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{{DiseaseDisorder infobox |
__NOTOC__
  Name          = Lyme disease |
{{Lyme disease}}
  ICD10          = {{ICD10|A|69|2|a|65}} |
{{About1|Borrelia burgdorferi}}
  ICD9          = {{ICD9|088.81}} |
  ICDO          = |
  Image          = Adult_deer_tick.jpg|
  Caption        = Nymphal and adult [[deer tick]]s can be carriers of Lyme disease. Nymphs are about the size of a poppy seed. |
  MedlinePlus    = 001319 |
  eMedicineSubj  = med |
  eMedicineTopic = 1346|
  DiseasesDB    = 1531 |
}}
{{SI}}
{{CMG}}


{{Editor Help}}
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'''Lyme disease''', or '''borreliosis''', is an [[emerging infectious disease]] caused by [[spirochete]] [[bacteria]] from the [[genus]] ''[[Borrelia]]''.<ref name=Sherris>{{cite book | author = Ryan KJ, Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | pages = 434&ndash;7 | publisher = McGraw Hill | year = 2004 | isbn = 0838585299}}</ref> The [[Vector (biology)|vector]] of infection is typically the bite of an infected black-legged or [[deer tick]], but other carriers (including other [[tick]]s in the genus ''[[Ixodes]]'') have been implicated.<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> ''[[Borrelia burgdorferi]]'' is the predominant cause of Lyme disease in the US and ''Borrelia afzelii'' and ''Borrelia garinii'' are in Europe.
{{CMG}}; {{AE}} {{Anmol}}


The disease presentation varies widely, and may include a rash and [[flu]]-like symptoms in its initial stage, then [[musculoskeletal]], [[arthritic]], [[neurologic]], [[psychiatric]] and [[cardiac]] manifestations. In a majority of cases, symptoms can be eliminated with [[antibiotics]], especially if treatment begins early in the course of illness. Late or inadequate treatment often leads to "late stage" Lyme disease that is disabling and difficult to treat.  [[Lyme disease controversy|Controversy]] over diagnosis, testing and treatment has led to two different standards of care.<ref name="Johnson-a">{{cite web | author = Johnson L | title = Lyme disease: two standards of care | publisher = International Lyme and Associated Diseases Society | date = 2005-02 | url = http://www.ilads.org/insurance.html | accessdate = 2007-08-21}}</ref><ref name="Johnson-b">{{cite journal | author = Johnson L, Stricker R | title = Treatment of Lyme disease: a medicolegal assessment. | journal = Expert Rev Anti Infect Ther | volume = 2 | issue = 4 | pages = 533-57 | year = 2004 | pmid = 15482219}}</ref>
{{SK}} Infection due to ''Borrelia burgdorferi'' sensu lato, Borreliosis, Lyme borreliosis, Steere's disease, Afzelius syndrome, Tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannworth syndrome, Lymphocytic meningoradiculitis
== [[Lyme disease overview|Overview]] ==


==History==
== [[Lyme disease historical perspective|Historical Perspective]] ==
The first record of a condition associated with Lyme disease dates to 1883 in Breslau (formerly in Germany) where physician Alfred Buchwald described a degenerative [[skin disorder]] now known as [[acrodermatitis chronica atrophicans]]. In 1909, [[Arvid Afzelius]] presented research about an expanding, ring-like lesion he had observed. Afzelius published his work 12 years later and speculated that the rash came from the bite of an ''Ixodes'' tick, and that meningitic symptoms and signs occur in a number of cases; this rash is now known as [[erythema migrans]] (EM), the skin rash found in early stage Lyme disease.<ref>{{cite journal | author = Lipschütz B | title = Zur Kenntnis der "Erythema chronicum migrans" | journal = Acta dermato-venereologica | language = German | year = 1931 | volume = 12 | pages = 100–2}}</ref> In 1911, parasitologist Andrew Balfour of the Wellcome Research Laboratory in Khartoum identified "infective granules" or spore-type "cysts" as the cause of persistence of spirochetal infection in the Sudanese Fowl.<ref>{{cite journal | author = Balfour A | title = The Infective Granule in Certain Protozoa Infections, as Illustrated by the Spirochaetosis of Sudanese Fowls | journal = THe British Medical Journal | year = 1911 | pages = 1296}}</ref>


In the 1920s, French physicians Garin and Bujadoux described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, and they postulated the symptoms were due to a spirochetal infection. In the 1940s, German neurologist [[Alfred Bannwarth]] described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions. 
== [[Lyme disease classification|Classification]] ==


In 1948 [[spirochete]]-like structures were observed in skin specimens by Swedish dermatologist Carl Lennhoff.<ref>{{cite journal | author = Lenhoff C | title =Spirochetes in aetiologically obscure diseases | journal = Acta Dermato-Venreol | year = 1948 | volume = 28 | pages = 295-324}}</ref> In the 1950s, relations between tick bite, lymphocytoma, EM and Bannwarth's syndrome are seen throughout Europe leading to the use of [[penicillin]] for treatment.<ref>{{cite journal |author=Bianchi GE |title=Penicillin therapy of lymphocytoma |journal=Dermatologica |volume=100 |issue=4-6 |pages=270-3 |year=1950 |pmid=15421023}}</ref><ref>{{cite journal |author=Hollstrom E |title=Successful treatment of erythema migrans Afzelius |journal=Acta Derm. Venereol. |volume=31 |issue=2 |pages=235-43 |year=1951 |pmid=14829185}}</ref><ref>{{cite journal |author=Paschoud JM |title=Lymphocytoma after tick bite. |language=German |journal=Dermatologica |volume=108 |issue=4-6 |pages=435-7 |year=1954 |pmid=13190934}}</ref>
== [[Lyme disease pathophysiology|Pathophysiology]] ==


Interest in [[tick-borne disease|tick-borne infections]] in the U.S. began with the first report of tick-borne [[relapsing fever]] (''Borrelia hermsii'') in 1915, following the recognition of five human patients in Colorado.<ref>{{cite journal | author = Meador CN | title = Five cases of relapsing fever originating in Colorado, with positive blood findings in two | journal = Colorado Medicine | year = 1915 | volume = 12 | pages = 365-9}}</ref>
== [[Lyme disease epidemiology and demographics|Epidemiology and Demographics]] ==


In 1970 a physician in Wisconsin named Rudolph Scrimenti reports the first case of EM in U.S. and treats it with penicillin based on European literature.<ref>{{cite journal |author=Scrimenti RJ |title=Erythema chronicum migrans |journal=Archives of dermatology |volume=102 |issue=1 |pages=104-5 |year=1970 |pmid=5497158}}</ref>
== [[Lyme disease causes|Causes]] ==


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 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=625-33 |year=2006 |pmid=17160599 |doi=10.1007/s00508-006-0687-x}}</ref> This was investigated by Dr. David Snydman and Dr.[[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 = 631-4 | year = 1996| pmid = 8933327}}</ref>
== [[Lyme disease differential diagnosis|Differentiating Lyme disease from other Diseases]] ==


Before 1976, elements of ''B. burgdorferi'' sensu lato infection were called or known as ''tickborne meningopolyneuritis'', ''Garin-Bujadoux syndrome'', ''Bannworth syndrome'', ''Afzelius syndrome'', ''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}}</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}}</ref> Lyme borreliosis or simply borreliosis.
== [[Lyme disease risk factors|Risk Factors]] ==


In 1976, Jay Sanford, a former physician at the [[Walter Reed Army Institute of Research]], published a chapter in the book ''The Biology of Parasitic Spirochetes.'' In it, Dr. Sanford stated:  "the ability of [[borrelia]], especially tick-borne strains, to persist in the brain and in the eye during remission after treatment with arsenic or with penicillin or even after apparent cure, is well known.” <ref name="Sanford">{{cite book | author = Sanford JP | chapter = Relapsing Fever—Treatment and Control | title = Biology of Parasitic [[Spirochetes]] | editor = Johnson RC (ed) | publisher = Academic Press | year = 1976 | isbn = 9780123870506}}</ref> Although the notion of persistent neurological infection was identified early on by military researchers such as Dr. Sanford, later Lyme researchers curiously denied the possibility of persistent ''Borrelia'' infection in the brain, with many researchers ignoring evidence of persistent infection.
== [[Lyme disease natural history, complications and prognosis|Natural History, Complications and Prognosis]] ==


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=22-6 |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 spirochete microorganisms 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.
== [[Lyme disease screening|Screening]] ==


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=352-61 |year=1988 |pmid=3056203}}</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=1404-6 |year=1990 |pmid=1978873}}</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=201-5 |year=1987 |pmid=3585913}}</ref>
== Diagnosis ==


==Cause==
[[Lyme disease history and symptoms|History and Symptoms]] | [[Lyme disease physical examination|Physical Examination]] | [[Lyme disease laboratory findings|Laboratory Findings]] |[[Lyme disease ECG|ECG]] |[[Lyme disease X-ray|X-ray]] |[[Lyme disease CT|CT scan]] |[[Lyme disease MRI|MRI]] |[[Lyme disease ultrasound|Ultrasound]] | [[Lyme disease other imaging findings|Other Imaging Findings]] | [[Lyme disease other diagnostic studies|Other Diagnostic Studies]]
{{main|Lyme disease microbiology}}


Lyme disease is caused by [[Gram-negative]] [[spirochetal]] [[bacteria]] from the [[genus]] ''[[Borrelia]]''. At least 37 ''Borrelia'' species have been described, 12 of which are Lyme related. 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=1741-55 | volume=150 | issue=Pt 6 | pmid= 15184561 | url=http://mic.sgmjournals.org/cgi/reprint/150/6/1741.pdf | format=PDF}}</ref>
== Treatment ==


Until recently it was thought that only three genospecies caused Lyme disease: ''B. burgdorferi'' sensu stricto (predominant in North America, but also in Europe), ''B. afzelii'', and ''B. garinii'' (both predominant in Eurasia). However, newly discovered genospecies have also been found to cause disease in humans.
[[Lyme disease medical therapy|Medical Therapy]] | [[Lyme disease surgery|Surgery]] | [[Lyme disease primary prevention|Primary Prevention]] | [[Lyme disease secondary prevention|Secondary Prevention]] | [[Lyme disease future or investigational therapies|Future or Investigational Therapies]]


===Transmission===
==Case Studies==


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 stage, as adult ticks do not become infected through feeding.<ref>{{cite web |url=http://www.cdc.gov/ncidod/dvbid/lyme/ld_transmission.htm |title=Lyme Disease Transmission | work = Lyme Disease |publisher = CDC | date = 2005-12-07 |accessdate=2007-08-21}}</ref>
[[Lyme disease case study one|Case #1]]


In Europe,  the commonly known sheep tick, castor bean tick, or European castor bean tick (''[[Ixodes ricinus]]'') is the transmitter.
{{Spirochetal diseases}}
 
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. Unfortunately, only about 20% of persons infected with Lyme disease by the deer tick are aware of having had any tick bite,<ref name="Wormser">{{cite journal | author=Wormser G, Masters E, Nowakowski J, ''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=958-65 | year=2005 | pmid= 16142659}}</ref> making early detection difficult in the absence of a rash. Another possible vector is the lone star tick (''Amblyomma americanum''), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well. These tick bites usually go unnoticed due to 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.
 
On the 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=5076-86 | year=2004 | pmid= 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF}}</ref> It was once thought to be a vector, although recent studies demonstrate that this tick species is not a competent vector of ''Borrelia burgdorferi'' sensu lato.<ref name="Ledin-k">{{cite journal | author = Ledin K, Zeidner N, Ribeiro J, "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}}</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=1482-6 | 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=121-8 | year=1995 | pmid = 7648832}}</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>
 
==Symptoms==
 
The [[Acute (medicine)|acute]] phase of Lyme disease infection is a characteristic reddish "bulls-eye" [[rash]], with accompanying [[fever]], [[malaise]], and musculoskeletal pain ([[arthralgia]] or [[myalgia]]).<ref name=Sherris /> The characteristic reddish "bull's-eye" rash (known as ''[[erythema chronicum migrans]]'') may be seen in up to 80% of early stage Lyme disease patients,<ref>{{cite web | author=CDC | title=Lyme Disease Erythema Migrans | date=2005-07-06 | accessdate = 2007-08-21 |  url=http://www.cdc.gov/ncidod/dvbid/lyme/ld_LymeDiseaseRashPhotos.htm}}</ref> appearing anywhere from one day to a month after a tick bite.<ref name="pmid11982305">{{cite journal | author=Donta ST | title=Late and chronic Lyme disease | journal=Med Clin North Am | year=2002 | pages=341-9, vii | volume=86 | issue=2 | pmid= 11982305 | url=http://www.immunesupport.com/library/print.cfm?ID=3579&t=CFIDS_FM}}</ref> The rash does not represent an [[allergic reaction]] to the bite, but rather a skin infection with the Lyme bacteria, [[Lyme disease microbiology|''Borrelia burgdorferi'' sensu lato]].
 
The [[incubation period]] from infection to the onset of symptoms is usually 1&ndash;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 uncommon.<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=528-32 |year=2003 |pmid=12905137}}</ref>
 
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=S1435-41 |year=1989 |pmid=2682955}}</ref>), neurologic symptoms (neuroborreliosis may occur in up to 18%<ref name="Ciesielski_1989" />), as well as 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= |volume=1 |issue=1 |pages=62 |year=2007 |pmid=17688693 |doi=10.1186/1752-1947-1-62}}</ref>
 
===Chronic symptoms===
Untreated or persistent cases may progress to a chronic form most commonly characterized by [[meningoencephalitis]], cardiac inflammation ([[myocarditis]]), and frank [[arthritis]].<ref name=Sherris /> It should be noted, however, that chronic Lyme disease can have a multitude of symptoms affecting numerous physiological systems: the symptoms appear [[heterogeneous]] in the affected population, which may be due to [[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 progession, 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]], [[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=111-6 |year=1988 |pmid=3421091}}</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=592-5 |year=1991 |pmid=2041438}}</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 /><ref>In rare cases, frank [[psychosis]] have 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 somataform 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.({{cite journal |author=Fallon BA, Nields JA |title=Lyme disease: a neuropsychiatric illness |journal=The American journal of psychiatry |volume=151 |issue=11 |pages=1571-83 |year=1994 |pmid=7943444}}{{cite journal |author=Hess A, Buchmann J, Zettl UK, ''et al'' |title=Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder |journal=Biol. Psychiatry |volume=45 |issue=6 |pages=795 |year=1999 |pmid=10188012}})</ref>
 
==Diagnosis==
Due to 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 [[Erythema migrans|EM rash]], which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when 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=62-6 | volume=282 | issue=1 | pmid= 10404913}}</ref><ref name="Hofmann">{{cite journal | author=Hofmann H | title=Lyme borreliosis--problems of serological diagnosis | journal=Infection | year=1996 | pages=470-2 | volume=24 | issue=6 | pmid= 9007597}}</ref> [[serology|Serological]] testing can be useful, but is not diagnostic.<ref name=Sherris />
 
Clinicians who diagnose strictly based on the [[#The CDC case definition|U.S. Centers for Disease Control (CDC) Case Definition for Lyme]] are in error, as the [[Centers for Disease Control|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>
 
Importantly, virtually no controlled studies of late lyme encephalopathy have been performed, and the CDC diagnostic criteria were not formulated for use on this entity. Once lyme disease is well established in the brain, it can occur as a very disabling diffuse encephalopathy which however is difficult to diagnose using standard serological or intrathecal testing for reasons outlined below. Lyme is a deep tissue infection and by the time encephalopathy is established, few if any CFS antibodies can be detetected, and PCR is unreliable. Seronegative disease can occur for the same reason that this phenomenon occurs in neurosyphilis, with incomplete or intercurrent antibiotic treatment abrogating the serum antibody response, but not eliminating the infection.
 
It is in this context that advanced imaging studies like SPECT or PET can provide objective evidence of global brain dysfunction. Resort is often made to neuropsychological testing, but a normal result does not rule out the illness, which can be very subtle and manifest as a disabling mood disorder accompanied by massive and debilitating fatigue, with few objective signs.
 
Diagnosis of late-stage Lyme disease it is often difficult due to 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=S1482-6 |year=1989 |pmid=2682960}}</ref> Lyme disease may be misdiagnosed as [[Multiple sclerosis]], [[rheumatoid arthritis]], [[fibromyalgia]], [[chronic fatigue syndrome]] (CFS), or other [[autoimmune]] and [[neurodegenerative]] diseases.
 
=== Physical Examination ===
 
<gallery>
Image:Borrelia image.jpg|''[[Borrelia]]'' bacteria, the causative agent of Lyme disease. Magnified 400 times.
Image:Ixodes scapularis.png|''[[Ixodes scapularis]]'', the primary vector of Lyme disease in eastern North America.
Image:BullseyeLymeDiseaseRash.jpg||Common bullseye rash pattern associated with Lyme Disease.
</gallery>
 
 
<gallery>
Image:lymebite.png|Characteristic "bulls-eye"-like rash caused by Lyme disease.
Image:erythema chronicum migrans (Lyme Disease).jpg|Erythema Chronicum Migrans
</gallery>
 
===Serology===
The [[serology|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&ndash;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=419-27 | 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=2105-9 | volume=156 | issue=18 | pmid = 8862103}}</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}}</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=1826-7 | volume=41 | issue=12 | pmid= 16288417}}</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 rarely susceptible to [[Type I and type II errors|false-positive]] results but can often show [[Type I and type II errors|false-negative]] results, and the overall reliability of PCR in this role remains unclear. 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=573-4, 577-8 |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 [[cerebral spinal 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=2010-5 |year=1995 |pmid=7501150 }}</ref>
 
New techniques for clinical evaluation if ''Borrelia'' infection are under investigation, including ''Lymphocyte transformation tests'' <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> and ''focus floating microscopy''.<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=213-22 |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=653-8 |year=2006 |pmid=17160603 |doi=10.1007/s00508-006-0692-0}}</ref>
 
===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=1120-2 |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 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=1661-70 |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, as 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 bite.  Late disease can occur many years after initial infection. The average time from symptom onset to diagnosis in these patients is about 4 years due to efforts by the CDC and infectious disease community's to cover-up the illness. Because seronegative disease can occur, and because CFS testing is often normal, lyme encephalopathy often becomes a diagnosis of exclusion: once all other possibilities are ruled out, LE becomes ruled in. Although the aberrant SPECT patterns are caused by cerebral vaculitis, 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.  MRI scans of patients with neurologic Lyme disease may demonstrate punctated [[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=903-7 |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=326-32 |year=2003 |pmid=12928508}}</ref>
 
==Prevention==
The currently recommended prevention practices are to avoid areas where ticks are found, wear clothing that covers the entire body when in a wooded area, use mosquito/tick repellent after exposure to wooded areas, and check all parts of the body (including hair) and clothing for ticks. Attached ticks should be removed promptly.<ref>{{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=509-12 |year=2002 |pmid=12061448}}</ref>
 
Protective clothing includes long-sleeve shirts and pants that are tucked into socks or boots. Also, light-colored clothing makes the tick more easily visible before it attaches itself.
 
A more effective, community wide method of preventing Lyme disease is to reduce in numbers the primary hosts on which the deer tick depends.
 
===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 effectively 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=779-84 |year=2004 |pmid=15311475 }}</ref> and in Mumford Cove, CT.<ref>Figure 2. p.4. DEP Wildlife Division: Managing Urban Deer in Connecticut 2nd edition June 2007</ref>.  The black-legged or deer tick (''Ixodes scapularis'') depends on the white-tailed deer for successful reproduction.
 
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 very low levels, too few 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 = p. 46 | accessdate = 2007-08-21}}</ref>
 
===Vaccination===
A [[vaccine]], called Lymerix, against a North American strain of the spirochetal bacteria was available from 1998 to 2002. It was produced by [[GlaxoSmithKline]] (GSK) and was based on the outer surface protein A (Osp-A) of ''Borrelia''. Osp-A causes the human [[immune system]] to create [[antibody|antibodies]] that attack that protein. When taking it off the market, GSK cited poor sales, need for frequent boosters, the high price of the vaccine, and exclusion of children. Some people believe that the actual reason was that the vaccine was neither safe nor effective. A group of patients who took Lymerix developed [[arthritis]], muscle pain and other troubling symptoms after vaccination. Class-action litigation against GSK followed. Cassidy v. SmithKline Beecham, No. 99-10423 (Ct. Common Pleas, PA state court) (common settlement case).<ref name="LymeInfo-Vaccine">Safety/Efficacy concerns re: Lyme vaccine: LYMErix [http://www.lymeinfo.net/vaccine2.html Controversy] ''LymeInfo.net''</ref><!-- This ref does not appear to meet WP:RS standards (MarcoTolo - 2007-08-21) -->
 
It was later learned that patients with the genetic [[allele]] HLA-DR4 were susceptible to T-cell cross-reactivity between [[epitope]]s of OspA and lymphocyte function-associated antigen in these patients causing an autoimmune reaction.<ref>{{cite journal |author=Willett TA, Meyer AL, Brown EL, Huber BT |title=An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=5 |pages=1303-8 |year=2004 |pmid=14742868 |doi=10.1073/pnas.0305680101 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=14742868}}</ref>


New vaccines are being researched using outer surface protein C (Osp-C) 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=628-34 |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=621-6 |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>
===Removal of ticks===
{{main|Tick#Removal}}
Many urban legends exist about the proper and effective method to remove a tick. Complete removal of the tick head is important; if the head is not completely removed, local infection of bite location may result.<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 has demonstrated that prompt removal of an infected tick, within approximately one day, reduces the risk of transmission to effectively zero percent.<ref>{{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=509-12 |year=2002 |pmid=12061448}}</ref>
==Treatment==
[[Antibiotics]] are the primary treatment for Lyme disease.<ref name=Sherris /> [[Penicillin]] was first demonstrated by researchers to be useful against ''Borrellia'' in the 1950s; today the antibiotics of choice are [[doxycycline]], [[amoxicillin]] and [[ceftriaxone]].<ref name=Sherris /> [[Macrolide]] antibiotics are also used.
Persons who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days. A three day course of [[doxycycline]] therapy may be considered for deer tick bites when the tick has been on the person for at least 12 hours. Patients should report any [[Erythema migrans]] over the subsequent two to six weeks. If there should be suspicion of disease, then a course of Doxycycline should be immediately given for ten days without awaiting serology tests which only yield positive results after an interval of one to two months.<!-- Advice given by Hosp. Trop. Med in 2004 to User:Davidruben-->
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=Muellegger RR, Zoechling N, Soyer HP, ''et al'' |title=No detection of Borrelia burgdorferi-specific DNA in erythema migrans lesions after minocycline treatment |journal=Archives of dermatology |volume=131 |issue=6 |pages=678-82 |year=1995 |pmid=7778919 }}</ref><ref>{{cite journal |author=Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L |title=Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi infection |journal=J. Am. Acad. Dermatol. |volume=28 |issue=2 Pt 2 |pages=312-4 |year=1993 |pmid=8436647 }}</ref>
===Antibiotic treatment controversy===
{{see|Lyme disease controversy}}
With little research conducted specifically on treatment for late/chronic Lyme disease, particularly lyme encephalopathy, treatment remains controversial. Currently there are two sets of peer-reviewed published guidelines in the United States; the International Lyme and Associated Diseases Society (ILADS)<ref>[http://www.ilads.org International Lyme and Associated Diseases Society (ILADS)]</ref> advocates extended courses of antibiotics for chronic Lyme patients in light of evidence of [[Lyme disease microbiology|persistent infection]], while the Infectious Diseases Society of America<ref>[http://www.idsociety.org/ Infectious Diseases Society of America]</ref> does not recognize chronic infection and recommends no treatment for persistent symptoms. [[Double-blind]], [[placebo|placebo-controlled]] trials of long-term antibiotics for chronic Lyme have produced mixed results.
A controversial new guideline developed by the American Academy of Neurology, finds conventionally recommended courses of antibiotics are highly effective for treating nervous system Lyme disease. They find no compelling evidence that prolonged treatment with antibiotics has any benefit in treating symptoms that persist following standard therapy. The guideline is endorsed by the Infectious Diseases Society of America (IDSA). However, these guidelines refer mostly to early acute lyme neuroborreliosis, as there is a paucity of studies on late lyme encephalopathy and parenchymal CNS disease. The guideline leader was John J. Halperin and was co-written by Gary Worsmer and Eugene Shapiro, neither of whom are neurologists. Halperin, Worsmer and Shapiro were all co-authors of the IDSA Lyme guidelines released in 2006 by the [http://www.journals.uchicago.edu/CID/journal/issues/v43n9/40897/40897.html Journal of Clinical Infectious Diseases]. There is significant disagreement with this guideline (www.ilads.org).
The latest double blind, randomized, [[placebo]]-controlled multicenter clincal study, done in Finland, results indicated that oral adjunct antibiotics were not justified in the treatment of patients with disseminated Lyme borreliosis who initially received intravenous antibiotics for 3 weeks. The researchers noted the clinical outcome of said patients should not be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. In patients with chronic post-treatment symptoms, persistent positive levels of antibodies did not seem to provide any useful information for further care of the patient.<ref>{{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=571-81 |year=2007 |pmid=17587070 |doi=10.1007/s10096-007-0340-2}}</ref>
===Antibiotic-resistant therapies===
Antibiotic treatment is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment.<ref>{{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=225-32 |year=1999 |pmid=10442678 }}</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 }}</ref> Experimental data is consensual on the deleterious consequences of systemic [[corticosteroid]] therapy. Corticosteroids are not indicated in Lyme disease.<ref>{{cite journal |author=Puéchal X |title=Non antibiotic treatments of Lyme borreliosis. |journal= Med Mal Infect |volume=[Epub ahead of print] |issue= |pages= |year=2007 |pmid=17376627 |doi=10.1016/j.medmal.2006.01.021}}</ref>
Antibiotic refractory patients with 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=123-7 |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]], [[Parkinsons]], [[Huntingtons 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=359-66 |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 = 1003-16 | year = 2003 | pmid = 12783604}}</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=334-6 |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=1090-4 |year=2006 |pmid=17172372}}</ref> However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including [[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 and/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 = 1340-5 | year = 2005 | pmid = 16040645}}</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}}</ref>
Though rare, Lyme disease can be fatal.<ref name="Kirsch">{{cite journal | author=Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A | title=Fatal adult respiratory distress syndrome in a patient with Lyme disease | journal=JAMA | year=1988 | pages=2737-9 | volume=259 | issue=18 | pmid= 3357244}}</ref><ref name="Oksi-b">{{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=2143-54 | volume=119 | issue=Pt 6 | pmid= 9010017}}</ref><ref name="Waniek">{{cite journal | author=Waniek C, Prohovnik I, Kaufman MA, Dwork AJ | title=Rapidly progressive frontal-type dementia associated with Lyme disease | journal=J Neuropsychiatry Clin Neurosci | year=1995 | pages=345-7 | volume=7 | issue=3 | pmid= 7580195}}</ref><ref name="Cary">{{cite journal | author=Cary NR, Fox B, Wright DJ, Cutler SJ, Shapiro LM, Grace AA | title=Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node | journal=Postgrad Med J | year=1990 | pages=134-6 | volume=66 | issue=772 | pmid= 2349186}}</ref>The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.<ref>{{ cite news | url = http://pqasb.pqarchiver.com/latimes/access/60144819.html?dids=60144819:60144819&FMT=ABS&FMTS=ABS:FT&type=current&date=Sep+26%2C+1990&author=&pub=Los+Angeles+Times+(pre-1997+Fulltext)&edition=&startpage=2&desc=HEALTH+First+Lyme+Disease+Death+Told | title = First Lyme Disease Death Told | work = Los Angeles Times | date = 1990-09-26}}</ref><!-- Need better ref, here -->
==Ecology==
Urbanization and other anthropogenic factors can be implicated in the spread of the Lyme disease into the human population. In many areas, expansion of suburban neighborhoods has led to the gradual deforestation of surrounding wooded areas and increasing "border" contact between humans and tick-dense areas. Human expansion has also resulted in a gradual reduction of the predators that normally hunt deer as well as mice, chipmunks and other small rodents -- the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission to Lyme residents has greatly increased.<ref name="LoGiudice">{{cite journal | author = LoGiudice K, Ostfeld R, Schmidt K, Keesing F | title = The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk. | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 2 | pages = 567-71 | year = 2003 | pmid = 12525705}}</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 = 1092-8 | 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=689-96 |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. (Note: At this stage, it is proposed that tick infestation may be controlled using acaricides ([[miticide]]).
Adult ticks may also transmit disease to humans. After feeding, female adult ticks lay their eggs on the ground, and the cycle is complete. On the west coast, Lyme disease is spread by the western black-legged tick (''Ixodes pacificus''), which has a different life cycle.
The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests that eliminating deer from smaller areas (less than 2.5 hectares or 6.2 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=1981-6 |year=2006 |pmid=16937637 }}</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 Center for Disease Control (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 now been reported in 49 of 50 states in the U.S, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). Charts and tables for Lyme disease statistics in the U.S. can be found at the [http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm CDC website].
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 couldn't 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 proven false as lizards are now known carriers of ticks in North America, Europe and North Africa. Indeed, the [[DNA]] of ''Borrelia'' has been detected in lizards, indicating that they can be 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=42-9 |year=2007 |pmid=17417956 |doi=10.1089/vbz.2006.0548}}</ref>
While ''B. burgdorferi'' is most associated with deer tick and the white tailed mouse, ''Borrelia afzelii'' is most frequently detected in rodent-feeding vector ticks, ''Borrelia garinii'' and ''Borrelia valaisiana'' appear to be associated with birds. Both rodents and birds are competent reservoir hosts for ''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. Lyme disease statistics for Europe can be found at [http://www.eurosurveillance.org/ew/2006/060622.asp Eurosurveillance website].
''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=2705-9 |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=229-35 |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=443-56 |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=170-4 |year=1993 |pmid=8284588 }}</ref> ''B. burgdorferi'' sensu stricto antigens in patients have been identified in Colombia and in 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=737-42 |year=2006 |pmid=16892633 }}</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=607-19 |year=2000 |pmid=10946521}}</ref> 
In Western and sub-Saharan Africa, tick-borne [[relapsing fever]] was first identified by the British physicians Joseph Dutton and John Todd in 1905. ''Borrelia'' in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that Lyme disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.<ref>{{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=155-8 |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=267-9 |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=109-11 |year=1991 |pmid=2040556}}</ref>  Cases of neuroborreliosis have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
To date, data shows that 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=279-94 |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=569-81 |year=2004 |pmid=15702720}}</ref>
==Controversy==
{{main|Lyme disease controversy}}
Most clinicians agree on the treatment of early Lyme disease infections.<ref name="Murray">{{cite journal | author = Murray T, Feder H | title = Management of tick bites and early Lyme disease: a survey of Connecticut physicians. | journal = Pediatrics | volume = 108 | issue = 6 | pages = 1367-70 | year = 2001 | pmid = 11731662}}</ref> There is, however, considerable disagreement regarding [[prevalence]] of the disease, diagnostic criteria, treatment of late-stage Lyme disease, and the likelihood of a chronic, antibiotic-resistant infections. Some authorities contend that Lyme disease is relatively rare, easily diagnosed with available blood tests, and most often easily treated with two to four weeks of antibiotics,<ref name="Wormser-b">{{cite journal | author = Wormser G | title = Clinical practice. Early Lyme disease. | journal = N Engl J Med | volume = 354 | issue = 26 | pages = 2794-801 | year = 2006 | pmid = 16807416}}</ref> while others propose that the disease is under-diagnosed, available blood tests are unreliable, and that extended antibiotic treatment is often necessary.<ref name="Stricker">{{cite journal | author=Stricker RB, Lautin A, Burrascano JJ | title=Lyme Disease: The Quest for Magic Bullets | journal=Chemotherapy | year=2006 | pages=53-59| volume=52 | issue=2 | pmid= 16498239}}</ref><ref name="Phillips-a">{{cite journal | author=Phillips SE, Harris NS, Horowitz R, Johnson L, Stricker RB | title=Lyme disease: scratching the surface | journal=Lancet | year=2005 | pages=1771 | volume=366 | issue=9499 | pmid= 16298211 | url=http://www.canlyme.com/lyme_scratching_the_surface_05.html}}</ref><ref name="Phillips-b">{{cite web | author=Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R | year=2003 | title=Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS position paper | format=PDF | work=International Lyme and Associated Diseases Society | url=http://www.ilads.org/files/position2.pdf | accessdate=2006-03-15}}</ref>
The majority of public health agencies such as the U.S. [[Centers for Disease Control]] maintain the former position. While this narrower position is sometimes described as the "mainstream" view of Lyme disease, published studies involving non-randomized surveys of physicians in [[endemic (epidemiology)|endemic]] areas found physicians evenly split in their views, with the majority recognizing [[seronegative]] Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.<ref name="Ziska">{{cite journal | author=Ziska MH, Donta ST, Demarest FC | title=Physician preferences in the diagnosis and treatment of Lyme disease in the United States | journal=Infection | year=1996 | pages=182-6 | volume=24 | issue=2 | pmid= 8740119}}</ref><ref name="Eppes">{{cite journal | author=Eppes SC, Klein JD, Caputo GM, Rose CD | title=Physician beliefs, attitudes, and approaches toward Lyme disease in an endemic area | journal=Clin Pediatr (Phila) | year=1994 | pages=130-4 | volume=33 | issue=3 | pmid= 8194286}}</ref>
In recent years a few prominent American Lyme researchers have received funding for the study of organisms that may have previously been used as [[bioweapons]] that could be used in bioterrorism attacks. The funding has been granted by various U.S. Government agencies including the [[National Institute of Health]] (NIH), and the [[National Institute of Allergy and Infectious Diseases]] (NIAID). 
For some, these grants have become a source of controversy. They argue that these researchers have a conflict of interest in receiving these U.S. Government funds due to the politicization of Lyme disease and their roles in the history of the controversy, others point out that the grants are warranted as the infectious agents that the researchers are studying for bioterror defense are similar in genetic makeup and [[pathogenesis]] of ''Borrelia'', such as [[tularemia]], [[brucellosis]] and [[Q fever]]. Nonetheless, although confusion exists, federal grants such as these comprise the main mechanism whereby infectious disease research is funded in the U.S.
In October 2006, further controversy erupted with the release of updated diagnosis and treatment guidelines from the [[Infectious Diseases Society of America]] (IDSA).<ref name=Showdown>{{cite news | title = New Lyme Disease Guidelines Spark Showdown | publisher = U.S. Department of Health and Human Services | date = 2006-11-09 | url = http://www.4woman.gov/news/english/535816.htm | accessdate = 2007-08-21}}</ref> The new IDSA recommendations are more restrictive than prior IDSA treatment guidelines for Lyme,<ref name="IDSA">{{cite journal | author = Wormser G, Dattwyler R, Shapiro E, ''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 | pmid = 17029130 | url=http://www.journals.uchicago.edu/CID/journal/issues/v43n9/40897/40897.html}}</ref> and now require either an EM rash or positive laboratory tests for diagnosis; seronegative Lyme disease is no longer acknowledged (except incidentally in early Lyme disease). The authors of the guidelines maintain that chronic Lyme disease does not result from persistent infection, and therefore treatment beyond 2-4 weeks is not recommended, even in late stage cases. An opposing viewpoint has been expressed by the International Lyme and Associated Disease Society (ILADS), which proposes extended antibiotic treatment beyond four weeks for both early and late Lyme disease.<ref>{{cite web | title = Treatment guidelines | year = 2007 | publisher = International Lyme and Associated Disease Society | url = http://www.ilads.org/guidelines.html | accessdate = 2007-08-21}}</ref>
==Advancing immunology research==
The role of [[T cells]] concomitant to ''Borrelia'' infection was first made in 1984,<ref>{{cite journal |author=Newman K, Johnson RC |title=T-cell-independent elimination of Borrelia turicatae |journal=Infect. Immun. |volume=45 |issue=3 |pages=572-6 |year=1984 |pmid=6332075}}</ref> and long term persistence of T cell [[lymphocyte]] responses to ''B. burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.<ref>{{cite journal |author=Krüger H, Pulz M, Martin R, Sticht-Groh V |title=Long-term persistence of specific T- and B-lymphocyte responses to Borrelia burgdorferi following untreated neuroborreliosis |journal=Infection |volume=18 |issue=5 |pages=263-7 |year=1990 |pmid=2276818}}</ref>  The role of [[Th1]] and [[interferon-gamma]] (IFN-gamma) in borrelia was first described in 1995.<ref>{{cite journal |author=Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, Bergström S |title=The outer surface proteins of Lyme disease borrelia spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications |journal=Clin. Exp. Immunol. |volume=101 |issue=3 |pages=453-60 |year=1995 |pmid=7664493}}</ref>  The [[cytokine]] pattern of Lyme disease, and the role of Th1 with down regulation of [[interleukin-10]] (IL-10) was first proposed in 1997.<ref>{{cite journal |author=Yin Z, Braun J, Neure L, ''et al'' |title=T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines |journal=Arthritis Rheum. |volume=40 |issue=1 |pages=69-79 |year=1997 |pmid=9008602}}</ref>
===Inflammation===
{{see|Innate immune system|Cell signaling networks}}
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-[[inflammatory]] immune process.  This pro-inflammatory process is a [[cell-mediated immunity]] and results in Th1 upregulation.  These studies have shown a significant decrease in [[cytokine]] output of (IL-10), an upregulation of [[Interleukin-6]] (IL-6), [[Interleukin-12]] (IL-12) and IFN-gamma and disregulation in [[TNF-alpha]] predominantly.<ref>{{cite journal |author=Shin JJ, Glickstein LJ, Steere AC |title=High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis |journal=Arthritis Rheum. |volume=56 |issue=4 |pages=1325-35 |year=2007 |pmid=17393419 |doi=10.1002/art.22441}}</ref>
These studies suggest that the host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. IFN-gamma alters gene expression by [[endothelium|endothelia]] exposed to ''B. burgdorferi'' in a manner that promotes recruitment of [[T cells]] and suppresses that of [[neutrophils]].
Studies also suggest suppressors of cytokine signaling (SOCS) [[proteins]] are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in [[macrophages]]. It is hypothesized that SOCS are induced by IL-10 and ''B. burgdorferi'' and its [[lipoproteins]] in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines.  IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators.
Researchers are also beginning to identify [[microglia]] as a previously unappreciated source of inflammatory mediator production following infection with ''B. burgdorferi''. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of [[NF-κB|nuclear factor-kappa B]] (NF-KB) by ''Borrelia''.<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}}</ref><ref>{{cite journal |author=Rasley A, Tranguch SL, Rati DM, Marriott I |title=Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to Borrelia burgdorferi or Neisseria meningitidis |journal=Glia |volume=53 |issue=6 |pages=583-92 |year=2006 |pmid=16419089 |doi=10.1002/glia.20314}}</ref>
Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in ''Borrelia'' infected patients.<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=112-6 |year=2005 |pmid=15893422 |doi=10.1016/j.neulet.2005.04.069}}</ref> IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease.<ref>{{cite web |url=http://www.columbia-lyme.org/flatp/treatment.html |title=Welcome to Lyme Disease Research Studies |accessdate=2007-08-23 |format= |work=}}</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=127-37 |year=1998 |pmid=9441573}}</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= |volume=15 |issue=1 |pages=34-38 |year=2006 |pmid=16501663 |doi=10.1016/j.jstrokecerebrovasdis.2005.08.009}}</ref>
===Neuroendocrine===
{{see|Signal transduction}}
A developing hypothesis is that the chronic secretion of [[Stress (medicine)|stress]] [[hormones]] as a result of ''Borrelia'' infection may reduce the effect of [[neurotransmitters]], or other 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=255-69 |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 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=685-9 |year=1994 |pmid=7865624}}</ref> Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric 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=167-70 |year=2006 |pmid=16909797}}</ref>
 
[[Antidepressants]] acting on serotonin, [[norepinephrine]] and [[dopamine]] receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a [[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}}</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=481-90 |year=2006 |pmid=16388933 |doi=10.1016/j.euroneuro.2005.11.011}}</ref>These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal [[pharmacotherapy]] of antibiotic refractory Lyme patients.
===New developments===
New research has also 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=112-6 |year=2005 |pmid=15893422 |doi=10.1016/j.neulet.2005.04.069}}</ref>
The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the ''Borrelia'' bacterium is still present in the host, or in the absence of the inciting pathogen in an [[autoimmune]] pattern.<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=705-17 |year=2006 |pmid=16842565 |doi=10.1111/j.1469-0691.2006.01440.x}}</ref>
Researchers hope that this new developing understanding of the [[biomolecular]] basis and [[pathology]] of cell-mediated signaling events caused by ''B. burgdorferi'' infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.
==Lyme funding and treatment controversy==
Many of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been heavily involved in both bioweapons research and commercial vaccine and diagnostic test development, which the Lyme patient community views  as a conflict of interest. <ref>Conflicts of Interest in Lyme Disease: Treatment, Laboratory Testing, and Vaccination, Lyme Disease Association Inc., 2001</ref>
In response to these and other concerns expressed by the expanding national community of patients, Richard Blumenthal, the Attorney General of Connecticut has launched an investigation exploring possible corruption.
To date, federal research aimed at developing treatments for chronic Lyme disease is roughly $30 million, as contrasted to a $22 billion budget for military biodefense.  Scientists setting Lyme treatment and diagnostic testing policy in the United States have a well publicised history in the biodefense field, and many have recently received lucrative biodefense grants for BSL-3 and BSL-4 Labs where, critics contend, Lyme treatment research lacks transparency, accountability and  focus on treatment research<ref>Biocontainment lab planned at Primate Center,
PONTCHARTRAIN NEWSPAPERS COVINGTON, St.Tammany News, www.newsbanner.com Dec. 13, 2004</ref><ref>"Lyme Disease is  Biowarfare Issue" by Elena Cooke, published/discussed by Dave Emory, WFMU Talk Show Host, 2007 http://ftrsupplemental.blogspot.com/2007/02/history-of-lyme-disease-as-bioweapon.html</ref>, though, it should be pointed out, that labs obtaining such grants are required to make their research findings publicly available via publication and focus their studies on issues pertinent to human health <ref>[http://grants1.nih.gov/grants/policy/policy.htm]</ref>. Most, including scientist, contend that the new grants and centers stimulate research by bringing together experts in the field and providing a stable source of funding.<ref>[http://www.ucihealth.com/News/Releases/06-05BiodefenseResearch.htm UCI Medical Centre, June 1, 2005]</ref>
In 2003, Lyme researcher Dr. Mark Klempner was appointed head of the new $1.6 billion biodefense top-security facility at [[Boston University]].<ref>[http://www.washingtonpost.com/wp-dyn/articles/A27646-2005Jan21.html Washington Post January 22, 2005]</ref> In 2004, Lyme researcher Dr. Jorge Benach,<ref>[http://www.nystar.state.ny.us/nl/archives2004/longislandA08-04.htm NYStar News Publication of the New York State Office of Science, Technology and Academic Research, August 2004]</ref> was reportedly chosen as a recipient for a $3 million biodefense research grant, and in 2005, Lyme researcher Dr. Alan Barbour was reportedly placed in charge of a $40 million dollar new biodefense complex based at UC Irvine.  <ref>[http://www.ucihealth.com/News/Releases/06-05BiodefenseResearch.htm UCI Medical Centre, June 1, 2005]</ref>
Former NIH [[Lyme disease]] program officer, Edward McSweegan has  published numerous articles and letters to editorial pages relating to biowarfare topics ranging from anthrax to plague.  Curiously, Mr. McSweegan's novel, Deliberate Release, is biowarfare thriller that describes the deliberate release of a germ weapon. <ref> McSweegan, Edward , "Deliberate Release", published September 20, 2002 by 1st Books Library, ISBN-10: 1403343535.</ref>
==References==
{{reflist|2}}
==External links==
{{Wikispecies|Borrelia}}
;'''General'''
*{{dmoz|/Health/Conditions_and_Diseases/Infectious_Diseases/Spirochetal/Lyme_Disease/}}
*[http://www.cdc.gov/ncidod/diseases/submenus/sub_lyme.htm CDC Lyme disease page]
*[http://columbia-lyme.org/flatp/lymeoverview.html Columbia University - Overview of Neuropsychiatric Lyme Disease]
*[http://www.eurosurveillance.org/ew/2006/060622.asp Eurosurveillance: Lyme disease in Europe]
*[http://www.merck.com/mmpe/sec14/ch174/ch174d.html Lyme Disease] ''The Merck Manual''
;'''Images'''
*[http://www.lib.uiowa.edu/hardin/md/lymediseasepictures.html Lyme disease images] (Hardin MD/Univ of Iowa)
;'''Professional societies, foundations, advocacy'''
*{{dmoz|/Health/Conditions_and_Diseases/Infectious_Diseases/Spirochetal/Lyme_Disease/Organizations/|Lyme disease organizations}}
*[http://www.nrftd.org/ National Research Fund of Tick-Borne Diseases]
;'''Other'''
*[http://www.lymeinfo.net/lymefiles.html Lyme Disease Medical Literature Summaries]
*[http://www.lyme-disease-research-database.com Lyme Disease Research Database]
*[http://www2.lymenet.org/domino/nl.nsf/By+Volume?OpenView&Start=1&Count=30&Expand=1#1 Prehistoric Lyme - (The History of Lyme Disease) Lymenet Newsletter Volume: 1 Issue: 24 25-Oct-93]
{{Spirochetal diseases}}
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Latest revision as of 22:34, 29 July 2020

Lyme disease Microchapters

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This page is about clinical aspects of the disease.  For microbiologic aspects of the causative organism(s), see Borrelia burgdorferi.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Synonyms and keywords: Infection due to Borrelia burgdorferi sensu lato, Borreliosis, Lyme borreliosis, Steere's disease, Afzelius syndrome, Tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannworth syndrome, Lymphocytic meningoradiculitis

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