme disease patients with cognitive symptoms, brain SPECT scans typically reveal a pattern of global hypoperfusion in a heterogeneous distribution through the ].<ref>Fallon BA, Das S, Plutchok JJ, et al: Functional brain imaging and neuropsychological testing in Lyme Disease. Clin Infectious Disease 25(s):57-63, 1997</ref> This pattern is not definite or specific for Lyme disease per se, as it can also be seen in other central nervous system (CNS) syndromes such as ] encephalopathy, viral encephalopathy, chronic ] use, and ]. The pattern found in Lyme patients is different from what one would see with normal controls or patients with ] or ]. | |||
| ] findings which are abnormal are often seen in both early and late Lyme disease. MRI scans among patients with neurologic Lyme disease may demonstrate punctated ] ] on T2-weighted images, similar to those seen in ] or inflammatory disorders such as ], ] (SLE), or cerebrovascular disease.<ref>Brian A. Fallon, MD, MPH, MEd Review of Lyme Neuroborreliosis 3th International Scientific Conference on Lyme Disease and other Tick-borne Disorders</ref>] and brainstem ] has been indicated with Lyme infection as well.<ref>Kalina P, Decker A, Kornel E, Halperin JJ. Lyme disease of the brainstem. Neuroradiology. 2005 Dec;47(12):903-7.</ref><ref>Aasly J, Nilsen G. Cerebral atrophy in Lyme disease. Neuroradiology. 1990;32(3):252.</ref><ref>Tarasow E, Ustymowicz A, Zajkowska J, Hermanowska-Szpakowicz T. Neurol Neurochir Pol. 2001 Sep-Oct;35(5):803-13</ref> | |||
| Diffuse white matter pathology can disrupt these ubiquitous ] connections and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status.<ref>Brian A. Fallon, M.D., John Keilp, Ph.D., Isak Prohovnik, Ph.D., Ronald Van Heertum, M.D. and J. John Mann, M.D. Regional Cerebral Blood Flow and Cognitive Deficits in Chronic Lyme Disease J Neuropsychiatry Clin Neurosci 15:326-332, August 2003 PMID 12928508</ref> | |||
| White matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. Spontaneous remission can occur in Multiple sclerosis, and resolution of MRI white matter hyperintensities, after antibiotic treatment, has been observed in Lyme disease.<ref>Brian A. Fallon, M.D., John Keilp, Ph.D., Isak Prohovnik, Ph.D., Ronald Van Heertum, M.D. and J. John Mann, M.D. Regional Cerebral Blood Flow and Cognitive Deficits in Chronic Lyme Disease J Neuropsychiatry Clin Neurosci 15:326-332, August 2003 PMID 12928508</ref> | |||
| ===Diagnosis of Late Stage Lyme Disease=== | |||
| In late stage Lyme disease it is often difficult to diagnose due to the multi-faceted appearance which can mimic symptoms of many ailments of better known diseases. For this reason Lyme has often been called the new "Great Imitator".<ref>Pachner AR "Neurologic manifestations of Lyme disease, the new "great imitator". Rev Infect Dis. 1989 Sep-Oct;11 Suppl 6:S1482-6.</ref> Lyme disease may be misdiagnosed as ], ], ], ] (CFS), or other ] and ] diseases, which leaves the infection untreated and allows it to disperse and invade various organs and tissue. | |||
| Some of these conditions may be misdiagnosed as Lyme disease, due to the wide range of symptoms found in Lyme disease, the questionable serology testing available, or due to physicians using Lyme disease as an explanation for an unknown malady. | |||
| ==Treatment== | |||
| The mainstay of treatment for Lyme disease is antibiotics. ] was first demonstrated by researchers to be useful against ''Borrellia'' in the 1950s. Today the antibiotics of choice are ], ] and ]. ] antibiotics are also used. | |||
| *] - ] properties stops synthesis of bacteria replication. Inhibits bacterial protein synthesis. | |||
| *] - ] properties do not kill bacterium, but do halt bacterial growth by inhibition of ] synthesis. | |||
| *] - (intravenous therapy) bactericidal properties kill bacterium. Has central nervous system penetration. | |||
| Persons who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days. A three day course of ] therapy may be considered for deer tick bites when the tick has been on the person for at least 12 hours.<!-- | |||
| --><ref name="AntibioticProphylaxis">Antibiotic Prophylaxis After Tick Bite | |||
| For Prevention Of Lyme Disease </ref> | |||
| Patients should be advised to report any ] over the subsequent two to six weeks. If there should be suspicion of disease, then a course of Doxycycline should be immediately given for ten days without awaiting serology tests which only yield positive results after an interval of one to two months.<!-- Advice given by Hosp. Trop. Med in 2004 to User:Davidruben--> | |||
| Traditional treatment of acute Lyme disease usually consists of a minimum two-week to one-month course of ], either doxycycline 100-200mg or amoxicillin 1500-2000mg per day. | |||
| In later stages, the bacteria disseminate throughout the body and may cross the ], making the infection more difficult to treat. Late diagnosed Lyme is treated with oral or IV antibiotics, frequently ], 2 grams per day, for a minimum of four weeks. ] is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.<ref>Muellegger RR, Zoechling N, Soyer HP, Hoedl S, Wienecke R, Volkenandt M, Kerl H.No detection of ''Borrelia burgdorferi''-specific DNA in erythema migrans lesions after minocycline treatment.Arch Dermatol. 1995 Jun;131(6):678-82.</ref> <ref>Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. Related Articles, "Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting ''Borrelia burgdorferi'' infection". J Am Acad Dermatol. 1993 Feb;28(2 Pt 2):312-4.</ref> | |||
| ===Antibiotic Treatment Controversy=== | |||
| {{see |Lyme disease controversy}} | |||
| With little research conducted specifically on treatment for late/chronic Lyme disease, treatment remains controversial. Currently there are two sets of peer-reviewed published guidelines in the United States; the International Lyme and Associated Diseases Society (ILADS)<ref></ref> advocates extended courses of antibiotics for chronic Lyme patients in light of evidence of ], while the Infectious Diseases Society of America<ref></ref> does not recognize chronic infection and recommends no treatment for persistent symptoms. ], ] trials of long-term antibiotics for chronic Lyme have produced mixed results. | |||
| An new guidelines developed by the ], finds conventionally recommended courses of antibiotics are highly effective for treating nervous system Lyme disease. They find no compelling evidence that prolonged treatment with antibiotics has any benefit in treating symptoms that persist following standard therapy. The guideline is endorsed by the Infectious Diseases Society of America (IDSA). The guideline leader was John J. Halperin and was co-written by Gary Worsmer and Eugene Shapiro. Halperin, Worsmer and Shapiro were all co-authors of the IDSA Lyme guidelines released in 2006 by the . | |||
| The latest double blind, randomized, ]-controlled multicenter clincal study, done in ], results indicated that oral adjunct antibiotics were not justified in the treatment of patients with disseminated Lyme borreliosis who initially received intravenous antibiotics for 3 weeks. The researchers noted the clinical outcome of said patients should not be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. | |||
| In patients with chronic post-treatment symptoms, persistent positive levels of antibodies did not seem to provide any useful information for further care of the patient.<ref>ksi J, Nikoskelainen J, Hiekkanen H, Lauhio A, Peltomaa M, Pitkaranta A, Nyman D, Granlund H, Carlsson SA, Seppala I, Valtonen V, Viljanen M. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis. 2007 Jun 22; PMID 17587070</ref> | |||
| ===Antibiotic Resistant Therapies=== | |||
| Antibiotic treatment is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment.<ref>Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK. ''Borrelia burgdorferi'' detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med. 1999 Jun;31(3):225-32. PMID 10442678</ref> <ref>Hartiala P, Hytonen J, Pelkonen J, Kimppa K, West A, Penttinen MA, Suhonen J, Lahesmaa R, Viljanen MK Transcriptional response of human dendritic cells to ''Borrelia garinii''--defective CD38 and CCR7 expression detected. J Leukoc Biol. 2007 Apr 17 PMID 17440035</ref> | |||
| Experimental data is consensual on the deleterious consequences of systemic ] therapy. Corticosteroids are not indicated in Lyme disease.<ref>Puechal X. | |||
| Med Mal Infect. 2007 Mar 19;</ref> | |||
| Lyme arthritis which is antibiotic resistant may be treated with ] or ].<ref>Massarotti EM. "Lyme arthritis". Med Clin North Am. 2002 Mar;86(2):297-309.</ref> | |||
| Antibiotic refractory patients with neuropathic pain responded well to ] monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study. The average dose leading to a clear-cut pain reduction was 700 mg.<ref>Weissenbacher S, Ring J, Hofmann H. Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage Lyme borreliosis: a pilot study. Dermatology. 2005;211(2):123-7.</ref> | |||
| The immunomodulating, neuroprotective and anti-inflammatory potential of ] may be helpful in late/chronic Lyme disease with neurological or other inflammatory manifestations. Minocycline is used in other ] and ] disorders such as ], ], ], ] (RA) and ].<ref>McCarty MF.Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders.Med Hypotheses. 2006;67(2):251-69.</ref> <ref>Familian A, Boshuizen RS, Eikelenboom P, Veerhuis R.Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation. Glia. 2006 Feb;53(3):233-40.</ref><ref>Minocycline as a neuroprotective agent. Neuroscientist. 2005 Aug;11(4):308-22.</ref><ref>Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M. Clinical potential of minocycline for neurodegenerative disorders. | |||
| Neurobiol Dis. 2004 Dec;17(3):359-66.</ref> A multi-center study is warranted. | |||
| ===Alternative Therapies=== | |||
| A number of other alternative therapies have been suggested, though clinical trials have not been conducted. For example, the use of ] (which is used conventionally to treat a number of other conditions), as an adjunct to antibiotics for Lyme has been discussed.<ref name="Taylor">{{cite journal | author = Taylor R, Simpson I | title = Review of treatment options for Lyme borreliosis. | journal = J Chemother | volume = 17 Suppl 2 | issue = | pages = 3-16 | year = 2005 | id = PMID 16315580}}</ref> Though there are no published data from clinical trials to support its use, preliminary results using a ] model suggest its effectiveness against '']'' both ] and ].<ref name=Pavia>{{cite journal | author = Pavia C | title = Current and novel therapies for Lyme disease. | journal = Expert Opin Investig Drugs | volume = 12 | issue = 6 | pages = 1003-16 | year = 2003 | id = PMID 12783604}}</ref> | |||
| ] approaches include ] because it contains the peptide ], which has been shown to exert profound inhibitory effects on lyme bacteria ].<ref>Lubke LL, & Garon CF. "The antimicrobial agent melittin exhibits powerful ''in vitro'' inhibitory effects on the Lyme disease spirochete." ''Clin Infect Dis'' 1997 Jul;25 Suppl 1:S48-51. PMID 9233664.</ref> The herb ], though not specifically studied for '']'' species, has been found to have both ] and ] properties against a wide range of organisms ] and ], leading some herbalists to recommend it for Lyme.<ref name="Buhner">{{cite book | last=Buhner | first=SH | title=Healing Lyme | year=2005 | publisher=Raven Press | location=Randolph, VT | id= ISBN 0-9708696-3-0}}</ref> | |||
| Manufacturers of concentrated active garlic extract, ], have recently reported results of their first ] for Lyme Disease patients. The study is unpublished.<ref> </ref> | |||
| Anecdotal clinical research has shown potential for the antifungal ] medications such as ] in the treatment of Lyme, but has yet to be repeated in a controlled study or postulated a developed hypothetical model for its use.<ref>Schardt FW. "Clinical effects of fluconazole in patients with neuroborreliosis". Eur J Med Res. 2004 Jul 30;9(7):334-6.</ref> | |||
| Anecdotal evidence also shows a potential for intravenous ascorbic acid ] therapy. | |||
| ==Prognosis== | |||
| For early cases, prompt treatment is usually curative.<ref>Krause PJ, Foley DT, Burke GS, Christianson D, Closter L, Spielman A; Tick-Borne Disease Study Group. Reinfection and relapse in early Lyme disease. Am J Trop Med Hyg. 2006 Dec;75(6):1090-4. | |||
| PMID 17172372</ref> However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including ], ], and ], and immune suppression in the patient (sometimes resulting from inappropriate treatment with steroids). | |||
| A meta-analysis published in 2005 found that some patients with Lyme disease have fatigue, joint and/or muscle pain, and ] symptoms persisting for years despite antibiotic treatment.<!-- | |||
| --><ref name="Cairns">{{cite journal | author = Cairns V, Godwin J | title = Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. | journal = Int J Epidemiol | volume = 34 | issue = 6 | pages = 1340-5 | year = 2005 | id = PMID 16040645}}</ref><!-- | |||
| --> Patients with Late Stage Lyme disease have been shown to experience a level of physical ] equivalent to that seen in ].<!-- | |||
| --><ref name="Klempner">{{cite journal | author=Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M, Weinstein A | title=Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease | journal=N Engl J Med | year=2001 | pages=85-92 | volume=345 | issue=2 | id=PMID 11450676}}</ref> | |||
| The disease can be fatal in and of itself; deaths have been reported.<!-- | |||
| --><ref name="Kirsch">{{cite journal | author=Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A | title=Fatal adult respiratory distress syndrome in a patient with Lyme disease | journal=JAMA | year=1988 | pages=2737-9 | volume=259 | issue=18 | id=PMID 3357244}}</ref><!-- | |||
| --><ref name="Oksi-b">{{cite journal | author=Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK | title=Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature | journal=Brain | year=1996 | pages=2143-54 | volume=119 | issue=Pt 6 | id=PMID 9010017}}</ref><!-- | |||
| --><ref name="Waniek">{{cite journal | author=Waniek C, Prohovnik I, Kaufman MA, Dwork AJ | title=Rapidly progressive frontal-type dementia associated with Lyme disease | journal=J Neuropsychiatry Clin Neurosci | year=1995 | pages=345-7 | volume=7 | issue=3 | id=PMID 7580195}}</ref><!-- | |||
| --><ref name="Cary">{{cite journal | author=Cary NR, Fox B, Wright DJ, Cutler SJ, Shapiro LM, Grace AA | title=Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node | journal=Postgrad Med J | year=1990 | pages=134-6 | volume=66 | issue=772 | id=PMID 2349186}}</ref><!-- | |||
| --><ref name="Reimers">{{cite journal | author=Reimers CD, de Koning J, Neubert U, Preac-Mursic V, Koster JG, Muller-Felber W, Pongratz DE, Duray PH | title=''Borrelia burgdorferi'' myositis: report of eight patients | journal=J Neurol | year=1993 | pages=278-83 | volume=240 | issue=5 | id=PMID 8326331}}</ref> | |||
| The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.<ref name="The Lyme Disease Memorial Page"></ref><ref></ref> | |||
| ==Controversy== | |||
| {{main|Lyme disease controversy}} | |||
| There is no doubt that Lyme disease exists, and most clinicians agree on the treatment of early Lyme disease.<!-- | |||
| --><ref name="Murray">{{cite journal | author = Murray T, Feder H | title = Management of tick bites and early Lyme disease: a survey of Connecticut physicians. | journal = Pediatrics | volume = 108 | issue = 6 | pages = 1367-70 | year = 2001 | id = PMID 11731662}}</ref><!-- | |||
| --> There is, however, considerable controversy as to the prevalence of the disease, the proper procedure for diagnosis and treatment of later stages, and the likelihood of a chronic, antibiotic-resistant Lyme infection. | |||
| On one side are those who believe that Lyme disease is relatively rare, easily diagnosed with available blood tests, and most often easily treated with two to four weeks of antibiotics.<!-- | |||
| --><ref name="Wormser-b">{{cite journal | author = Wormser G | title = Clinical practice. Early Lyme disease. | journal = N Engl J Med | volume = 354 | issue = 26 | pages = 2794-801 | year = 2006 | id = PMID 16807416}}</ref><!-- | |||
| --> On the other side are those who believe that Lyme disease is under-diagnosed, that available blood tests are unreliable, and that extended antibiotic treatment is often necessary.<!-- | |||
| --><ref name="Stricker">{{cite journal | author=Stricker RB, Lautin A, Burrascano JJ | title=Lyme Disease: The Quest for Magic Bullets | journal=Chemotherapy | year=2006 | pages=53-59| volume=52 | issue=2 | id=PMID 16498239}}</ref><!-- | |||
| --><ref name="Phillips-a">{{cite journal | author=Phillips SE, Harris NS, Horowitz R, Johnson L, Stricker RB | title=Lyme disease: scratching the surface | journal=Lancet | year=2005 | pages=1771 | volume=366 | issue=9499 | id=PMID 16298211 | url=http://www.canlyme.com/lyme_scratching_the_surface_05.html}}</ref><!-- | |||
| --><ref name="Phillips-b">{{cite web | author=Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R | year=2003 | title=Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS position paper | format=PDF | work=International Lyme and Associated Diseases Society | url=http://www.ilads.org/files/position2.pdf | accessdate=2006-03-15}}</ref><!-- | |||
| --><ref name="Harvey">{{cite journal | author=Harvey WT, Salvato P | title='Lyme disease': ancient engine of an unrecognized borreliosis pandemic? | journal=Med Hypotheses | year=2003 | pages=742-59 | volume=60 | issue=5 | id=PMID 12710914 | url=http://www.ilads.org/files/harvey.pdf | format=PDF}}</ref> | |||
| The majority of public health agencies such as the U.S. ] maintain the former position. While this narrower position is sometimes described as the "mainstream" view of Lyme disease, published studies involving non-randomized surveys of physicians in ] areas found physicians evenly split in their views, with the majority recognizing ] Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.<!-- | |||
| --><ref name="Ziska">{{cite journal | author=Ziska MH, Donta ST, Demarest FC | title=Physician preferences in the diagnosis and treatment of Lyme disease in the United States | journal=Infection | year=1996 | pages=182-6 | volume=24 | issue=2 | id=PMID 8740119}}</ref><!-- | |||
| --><ref name="Eppes">{{cite journal | author=Eppes SC, Klein JD, Caputo GM, Rose CD | title=Physician beliefs, attitudes, and approaches toward Lyme disease in an endemic area | journal=Clin Pediatr (Phila) | year=1994 | pages=130-4 | volume=33 | issue=3 | id=PMID 8194286}}</ref> | |||
| In recent years a few prominent American Lyme researchers have received funding for the study of organisms known as ] that could be used in ] attacks. The funding has been granted by various U.S. Government agencies including the ] (NIH), and the ] (NIAID). | |||
| In 2003, Lyme researcher Dr. Mark Klempner was appointed the head of a new National Bio-containment Laboratory at ] called the ].<ref></ref> In 2004, ] was chosen as a recipient for a $3 million NIH research grant at the State University of New York at Stony Brook,<ref></ref>. In 2005 Dr. Alan Barbour of ] was awarded $40 million over four years to establish the . <ref></ref> | |||
| These grants have become a source of controversy. Some argue that these researchers have a conflict of interest in receiving these U.S. Government funds due to the politicization of Lyme disease and their roles in the history of the controversy, others cite that the grants are warranted as the infectious agents that the researchers are studying for bioterror defense are similar to the genetic makeup and ] of ''Borrelia'', such as ], ] and ]. | |||
| In October 2006, the Lyme controversy became further entangled with the release of updated diagnosis and treatment guidelines from the ] (IDSA).<ref name=Showdown>{{cite news | title = New Lyme Disease Guidelines Spark Showdown | publisher = U.S. Department of Health and Human Services | date = 2006-11-09 | url = http://www.4woman.gov/news/english/535816.htm | accessdate = 2006-11-17 }}</ref> The new IDSA recommendations are more restrictive than prior IDSA treatment guidelines for Lyme.<ref name="IDSA">{{cite journal | author = Wormser G, Dattwyler R, Shapiro E, Halperin J, Steere A, Klempner M, Krause P, Bakken J, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler J, Nadelman R | title = The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. | journal = Clin Infect Dis | volume = 43 | issue = 9 | pages = 1089-134 | year = 2006 | id = PMID 17029130 | url=http://www.journals.uchicago.edu/CID/journal/issues/v43n9/40897/40897.html}}</ref> The guidelines are published by the ] . | |||
| The new guidelines now require either an EM rash or positive laboratory tests for diagnosis. Seronegative Lyme disease is no longer acknowledged, except in early Lyme. The authors of the guidelines maintain that chronic Lyme disease does not result from persistent infection, and therefore treatment beyond 2-4 weeks is not recommended by the IDSA, even in late stage cases. | |||
| An opposing group of doctors making up the International Lyme and Associated Disease Society (ILADS) have purported the use of antibiotic treatment beyond four weeks for both early and late Lyme. The ILADS are available through ]. | |||
| ==Advancing Immunology Research== | |||
| The role of ] concomitant to ''Borrelia'' infection was first made in 1984,<ref>Newman K Jr, Johnson RC."T-cell-independent elimination of ''Borrelia turicatae''".Infect Immun. 1984and lymphocyte subsets". Zentralbl Bakteriol Mikrobiol Hyg . 1986 Dec;263(1-2):151-9</ref> and long term persistance of T cell ] responses to ''B. burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.<ref>Kruger H, Pulz M, Martin R, Sticht-Groh V. "Long-term persistence of specific T- and B-lymphocyte responses to ''Borrelia burgdorferi'' following untreated neuroborreliosis". | |||
| Infection. 1990 Sep-Oct;18(5):263-7.</ref> The role of ] and ] (IFN-gamma) in borrelia was first described in 1995.<ref>Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, Bergstrom S. "The outer surface proteins of Lyme disease ''Borrelia'' spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications". | |||
| Clin Exp Immunol. 1995 Sep;101(3):453-60.</ref> The ] pattern of Lyme disease, and the role of Th1 with down regulation of ] (IL-10) was first proposed in 1997.<ref> Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J. "T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines". Arthritis Rheum. 1997 Jan;40(1):69-79.</ref> | |||
| ===Inflammation=== | |||
| {{see|Innate immune system|Cell signaling networks}} | |||
| Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-] immune process. This pro-inflammatory process is a ] and results in Th1 upregulation. These studies have shown a significant decrease in ] output of (IL-10), an upregulation of ] (IL-6), ] (IL-12) and IFN-gamma and disregulation in ] predominantly.<ref>Shin JJ, Glickstein LJ, Steere AC."High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory Lyme arthritis". Arthritis Rheum. 2007 Mar 28;56(4):1325-1335</ref> | |||
| These studies suggest that the host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. IFN-gamma alters gene expression by ] exposed to ''B. burgdorferi'' in a manner that promotes recruitment of ] and suppresses that of ]. | |||
| Studies also suggest suppressors of cytokine signaling (SOCS) ] are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in ]. It is hypothesized that SOCS are induced by IL-10 and ''Borellia burgdorferi'' and its ] in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines. IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators. | |||
| Researchers are also beginning to identify ] as a previously unappreciated source of inflammatory mediator production following infection with ''Borellia burgdorferi''. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of ] (NF-KB) by ''Borrelia''.<ref>Rasley A, Anguita J, Marriott I. "''Borrelia burgdorferi'' induces inflammatory mediator production by murine microglia". J Neuroimmunol. 2002 Sep;130(1-2):22-31</ref><ref>Rasley A, Tranguch SL, Rati DM, Marriott I. "Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to ''Borrelia burgdorferi'' or ''Neisseria meningitidis''". Glia. 2006 Apr 15;53(6):583-92.</ref><ref>Ebnet K, Brown KD, Siebenlist UK, Simon MM, Shaw S."''Borrelia burgdorferi'' activates nuclear factor-kappa B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts". J Immunol. 1997 Apr 1;158(7):3285-92.</ref> | |||
| Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in ''Borrelia'' infected patients.<ref>Ramesh G, Philipp MT. "Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to ''Borrelia burgdorferi'' lipoproteins". Neurosci Lett. 2005 Aug 12-19;384(1-2):112-6.</ref> IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease.<ref> Columbia University Lyme Disease Treatment Studies</ref><ref>Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128: 127–37.The Pathophysiologic Roles of Interleukin-6 in Human Disease. Annals of Internal Medicine</ref>IL-6 is also significantly indicated in cognitive impairment.<ref>Wright CB, Sacco RL, Rundek TR, Delman JB, Rabbani LE, Elkind MS." Interleukin-6 is associated with cognitive function: the Northern Manhattan Study". J Stroke Cerebrovasc Dis. 2006;15(1):34-38</ref> | |||
| ===Neuroendocrine=== | |||
| {{see|Signal transduction}} | |||
| A developing hypothesis is that the chronic secretion of ] ] as a result of ''Borrelia'' infection may reduce the effect of ], or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically ] and ], the major stress hormones. <ref>Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 2005;12(5):255-69</ref><ref>Calcagni E, Elenkov I. "Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases". Ann N Y Acad Sci. 2006 Jun;1069:62-76.</ref>This process is mediated via the ]. Additionally ], a precursor to ] appears to be reduced within the CNS in a number of infectious diseases that affect the brain, including Lyme.<ref>Gasse T, Murr C, Meyersbach P, Schmutzhard E, Wachter H, Fuchs D. Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy. Eur J Clin Chem Clin Biochem. 1994 Sep;32(9):685-9.</ref> Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with Lyme borreliosis.<ref> Zajkowska J, Grygorczuk S, Kondrusik M, Pancewicz S, Hermanowska-Szpakowicz T. Przegl Epidemiol. 2006;60 Suppl 1:167-70 PMID 16909797</ref> | |||
| ] acting on serotonin, ] and ] receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a ] process.<ref>Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio." J Clin Psychopharmacol. 2001 Apr;21(2):199-206</ref><ref>Maes M."The immunoregulatory effects of antidepressants". Hum Psychopharmacol. 2001 Jan;16(1):95-103</ref><ref>Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E."The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". Int Immunopharmacol. 2005 Mar;5(3):609-18.</ref> Antidepressants have also been shown to suppress TH1 upregulation.<ref>Diamond M, Kelly JP, Connor TJ. "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". Eur Neuropsychopharmacol. 2006 Oct;16(7):481-90.</ref>These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal ] of antibiotic refractory Lyme patients. | |||
| ===New Developments=== | |||
| New research has also found that chronic Lyme patients have higher amounts of ''Borrelia''-specific ] (FoxP3) than healthy controls, indicating that ]s might also play a role, by ], in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.<ref>Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C. "Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic ''Borrelia''-exposed individuals." Clin Exp Immunol. 2007 Jan;147(1):18-27</ref> The signaling pathway ] (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from ''Borrelia''.<ref>Olson CM, Hedrick MN, Izadi H, Bates TC, Olivera ER, Anguita J. "p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to ''Borrelia burgdorferi'' antigens." Infect Immun. 2007 Jan;75(1):270-7. Epub 2006 Oct 30.</ref><ref>Ramesh G, Philipp MT. "Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to ''Borrelia burgdorferi'' lipoproteins". Neurosci Lett. 2005 Aug 12-19;384(1-2):112-6</ref> | |||
| The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the ''Borrelia'' bacterium is still present in the host, or in the absence of the inciting pathogen in an ] pattern.<ref>Shin JJ, Glickstein LJ, Steere AC. "High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis". Arthritis Rheum. 2007 Mar 28;56(4):1325-1335</ref><ref>Kisand KE, Prukk T, Kisand KV, Luus SM, Kalbe I, Uibo R. "Propensity to excessive proinflammatory response in chronic Lyme borreliosis". APMIS. 2007 Feb;115(2):134-41.</ref><ref>Dame TM, Orenzoff BL, Palmer LE, Furie MB. "IFN-gamma alters the response of ''Borrelia burgdorferi''-activated endothelium to favor chronic inflammation".J Immunol. 2007 Jan 15;178(2):1172-9.</ref><ref>Dennis VA, Jefferson A, Singh SR, Ganapamo F, Philipp MT. "Interleukin-10 anti-inflammatory response to ''Borrelia burgdorferi'', the agent of Lyme disease: a possible role for suppressors of cytokine signaling 1 and 3".Infect Immun. 2006 Oct;74(10):5780-9. </ref><ref>Ghosh S, Seward R, Costello CE, Stollar BD, Huber BT "Autoantibodies from synovial lesions in chronic, antibiotic treatment-resistant Lyme arthritis bind cytokeratin-10". J Immunol. 2006 Aug 15;177(4):2486-94.</ref><ref>Rasley A, Anguita J, Marriott I. "''Borrelia burgdorferi'' induces inflammatory mediator production by murine microglia". J Neuroimmunol. 2002 Sep;130(1-2):22-31.</ref> | |||
| Researchers hope that this new developing understanding of the ] basis and ] of cell-mediated signaling events caused by ''Borrelia burgdorferi'' infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease. | |||
| ==External links== | |||
| {{Wikispecies|Borrelia}} | |||
| '''Medical Resources''' | |||
| * {{MeshName|Lyme}} | |||
| * {{eMedicineDictionary|Lyme+disease}} | |||
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| '''Government and university resources''' | |||
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| '''Professional societies, disease foundations and advocacy resources''' | |||
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| '''Other resources, memorials etc.''' | |||
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| * ''The Merck Manual'' | |||
| * ''The Merck Manual—Home Edition'' | |||
| * | |||
| ==References== | |||
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