Lyme disease
244113
226115465
2008-07-16T21:54:24Z
Okiefromokla
5736838
Reverted edits by [[Special:Contributions/68.80.138.36|68.80.138.36]] to last version by Arcadian (using [[WP:HG|Huggle]])
{{Infobox Disease
| Name = Lyme Disease
| Image = Adult deer tick.jpg
| Caption = Nymphal and adult [[Ixodes scapularis|deer tick]]s can be carriers of Lyme disease. Nymphs are about the size of a poppy seed.
| DiseasesDB = 1531
| ICD10 = {{ICD10|A|69|2|a|65}}
| ICD9 = {{ICD9|088.81}}
| MedlinePlus = 001319
| eMedicineSubj = med
| eMedicineTopic = 1346
| MeshID = D008193
}}
'''Lyme disease''', or '''borreliosis''', is an [[emerging infectious disease]] caused by at least three [[species]] of [[bacteria]] belonging to the [[genus]] ''[[Borrelia]]''.<ref name=Sherris>{{cite book | author = Ryan KJ, Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | pages = 434–437 | publisher = McGraw Hill | year = 2004 | isbn = 0838585299}}</ref> ''[[Borrelia burgdorferi]]'' is the predominant cause of Lyme disease in the [[United States]], whereas ''Borrelia afzelii'' and ''Borrelia garinii'' are implicated in most European cases.
Lyme disease is the most common [[tick-borne disease]] in the [[Northern Hemisphere]]. ''Borrelia'' is transmitted to humans by the bite of infected hard [[ticks]] belonging to several species of the genus ''[[Ixodes]]''.<ref name=Baron>{{cite book | author = Johnson RC | chapter = Borrelia | title = Baron's Medical Microbiology ''(Baron S ''et al'', eds.)| edition = 4th ed. | publisher = Univ of Texas Medical Branch | year = 1996 | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=mmed.section.1965 | isbn = 0-9631172-1-1 }}</ref> Early manifestations of infection may include [[fever]], headache, fatigue, and a characteristic skin rash called [[Erythema chronicum migrans|erythema migrans]]. Left untreated, late manifestations involving the joints, heart, and nervous system can occur. In a majority of cases, symptoms can be eliminated with [[antibiotics]], especially if diagnosis and treatment occur early in the course of illness. Late, delayed, or inadequate treatment can lead to late manifestations of Lyme disease which can be disabling and difficult to treat.
Some groups have argued that "chronic" Lyme disease is responsible for a range of [[medically unexplained symptoms]] beyond the objectively recognized manifestations of late Lyme disease, and that long-term antibiotic treatment is warranted in such cases.<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 = 533–557 | year = 2004 | pmid = 15482219 | doi = 10.1586/14787210.2.4.533}}</ref> However, a series of [[randomized controlled trial]]s found no significant benefit from prolonged antibiotic treatment in such patients,<ref name="rct1">{{cite journal |author=Klempner MS, Hu LT, Evans J, ''et al'' |title=Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease |journal=N. Engl. J. Med. |volume=345 |issue=2 |pages=85–92 |year=2001 |month=July |pmid=11450676 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11450676&promo=ONFLNS19}}</ref><ref name="rct2">{{cite journal |author=Kaplan RF, Trevino RP, Johnson GM, ''et al'' |title=Cognitive function in post-treatment Lyme disease: do additional antibiotics help? |journal=Neurology |volume=60 |issue=12 |pages=1916–22 |year=2003 |month=June |pmid=12821733 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12821733}}</ref><ref name="rct3">{{cite journal |author=Krupp LB, Hyman LG, Grimson R, ''et al'' |title=Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial |journal=Neurology |volume=60 |issue=12 |pages=1923–30 |year=2003 |month=June |pmid=12821734 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12821734}}</ref> and most expert groups including the [[Infectious Diseases Society of America]] and the [[American Academy of Neurology]] have found that existing [[scientific evidence]] does not support a role for ''Borrelia'' nor ongoing antibiotic treatment in such cases.<ref name="nejm-feder">{{cite journal |author=Feder HM, Johnson BJ, O'Connell S, ''et al'' |title=A critical appraisal of "chronic Lyme disease" |journal=N. Engl. J. Med. |volume=357 |issue=14 |pages=1422–30 |year=2007 |month=October |pmid=17914043 |doi=10.1056/NEJMra072023 }}</ref><ref>[http://www.idsociety.org/lymediseasefacts.htm Frequently Asked Questions about Lyme Disease], from the [[Infectious Diseases Society of America]]. Released October 2006; accessed [[June 24]], [[2008]].</ref>
==Symptoms==
Lyme disease can affect multiple body systems, producing a range of potential symptoms. Not all patients with Lyme disease will have all symptoms, and many of the symptoms are not specific to Lyme disease but can occur in other diseases as well. The [[incubation period]] from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (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>{{cite web | author = Edlow JA | title = Lyme disease | url = http://www.emedicine.com/derm/topic536.htm | date = 2007-01-25 | accessdate = 2007-08-21 | publisher = eMedicine}}</ref> [[Asymptomatic]] infection exists but is found in less than 7% of infected individuals in the United States.<ref name="pmid12905137">{{cite journal |author=Steere AC, Sikand VK, Schoen RT, Nowakowski J |title=Asymptomatic infection with ''Borrelia burgdorferi'' |journal=Clin. Infect. Dis. |volume=37 |issue=4 |pages=528–532 |year=2003 |pmid=12905137 |doi=10.1086/376914}}</ref> Asymptomatic infection may be much more common among those infected in Europe.<ref name="pmid9556169">{{cite journal |author=Fahrer H, Sauvain MJ, Zhioua E, Van Hoecke C, Gern LE |title=Longterm survey (7 years) in a population at risk for Lyme borreliosis: what happens to the seropositive individuals? |journal=Eur. J. Epidemiol. |volume=14 |issue=2 |pages=117–123 |year=1998 |pmid=9556169 |doi=}}</ref>
===Stage 1 – Early localized infection===
[[Image:Bullseye Lyme Disease Rash.jpg|thumb|180px|right|Common bullseye rash pattern associated with Lyme Disease.]][[Image:lymebite.png|right|thumb|Characteristic "bulls-eye"-like rash caused by Lyme disease.]]
The classic sign of early local infection is a circular, outwardly expanding rash called [[erythema chronicum migrans]] (also erythema migrans or EM), which occurs at the site of the tick bite 3 to 32 days after being bitten.<ref name="isbn0-07-159991-6">{{cite book |author=Fauci, Anthony S. |title=Harrison's Principles of Internal Medicine: Editors, Anthony S. Fauci ... [Et Al.] |publisher=McGraw-Hill Medical Publishing |year=2008 |pages=Chapter 166 |isbn=0-07-159991-6}}</ref> The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes [[wikt:indurate|indurated]]; the outer edge remains red; and the portion in between clears – giving the appearance of a [[bullseye]]. However, the partial clearing is uncommon, and thus a true bullseye occurs in as few as 9% of cases.<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. |volume=136 |issue=6 |pages=421–428 |year=2002 |month=March |pmid=11900494 |url=http://www.annals.org/cgi/reprint/136/6/421.pdf|format=PDF}}</ref>
Erythema migrans is thought to occur in about 80% of infected patients.<ref name="isbn0-07-159991-6">{{cite book |author=Fauci, Anthony S |title=Harrison's Principles of Internal Medicine: Editors, Anthony S. Fauci ... [Et Al.] |publisher=McGraw-Hill Medical Publishing |year=2008 |pages=Chapter 166 |isbn=0-07-159991-6 }}</ref> Patients can also experience flu-like symptoms such as headache, muscle soreness, fever, and malaise.<ref name="pmid14987414">{{cite journal |author=Auwaerter PG, Aucott J, Dumler JS |title=Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment |journal=[[Expert Rev Mol Med]] |volume=6 |issue=2 |pages=1–22 |year=2004 |month=January |pmid=14987414 |doi=10.1017/S1462399404007276 |url=}}</ref>
Lyme disease can progress to later stages even in patients who do not develop a rash.<ref name="pmid12543291">{{cite journal |author=Steere AC, Dhar A, Hernandez J, ''et al'' |title=Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease |journal=[[Am. J. Med.]] |volume=114 |issue=1 |pages=58–62 |year=2003 |month=January |pmid=12543291 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934302014407}}</ref>
===Stage 2 – Early disseminated infection===
Within days to weeks after the onset of local infection, the [[borrelia]] bacteria may begin to spread through the bloodstream. Erythema migrans may develop at sites across the body that bear no relation to the original tick bite.<ref name="pmid18452799">{{cite journal |author=Dandache P, Nadelman RB |title=Erythema migrans |journal=[[Infect. Dis. Clin. North Am.]] |volume=22 |issue=2 |pages=235–60, vi |year=2008 |month=June |pmid=18452799 |doi=10.1016/j.idc.2007.12.012 |url=}}</ref> Other discrete symptoms include loss of muscle tone on one or both sides of the face (called facial or [[Bell's palsy]]), severe headaches and neck stiffness, shooting pains that may interfere with sleep, heart palpitations and dizziness caused by changes in heartbeat, and migrating joint pains. Some of these symptoms may resolve, even without treatment.{{Fact|date=July 2008}}
===Stage 3 – Late persistent infection===
After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms affecting many organs of the body including the brain, nerves, eyes, joints and heart. Shooting pains, numbness or tingling in the hands or feet, problems with concentration and short term memory, severe weakness, vision problems, intolerance to sound and touch, [[Vertigo (medical)|Vertigo]], [[back pain]], [[heart block]], psychiatric disorders, and swelling of joints are just some of the myriad disabling symptoms that can occur.
Other less common findings in acute Lyme disease include cardiac manifestations (up to 10% of patients may have cardiac manifestations including heart block and [[palpitations]]<ref name="Ciesielski_1989">{{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=S1435–1441 |year=1989 |pmid=2682955}}</ref>), and neurologic symptoms ([[neuroborreliosis]] may occur in up to 18%<ref name="Ciesielski_1989" />). In addition, simple altered mental status as the sole presenting symptom has been reported in early neuroborreliosis.<ref>{{cite journal |author=Chabria SB, Lawrason J |title=Altered mental status, an unusual manifestation of early disseminated Lyme disease: A case report |journal= Journal of Medical Case Reports|volume=1 |issue=1 |pages=62 |year=2007 |pmid=17688693 |doi=10.1186/1752-1947-1-62}}</ref> Patients have been known to get [[Baker's cyst]]s.
===Chronic symptoms===
Cases may progress to a chronic form most commonly characterized by [[meningoencephalitis]], cardiac inflammation ([[myocarditis]]), frank [[arthritis]], and [[Fatigue (medical)|fatigue]].<ref name=Sherris /> Chronic Lyme disease can have a multitude of symptoms affecting numerous physiological systems: the symptoms appear [[heterogeneous]] in the affected population, which may be caused by [[innate immunity]] or variations in ''Borrelia'' bacteria. Late symptoms of Lyme disease can appear months or years after initial infection and often progress in cumulative fashion over time. Neuropsychiatric symptoms often develop much later in the disease progression, much like tertiary [[neurosyphilis]].
In addition to the acute symptoms, chronic Lyme disease can be manifested by a wide-range of neurological disorders, either [[central nervous system|central]] or [[peripheral nervous system|peripheral]], including [[encephalitis]] or [[encephalomyelitis]], [[Fasciculation|muscle twitching]], heightened sensitivity to touch, sound and light, paralysis<ref>{{cite journal |author=Salonen R et al |title=Lyme borreliosis associated with complete flaccid paraplegia |journal=J. Infect. |volume=28 |issue=2 |pages=181–184 |year=1994 |pmid=8034998 |doi=10.1016/S0163-4453(94)95660-X}}</ref> [[polyneuropathy]] or [[paresthesia]], and [[balance disorder|vestibular symptoms]] or other [[Otolaryngology|otolaryngologic]] symptoms,<ref>{{cite journal |author=Rosenhall U, Hanner P, Kaijser B |title=''Borrelia'' infection and vertigo |journal=Acta Otolaryngol. |volume=106 |issue=1–2 |pages=111–116 |year=1988 |pmid=3421091 |doi=10.3109/00016488809107377}}</ref><ref>{{cite journal |author=Moscatello AL, Worden DL, Nadelman RB, Wormser G, Lucente F |title=Otolaryngologic aspects of Lyme disease |journal=Laryngoscope |volume=101 |issue=6 Pt 1 |pages=592–595 |year=1991 |pmid=2041438 |doi=10.1288/00005537-199106000-00004}}</ref> among others. Neuropsychiatric disturbances can occur (possibly from a low-level [[encephalitis]]), which may lead to symptoms of [[memory loss]], [[sleep disturbance]]s, or changes in [[Mood (psychology)|mood]] or [[Affect (psychology)|affect]].<ref name=Sherris /> In rare cases, frank [[psychosis]] has been attributed to chronic Lyme disease effects, including mis-diagnoses of [[schizophrenia]] and [[bipolar disorder]]. Panic attack and anxiety can occur, also delusional behavior, including somatoform delusions, sometimes accompanied by a [[depersonalization]] or derealization syndrome similar to what was seen in the past in the [[prodromal]] or early stages of general [[paresis]].<ref>{{cite journal |author=Fallon BA, Nields JA |title=Lyme disease: a neuropsychiatric illness |journal=The American journal of psychiatry |volume=151 |issue=11 |pages=1571–1583 |year=1994 |pmid=7943444}}</ref><ref>{{cite journal |author=Hess A, Buchmann J, Zettl UK, ''et al'' |title=''Borrelia burgdorferi'' central nervous system infection presenting as an organic schizophrenia-like disorder |journal=Biol. Psychiatry |volume=45 |issue=6 |pages=795 |year=1999 |pmid=10188012 |doi=10.1016/S0006-3223(98)00277-7}})</ref>
==Cause==
{{main|Lyme disease microbiology}}
[[Image:Borrelia image.jpg|thumb|right|''[[Borrelia]]'' bacteria, the causative agent of Lyme disease. Magnified 400 times.]]
[[Image:Ixodes scapularis.png|thumb|right|''[[Ixodes scapularis]]'', the primary vector of Lyme disease in eastern North America.]]
Lyme disease is caused by [[Gram-negative]] [[spirochetal]] [[bacteria]] from the [[genus]] ''[[Borrelia]]''. At least 11 ''Borrelia'' species have been described, 3 of which are Lyme related.<ref name=Wang/><ref>{{cite journal |author=Derdáková M, Lencáková D |title=Association of genetic variability within the Borrelia burgdorferi sensu lato with the ecology, epidemiology of Lyme borreliosis in Europe |journal=Ann Agric Environ Med |volume=12 |issue=2 |pages=165–72 |year=2005 |pmid=16457468 |doi= |url=http://www.aaem.pl/pdf/12165.htm}}</ref> The ''Borrelia'' [[species]] known to cause Lyme disease are collectively known as ''Borrelia burgdorferi'' [[sensu lato]], and have been found to have greater [[genetic diversity|strain diversity]] 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=1741–1755 | volume=150 | issue=Pt 6 | pmid= 15184561 | url=http://mic.sgmjournals.org/cgi/reprint/150/6/1741.pdf | format=PDF | doi=10.1099/mic.0.26944-0}}</ref>
Three closely-related species of spirochetes are well-established as causing Lyme disease and are probably responsible for the large majority of cases: ''B. burgdorferi'' [[sensu stricto]] (predominant in [[North America]], but also in [[Europe]]), ''B. afzelii'', and ''B. garinii'' (both predominant in [[Eurasia]]).<ref name=Wang>{{cite journal |author=Wang G, van Dam AP, Schwartz I, Dankert J |title=Molecular typing of Borrelia burgdorferi sensu lato: taxonomic, epidemiological, and clinical implications |journal=Clin. Microbiol. Rev. |volume=12 |issue=4 |pages=633–53 |year=1999 |month=October |pmid=10515907 |pmc=88929 |doi= |url=http://cmr.asm.org/cgi/pmidlookup?view=long&pmid=10515907}}</ref> Some studies have also proposed that ''B. bissettii'' and ''B. valaisiana'' may sometimes infect humans, but these species do not seem to be important causes of disease.{{fact|date=July 2008}}
===Transmission===
Hard-bodied [[tick]]s of the genus ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of Lyme disease.<ref name=Sherris /> The majority of infections are caused by ticks in the [[Nymph (biology)|nymph stage]], since adult ticks are more easily detected and removed as a consequence of their relatively large size.{{Fact|date=May 2008}}
In Europe, the sheep tick, castor bean tick, or European castor bean tick (''[[Ixodes ricinus]]'') is the transmitter.{{fact|date=July 2008}}
In North America, the black-legged tick or deer tick (''[[Ixodes scapularis]]'') has been identified as the key to the disease's spread on the east coast. Only about 20% of people 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, ''et al'' | 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=958–965 | year=2005 | pmid= 16142659 | doi=10.1086/432935}}</ref> making early detection difficult in the absence of a rash. 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. The lone star tick (''[[Amblyomma americanum]]''), which is found throughout the [[Southeastern United States]] as far west as [[Texas]], has been ruled out as a vector of the Lyme disease spirochete ''Borrelia burgdorferi'',{{Fact|date=May 2008}} though it may be implicated with a clinical syndrome southern tick associated rash illness (STARI), which resembles the skin lesions of Lyme disease.<ref>{{cite journal | author=Ledin KE, ''et al'' | title=Borreliacidal activity of saliva of the tick ''Amblyomma americanum'' | journal=Med Vet Entomol | volume=19 | issue=1 | pages=90–95 | year=2005 | pmid= 15752182 | doi=10.1111/j.0269-283X.2005.00546.x}}</ref>
On the [[West Coast of the United States|West Coast]], the primary vector is the western black-legged tick (''[[Ixodes pacificus]]'').<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=5076–5086 | year=2004 | pmid= 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF | doi=10.1128/JCM.42.11.5076-5086.2004}}</ref> The tendency of this tick species to feed predominantly on host species that are resistant to ''Borrelia'' infection appears to diminish transmission of Lyme disease in the West.<ref name="pmid15709249">{{cite journal |author=Eisen L, Eisen RJ, Lane RS |title=The roles of birds, lizards, and rodents as hosts for the western black-legged tick ''Ixodes pacificus'' |journal=J. Vector Ecol. |volume=29 |issue=2 |pages=295–308 |year=2004 |pmid=15709249 |doi=}}</ref><ref name="pmid16995383">{{cite journal |author=Lane RS, Mun J, Eisen L, Eisen RJ |title=Refractoriness of the western fence lizard (''Sceloporus occidentalis'') to the Lyme disease group spirochete ''Borrelia bissettii'' |journal=J. Parasitol. |volume=92 |issue=4 |pages=691–696 |year=2006 |pmid=16995383 |doi=}}</ref>
While Lyme spirochetes have been found in insects other than ticks,<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=1482–1486 | year=1988 | pmid= 3170711 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=266646&blobtype=pdf | format=PDF}}</ref> reports of actual infectious transmission appear to be rare.<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 | pmid = 2342543 | url=http://cassia.org/library/N_Engl_J_Med_1990_Jun_14,322(24),1752.htm}}</ref> [[Sexually transmitted infection|Sexual transmission]] 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 | year=2001 | url=http://www.anapsid.org/lyme/bach.html}}</ref> and breast milk,<ref name="Schmidt">{{cite journal | author=Schmidt B, Aberer E, Stockenhuber C, ''et al'' | 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=121–128 | year=1995 | pmid = 7648832 | doi=10.1016/0732-8893(95)00027-8}}</ref> however 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 | format = PDF | date = 2003-02-01 | accessdate = 2007-03-22}}</ref>
Congenital transmission of Lyme disease can occur from an infected mother to [[fetus]] through the [[placenta]] during pregnancy, however prompt antibiotic treatment appears to prevent fetal harm.<ref>{{cite journal |author=Walsh CA, Mayer EW, Baxi LV |title=Lyme disease in pregnancy: case report and review of the literature |journal=Obstetrical & gynecological survey |volume=62 |issue=1 |pages=41–50 |year=2007 |pmid=17176487 |doi=10.1097/01.ogx.0000251024.43400.9a}}</ref>
==Tick borne co-infections==
<!-- The CDC paper below backs up some of this but the language used doesn't really fit with the paper. -->
Ticks that transmit ''B. burgorferi'' to humans can also carry and transmit several other parasites such as ''[[Babesia microti]]'' and ''[[Anaplasma phagocytophilum]]'', which cause the diseases [[babesiosis]] and [[human granulocytic anaplasmosis]] (HGA), respectively. Among early Lyme disease patients, depending on their location, 2-12% will also have HGA and 2-40% will have babesiosis.<ref name="pmid16807416">{{cite journal |author=Wormser GP |title=Clinical practice. Early Lyme disease |journal=[[N. Engl. J. Med.]] |volume=354 |issue=26 |pages=2794–801 |year=2006 |month=June |pmid=16807416 |doi=10.1056/NEJMcp061181 |url=}}</ref> [[Cat scratch fever]] is another common co-infection, although there is debate among experts on this topic on tick-to-human transmission.{{Fact|date=July 2008}}
Co-infections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the co-infections and not Borrelia, making diagnosis difficult and often elusive. The [[Centers for Disease Control]] (CDC)'s emerging infections diseases department did a study in rural [[New Jersey]] of 100 ticks and found that 55% of the ticks were infected with at least one of the pathogens.<ref name="pmid9452402">{{cite journal |author=Varde S, Beckley J, Schwartz I |title=Prevalence of tick-borne pathogens in Ixodes scapularis in a rural New Jersey County |journal=Emerging Infect. Dis. |volume=4 |issue=1 |pages=97–9 |year=1998 |pmid=9452402 |url=http://www.cdc.gov/ncidod/eid/vol4no1/varde.htm}}</ref>
==Diagnosis==
Lyme disease is diagnosed clinically based on symptoms, objective physical findings (such as erythema migrans, facial palsy, or arthritis), a history of possible exposure to infected ticks, as well as serological tests.
When making a diagnosis of Lyme disease, health care providers should consider other diseases that may cause similar illness. Not all patients with Lyme disease will develop the characteristic bulls-eye rash, and many may not recall a tick bite. Laboratory testing is not recommended for persons who do not have symptoms of Lyme disease.
Because of the difficulty in [[Microbiological culture|culturing]] ''Borrelia'' bacteria in the laboratory, diagnosis of Lyme disease is typically based on the clinical exam findings and a history of exposure to [[endemic (epidemiology)|endemic]] Lyme areas.<ref name="Sherris" /> The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when [[serology|serologies]] are negative.<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=62–66 | volume=282 | issue=1 | pmid= 10404913 | doi=10.1001/jama.282.1.62}}</ref><ref name="Hofmann">{{cite journal | author=Hofmann H | title=Lyme borreliosis—problems of serological diagnosis | journal=Infection | year=1996 | pages=470–472 | volume=24 | issue=6 | pmid= 9007597 | doi=10.1007/BF01713052}}</ref> Serological testing can be used to support a clinically suspected case but is not diagnostic.<ref name=Sherris /> Clinicians who diagnose strictly based on the CDC Case Definition for Lyme may be in error, since the CDC explicitly states that this definition is intended for [[Clinical surveillance|surveillance]] purposes only and is "not intended to be used in clinical diagnosis."<!-- Need a citation that suggests this mis-use of the Epi case definition is a current, on-going problem --><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 | year = 1996 | accessdate=2007-08-23}}</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 | date = 2004-01-24 | accessdate=2007-08-23}}</ref>
Diagnosis of late-stage Lyme disease is often difficult because of the multi-faceted appearance which can mimic symptoms of many other diseases. For this reason, Lyme has often been called the new "great imitator".<ref>{{cite journal |author=Pachner AR |title=Neurologic manifestations of Lyme disease, the new "great imitator" |journal=Rev. Infect. Dis. |volume=11 Suppl 6 |issue= |pages=S1482–1486 |year=1989 |pmid=2682960}}</ref> Lyme disease may be misdiagnosed as [[multiple sclerosis]], [[rheumatoid arthritis]], [[fibromyalgia]], [[chronic fatigue syndrome]] (CFS), [[lupus]], or other [[autoimmune]] and [[neurodegenerative]] diseases.
===Laboratory testing===
Several forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. Most recommended tests are blood tests that measure [[antibodies]] made in response to the infection. These tests may be falsely negative in patients with early disease, but they are quite reliable for diagnosing later stages of disease.
The serological laboratory tests most widely available and employed are the [[Western blot]] and [[ELISA]]. A two-tiered protocol is recommended by the [[Centers for Disease Control|CDC]]: the more [[sensitive]] ELISA is performed first, if it is positive or equivocal, the more [[Specificity (tests)|specific]] Western blot is run. The reliability of testing in diagnosis remains controversial,<ref name=Sherris /> however studies show the Western blot [[IgM]] has a specificity of 94–96% for patients with clinical symptoms of early Lyme disease.<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=419–427 | volume=33 | issue=2 | 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=2105–2109 | volume=156 | issue=18 | pmid = 8862103 | doi=10.1001/archinte.156.18.2105}}</ref>
Erroneous test results have been widely reported in both early and late stages of the disease. These errors can be caused by several factors, including antibody cross-reactions from other infections including [[Epstein-Barr virus]] and [[cytomegalovirus]],<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 | pmid= 10378140 | doi=10.1007/BF02561539}}</ref> as well as [[herpes simplex virus]].<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=1826–1827 | volume=41 | issue=12 | pmid= 16288417 | doi=10.1086/498319}}</ref>
[[Polymerase chain reaction]] (PCR) tests for Lyme disease have also been developed to detect the genetic material ([[DNA]]) of the Lyme disease spirochete. PCR tests are susceptible to [[Type I and type II errors|false-positive]] results from poor laboratory technique.<ref name="pmid11438915">{{cite journal |author=Molloy PJ, Persing DH, Berardi VP |title=False-positive results of PCR testing for Lyme disease |journal=Clin. Infect. Dis. |volume=33 |issue=3 |pages=412–413 |year=2001 |pmid=11438915 |doi=}}</ref> Even when properly performed, PCR often shows [[Type I and type II errors|false-negative]] results with blood and CSF specimens.<ref name="pmid16020686">{{cite journal |author=Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP |title=Diagnosis of Lyme borreliosis |journal=Clin. Microbiol. Rev. |volume=18 |issue=3 |pages=484–509 |year=2005 |pmid=16020686 |doi=10.1128/CMR.18.3.484-509.2005}}</ref> Hence PCR is not widely performed for diagnosis of Lyme disease. However PCR may have a role in diagnosis of Lyme arthritis because it is highly sensitive in detecting ''ospA'' DNA in synovial fluid.<ref name="pmid8272083">{{cite journal |author=Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC |title=Detection of ''Borrelia burgdorferi'' DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis |journal=N. Engl. J. Med. |volume=330 |issue=4 |pages=229–234 |year=1994 |pmid=8272083 |doi=}}</ref> With the exception of PCR, there is no currently practical means for detection of the presence of the organism, as serologic studies only test for [[antibodies]] 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>{{cite journal |author=Burdash N, Fernandes J |title=Lyme borreliosis: detecting the great imitator |journal=The Journal of the American Osteopathic Association |volume=91 |issue=6 |pages=573–574, 577–578 |year=1991 |pmid=1874654 |url=http://www.jaoa.org/cgi/content/abstract/91/6/573}}</ref>
Western blot, ELISA and PCR can be performed by either blood test via [[venipuncture]] or [[cerebrospinal fluid]] (CSF) via [[lumbar puncture]]. 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>{{cite journal |author=Coyle PK, Schutzer SE, Deng Z, ''et al'' |title=Detection of ''Borrelia burgdorferi''-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease |journal=Neurology |volume=45 |issue=11 |pages=2010–2015 |year=1995 |pmid=7501150 }}</ref>
New techniques for clinical testing of ''Borrelia'' infection have been developed, such as LTT-[[MELISA]],<ref>{{cite journal |author=Valentine-Thon E, Ilsemann K, Sandkamp M |title=A novel lymphocyte transformation test (LTT-MELISA) for Lyme borreliosis |journal=Diagn. Microbiol. Infect. Dis. |volume=57 |issue=1 |pages=27–34 |year=2007 |pmid=16876371 |doi=10.1016/j.diagmicrobio.2006.06.008}}</ref> which is capable of identifying the active form of ''Borrelia'' infection (Lyme disease). Others, such as ''focus floating microscopy'', are under investigation.<ref>{{cite journal |author=Eisendle K, Grabner T, Zelger B |title=Focus floating microscopy: "gold standard" for cutaneous borreliosis? |journal=Am. J. Clin. Pathol. |volume=127 |issue=2 |pages=213–222 |year=2007 |pmid=17210530 |doi=10.1309/3369XXFPEQUNEP5C}}</ref> New research indicates [[chemokine]] [[CXCL13]] may also be a possible marker for neuroborreliosis.<ref>{{cite journal |author=Cadavid D |title=The mammalian host response to ''borrelia'' infection |journal=Wien. Klin. Wochenschr. |volume=118 |issue=21–22 |pages=653–658 |year=2006 |pmid=17160603 |doi=10.1007/s00508-006-0692-0}}</ref>
Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. These tests include urine antigen tests, immunofluorescent staining for cell wall-deficient forms of Borrelia burgdorferi, and lymphocyte transformation tests. In general, CDC does not recommend these tests.
===Imaging===
[[Single photon emission computed tomography]] (SPECT) imaging has been used to look for [[cerebral]] [[perfusion|hypoperfusion]] indicative of Lyme encephalitis in the patient.<ref>{{cite journal |author=Sumiya H, Kobayashi K, Mizukoshi C, ''et al'' |title=Brain perfusion SPECT in Lyme neuroborreliosis |journal=J. Nucl. Med. |volume=38 |issue=7 |pages=1120–1122 |year=1997 |pmid=9225802 }}</ref> Although SPECT is not a diagnostic tool itself, it may be a useful method of determining brain function.
In Lyme disease patients, cerebral hypoperfusion of frontal [[Basal ganglia|subcortical]] and [[Cerebral cortex|cortical]] structures has been reported.<ref>{{cite journal |author=Logigian EL, Johnson KA, Kijewski MF, ''et al'' |title=Reversible cerebral hypoperfusion in Lyme encephalopathy |journal=Neurology |volume=49 |issue=6 |pages=1661–1670 |year=1997 |pmid=9409364 }}</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 [[white matter]].<ref>{{cite journal |author=Fallon BA, Das S, Plutchok JJ, Tager F, Liegner K, Van Heertum R |title=Functional brain imaging and neuropsychological testing in Lyme disease |journal=Clin. Infect. Dis. |volume=25 Suppl 1 |issue= |pages=S57–63 |year=1997 |pmid=9233666 }}</ref> This pattern is not specific for Lyme disease, since it can also be seen in other central nervous system (CNS) syndromes such as [[HIV]] encephalopathy, viral encephalopathy, chronic [[cocaine]] use, and [[vasculitides]]. However, most of these syndromes can be ruled out easily through standard serologic testing and careful patient history taking.
The presence of global cerebral hypoperfusion deficits on SPECT in the presence of characteristic neuropsychiatric features should dramatically raise suspicion for Lyme encephalopathy among patients who inhabit or have traveled to endemic areas, regardless of patient recall of tick bites.{{Fact|date=August 2007}} Late disease can occur many years after initial infection. The average time from symptom onset to diagnosis in these patients is about 4 years. Because seronegative disease can occur, and because CSF testing is often normal, Lyme encephalopathy often becomes a diagnosis of exclusion: once all other possibilities are ruled out, Lyme encephalopathy becomes ruled in. Although the aberrant SPECT patterns are caused by cerebral vasculitis, a vasculitide, brain biopsy is not commonly performed for these cases as opposed to other types of cerebral vasculitis.
Abnormal [[magnetic resonance imaging]] (MRI) findings are often seen in both early and late Lyme disease.{{Fact|date=August 2007}} MRI scans of patients with neurologic Lyme disease may demonstrate punctuated [[white matter]] [[lesions]] on T2-weighted images, similar to those seen in [[demyelinating]] or inflammatory disorders such as [[multiple sclerosis]], [[systemic lupus erythematosus]] (SLE), or cerebrovascular disease.<ref>{{cite conference | last=Fallon | first=BA | title=Review of Lyme Neuroborreliosis | conference=3th International Scientific Conference on Lyme Disease and other Tick-borne Disorders | url=http://www.medscape.com/viewarticle/412987 | year=2000}}</ref> [[Cerebral atrophy]] and brainstem [[neoplasm]] has been indicated with Lyme infection as well.<ref>{{cite journal |author=Kalina P, Decker A, Kornel E, Halperin JJ |title=Lyme disease of the brainstem |journal=Neuroradiology |volume=47 |issue=12 |pages=903–907 |year=2005 |pmid=16158278 |doi=10.1007/s00234-005-1440-2}}</ref>
Diffuse white matter pathology can disrupt these ubiquitous [[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. Spontaneous [[remission (medicine)|remission]] can occur in multiple sclerosis, and resolution of MRI white matter hyper-intensities, after antibiotic treatment, has been observed in Lyme disease.<ref>{{cite journal |author=Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ |title=Regional cerebral blood flow and cognitive deficits in chronic Lyme disease |journal=The Journal of neuropsychiatry and clinical neurosciences |volume=15 |issue=3 |pages=326–332 |year=2003 |pmid=12928508}}</ref>
==Prevention==
Attached ticks should be removed promptly.<ref name="piesman2002">{{cite journal |author=Piesman J, Dolan MC |title=Protection against Lyme disease spirochete transmission provided by prompt removal of nymphal ''Ixodes scapularis'' (Acari: Ixodidae) |journal=J Med Entomol |volume=39 |issue=3 |pages=509–512 |year=2002 |pmid=12061448}}</ref> Protective clothing includes a hat and long-sleeved shirts and long pants that are tucked into socks or boots. Light-colored clothing makes the tick more easily visible before it attaches itself. People should use special care in handling and allowing outdoor pets inside homes because they can bring ticks into the house.
A more effective, community wide method of preventing Lyme disease is to reduce the numbers of primary hosts on which the deer tick depends such as rodents, other small mammals, and deer. Reduction of the deer population may over time help break the reproductive cycle of the deer ticks and their ability to flourish in suburban and rural areas.<ref>http://www.ct.gov/caes/lib/caes/documents/publications/bulletins/b1010.pdf</ref>
===Management of host animals===
Lyme and all other deer-tick-borne diseases can be prevented on a regional level by reducing the deer population that the ticks depend on for reproductive success. This has been demonstrated in the communities of [[Monhegan, Maine]]<ref name="Rand">{{cite journal |author=Rand PW, Lubelczyk C, Holman MS, Lacombe EH, Smith RP |title=Abundance of ''Ixodes scapularis'' (Acari: Ixodidae) after the complete removal of deer from an isolated offshore island, endemic for Lyme Disease |journal=J. Med. Entomol. |volume=41 |issue=4 |pages=779–784 |year=2004 |pmid=15311475 }}</ref> and in Mumford Cove, Connecticut.<ref>{{cite web | title=Managing Urban Deer in Connecticut, Figure 2, p.4. | publisher=Connecticut Department of Environmental Protection - Wildlife Division | work=2nd edition | date= June 2007 | url=http://www.ct.gov/dep/lib/dep/wildlife/pdf_files/game/urbandeer07.pdf | format=PDF | accessdate=2008-05-02 }}</ref> The black-legged or deer tick (''Ixodes scapularis'') depends on the white-tailed deer for successful reproduction.
For example, in the US, it is suggested that by reducing the deer population back to healthy levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates), the tick numbers can be brought down to levels too low to spread Lyme and other tick-borne diseases.<ref>{{cite web | author = Stafford KC | title = Tick Management Handbook | url = http://www.ct.gov/caes/lib/caes/documents/special_features/TickHandbook.pdf | format = PDF | year = 2004 | publisher = Connecticut Agricultural Experiment Station and Connecticut Department of Public Health | pages =46 | accessdate = 2007-08-21}}</ref>
===Vaccination===
A [[vaccine|recombinant vaccine]] against Lyme disease, based on the outer surface protein A (OspA) of ''B. burgdorferi'', was developed by [[GlaxoSmithKline]]. In [[clinical trial]]s involving more than 10,000 people, the vaccine, called LYMErix, was found to confer protective immunity to ''Borrelia'' in 76% of adults and 100% of children with only mild or moderate and transient [[adverse effect]]s.<ref>{{cite journal |author=Poland GA, Jacobson RM |title=The prevention of Lyme disease with vaccine |journal=Vaccine |volume=19 |issue=17-19 |pages=2303–8 |year=2001 |month=March |pmid=11257352 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0264410X0000520X}}</ref> LYMErix was approved on the basis of these trials by the U.S. [[Food and Drug Administration]] (FDA) on [[December 21]], [[1998]].
Following approval of the vaccine, its entry in clinical practice was slower than expected for a variety of reasons including its cost, which was often not reimbursed by insurance companies.<ref>[http://query.nytimes.com/gst/fullpage.html?res=9C05E4D71238F930A25755C0A96F958260 Lukewarm Response To New Lyme Vaccine], by Claudia Rowe. Published in the ''[[New York Times]]'' on [[June 13]] [[1999]]; accessed [[July 11]] [[2008]].</ref> Subsequently, hundreds of vaccine recipients reported that they had developed [[autoimmunity|autoimmune]] side effects. Supported by some patient advocacy groups, a number of [[class-action lawsuit]]s were filed against GlaxoSmithKline alleging that the vaccine had caused these health problems. These claims were investigated by the FDA and the U.S. [[Centers for Disease Control]] (CDC), who found no connection between the vaccine and the autoimmune complaints.<ref name="uphill">{{cite journal |author=Abbott A |title=Lyme disease: uphill struggle |journal=Nature |volume=439 |issue=7076 |pages=524–5 |year=2006 |month=February |pmid=16452949 |doi=10.1038/439524a |url=}}</ref>
Despite the lack of evidence that the complaints were caused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. market by GlaxoSmithKline in February 2002<ref>[http://query.nytimes.com/gst/fullpage.html?res=9C00E5D71531F93BA15751C0A9649C8B63 Sole Lyme Vaccine Is Pulled Off Market], published in the ''[[New York Times]]'' on [[February 28]] [[2002]]; accessed [[July 11]] [[2008]].</ref> in the setting of negative media coverage and fears of vaccine side effects.<ref name="cautionary">{{cite journal |author=Nigrovic LE, Thompson KM |title=The Lyme vaccine: a cautionary tale |journal=Epidemiol. Infect. |volume=135 |issue=1 |pages=1–8 |year=2007 |month=January |pmid=16893489 |doi=10.1017/S0950268806007096 |url=}}</ref><ref name="uphill"/> The fate of LYMErix was described in the medical literature as a "cautionary tale";<ref name="cautionary"/> an editorial in ''[[Nature (journal)|Nature]]'' cited the withdrawal of LYMErix as an instance in which "unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations,"<ref name="safe">{{cite journal |author= |title=When a vaccine is safe |journal=Nature |volume=439 |issue=7076 |pages=509 |year=2006 |month=February |pmid=16452935 |doi=10.1038/439509a |url=}}</ref> while the original developer of the OspA vaccine at the [[Max Planck Institute]] told ''Nature'': "This just shows how irrational the world can be... There was no scientific justification for the first OspA vaccine [LYMErix] being pulled."<ref name="uphill"/>
New vaccines are being researched using outer surface protein C (OspC) and [[Glycolipid|glycolipoprotein]] as methods of immunization.<ref>{{cite journal |author=Earnhart CG, Marconi RT |title=OspC phylogenetic analyses support the feasibility of a broadly protective polyvalent chimeric Lyme disease vaccine |journal=Clin. Vaccine Immunol. |volume=14 |issue=5 |pages=628–634 |year=2007 |pmid=17360854 |doi=10.1128/CVI.00409-06}}</ref><ref>{{cite journal |author=Pozsgay V, Kubler-Kielb J |title=Synthesis of an experimental glycolipoprotein vaccine against Lyme disease |journal=Carbohydr. Res. |volume=342 |issue=3–4 |pages=621–626 |year=2007 |pmid=17182019 |doi=10.1016/j.carres.2006.11.014 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17182019&query_hl=35&itool=pubmed_docsum}}</ref>
===Tick removal===
Many [[urban legend]]s exist about the proper and effective method to remove a tick, however it is generally agreed that the most effective method is to pull it straight out with tweezers.<ref name=JAMA_2007>{{cite journal |author=Zeller JL, Burke AE, Glass RM |title=JAMA patient page. Lyme disease |journal=JAMA |volume=297 |issue=23 |pages=2664 |year=2007 |pmid=17579234 |doi=10.1001/jama.297.23.2664 | url = http://jama.ama-assn.org/cgi/content/full/297/23/2664}}</ref> Data have demonstrated that prompt removal of an infected tick, within approximately 36 hours, reduces the risk of transmission to nearly zero; however the small size of the tick, especially in the nymph stage, may make detection difficult.<ref name="piesman2002"/>
==Treatment==
[[Antibiotics]] are the primary treatment for Lyme disease; the most appropriate antibiotic treatment depends upon the patient and the stage of the disease.<ref name=Sherris /> The antibiotics of choice are [[doxycycline]] (in adults), [[amoxicillin]] (in children), and [[ceftriaxone]]. Alternative choices are [[cefuroxime]] and [[cefotaxime]].<ref name=Sherris /> [[Macrolide]] antibiotics have limited efficacy when used alone. Physicians who treat chronic Lyme disease have noted that combining a macrolide antibiotic such as [[clarithromycin]] (biaxin) with [[hydroxychloroquine]] (plaquenil) is especially effective in treatment of chronic Lyme disease.<ref name="Donta 2003">{{cite journal |author=Donta ST |title=Macrolide therapy of chronic Lyme Disease |journal=Med. Sci. Monit. |volume=9 |issue=11 |pages=PI136–142 |year=2003 |month=November |pmid=14586290 |doi= |url=http://www.medscimonit.com/fulltxt.php?ICID=13388}}</ref> It is thought that the hydroxychloroquine raises the pH of intracellular acidic [[vacuoles]] in which ''B. burgdorferi'' may reside; raising the pH is thought to activate the macrolide antibiotic, allowing it to inhibit protein synthesis by the spirochete.<ref name="Donta 2003"/>
Results of a recent double blind, randomized, [[placebo]]-controlled multicenter clinical study, done in [[Finland]], indicated that oral adjunct antibiotics were not justified in the treatment of patients with disseminated Lyme borreliosis who initially received intravenous antibiotics for three 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>{{cite journal |author=Oksi J, Nikoskelainen J, Hiekkanen H, ''et al'' |title=Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study |journal=Eur. J. Clin. Microbiol. Infect. Dis. |volume=26 |issue=8 |pages=571–581 |year=2007 |pmid=17587070 |doi=10.1007/s10096-007-0340-2}}</ref>
In later stages, the bacteria disseminate throughout the body and may cross the [[blood-brain barrier]], making the infection more difficult to treat. Late diagnosed Lyme is treated with oral or IV antibiotics, frequently [[ceftriaxone]], 2 grams per day, for a minimum of four weeks. [[Minocycline]] is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.<ref>{{cite journal |author=Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC |title=Minocycline for short-term neuroprotection |journal=Pharmacotherapy |volume=26 |issue=4 |pages=515–21 |year=2006 |month=April |pmid=16553511 |doi=10.1592/phco.26.4.515 |url=}}</ref>
==="Post-Lyme syndrome" and "chronic Lyme disease"===
Some Lyme disease patients who have completed a course of antibiotic treatment continue to have symptoms such as severe fatigue, sleep disturbance, and cognitive difficulties. Some groups have attributed these symptoms to persistent infection with ''Borrelia'' and have advocated long-term antibiotic treatment in such cases.<ref>{{cite journal |author=Cameron D, Gaito A, Harris N, ''et al'' |title=Evidence-based guidelines for the management of Lyme disease |journal=Expert Rev Anti Infect Ther |volume=2 |issue=1 Suppl |pages=S1–13 |year=2004 |pmid=15581390}}</ref> However, three [[randomized controlled trial]]s showed no benefit from long-term antibiotic treatment in such patients.<ref name="rct1"/><ref name="rct2"/><ref name="rct3"/> A fourth randomized trial, published in 2008 by a group which advocates long-term antibiotic treatment, reported a short-term and statistically insignificant improvement in cognition with the antibiotic [[ceftriaxone]], but this improvement was not maintained in the long-term.<ref name="pmid17928580">{{cite journal |author=Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, Nelson DR, Sackeim HA |title=A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy |journal=Neurology |volume=70 |issue=13 |pages=992–1003 |year=2008 |month=March |pmid=17928580 |doi=10.1212/01.WNL.0000284604.61160.2d}}</ref> These trials identified significant side effects and risks of prolonged antibiotic therapy, and at least one death has been reported from complications of a 27-month course of intravenous antibiotics for an unsubstantiated diagnosis of "chronic Lyme disease".<ref name="pmid11049799">{{cite journal |author=Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM |title=Death from inappropriate therapy for Lyme disease |journal=Clin. Infect. Dis. |volume=31 |issue=4 |pages=1107–9 |year=2000 |month=October |pmid=11049799 |doi= |url=http://www.journals.uchicago.edu/cgi-bin/resolve?CID994157}}</ref>
Thus, most medical authorities, including the [[Infectious Diseases Society of America]] and the [[American Academy of Neurology]], have found that there is no convincing evidence that ''Borrelia'' is implicated in the various syndromes of "chronic Lyme disease", and recommend against long-term antibiotic treatment as ineffective and possibly harmful.<ref name="idsa guideline">{{cite journal |author=Wormser GP, Dattwyler RJ, Shapiro ED, ''et al'' |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 |month=November |pmid=17029130 |doi=10.1086/508667}}</ref><ref name="pmid17522387">{{cite journal |author=Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, Krupp L, Gronseth G, Bever CT |title=Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology |journal=Neurology |volume=69 |issue=1 |pages=91–102 |year=2007 |pmid=17522387 |doi=10.1212/01.wnl.0000265517.66976.28}}</ref><ref name="nejm-feder"/>
===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>{{cite journal |author=Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK |title=''Borrelia burgdorferi'' detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis |journal=Ann. Med. |volume=31 |issue=3 |pages=225–232 |year=1999 |pmid=10442678 |doi=10.3109/07853899909115982 }}</ref><ref>{{cite journal |author=Hartiala P, Hytönen J, Pelkonen J, ''et al'' |title=Transcriptional response of human dendritic cells to ''Borrelia garinii''—defective CD38 and CCR7 expression detected |journal=J. Leukoc. Biol. |volume=82 |issue=1 |pages=33–43 |year=2007 |pmid=17440035 |doi=10.1189/jlb.1106709}}</ref> Lyme arthritis which is antibiotic resistant may be treated with [[hydroxychloroquine]] or [[methotrexate]].<ref>{{cite journal |author=Massarotti EM |title=Lyme arthritis |journal=Med. Clin. North Am. |volume=86 |issue=2 |pages=297–309 |year=2002 |pmid=11982303 |doi=10.1016/S0025-7125(03)00088-9 }}</ref> Experimental data are consensual on the deleterious consequences of systemic [[corticosteroid]] therapy. [[Corticosteroid]]s are not indicated in Lyme disease.<ref>{{cite journal |author=Puéchal X |title=[Non antibiotic treatments of Lyme borreliosis] |language=French |journal=Med Mal Infect |volume=37 |issue=7–8 |pages=473–8 |year=2007 |pmid=17376627 |doi=10.1016/j.medmal.2006.01.021}}</ref>
Antibiotic refractory patients with [[neuropathy|neuropathic]] pain responded well to [[gabapentin]] monotherapy with residual pain after intravenous [[ceftriaxone]] treatment in a pilot study.<ref>{{cite journal |author=Weissenbacher S, Ring J, Hofmann H |title=Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage lyme borreliosis: a pilot study |journal=Dermatology (Basel) |volume=211 |issue=2 |pages=123–127 |year=2005 |pmid=16088158 |doi=10.1159/000086441}}</ref> The immunomodulating, neuroprotective and anti-inflammatory potential of [[minocycline]] may be helpful in late/chronic Lyme disease with neurological or other inflammatory manifestations. Minocycline is used in other [[neurodegenerative]] and [[inflammatory]] disorders such as [[multiple sclerosis]], [[Parkinson's disease]], [[Huntington's disease]], [[rheumatoid arthritis]] (RA) and [[ALS]].<ref>{{cite journal |author=Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M |title=Clinical potential of minocycline for neurodegenerative disorders |journal=Neurobiol. Dis. |volume=17 |issue=3 |pages=359–366 |year=2004 |pmid=15571972 |doi=10.1016/j.nbd.2004.07.012}}</ref>
===Alternative therapies===
A number of other alternative therapies have been suggested, though clinical trials have not been conducted. For example, the use of [[hyperbaric oxygen therapy]] (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 | pmid = 16315580}}</ref> Though there are no published data from clinical trials to support its use, preliminary results using a [[murine|mouse]] model suggest its effectiveness against ''B. burgdorferi'' both [[in vitro]] and [[in vivo]].<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 = 1003–1016 | year = 2003 | pmid = 12783604 | doi = 10.1517/13543784.12.6.1003}}</ref> Anecdotal clinical research has shown potential for the antifungal [[azole]] medications such as [[Fluconazole|diflucan]] 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>{{cite journal |author=Schardt FW |title=Clinical effects of fluconazole in patients with neuroborreliosis |journal=Eur. J. Med. Res. |volume=9 |issue=7 |pages=334–336 |year=2004 |pmid=15337633 }}</ref>
[[Alternative medicine]] approaches include [[bee venom]] because it contains the peptide [[melittin]], which has been shown to exert inhibitory effects on Lyme bacteria [[in vitro]];<ref>{{cite journal |author=Lubke LL, Garon CF |title=The antimicrobial agent melittin exhibits powerful ''in vitro'' inhibitory effects on the Lyme disease spirochete |journal=Clin. Infect. Dis. |volume=25 Suppl 1 |issue= |pages=S48–51 |year=1997 |pmid=9233664 }}</ref> no clinical trials of this treatment have been carried out, however.
==Prognosis==
For early cases, prompt treatment is usually curative.<ref>{{cite journal |author=Krause PJ, Foley DT, Burke GS, Christianson D, Closter L, Spielman A |title=Reinfection and relapse in early Lyme disease |journal=Am. J. Trop. Med. Hyg. |volume=75 |issue=6 |pages=1090–1094 |year=2006 |pmid=17172372}}</ref> However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, and simultaneous infection with other tick-borne diseases (co-infections) including [[ehrlichiosis]], [[babesiosis]], and [[bartonella]], and immune suppression in the patient.
A [[meta-analysis]] published in 2005 found that some patients with Lyme disease have fatigue, joint or muscle pain, and [[neurocognitive]] 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 = 1340–1345 | year = 2005 | pmid = 16040645 | doi = 10.1093/ije/dyi129}}</ref> Patients with late stage Lyme disease have been shown to experience a level of physical [[disability]] equivalent to that seen in [[congestive heart failure]].<ref name="Klempner">{{cite journal | author=Klempner MS, Hu LT, Evans J, ''et al'' | 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 | pmid= 11450676 | doi=10.1056/NEJM200107123450202}}</ref> In rare cases, Lyme disease can be fatal.<ref name="fatal-cases">Fatal cases of Lyme disease reported in the medical literature include:
* {{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=2737–2739 | volume=259 | issue=18 | pmid= 3357244 | doi=10.1001/jama.259.18.2737}}
* {{cite journal | author=Oksi J, Kalimo H, Marttila RJ, ''et al'' | title=Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature | journal=Brain | year=1996 | pages=2143–2154 | volume=119 | issue=Pt 6 | pmid= 9010017 | doi=10.1093/brain/119.6.2143}}
* {{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=345–347 | volume=7 | issue=3 | pmid= 7580195}}
* {{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=134–136 | volume=66 | issue=772 | pmid= 2349186}}</ref>
==Ecology==
[[Urbanization]] and other [[anthropogenic]] factors can be implicated in the spread of Lyme disease to humans. 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 (biology)|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 = 567–571 | year = 2003 | pmid = 12525705 | doi = 10.1073/pnas.0233733100}}</ref><ref name="Patz">{{cite journal | author = Patz J, Daszak P, Tabor G, ''et al'' | title = Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence | journal = Environ Health Perspect | volume = 112 | issue = 10 | pages = 1092–1098 | year = 2004 | pmid = 15238283}}</ref> Researchers are also investigating possible links between [[global warming]] and the spread of vector-borne diseases including Lyme disease.<ref name="Khasnis">{{cite journal |author=Khasnis AA, Nettleman MD |title=Global warming and infectious disease |journal=Arch. Med. Res. |volume=36 |issue=6 |pages=689–696 |year=2005 |pmid=16216650 |doi=10.1016/j.arcmed.2005.03.041}}</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. At this stage, tick infestation may be controlled using acaricides ([[miticide]]s).
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 of the United States]], 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 [[hectares|ha]] or 6 [[acres]]) 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 SE, Cattadori IM, Tagliapietra V, Rizzoli AP, Hudson PJ |title=Localized deer absence leads to tick amplification |journal=Ecology |volume=87 |issue=8 |pages=1981–1986 |year=2006 |pmid=16937637 |doi=10.1890/0012-9658(2006)87[1981:LDALTT]2.0.CO;2 }}</ref>
==Epidemiology==
Lyme disease is the most common tick-borne disease in North America and Europe and one of the fastest-growing infectious diseases in the United States. 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>{{cite web | url = http://www.cdc.gov/ncidod/dvbid/lyme/ld_UpClimbLymeDis.htm | author = CDC | title = Reported Cases of Lyme Disease by Year, United States, 1991–2005 | date = 2006-10-02 | accessdate = 2007-08-20}}</ref>
Although Lyme disease has 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).<ref>http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm</ref> New 2008 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.<ref>http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm</ref> Effective January 2008, the CDC gives equal weight to laboratory evidence from 1) a positive culture for ''B. burgdorferi''; 2) two-tier testing (ELISA screening and Western Blot confirming); or 3) single-tier IgG (old infection) Western Blot. Previously, the CDC only included laboratory evidence based on (1) and (2) in their surveillance case definition. The case definition now includes the use of Western Blot without prior ELISA screen.
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 ''B. burgdorferi'' sensu lato was hindered in its ability to be maintained in an enzootic cycle in [[California]] because it was assumed the large lizard population would dilute the prevalence of ''B. burgdorferi'' in local tick populations, but this has since been brought into question as some evidence has suggested that lizards can become infected.<ref>{{cite journal |author=Swanson KI, Norris DE |title=Detection of Borrelia burgdorferi DNA in lizards from Southern Maryland |journal=Vector Borne Zoonotic Dis. |volume=7 |issue=1 |pages=42–49 |year=2007 |pmid=17417956 |doi=10.1089/vbz.2006.0548}}</ref> Except for one study in Europe,<ref name="pmid16820453">{{cite journal |author=Richter D, Matuschka FR |title=Perpetuation of the Lyme disease spirochete Borrelia lusitaniae by lizards |journal=Appl. Environ. Microbiol. |volume=72 |issue=7 |pages=4627–4632 |year=2006 |month=July |pmid=16820453 |doi=10.1128/AEM.00285-06 |url=}}</ref> much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated that lizards are able to infect naive ticks feeding upon them.<ref name="pmid17626342">{{cite journal |author=Giery ST, Ostfeld RS |title=The role of lizards in the ecology of Lyme disease in two endemic zones of the northeastern United States |journal=J. Parasitol. |volume=93 |issue=3 |pages=511–517 |year=2007 |month=June |pmid=17626342 |doi= |url=}}</ref><ref name="pmid17427701">{{cite journal |author=Amore G, Tomassone L, Grego E, ''et al'' |title=Borrelia lusitaniae in immature Ixodes ricinus (Acari: Ixodidae) feeding on common wall lizards in Tuscany, central Italy |journal=J. Med. Entomol. |volume=44 |issue=2 |pages=303–307 |year=2007 |month=March |pmid=17427701 |doi= |url=}}</ref><ref name="pmid17417956">{{cite journal |author=Swanson KI, Norris DE |title=Detection of Borrelia burgdorferi DNA in lizards from Southern Maryland |journal=Vector Borne Zoonotic Dis. |volume=7 |issue=1 |pages=42–49 |year=2007 |pmid=17417956 |doi=10.1089/vbz.2006.0548 |url=}}</ref><ref name="pmid17326941">{{cite journal |author=Majláthová V, Majláth I, Derdáková M, Víchová B, Pet'ko B |title=Borrelia lusitaniae and green lizards (Lacerta viridis), Karst Region, Slovakia |journal=Emerging Infect. Dis. |volume=12 |issue=12 |pages=1895–1901 |year=2006 |month=December |pmid=17326941 |doi= |url=http://www.cdc.gov/ncidod/eid/vol12no12/06-0784.htm}}</ref> As some experiments suggest lizards are refractory to infection with Borrelia, it appears likely their involvement in the enzootic cycle is more complex and species-specific.<ref name="pmid16995383">{{cite journal |author=Lane RS, Mun J, Eisen L, Eisen RJ |title=Refractoriness of the western fence lizard (Sceloporus occidentalis) to the Lyme disease group spirochete Borrelia bissettii |journal=J. Parasitol. |volume=92 |issue=4 |pages=691–696 |year=2006 |month=August |pmid=16995383 |doi= |url=}}</ref>
While ''B. burgdorferi'' is most associated with ticks hosted by [[white-tailed deer]] and [[White-footed Mouse|white-footed mice]], ''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 ''B. 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 Europe, cases of ''B. burgdorferi'' sensu lato infected ticks are found predominantly in [[Norway]], [[Netherlands]], [[Germany]], [[France]], [[Italy]], [[Slovenia]] and [[Poland]], but have been isolated in almost every country on the continent.<ref>http://www.eurosurveillance.org/ew/2006/060622.asp</ref>
''B. burgdorferi'' sensu lato infested ticks are being found more frequently in [[Japan]], as well as in Northwest [[China]] and far eastern [[Russia]].<ref>{{cite journal |author=Li M, Masuzawa T, Takada N, ''et al'' |title=Lyme disease Borrelia species in northeastern China resemble those isolated from far eastern Russia and Japan |journal=Appl. Environ. Microbiol. |volume=64 |issue=7 |pages=2705–2709 |year=1998 |pmid=9647853 |url=http://aem.asm.org/cgi/content/full/64/7/2705?view=long&pmid=9647853}}</ref><ref>{{cite journal |author=Masuzawa T |title=Terrestrial distribution of the Lyme borreliosis agent Borrelia burgdorferi sensu lato in East Asia |journal=Jpn. J. Infect. Dis. |volume=57 |issue=6 |pages=229–235 |year=2004 |pmid=15623946 |url = http://www.nih.go.jp/JJID/57/229.html}}</ref> ''Borrelia'' has been isolated in [[Mongolia]] as well.<ref>{{cite journal |author=Walder G, Lkhamsuren E, Shagdar A, ''et al'' |title=Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia |journal=Int. J. Med. Microbiol. |volume=296 Suppl 40 |issue= |pages=69–75 |year=2006 |pmid=16524782 |doi=10.1016/j.ijmm.2006.01.031}}</ref>
In [[South America]] tick-borne disease recognition and occurrence is rising. Ticks carrying ''B. 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>{{cite journal |author=Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH |title=Description of Lyme disease-like syndrome in Brazil. Is it a new tick borne disease or Lyme disease variation? |journal=Braz. J. Med. Biol. Res. |volume=40 |issue=4 |pages=443–456 |year=2007 |pmid=17401487 }}</ref> The first reported case of Lyme disease in Brazil was made in 1993 in [[Sao Paulo]].<ref>{{cite journal |author=Yoshinari NH, Oyafuso LK, Monteiro FG, ''et al'' |title=Lyme disease. Report of a case observed in Brazil |language=Portuguese |journal=Revista do Hospital das Clínicas |volume=48 |issue=4 |pages=170–174 |year=1993 |pmid=8284588 }}</ref> ''B. burgdorferi'' sensu stricto antigens in patients have been identified in [[Colombia]] and [[Bolivia]].
In Northern Africa ''B. burgdorferi'' sensu lato has been identified in [[Morocco]], [[Algeria]], [[Egypt]] and [[Tunisia]].<ref>{{cite journal |author=Bouattour A, Ghorbel A, Chabchoub A, Postic D |title=Lyme borreliosis situation in North Africa |language=French |journal=Archives de l'Institut Pasteur de Tunis |volume=81 |issue=1–4 |pages=13–20 |year=2004 |pmid=16929760 }}</ref><ref>{{cite journal |author=Dsouli N, Younsi-Kabachii H, Postic D, ''et al'' |title=Reservoir role of lizard Psammodromus algirus in transmission cycle of Borrelia burgdorferi sensu lato (Spirochaetaceae) in Tunisia |journal=J. Med. Entomol. |volume=43 |issue=4 |pages=737–742 |year=2006 |pmid=16892633 |doi=10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2 }}</ref><ref>{{cite journal |author=Helmy N |title=Seasonal abundance of Ornithodoros (O.) savignyi and prevalence of infection with Borrelia spirochetes in Egypt |journal=Journal of the Egyptian Society of Parasitology |volume=30 |issue=2 |pages=607–619 |year=2000 |pmid=10946521}}</ref>
Lyme disease in sub-Saharan is presently unknown, but evidence indicates that Lyme disease may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.<ref>{{cite journal |author=Fivaz BH, Petney TN |title=Lyme disease—a new disease in southern Africa? |journal=Journal of the South African Veterinary Association |volume=60 |issue=3 |pages=155–158 |year=1989 |pmid=2699499}}</ref> In East Africa, two cases of Lyme disease have been reported in [[Kenya]].<ref>{{cite journal |author=Jowi JO, Gathua SN |title=Lyme disease: report of two cases |journal=East African medical journal |volume=82 |issue=5 |pages=267–269 |year=2005 |pmid=16119758}}</ref>
In [[Australia]] 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>{{cite journal |author=Piesman J, Stone BF |title=Vector competence of the Australian paralysis tick, Ixodes holocyclus, for the Lyme disease spirochete Borrelia burgdorferi |journal=Int. J. Parasitol. |volume=21 |issue=1 |pages=109–111 |year=1991 |pmid=2040556 |doi=10.1016/0020-7519(91)90127-S}}</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.
[[Northern hemisphere]] temperate regions are most endemic for Lyme disease.<ref>{{cite journal |author=Grubhoffer L, Golovchenko M, Vancová M, Zacharovová-Slavícková K, Rudenko N, Oliver JH |title=Lyme borreliosis: insights into tick-/host-borrelia relations |journal=Folia Parasitol. |volume=52 |issue=4 |pages=279–294 |year=2005 |pmid=16405291}}</ref><ref>{{cite journal |author=Higgins R |title=Emerging or re-emerging bacterial zoonotic diseases: bartonellosis, leptospirosis, Lyme borreliosis, plague |journal=Rev. - Off. Int. Epizoot. |volume=23 |issue=2 |pages=569–581 |year=2004 |pmid=15702720}}</ref>
==Controversy and politics==
While there is general agreement on the optimal treatment of early Lyme disease, considerable controversy has attached to the existence, [[prevalence]], diagnostic criteria, and treatment of "chronic" Lyme disease. Most medical authorities—including the [[Infectious Diseases Society of America]] (IDSA), the [[American Academy of Neurology]], and the [[Centers for Disease Control]]—do not recommend long-term antibiotic treatment for "chronic" Lyme disease, based on evidence that such treatment is ineffective and potentially harmful.
Groups of patients, patient advocates, and physicians who support the concept of chronic Lyme disease have organized to lobby for insurance coverage of long-term antibiotic therapy, which most insurers deny given medical opinion that it is ineffective and potentially harmful.<ref name="forbes">{{cite news | author = Whelan, David |url = http://www.forbes.com/business/healthcare/forbes/2007/0312/096.html |title = Lyme Inc | work = [[Forbes (magazine)|Forbes]] | date = 2007-03-12 | accessdate = 2008-06-24}}</ref> As part of this controversy, Connecticut [[Attorney General]] [[Richard Blumenthal]] opened an [[antitrust]] investigation against the IDSA, accusing the IDSA panel of undisclosed [[conflict of interest|conflicts of interest]] and of unduly dismissing alternative therapies. This investigation was closed on [[May 1]], [[2008]] without formal charges; the IDSA agreed to a review of its guidelines by a panel of independent scientists and physicians.<ref name="amnews">{{cite web | url = http://www.ama-assn.org/amednews/2008/06/09/hlsa0609.htm |title = Lyme treatment accord ends antitrust probe | author = Landers, Susan J | work = American Medical News | date = 2008-06-09 | accessdate = 2008-06-24}}</ref> Blumenthal's corresponding [[press release]] announcing the agreement focused on alleged wrongdoing by the IDSA,<ref>{{cite press release |url = http://www.ct.gov/ag/cwp/view.asp?a=2795&q=414284 |title = Attorney General's Investigation Reveals Flawed Lyme Disease Guideline Process, IDSA Agrees To Reassess Guidelines, Install Independent Arbiter | publisher = State of Connecticut Attorney General's Office | date = 2008-05-01 | accessdate = 2008-06-24}}</ref> while the IDSA's press release focused on the fact that the medical validity of the IDSA guidelines was not challenged.<ref>{{cite press release | url = http://www.idsociety.org/Content.aspx?id=11182 |title = Agreement Ends Lyme Disease Investigation By Connecticut Attorney General: Medical Validity of IDSA Guidelines Not Challenged | publisher = [[Infectious Diseases Society of America]] | date = 2008-05-01 | accessdate = 2008-06-24}}</ref> Paul G. Auwaerter, director of infectious disease at [[Johns Hopkins School of Medicine]], cited this political controversy as an example of the "poisonous atmosphere" surrounding Lyme disease research which has led younger researchers to avoid the field.<ref name="amnews"/>
In 2001, the ''[[New York Times Magazine]]'' reported that [[Allen Steere]], chief of immunology and rheumatology at [[New England Medical Center]] and a leading expert on Lyme disease, had been harassed, stalked, and threatened by patients and patient advocacy groups angry at his refusal to substantiate their diagnoses of "chronic" Lyme disease and endorse long-term antibiotic therapy.<ref name="nyt-steere">{{cite news|author=Grann, David |url=http://www.nytimes.com/2001/06/17/magazine/17LYMEDISEASE.htm |title=Stalking Dr. Steere Over Lyme Disease |work = [[New York Times Magazine]] |date = 2001-06-17 |accessdate = 2008-06-25}}</ref> Because of death threats, security guards were assigned to Steere.<ref name="uphill"/>
A significant amount of inaccurate information on Lyme disease exists on the [[Internet]]. A 2004 study found that 9 of 19 websites surveyed contained major inaccuracies. Sites found to be good sources of accurate information in this study included those of the [[American College of Physicians]], the [[Centers for Disease Control]], the [[Food and Drug Administration]], and [[Johns Hopkins University]] (www.hopkins-arthritis.org).<ref name="pmid15626946">{{cite journal |author=Cooper JD, Feder HM |title=Inaccurate information about lyme disease on the internet |journal=Pediatr. Infect. Dis. J. |volume=23 |issue=12 |pages=1105–8 |year=2004 |month=December |pmid=15626946 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0891-3668&volume=23&issue=12&spage=1105}}</ref>
==Pathophysiology==
''Borrelia burgdorferi'' has the ability to disseminate to numerous organs during the course of disease. The spirochete has been found in many tissues, including the skin, heart, joint, peripheral nervous system, and central nervous system.<ref name="pmid15085185">{{cite journal |author=Steere AC, Coburn J, Glickstein L |title=The emergence of Lyme disease |journal=[[J. Clin. Invest.]] |volume=113 |issue=8 |pages=1093–101 |year=2004 |month=April |pmid=15085185 |pmc=385417 |doi=10.1172/JCI21681 |url=}}</ref><ref name="pmid17509489">{{cite journal |author=Pachner AR, Steiner I |title=Lyme neuroborreliosis: infection, immunity, and inflammation |journal=[[Lancet Neurol]] |volume=6 |issue=6 |pages=544–52 |year=2007 |month=June |pmid=17509489 |doi=10.1016/S1474-4422(07)70128-X |url=}}</ref> Many of the signs and symptoms of Lyme disease are a consequence of the inflammatory response to the presence of the spirochete in those tissues. <ref name="pmid14987414">{{cite journal |author=Auwaerter PG, Aucott J, Dumler JS |title=Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment |journal=[[Expert Rev Mol Med]] |volume=6 |issue=2 |pages=1–22 |year=2004 |month=January |pmid=14987414 |doi=10.1017/S1462399404007276 |url=}}</ref>
''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. <ref name="pmid16698304">{{cite journal |author=Fikrig E, Narasimhan S |title=''Borrelia burgdorferi''--traveling incognito? |journal=[[Microbes Infect.]] |volume=8 |issue=5 |pages=1390–9 |year=2006 |month=April |pmid=16698304 |doi=10.1016/j.micinf.2005.12.022 |url=}}</ref> 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 is associated with the appearance of the characteristic EM lesion.<ref name="pmid15085185">{{cite journal |author=Steere AC, Coburn J, Glickstein L |title=The emergence of Lyme disease |journal=[[J. Clin. Invest.]] |volume=113 |issue=8 |pages=1093–101 |year=2004 |month=April |pmid=15085185 |pmc=385417 |doi=10.1172/JCI21681 |url=}}</ref> However [[neutrophils]], which are necessary to eliminate the spirochetes from the skin, fail to appear in the developing EM lesion thereby permitting the bacteria to survive and eventually spread throughout the body.<ref name="pmid17404293">{{cite journal |author=Xu Q, Seemanapalli SV, Reif KE, Brown CR, Liang FT |title=Increasing the recruitment of neutrophils to the site of infection dramatically attenuates ''Borrelia burgdorferi'' infectivity |journal=[[J. Immunol.]] |volume=178 |issue=8 |pages=5109–15 |year=2007 |month=April |pmid=17404293 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=17404293}}</ref>
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 clinical manifestations of disseminated disease. The spread of ''B. burgdorferi'' is aided by the attachment of the host protease [[plasmin]] to the surface of the spirochete. <ref name="pmid9215633">{{cite journal |author=Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL |title=Plasminogen is required for efficient dissemination of ''B. burgdorferi'' in ticks and for enhancement of spirochetemia in mice |journal=[[Cell]] |volume=89 |issue=7 |pages=1111–9 |year=1997 |month=June |pmid=9215633 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80298-6}}</ref> The bacteria may persist at these sites for months or even years despite active production of anti-''B. burgdorferi'' antibodies by the immune response. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by the immune response, [[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. <ref name="pmid18097481">{{cite journal |author=Rupprecht TA, Koedel U, Fingerle V, Pfister HW |title=The pathogenesis of Lyme neuroborreliosis: from infection to inflammation |journal=[[Mol. Med.]] |volume=14 |issue=3-4 |pages=205–12 |year=2008 |pmid=18097481 |pmc=2148032 |doi=10.2119/2007-00091.Rupprecht |url=}}</ref><ref name="pmid17600717">{{cite journal |author=Cabello FC, Godfrey HP, Newman SA |title=Hidden in plain sight: ''Borrelia burgdorferi'' and the extracellular matrix |journal=[[Trends Microbiol.]] |volume=15 |issue=8 |pages=350–4 |year=2007 |month=August |pmid=17600717 |doi=10.1016/j.tim.2007.06.003 |url=}}</ref>
In the brain ''B. burgdorferi'' may induce [[astrocytes]] to undergo astrogliosis (proliferation followed by [[apoptosis]]), which may contribute to neurodysfunction.<ref name="pmid12938230">{{cite journal |author=Ramesh G, Alvarez AL, Roberts ED, ''et al'' |title=Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes |journal=[[Eur. J. Immunol.]] |volume=33 |issue=9 |pages=2539–50 |year=2003 |month=September |pmid=12938230 |doi=10.1002/eji.200323872 |url=}}</ref> The spirochetes may also induce host cells to secrete products toxic to nerve cells, including [[quinolinic acid]] and the [[cytokines]] IL-6 and TNF-alpha, which can produce fatigue and malaise.<ref name="pmid1531156">{{cite journal |author=Halperin JJ, Heyes MP |title=Neuroactive kynurenines in Lyme borreliosis |journal=[[Neurology]] |volume=42 |issue=1 |pages=43–50 |year=1992 |month=January |pmid=1531156 |doi= |url=}}</ref><ref>{{cite web |url=http://www.columbia-lyme.org/flatp/treatment.html |title= Treatment of Lyme Disease |publisher = Columbia University |accessdate=2007-08-23}}</ref><ref>{{cite journal |author=Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP |title=The pathophysiologic roles of interleukin-6 in human disease |journal=Ann. Intern. Med. |volume=128 |issue=2 |pages=127–137 |year=1998 |pmid=9441573}}</ref> Both [[microglia]] and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete.<ref name="pmid12938230"/><ref>{{cite journal |author=Rasley A, Anguita J, Marriott I |title=Borrelia burgdorferi induces inflammatory mediator production by murine microglia |journal=J. Neuroimmunol. |volume=130 |issue=1–2 |pages=22–31 |year=2002 |pmid=12225885 |doi=10.1016/S0165-5728(02)00187-X}}</ref> IL-6 is also significantly indicated in cognitive impairment.<ref>{{cite journal |author=Wright CB, Sacco RL, Rundek TR, ''et al'' |title=Interleukin-6 is associated with cognitive function: the Northern Manhattan Study |journal= Journal of Stroke and Cerebrovascular Diseases|volume=15 |issue=1 |pages=34–38 |year=2006 |pmid=16501663 |doi=10.1016/j.jstrokecerebrovasdis.2005.08.009}}</ref>
A developing hypothesis is that the chronic secretion of [[Stress (medicine)|stress]] [[hormone]]s as a result of ''Borrelia'' infection may reduce the effect of [[neurotransmitter]]s, or other [[Receptor (biochemistry)|receptors]] in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically [[glucocorticoids]] and [[catecholamines]], the major stress hormones.<ref>{{cite journal |author=Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP |title=Cytokine dysregulation, inflammation and well-being |journal=Neuroimmunomodulation |volume=12 |issue=5 |pages=255–269 |year=2005 |pmid=16166805 |doi=10.1159/000087104}}</ref><ref>{{cite journal |author=Calcagni E, Elenkov I |title=Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases |journal=Ann. N. Y. Acad. Sci. |volume=1069 |issue= |pages=62–76 |year=2006 |pmid=16855135 |doi=10.1196/annals.1351.006}}</ref> This process is mediated via the [[hypothalamic-pituitary-adrenal axis]]. Additionally [[tryptophan]], a precursor to [[serotonin]] appears to be reduced within the [[central nervous system]] (CNS) in a number of infectious diseases that affect the brain, including Lyme.<ref>{{cite journal |author=Gasse T, Murr C, Meyersbach P, ''et al'' |title=Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy |journal=European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies |volume=32 |issue=9 |pages=685–689 |year=1994 |pmid=7865624}}</ref> Researchers are investigating if this neurohormone secretion is the cause of [[Neuropsychiatry|neuropsychiatric]] disorders developing in some patients with borreliosis.<ref>{{cite journal |author=Zajkowska J, Grygorczuk S, Kondrusik M, Pancewicz S, Hermanowska-Szpakowicz T |title=New aspects of pathogenesis of Lyme borreliosis |language=Polish |journal=Przegla̧d epidemiologiczny |volume=60 Suppl 1 |issue= |pages=167–170 |year=2006 |pmid=16909797}}</ref>
[[Antidepressants]] acting on serotonin, [[norepinephrine]] and [[dopamine]] receptors have been shown to be [[Immunomodulator|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 [[Psychoneuroimmunology|psycho-neuroimmunological]] process.<ref>{{cite journal |author=Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M |title=Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio |journal=Journal of clinical psychopharmacology |volume=21 |issue=2 |pages=199–206 |year=2001 |pmid=11270917 |doi=10.1097/00004714-200104000-00012}}</ref> Antidepressants have also been shown to suppress Th1 upregulation.<ref>{{cite journal |author=Diamond M, Kelly JP, Connor TJ |title=Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade |journal=European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology |volume=16 |issue=7 |pages=481–490 |year=2006 |pmid=16388933 |doi=10.1016/j.euroneuro.2005.11.011}}</ref>
===Immunological studies===
Research has found that chronic Lyme patients have higher amounts of ''Borrelia''-specific [[FoxP3|forkhead box P3]] (FoxP3) than healthy controls, indicating that [[regulatory T cell]]s might also play a role, by [[immunosuppression]], in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.<ref>{{cite journal |author=Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C |title=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 |journal=Clin. Exp. Immunol. |volume=147 |issue=1 |pages=18–27 |year=2007 |pmid=17177959 |doi=10.1111/j.1365-2249.2006.03245.x}}</ref> The signaling pathway [[P38 mitogen-activated protein kinases]] (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from ''Borrelia''.<ref>{{cite journal |author=Ramesh G, Philipp MT |title=Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to ''Borrelia burgdorferi'' lipoproteins |journal=Neurosci. Lett. |volume=384 |issue=1–2 |pages=112–116 |year=2005 |pmid=15893422 |doi=10.1016/j.neulet.2005.04.069}}</ref>
These immunological studies suggest that 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. This would be a form of pathogen-induced [[autoimmune]] disease.<ref>{{cite journal |author=Singh SK, Girschick HJ |title=Toll-like receptors in ''Borrelia burgdorferi''-induced inflammation |journal=Clin. Microbiol. Infect. |volume=12 |issue=8 |pages=705–717 |year=2006 |pmid=16842565 |doi=10.1111/j.1469-0691.2006.01440.x}}</ref> It is therefore possible that chronic symptoms could come from an autoimmune reaction, even after the spirochetes have been eliminated from the body. This hypothesis may explain chronic arthritis that persists after antibiotic therapy, but the wider application of this hypothesis is controversial.<ref>{{cite journal |author=Weinstein A, Britchkov M |title=Lyme arthritis and post-Lyme disease syndrome |journal=Curr Opin Rheumatol |volume=14 |issue=4 |pages=383–7 |year=2002 |month=July |pmid=12118171}}</ref><ref>{{cite journal |author=Bolz DD, Weis JJ |title=Molecular mimicry to Borrelia burgdorferi: pathway to autoimmunity? |journal=Autoimmunity |volume=37 |issue=5 |pages=387–92 |year=2004 |month=August |pmid=15621562 |doi=10.1080/08916930410001713098}}</ref>
==History==
The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in [[Wrocław]], [[Poland]] (then known as [[Breslau]], [[Germany]]) where physician Alfred Buchwald described a man who had suffered for 16 years with a degenerative [[skin disorder]] now known as [[acrodermatitis chronica atrophicans]]. At a 1909 research conference, Swedish dermatologist [[Arvid Afzelius]] presented a study about an expanding, ring-like lesion he had observed in an older woman following the bite of a sheep tick. He named the lesion ''erythema migrans''.<ref>{{cite journal | author = Afzelius A | title = Verhandlungen der Dermatologischen Gesellshaft zu Stockholm | journal = Archives of Dermatology and Syphilis | language = German | year = 1910 | volume = 101 | pages = 100–102}}</ref> The skin condition now known as borrelial [[lymphocytoma]] was first described in 1911.<ref>{{cite journal | author = Burckhardt JL | title = Zur Frage der Follikel- und Keimzentrenbildung in der Haut | journal = Frankfurter Zeitschrift fur Pathologie | language = German | year = 1911 | volume = 6 | pages = 352–359}}</ref>
Neurological problems following tick bites were recognized starting in the 1920s. French physicians Garin and Bujadoux described a farmer with a painful sensory [[radiculitis]] accompanied by mild [[meningitis]] following a tick bite. A large ring-shaped rash was also noted, although the doctors did not relate it to the meningoradiculitis. In 1930, the Swedish dermatologist Sven Hellerstrom was the first to propose that EM and neurological symptoms following a tick bite were related.<ref>{{cite journal | author = Hellerstrom S | title = Erythema chronicum migrans Afzelii | journal = Archiv Dermatologie and Venereologie (Stockholm) | language = German | year = 1930 | volume = 11 | pages = 315–321}}</ref> In the 1940s, German neurologist [[Alfred Bannwarth]] described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.
Carl Lennhoff, who worked at the [[Karolinska Institute]] in Sweden, believed that many skin conditions were caused by spirochetes. In 1948, he used a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM.<ref>{{cite journal | author = Lenhoff C | title =Spirochetes in aetiologically obscure diseases | journal = Acta Dermato-Venreol | year = 1948 | volume = 28 | pages = 295–324}}</ref> Although his conclusions were later shown to be erroneous, interest in the study of spirochetes was sparked. In 1949, Nils Thyresson, who also worked at the Karolinska Institute, was the first to treat ACA with penicillin.<ref name="pmid18140373">{{cite journal |author=Thyresson N |title=The penicillin treatment of acrodermatitis atrophicans chronica (Herxheimer) |journal=Acta Derm. Venereol. |volume=29 |issue=6 |pages=572–621 |year=1949 |pmid=18140373 |doi= |url=}}</ref> In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarth's syndrome was recognized throughout Europe leading to the widespread use of [[penicillin]] for treatment in Europe.<ref>{{cite journal |author=Bianchi GE |title=Penicillin therapy of lymphocytoma |journal=Dermatologica |volume=100 |issue=4–6 |pages=270–273 |year=1950 |pmid=15421023}}</ref><ref>{{cite journal |author=Paschoud JM |title=Lymphocytoma after tick bite |language=German |journal=Dermatologica |volume=108 |issue=4–6 |pages=435–437 |year=1954 |pmid=13190934}}</ref>
In 1970 a dermatologist in [[Wisconsin]] named Rudolph Scrimenti recognized an EM lesion in a patient after recalling a paper by Hellerstrom that had been reprinted in an American science journal in 1950. This was the first documented case of EM in the United States. Based on the European literature, he treated the patient with penicillin.<ref>{{cite journal |author=Scrimenti RJ |title=Erythema chronicum migrans |journal=Archives of dermatology |volume=102 |issue=1 |pages=104–105 |year=1970 |pmid=5497158 |doi=10.1001/archderm.102.1.104}}</ref>
The full [[syndrome]] now known as Lyme disease was not recognized until a cluster of cases originally thought to be [[juvenile rheumatoid arthritis]] was identified in three towns in southeastern [[Connecticut]] in 1975, including the towns [[Lyme, Connecticut|Lyme]] and [[Old Lyme]], which gave the disease its popular name.<ref>{{cite journal |author=Steere AC |title=Lyme borreliosis in 2005, 30 years after initial observations in Lyme, Connecticut |journal=Wien. Klin. Wochenschr. |volume=118 |issue=21–22 |pages=625–633 |year=2006 |pmid=17160599 |doi=10.1007/s00508-006-0687-x}}</ref> This was investigated by physicians David Snydman and [[Allen Steere]] of the [[Epidemic Intelligence Service]], and by others from [[Yale University]]. 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=631–634 | year=1996| pmid=8933327 | doi=10.1016/S0736-4679(96)00143-6}}</ref>
Before 1976, elements of ''B. burgdorferi'' sensu lato infection were called or known as tickborne meningopolyneuritis, Garin-Bujadoux syndrome, Bannworth syndrome, Afzelius syndrome, [[Montauk, New York|Montauk Knee]] or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease,<ref>{{cite journal |author=Mast WE, Burrows WM |title=Erythema chronicum migrans and "Lyme arthritis" |journal=JAMA |volume=236 |issue=21 |pages=2392 |year=1976 |pmid=989847 |doi=10.1001/jama.236.21.2392d}}</ref><ref>{{cite journal |author=Steere AC, Malawista SE, Snydman DR, ''et al'' |title=Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities |journal=Arthritis Rheum. |volume=20 |issue=1 |pages=7–17 |year=1977 |pmid=836338 |doi=10.1002/art.1780200102}}</ref> Lyme borreliosis or simply borreliosis.
In 1980 Steere, et al, began to test [[antibiotics|antibiotic]] regimens in adult patients with Lyme disease.<ref>{{cite journal |author=Steere AC, Hutchinson GJ, Rahn DW, ''et al'' |title=Treatment of the early manifestations of Lyme disease |journal=Ann. Intern. Med. |volume=99 |issue=1 |pages=22–26 |year=1983 |pmid=6407378}}</ref> In 1982 a novel [[spirochete]] was cultured from the mid-gut of ''Ixodes'' ticks in [[Shelter Island]], New York, and subsequently from patients with Lyme disease. The infecting agent was then identified by [[Jorge Benach]] at the [[State University of New York at Stony Brook]], and soon after isolated by [[Willy Burgdorfer]], a researcher at the [[National Institutes of Health]], who specialized in the study of arthropod-borne bacteria such as ''Borrelia'' and ''[[Rickettsia]]''. The spirochete was named ''Borrelia burgdorferi'' in his honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with [[Alan Barbour]].
After identification ''B. burgdorferi'' as the causative agent of Lyme disease, antibiotics were selected for testing, guided by ''in vitro'' antibiotic sensitivities, including [[tetracycline antibiotics]], [[amoxicillin]], [[cefuroxime axetil]], intravenous and intramuscular penicillin and intravenous [[ceftriaxone]].<ref>{{cite journal |author=Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ |title=New chemotherapeutic approaches in the treatment of Lyme borreliosis |journal=Ann. N. Y. Acad. Sci. |volume=539 |issue= |pages=352–361 |year=1988 |pmid=3056203 |doi=10.1111/j.1749-6632.1988.tb31869.x}}</ref><ref>{{cite journal |author=Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ |title=Amoxycillin plus probenecid versus doxycycline for treatment of ''erythema migrans'' borreliosis |journal=Lancet |volume=336 |issue=8728 |pages=1404–1406 |year=1990 |pmid=1978873 |doi=10.1016/0140-6736(90)93103-V}}</ref> The mechanism of tick transmission was also the subject of much discussion. ''B. burgdorferi'' spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occurred via tick salivary glands.<ref>{{cite journal |author=Ribeiro JM, Mather TN, Piesman J, Spielman A |title=Dissemination and salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae) |journal=J. Med. Entomol. |volume=24 |issue=2 |pages=201–205 |year=1987 |pmid=3585913}}</ref>
==References==
{{reflist|2}}
==External links==
{{Wikispecies|Borrelia}}
;'''General'''
*{{dmoz|/Health/Conditions_and_Diseases/Infectious_Diseases/Spirochetal/Lyme_Disease/}}
*{{dmoz|/Health/Conditions_and_Diseases/Infectious_Diseases/Spirochetal/Lyme_Disease/Organizations/|Lyme disease organizations}}
*[http://www.cdc.gov/ncidod/diseases/submenus/sub_lyme.htm CDC Lyme disease page]
**[http://www.cdc.gov/niosh/topics/lyme/ National Institute for Occupational Safety and Health - Lyme Disease Page]
*[http://columbia-lyme.org/flatp/lymeoverview.html Columbia University - Overview of Neuropsychiatric Lyme Disease]
*[http://www.merck.com/mmpe/sec14/ch174/ch174d.html Lyme Disease] ''The Merck Manual''
*[http://chppm-www.apgea.army.mil/documents/FACT/18-011-0406-LymeDiseaseJTF-April2006.pdf US Army Factsheet on Lyme Disease] (CHPPM's Entomological Sciences Program)
*[http://chppm-www.apgea.army.mil/3d/tick/Xyber-tick.html Interactive Image of ''Ixodes scapularis'', Deer Tick or Blacklegged Tick] (CHPPM's Entomological Sciences Program)
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