| Lyme Disease Classification and external resources |
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| Nymphal and adult deer ticks can be carriers of Lyme disease. Ixodes scapularis, commonly known as the deer tick or blacklegged tick (although some people reserve the latter term for Ixodes pacificus Nymphs are about the size of a poppy seed. | |
| ICD-9 | 088.81 |
| DiseasesDB | 1531 |
| MedlinePlus | 001319 |
| eMedicine | med/1346 |
Lyme disease, or borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors An emerging infectious disease (EID is an Infectious disease whose incidence has increased in the past 20 years and threatens to increase in the near future In Biology, a species is one of the basic units of Biological classification and a Taxonomic rank. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have A genus (plural genera from Γένος Latin genus "descent family type gender" is a low-level Taxonomic Borrelia is a Genus of Bacteria of the Spirochete phylum It causes Borreliosis, a Zoonotic, vector-borne disease [1] Borrelia burgdorferi is the predominant cause of Lyme disease in the U. See also Lyme disease microbiology Borrelia burgdorferi is species of Bacteria of the spirochete class of the Genus S. , 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. The bacteria are transmitted to humans by the bite of infected hard ticks belonging to several species of the genus Ixodes. Ixodes is a genus of hard-bodied Ticks (family Ixodidae) It includes important disease vectors of animals and humans ( Tick-borne disease [2] Early manifestations of infection may include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. Fever (also known as pyrexia, from the Greek pyretos meaning fire or a febrile response, from the Latin word Febris 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 begins early in the course of illness. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa Late, delayed, or inadequate treatment can lead to "late stage" or "chronic" Lyme disease that can be disabling and difficult to treat. Controversy over diagnosis, testing and treatment has led to two different standards of care. For the English law, see Standard of care in English law. In Tort law, the standard of care is the degree of prudence and caution [3][4]
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Symptoms
The Lyme disease bacterium can infect several parts of the body, producing different symptoms at different times. Not all patients with Lyme disease will have all symptoms, and many of the symptoms can occur with other diseases as well.
One early sign of infection is a circular rash called erythema migrans or EM, which occurs at the site of the tick bite. The rash, sometimes referred to as a "bullseye" rash, expands over a period of several days, reaching up to 12 inches (30 cm) across. Most EM lesions remain red throughout or are redder in the center. Only 9% of EM lesions exhibit the central clearance of the classic bull's eye appearance, however. [5] The rash may be warm but is not usually painful. Some patients develop additional EM lesions in other areas of the body after several days.
It is important to note that the EM rash, though considered a "classic" sign of Lyme disease, occurs in less than half of all patients. . [6]The disease can progress even in patients who do not develop the rash. Patients may also experience flu-like symptoms of fatigue, chills, fever, headache, muscle and joint aches, and swollen lymph nodes. In some cases, these may be the only symptoms of infection.
If left untreated, the infection may spread to other parts of the body within a few days to weeks, producing an array of discrete symptoms. These include loss of muscle tone on one or both sides of the face (called facial or "Bell's palsy), severe headaches and neck stiffness caused by meningitis, 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.
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, back pain, heart block, psychiatric disorders, and swelling of joints are just some of the myriad of disabling symptoms that can occur.
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). Incubation period is the Time elapsed between exposure to a Pathogenic Organism, or Chemical or radiation, and when Symptoms Symptoms most often occur from May through September because the nymphal stage of the tick is responsible for most cases. [7] Asymptomatic infection exists but is found in less than 7% of infected individuals in the United States. [8] Asymptomatic infection may be much more common among those infected in Europe. [9]
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[10]), and neurologic symptoms (neuroborreliosis may occur in up to 18%[10]). A heart block is a disease in the electrical system of the Heart. A palpitation (medical term ectopic heart beat) is an abnormal awareness of the beating of the Heart, whether it is too slow too fast irregular Neuroborreliosis is a disorder of the Central nervous system caused by infection with a Spirochete of the genus Borrelia. In addition, simple altered mental status as the sole presenting symptom has been reported in early neuroborreliosis. [11] Patients have been known to get Baker's cysts. A Baker's cyst, otherwise known as a Popliteal Cyst, is a benign swelling found behind the Knee Joint.
Chronic symptoms
Cases may progress to a chronic form most commonly characterized by meningoencephalitis, cardiac inflammation (myocarditis), frank arthritis, and fatigue. Meningoencephalitis (ˌmɛnɪnˈgo ɛnˌsɛfəˈlaɪtɪs from Greek: meninges- membranes enkephalos brain and -itis inflammation is In Medicine ( Cardiology) myocarditis is Inflammation of the Myocardium, the muscular part of the Heart. Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body [1] 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. Heterogeneous is an adjective used to describe an object or system consisting of multiple items having a large number of structural variations Immune system|Adaptive immune systemThe innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner 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. Syphilis is a Sexually transmitted disease caused by the spirochetal Bacterium Treponema pallidum pallidum.
In addition to the acute symptoms, chronic Lyme disease can be manifested by a wide-range of neurological disorders, either central or peripheral, including encephalitis or encephalomyelitis, muscle twitching, polyneuropathy or paresthesia, and vestibular symptoms or other otolaryngologic symptoms[12][13], among others. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. The peripheral nervous system ( PNS) resides or extends outside the Central nervous system (CNS which consists of the Brain and Spinal cord. Encephalitis is an acute Inflammation of the Brain, commonly caused by a viral Infection. Encephalomyelitis is a general term for Inflammation of the Brain and Spinal cord, describing a number of disorders Acute disseminated A fasciculation (or "muscle Twitch " is a small local involuntary Muscle contraction (twitching visible under the skin arising from the spontaneous discharge Polyneuropathy is a Neurological disorder that occurs when many Peripheral nerves throughout the body malfunction simultaneously Paresthesia (pron /ˌpɛɹɪsˈθiʒə/ paraesthesia in British English, pron A balance disorder is a disturbance that causes an individual to feel unsteady giddy woozy or have a sensation of movement spinning or floating Otolaryngology is the branch of Medicine that specializes in the diagnosis and treatment of Ear, Nose, Throat, and head and neck disorders Neuropsychiatric disturbances can occur (possibly from a low-level encephalitis), which may lead to symptoms of memory loss, sleep disturbances, or changes in mood or affect. Encephalitis is an acute Inflammation of the Brain, commonly caused by a viral Infection. Memory loss can have many causes Alzheimer's disease is an illness which can cause mild to severe memory loss A sleep disorder (somnipathy is a medical disorder of the Sleep patterns of a person or animal A mood is a relatively long lasting affective or emotional state Affect, like the adjective affective, refers to the experience of feeling or Emotion. [1] In rare cases, frank psychosis has been attributed to chronic Lyme disease effects, including mis-diagnoses of schizophrenia and bipolar disorder. Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn 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. [14][15]
Cause
Lyme disease is caused by Gram-negative spirochetal bacteria from the genus Borrelia. Gram-negative bacteria are those Bacteria that do not retain Crystal violet dye in the Gram staining protocol Spirochaetes is a phylum of distinctive Gram-negative bacteria, which have long helically coiled cells The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have A genus (plural genera from Γένος Latin genus "descent family type gender" is a low-level Taxonomic Borrelia is a Genus of Bacteria of the Spirochete phylum It causes Borreliosis, a Zoonotic, vector-borne disease 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 strain diversity than previously estimated. In Biology, a species is one of the basic units of Biological classification and a Taxonomic rank. Sensu is a Latin term meaning "in the sense of"It is used in fields including biology geology and law in the phrases sensu stricto Genetic diversity is a level of Biodiversity that refers to the total number of genetic characteristics in the genetic makeup of a species [16]
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. Sensu is a Latin term meaning "in the sense of"It is used in fields including biology geology and law in the phrases sensu stricto afzelii, and B. garinii (both predominant in Eurasia). For the superstate in George Orwell 's novel see Nations of Nineteen Eighty-Four. However, newly discovered genospecies have also been found to cause disease in humans. "There are over 300 strains of Borrelia world wide"[17]. It is presently unknown how many of these cause lyme, but some or many of them may.
Transmission
Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease. Tick is the common name for the small Arachnids in Superfamily Ixodoidea that along with other Mites constitute the Acarina. Ixodes is a genus of hard-bodied Ticks (family Ixodidae) It includes important disease vectors of animals and humans ( Tick-borne disease In Epidemiology, a vector is an Organism that does not cause Disease itself but which transmits Infection by conveying Pathogens from [1] The majority of infections are caused by ticks in the nymph stage, since adult ticks are more easily detected and removed as a consequence of their relatively large size.
In Europe, the sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus) is the transmitter. Ixodes ricinus, known as the sheep tick or castor bean tick, is a hard-bodied Tick (family Ixodidae) of Europe.
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. Ixodes scapularis, commonly known as the deer tick or blacklegged tick (although some people reserve the latter term for Ixodes pacificus Only about 20% of persons infected with Lyme disease by the deer tick are aware of having had any tick bite,[18] 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 U. Amblyomma americanum, or lone star tick is a species of Tick in the genus Amblyomma. S. as far west as Texas, has been ruled out as a vector of the Lyme disease spirochete Borrelia burgdorferi, though it may be implicated with a clinical syndrome southern tick associated rash illness (STARI), which resembles the skin lesions of Lyme disease. Texas ( is a state geographically located in the South Central United States and is also known as the Lone Star State. [19]
On the west coast, the primary vector is the western black-legged tick (Ixodes pacificus). [20] 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[21][22].
While Lyme spirochetes have been found in insects other than ticks,[23] reports of actual infectious transmission appear to be rare. [24] Sexual transmission has been anecdotally reported; Lyme spirochetes have been found in semen[25] and breast milk,[26] however transmission of the spirochete by these routes is not known to occur. A sexually transmitted disease ( STD) or venereal disease ( VD) is an illness that has a significant probability of transmission between Humans [27]
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. A fetus (or foetus or fœtus) is a developing Mammal or other Viviparous Vertebrate, after the Embryonic stage and The placenta is an Ephemeral organ present in placental Vertebrates, such as Eutherial Mammals and Sharks during Gestation [28]
Tick borne co-infections
Ticks that transmit Lyme Disease also carry and transmit several other parasitic diseases to humans. Thus more physicians are referring to the disease as Lyme and other tick borne illness, and not simply "Lyme".
Babesia infection is becoming more commonly recognized, especially in patients who have Lyme Disease. Babesia is a piroplasmid Protozoal Parasite of blood cells and is found in the phylum Apicomplexa. Ehrlichiosis is another common co-infection found among people with Lyme Disease. Ehrlichiosis (ˌɛrlɨkiˈoʊsɨs also known as canine rickettsiosis, canine hemorrhagic fever, canine typhus, tracker dog disease, and (Anaplasma phagocytophila, Human Granulocytic Ehrlichiosis HGE, Human Monocytic Ehrlichiosis HME ) It is also said that Bartonella or Cat Scratch Fever is another common co-infection, although there is debate among experts on this topic on tick to human transmission. Bartonella (formerly known as Rochalimaea) is a Genus of Gram-negative bacteria.
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 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. [1]
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 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 Lyme areas. A microbiological culture, AKA microbial culture, is a method of multiplying microbial organisms by letting them reproduce in predetermined culture media under controlled laboratory In Epidemiology, an Infection is said to be endemic (from Greek en- in or within + demos people in a Population when [1] The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologies are negative. Serology is the scientific study of blood serum. In practice the term usually refers to the Diagnostic identification of antibodies in the serum [29][30] Serological testing can be used to support a clinically suspected case but is not diagnostic. [1] Clinicians who diagnose strictly based on the Centers for Disease Control (CDC) Case Definition for Lyme may be in error, since the CDC explicitly states that this definition is intended for surveillance purposes only and is "not intended to be used in clinical diagnosis. The Centers for Disease Control and Prevention (or CDC) is an agency of the United States Department of Health and Human Services based in unincorporated Clinical surveillance (or Syndromic surveillance) refers to the Surveillance (systematic collection analysis and interpretation of health data about a clinical "[31][32]
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". [33] Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS), lupus, or other autoimmune and neurodegenerative diseases. Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Rheumatoid arthritis ( RA) is a chronic systemic autoimmune disorder that causes the Immune system to attack the Joints, where Fibromyalgia (FM is a disorder classified by the presence of chronic widespread Pain and tactile Allodynia. Chronic fatigue syndrome ( CFS) is the most common name given to a poorly understood variably debilitating disorder or disorders of uncertain causation Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Neurodegenerative Disease ( Greek νέυρο- néuro-, "nerval" and Latin dēgenerāre, "to decline" or "to
Laboratory testing
Several forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. Most recommend 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. The western blot (alternatively immunoblot) is an Analytical technique used to detect specific Proteins in a given sample of tissue homogenate or Enzyme-Linked ImmunoSorbent Assay, also called ELISA, Enzyme ImmunoAssay or EIA, is a biochemical technique used mainly in Immunology A two-tiered protocol is recommended by the CDC: the more sensitive ELISA is performed first, if it is positive or equivocal, the more specific Western blot is run. The Centers for Disease Control and Prevention (or CDC) is an agency of the United States Department of Health and Human Services based in unincorporated The reliability of testing in diagnosis remains controversial,[1] however studies show the Western blot IgM has a specificity of 94–96% for patients with clinical symptoms of early Lyme disease. Immunoglobulin M, or IgM for short is a basic Antibody that is present on B cells It is the primary antibody against A and B [34][35]
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,[36] as well as herpes simplex virus. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily The Epstein-Barr Virus ( EBV) also called Human herpesvirus 4 (HHV-4 is a Virus of the herpes family (which includes Herpes Cytomegalovirus (CMV (from the Greek cyto-, "cell" and -megalo-, "large" is a viral Herpes simplex virus 1 and 2 ( HSV-1 and HSV-2) are two species of the herpes virus family Herpesviridae, which cause infections [37]
Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known PCR tests are susceptible to false-positive results from poor laboratory technique. In Statistics, the terms Type I error (also α error, or false positive) and type II error ( β error, or a false negative [38] Even when properly performed, PCR often shows false-negative results with blood and CSF specimens. In Statistics, the terms Type I error (also α error, or false positive) and type II error ( β error, or a false negative [39] 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. [40] 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. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily 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. [41]
Western blot, ELISA and PCR can be performed by either blood test via venipuncture or cerebrospinal fluid (CSF) via lumbar puncture. In medicine venipuncture or venepuncture (also known as phlebotomy, venesection, blood draw, drawing blood or taking blood Cerebrospinal fluid ( CSF) Liquor cerebrospinalis, is a clear Bodily fluid that occupies the Subarachnoid space and the Ventricular system In Medicine, a lumbar puncture (colloquially known as a spinal tap) is a Diagnostic and at times therapeutic procedure that is performed in order 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. [42]
New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA[43], which is capable of identifying the active form of Borrelia infection (Lyme disease). Melisa is a genus of moth in the family Arctiidae. Others, such as focus floating microscopy, are under investigation. [44] New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis. Chemokines are a family of small Cytokines, or Proteins secreted by cells Proteins are classified as chemokines according to shared structural characteristics Chemokine (C-X-C motif ligand 13 (CXCL13 is a small Cytokine belonging to the CXC Chemokine family that is also known as B lymphocyte chemoattractant [45]
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 hypoperfusion indicative of Lyme encephalitis in the patient. Single photon emission computed tomography (SPECT or less commonly SPET is a Nuclear medicine tomographic imaging technique using Gamma rays. In Physiology, perfusion is the process of nutritive delivery of Arterial Blood to a Capillary bed in the Biological tissue. [46] 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 subcortical and cortical structures has been reported. The basal ganglia (or basal nuclei) are a group of nuclei in the Brain interconnected with the Cerebral cortex, Thalamus and The cerebral cortex is a structure within the Brain that plays a key role in Memory, Attention, perceptual Awareness, Thought, [47] 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. White matter is one of the three main solid components of the Central nervous system. [48] 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. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome Cocaine ( benzoylmethyl ecgonine) is a Crystalline Tropane Alkaloid that is obtained from the leaves of the Coca plant Vasculitis (plural vasculitides) a group of diseases featuring Inflammation of the wall of Blood vessels including veins ( Phlebitis) arteries 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. 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 CFS 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. 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. White matter is one of the three main solid components of the Central nervous system. A lesion is any abnormal tissue found on or in an organism usually damaged by disease or trauma Myelin is an electrically-insulating Dielectric Phospholipid layer that surrounds only the Axons of many Neurons It is an outgrowth Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Systemic lupus erythematosus ( SLE or lupus,) is a chronic autoimmune disease that can be fatal though with recent medical advances fatalities are becoming [49] Cerebral atrophy and brainstem neoplasm has been indicated with Lyme infection as well. Cerebral atrophy is a common feature of many of the diseases that affect the Brain. [50]
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 can occur in multiple sclerosis, and resolution of MRI white matter hyper-intensities, after antibiotic treatment, has been observed in Lyme disease. Remission is the state of absence of Disease activity in patients with known Chronic illness. [51]
Prevention
Attached ticks should be removed promptly. [52] 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 your 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. [2]
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[53] and in Mumford Cove, Connecticut. Monhegan is a plantation on an island of the same name in Lincoln County, Maine, United States, about off the coast [54] 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. [55]
Vaccination
A vaccine, called Lymerix, against a North American strain of the spirochetal bacteria was approved by the United States FDA on December 21, 1998. A vaccine is a biological preparation which is used to establish or improve immunity to a particular disease Events 69 - The end of the Year of the four emperors: Following Galba, Otho and Vitellius, Vespasian Year 1998 ( MCMXCVIII) was a Common year starting on Thursday (link will display full 1998 Gregorian calendar) It was produced by GlaxoSmithKline (GSK) and was based on the outer surface protein A (OspA) of B. GlaxoSmithKline plc () is a United Kingdom -based pharmaceutical, biological and Healthcare Company. burgdorferi. OspA causes the human immune system to create antibodies that attack that protein. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily
A group of patients who took Lymerix developed arthritis, muscle pain and other troubling symptoms after vaccination. Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body A class-action lawsuit against GSK was filed on December 14, 1999. In Law, a class action or a representative action is a form of Lawsuit where a large group of people collectively bring a claim to court Events 1287 - St Lucia's flood: The Zuider Zee sea wall in the Netherlands collapses killing over 50000 people Year 1999 ( MCMXCIX) was a Common year starting on Friday (link will display full 1999 Gregorian calendar) [56] On February 26, 2002, GSK decided to withdraw Lymerix from the market citing poor sales, need for frequent boosters, the high price of the vaccine, and the exclusion of children. Events 747 BC - Epoch (origin of Ptolemy 's Nabonassar Era 364 - Valentinian I is proclaimed See also 2002 (disambiguation Year 2002 ( MMII) was a Common year starting on Tuesday of the Gregorian calendar. This was in addition to the numerous financial settlements made because of the vaccine.
While Lymerix was initially being marketed, it was learned that patients with the genetic allele HLA-DR4 were susceptible to T-cell cross-reactivity between epitopes of OspA and lymphocyte function-associated antigen in these patients causing an autoimmune reaction. An allele (ˈæliːl (UK /əˈliːl/ (US (from the Greek αλληλος allelos, meaning each other) is one member of a pair or series of different forms An epitope, also known as antigenic determinant, is the part of a Macromolecule that is recognized by the Immune system, specifically by antibodies [57]
New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization. Glycolipids are Carbohydrate -attached Lipids. Their role is to provide Energy and also serve as markers for cellular recognition [58][59]
Removal of ticks
Many urban legends 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, making sure not to squeeze the tick or break its head off. An urban legend or urban myth is a form of modern Folklore consisting of stories thought to be factual by those circulating them Another method is to wrap dental floss around the tick and then pull up to remove it. Gently pinch the tick and drag. Complete removal of the tick head is important; if the head is not completely removed, local infection of bite location may result. However, an alternative method to remove a tick is covering it and surrounding area with an oil thus causing the tick to suffocate. This method is not recommended over standard removal with tweezers, though, as it can irritate the tick and cause it to burrow deeper or regurgitate its stomach contents, increasing the likelihood of disease transmission. [60] Data have demonstrated that prompt removal of an infected tick, within approximately 36 hours, reduces the risk of transmission to nearly zero percent ; however the small size of the tick, especially in the nymph stage, may make detection difficult. [52]
Treatment
Antibiotics are the primary treatment for Lyme disease, but the most appropriate antibiotic treatment depends upon the patient and the stage of the disease. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa [1] The antibiotics of choice are doxycycline (in adults), amoxicillin (in children), and ceftriaxone. Doxycycline ( INN) (ˌdɒksɪˈsaɪkliːn is a member of the Tetracycline antibiotics group and is commonly used to treat a variety of Infections Doxycycline Amoxicillin ( INN) or amoxycillin ( BAN) is a moderate-spectrum bacteriolytic β-lactam antibiotic used to treat Bacterial Infections Ceftriaxone ( INN) (ˌsɛftraɪˈæksoʊn/ /ˌkɛf- is a third-generation Cephalosporin Antibiotic. Alternative choices are cefuroxime and cefotaxime. [1] Macrolide antibiotics have limited efficacy when used alone. The macrolides are a group of drugs (typically Antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic Many 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. Clarithromycin is a Macrolide Antibiotic used to treat Pharyngitis, Tonsillitis, acute maxillary Sinusitis, acute bacterial exacerbation Hydroxychloroquine is an Antimalarial drug sold under the trade name Plaquenil, also used to reduce inflammation in the treatment of Rheumatoid arthritis [61] It is thought that the hydroxychloroquine raises the pH of intracellular acidic vacuoles in which B. In general vacuole functions include Removing unwanted structural debris Isolating materials that might be harmful or a threat to the cell Containing burgdorferi may reside; raising the pH is thought to activate the macrolide antibiotic, allowing it to inhibit protein synthesis by the spirochete. [61]
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 3 weeks. Placebo is a substance or procedure a patient accepts as medicine or therapy but which has no specific therapeutic activity Finland, officially the Republic of Finland ( is a Nordic country situated in the Fennoscandian region of northern Europe. 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. [62]. However, this study has been criticized by the International Lyme and Associated Diseases Society (ILADS), on the grounds that 1) treatment over years is often necessary to produce noticeable improvement in chronic Lyme patients and 2) the antibiotics used were cell wall antibiotics which may act relatively slowly against Lyme disease.
In later stages, the bacteria disseminate throughout the body and may cross the blood-brain barrier, making the infection more difficult to treat. The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic Late diagnosed Lyme is treated with oral or IV antibiotics, frequently ceftriaxone, 2 grams per day, for a minimum of four weeks. Ceftriaxone ( INN) (ˌsɛftraɪˈæksoʊn/ /ˌkɛf- is a third-generation Cephalosporin Antibiotic. Minocycline is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier. Minocycline hydrochloride, also known as minocycline, is a member of the broad spectrum Tetracycline antibiotics, and has a broader spectrum than the other members [63]
Therapies for "post-Lyme syndrome"/"chronic Lyme disease"
- Further information: Lyme disease controversy
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. It is currently unclear whether persisting symptoms following antibiotic treatment result from continuing low-level B. burgdorferi infection or from residual effects of the infection prior to treatment. Currently there are two sets of peer-reviewed published guidelines in the United States. The International Lyme and Associated Diseases Society[64] advocates extended courses of antibiotics for chronic Lyme patients in light of evidence of persistent infection following "standard" antibiotic treatment of some Lyme disease patients. In contrast, the Infectious Diseases Society of America[65], which favors the term "post-Lyme syndrome" to describe the condition in these patients, does not believe persisting symptoms following standard antibiotic treatment results from chronic infection and does not recommend additional antibiotic treatment.
Three double-blind, placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results. The blind method is a part of the Scientific method, used to prevent research outcomes from being influenced by either the Placebo effect or the Observer Placebo is a substance or procedure a patient accepts as medicine or therapy but which has no specific therapeutic activity In all three studies, the subjects had persisting symptoms despite being treated with a standard course of antibiotics for Lyme disease. The first published study failed to detect any benefit of a 90-day course of antibiotics. [66] However, the patients enrolled in the study may have been unusually difficult to treat as suggested by their previous multiple antibiotic treatment failures and their lengthy illness prior to the study; hence the results may not be generalizable to others with post-Lyme syndrome. [67] Further, the study has been criticized for failing to run the antibiotic treatment over a long enough period to take into account the very gradual improvement of chronic Lyme patients seen over many months or even years on antibiotics. [67] The second clinical trial, which used slightly different enrollment criteria and outcome measures, noted improvement in disabling fatigue that was sustained for six months following antibiotic therapy. [68] The most recent trial was published by a group known to favor prolonged treatment with antibiotics. [69] They found that subjects with post-treatment cognitive impairment exhibited some improvement following intravenous cefriaxone treatment for 10 weeks. However, the cognitive gains were lost when the subjects were examined 14 weeks following treatment. [70] There is disagreement with the interpretation of the data. ILADS believes that the relapse observed following the termination of antibiotic therapy is consistent with persistent infection with B. burgdorferi, whereas the lack of lasting improvement is cited in the editorial accompanying the article as evidence that prolonged antibiotic treatment is not helpful. [69]
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. The American Academy of Neurology (AAN is a professional society for neurologists and neuroscientists [71] They find no compelling evidence that prolonged treatment with antibiotics has any benefit in treating symptoms that persist following previous standard antibiotic therapy. The new guideline was touted as independent corroboration of the IDSA guideline and was quickly endorsed by the IDSA. However ILADS has accused AAN of simply repackaging the IDSA guidelines as three coauthors of the new guideline, including the lead author, were also coauthors of the IDSA Lyme guideline. There is significant disagreement with this guideline.
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. [72][73] Lyme arthritis which is antibiotic resistant may be treated with hydroxychloroquine or methotrexate. Hydroxychloroquine is an Antimalarial drug sold under the trade name Plaquenil, also used to reduce inflammation in the treatment of Rheumatoid arthritis [74] Experimental data are consensual on the deleterious consequences of systemic corticosteroid therapy. Corticosteroids are a class of Steroid hormones that are produced in the Adrenal cortex. Corticosteroids are not indicated in Lyme disease. [75]
Antibiotic refractory patients with neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study. Gabapentin (brand name Neurontin) is a medication originally developed for the treatment of Epilepsy. [76] The immunomodulating, neuroprotective and anti-inflammatory potential of minocycline may be helpful in late/chronic Lyme disease with neurological or other inflammatory manifestations. Minocycline hydrochloride, also known as minocycline, is a member of the broad spectrum Tetracycline antibiotics, and has a broader spectrum than the other members Minocycline is used in other neurodegenerative and inflammatory disorders such as multiple sclerosis, Parkinsons, Huntington's disease, rheumatoid arthritis (RA) and ALS. Neurodegenerative Disease ( Greek νέυρο- néuro-, "nerval" and Latin dēgenerāre, "to decline" or "to Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the Central nervous system that often impairs the sufferer's Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder characterized after Rheumatoid arthritis ( RA) is a chronic systemic autoimmune disorder that causes the Immune system to attack the Joints, where [77]
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. Hyperbaric medicine, also known as hyperbaric oxygen therapy (HBOT is the medical use of Oxygen at a higher than Atmospheric pressure. [78] Though there are no published data from clinical trials to support its use, preliminary results using a mouse model suggest its effectiveness against B. The Old World rats and mice, part of the Subfamily Murinae in the family Muridae, comprise at least 519 species burgdorferi both in vitro and in vivo. In vitro ( Latin: within the glass refers to the technique of performing a given experiment in a controlled environment outside of a living Organism In vivo ( Latin: within the living means that which takes place inside an organism. [79] Anecdotal clinical research has shown potential for the antifungal azole medications such as 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. An azole is a class of five-membered Nitrogen Heterocyclic ring compounds containing at least one other noncarbon atom nitrogen sulfur or oxygen Fluconazole ( INN) (fluːˈkɒnəzoʊl is a Triazole Antifungal drug used in the treatment and prevention of superficial and systemic fungal infections [80]
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;[81] no clinical trials of this treatment have been carried out, however. The term alternative medicine, as used in the modern western world encompasses any healing practice "that does not fall within the realm of conventional Medicine. Melittin is the principal active component of Bee venom, and is a powerful stimulator of Phospholipase A2. In vitro ( Latin: within the glass refers to the technique of performing a given experiment in a controlled environment outside of a living Organism
Prognosis
For early cases, prompt treatment is usually curative. [82] 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 (co-infections), including; ehrlichiosis, babesiosis, and bartonella, and immune suppression in the patient. Ehrlichiosis (ˌɛrlɨkiˈoʊsɨs also known as canine rickettsiosis, canine hemorrhagic fever, canine typhus, tracker dog disease, and Babesiosis is a malaria-like Parasitic disease caused by Babesia, a Genus of Protozoal piroplasms Bartonella (formerly known as Rochalimaea) is a Genus of Gram-negative bacteria.
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. Neurocognitive is a term used to describe Cognitive functions closely linked to the function of particular areas Neural pathways or cortical networks in [83] Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply [84]
In rare cases, Lyme disease can be fatal. [85][86][87][88]The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11. [89]
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. [90][91] Researchers are also investigating possible links between global warming and the spread of vector-borne diseases including Lyme disease. Global warming is the increase in the average measured temperature of the [92]
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)). Miticides or acaricides are Pesticides that kill Mites Antibiotic miticides Carbamate miticides Formamidine miticides
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 ha or 6 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots". Explanation The hectare is commonly used in most countries around the world especially in domains concerned with land planning and management such as Agriculture, The acre is a unit of Area in a number of different systems including the imperial and U [93]
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. [94]
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)[3]. New 2008 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases. [4] 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. California ( is a US state on the West Coast of the United States, along the Pacific Ocean. burgdorferi in local tick populations, but this has since been brought into question as some evidence has suggested that lizards can become infected. [95] Except for one study in Europe [96], 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 [97][98][99][100]. 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 [22].
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[5]. Norway ( Norwegian: Norge ( Bokmål) or Noreg ( Nynorsk) officially the Kingdom of Norway, is a Constitutional The Netherlands ( Dutch:, ˈnedərlɑnt is the European part of the Kingdom of the Netherlands, which consists of the Netherlands the Netherlands Germany, officially the Federal Republic of Germany ( ˈbʊndəsʁepuˌbliːk ˈdɔʏtʃlant is a Country in Central Europe. This article is about the country For a topic outline on this subject see List of basic France topics. Italy (Italia officially the Italian Republic, (Repubblica Italiana is located on the Italian Peninsula in Southern Europe, and on the two largest Slovenia, officially the Republic of Slovenia (Republika Slovenija) is a Country in southern Central Europe bordering Italy to the west Poland (Polska officially the Republic of Poland
B. burgdorferi sensu lato infested ticks are being found more frequently in Japan, as well as in Northwest China and far eastern Russia. For a topic outline on this subject see List of basic Japan topics. China ( Wade-Giles ( Mandarin) Chung¹kuo² is a cultural region, an ancient Civilization, and depending on perspective a National Russia (Россия Rossiya) or the Russian Federation ( Rossiyskaya Federatsiya) is a transcontinental Country extending [101][102] Borrelia has been isolated in Mongolia as well. Mongolia (mɒŋˈɡoʊliə, literally Mongol country/nation,) is a Landlocked Country in East [103]
In South America tick-borne disease recognition and occurrence is rising. South America is a Continent of the Americas, situated entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a 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. |utc_offset = -2 to -4 |time_zone_DST = BRST |utc_offset_DST = -2 to -5 |cctld [104] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo. São Paulo ( is the largest city in Brazil, with its metropolitan area ranking among the largest urban areas in the world [105] B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and Bolivia. Colombia (kəˈlʌmbɪə officially the Republic of Colombia () is a country in northwestern South America. The Republic of Bolivia (República de Bolivia) named after Simón Bolívar, is a Landlocked country in central South America.
In Northern Africa B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia. Morocco (المغرب "al-Maghrib" officially the Kingdom of Morocco (المملكة المغربية is a country located in North Africa Algeria ( ar [[Arabic]] الجزائر, Al Jaza'ir ælʤæˈzæːʔir Amazigh: ⴷⵥⴰⵢⴻⵔ Dzayer) officially the People's This article is about the country of Egypt For a topic outline on this subject see List of basic Egypt topics. Tunisia (تونس Tūnis officially the Tunisian Republic ( is a country located in North Africa. [106][107][108]
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. [109] In East Africa, two cases of Lyme disease have been reported in Kenya. The Republic of Kenya is a country in East Africa. It is bordered by Ethiopia to the north Somalia to the northeast Tanzania to the south [110]
In Australia there is no definitive evidence for the existence of B. For a topic outline on this subject see List of basic Australia topics. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease. [111] 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. Northern Hemisphere is the half of a Planet that is North of the Equator —the word hemisphere literally means 'half ball' [112][113]
Controversy and politics
Most clinicians agree on the treatment of early Lyme disease infections. [114] There is, however, considerable disagreement regarding prevalence of the disease, diagnostic criteria, treatment of late-stage Lyme disease, and the likelihood of chronic, antibiotic-resistant infections. In Epidemiology, the prevalence of a Disease in a Statistical population is defined as the total number of cases of the disease in the population at a given 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,[115] while others propose that the disease is under-diagnosed, available blood tests are unreliable, and that extended antibiotic treatment is often necessary. [116][117][118]
Disagreement on the guidelines for diagnosis and treatment of Lyme disease has been a constant source of controversy and high emotions. In October 2006, further controversy erupted with the release of updated diagnosis and treatment guidelines from the Infectious Diseases Society of America (IDSA). The Infectious Diseases Society of America (IDSA is a medical association representing physicians scientists and other health care professionals who specialize in Infectious diseases [119] The new IDSA recommendations are more restrictive than prior IDSA treatment guidelines for Lyme,[120] 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. [121] The majority of public health agencies such as the U. S. Centers for Disease Control maintain the position espoused by the IDSA's Lyme guidelines committee.
However, these IDSA Lyme guidelines have now been called into question following an investigation by the Connecticut Attorney General, who found glaring conflicts of interest and an unwillingness to consider evidence regarding chronic Lyme disease. [122] This is discussed in more detail below.
Published studies involving non-randomized surveys of physicians in 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, suggesting that there is much disagreement and confusion on this topic. [123][124]
Some of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been involved in both commercial vaccine and diagnostic test development, which some view as a conflict of interest. [125]
On May 1, 2008, Connecticut Attorney General Richard Blumenthal announced news of a settlement in a landmark antitrust investigation into the Lyme Disease Treatment Guidelines Process of the Infectious Diseases Society of America (IDSA). Events 305 - Diocletian and Maximian retire from the office of Roman Emperor. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common [6] According to Blumenthal's report, the IDSA panel systematically excluded divergent opinions on the benefits of long-term antibiotic treatment for Lyme disease. Some IDSA panel members were found to have entered into questionable arrangements with commercial interests which could have caused conflicts of interest to arise in their work in producing the IDSA guidelines. What he referred to as "flawed" work have been used as a basis for Lyme diagnostic and treatment policies worldwide, and for denial of medical insurance coverage across the United States. A thorough external review of the existing IDSA guidelines on Lyme Disease has now been promised.
A disproportionate number of scientists involved in Lyme treatment and diagnostic testing policy in the United States have a well publicized history in biodefense research. Lyme disease investigators Mark Klempner of Boston University,[126][127] and Alan Barbour of UC Irvine[128] have recently been placed in charge of new biowarfare "Centres of Excellence". For similarly-named academic institutions see Education in Boston MA. The University of California Irvine is a public Coeducational Research university situated in Irvine, California. Many others have a history of involvement in biowarfare research such as Jorge Benach , of the State University of New York,[129] and Allen Steere, perhaps the most well-known Lyme scientist in the world. Jorge Benach is a medical researcher at the State University of New York (SUNY at Stony Brook in New York state [130]
The selection of leading Lyme researchers for such senior posts in biodefense and the fact that so many Lyme researchers are members of the elite Epidemic Intelligence Service (originally set up for biowarfare research during the Cold War) has fueled theories that Lyme disease is clandestinely connected with biological warfare. In recent years, the discovery of a number of documents referring to the study of Lyme disease at BSL-4 (Biosafety Level 4) labs, the highest level of biocontainment which is reserved for highly infectious and deadly disease agents, has only served to stoke suspicion further. An example of one such document, is a section on biocontainment in a 2003 letter from the director of a California Health Department concerning a bid for a biodefense grant, where possible research at a new lab is discussed. [131] Further examples include an article in which the Associated Press reported that Lyme was being studied at a new biowarfare research facility in Texas, and the National Institutes of Health (NIH) editing of a document on their website to remove the phrase "Lyme disease" from a page listing diseases studied at top security level. [132]
No discussion of Lyme can be complete without mentioning that there is a completely different approach to Lyme etiology and treatment. This approach bypasses the so-called controversy between IDSA and ILADS; and, it is thoroughly presented and backed up with innumerable references at http://bacteriality.com. Bnk wkpd (talk) 19:39, 6 June 2008 (UTC)
Advancing immunology research
Long term persistence of T cell lymphocyte responses to B. A lymphocyte is a type of White blood cell in the Vertebrate Immune system. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990. [133] The role of Th1 and interferon-gamma (IFN-gamma) in borrelia was first described in 1995. T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or Interferon-gamma ( IFN-γ) is a Dimerized soluble Cytokine that is the only member of the type II class of Interferons This interferon was originally [134] The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997. Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Interleukin -10 (IL-10 or IL10 also known as human cytokine synthesis inhibitory factor (CSIF is an anti- Inflammatory Cytokine. [135]
Inflammation
- Further information: Innate immune system and Cell signaling networks
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. Immune system|Adaptive immune systemThe innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner Cell signaling is part of a Complex system of Communication that governs basic cellular activities and coordinates cell actions Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. Cell-mediated immunity is an Immune response that does not involve Antibodies or complement but rather involves the activation of Macrophages 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. Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular For Il-12 see also Ilyushin Il-12 Interleukin 12 ( IL-12) is an Interleukin that is naturally produced by Dendritic Tumor necrosis factor ( TNF, cachexin or cachectin and formally known as Tumor necrosis factor-alpha) is a Cytokine involved in systemic [136]
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 endothelia exposed to B. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils. T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of White blood cells in humans and form an essential part of the
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. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that 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. A lipoprotein is a biochemical assembly that contains both Proteins and Lipids The lipids or their derivatives may be covalently or non-covalently bound 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. Microglia are a type of Glial cell that acts as the first and main form of active immune defense in the Central nervous system (CNS burgdorferi. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of nuclear factor-kappa B (NF-KB) by Borrelia. NF-κB ( nuclear factor-kappa B) is a protein complex that is a Transcription factor. [137][138]
Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in Borrelia infected patients. [139] IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease. [140][141]IL-6 is also significantly indicated in cognitive impairment. [142]
Neuroendocrine
- Further information: Signal transduction
A developing hypothesis is that the chronic secretion of 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. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body See Chemical synapse for an introduction to concepts and terminology used in this article Glucocorticoids (GC are a class of Steroid hormones characterised by an ability to bind with the glucocorticoid receptor ( GR) and trigger similar effects [143][144]This process is mediated via the Hypothalamic-pituitary-adrenal axis. The hypothalamic-pituitary-adrenal axis ( HPA or HTPA axis) also known as the Limbic -hypothalamic-pituitary-adrenal axis (LHPA axis is a complex set of direct influences 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. Tryptophan (abbreviated as Trp or W) is one of the 20 standard amino acids, as well as an Essential amino acid in the Human diet Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons [145] Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with borreliosis. [146]
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 psycho-neuroimmunological process. An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates Psychoneuroimmunology (PNI is the study of the interaction between psychological processes and the nervous and immune systems of the human body [147] Antidepressants have also been shown to suppress Th1 upregulation. [148]These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal pharmacotherapy of antibiotic refractory Lyme patients. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease
New developments
New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FOXP3 ( Forkhead box P3 is a Gene involved in Immune system responses Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the Immune system Immunosuppression involves an act that reduces the activation or Efficacy of the Immune system. FoxP3 are a specific marker of regulatory T cells. [149] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from Borrelia. See also Mitogen-activated protein kinases P38 mitogen-activated protein kinases are a class of Mitogen-activated protein kinases which are responsive [150]
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. Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues [151] This interpretation must however be considered against the evidence (above) for persistence of the 'spore' form of Borrelia in human and animal hosts, and the tendency for relapses to occur after antibiotics are continued. It is possible that whereas some chronic Lyme patients retain actual populations of live spirochaetes, others have symptoms brought on only by an inflammatory or auto-immune reaction.
Researchers hope that this new developing understanding of the biomolecular basis and pathology of cell-mediated signaling events caused by B. A biomolecule is any organic Molecule that is produced by living Organisms including large Polymeric molecules such as Proteins Pathology (from Greek grc πάθος pathos, "fate harm" and grc -λογία -logia) is the study and 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.
History
The early European studies of what is now known as Lyme disease described its various skin manifestations. The first such study dates to 1883 in Wrocław, Poland (then known as Breslau, Germany) where physician Alfred Buchwald described a man who had suffered for sixteen years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans. Wrocław (Breslau Vratislav Vratislavia or Wratislavia Yiddish: ברעסלוי) is the chief City of the historical region of Lower Silesia Poland (Polska officially the Republic of Poland Wrocław (Breslau Vratislav Vratislavia or Wratislavia Yiddish: ברעסלוי) is the chief City of the historical region of Lower Silesia Germany, officially the Federal Republic of Germany ( ˈbʊndəsʁepuˌbliːk ˈdɔʏtʃlant is a Country in Central Europe. In Medicine, a dermatosis is a generic term for disease of the skin. Acrodermatitis chronica atrophicans (ACA also known as Pick-Herxheimer disease is a Skin rash indicative of the third or late stage of European Lyme borreliosis. 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. Arvid Afzelius (1857-1923 was a Swedish Dermatologist. As a student at the Karolinska institutet, Afzelius studied under the prominent dermatologist He named the lesion erythema migrans. [152] The skin condition now known as borrelial lymphocytoma was first described in 1911. [153]
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. Radicular Pain, or Radiculitis, is pain "radiated" along the dermatome (sensory distribution of a Nerve due to inflammation or other irritation Meningitis is Inflammation of the protective membranes covering the Brain and Spinal cord, known collectively as the Meninges. 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. [154] 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. German Neurologist, 1903-1970 Munich. Credited for discovering cases of lymphocytic meningoradiculitis with Facial nerve palsies, an early description
Carl Lennhoff, who worked at the Karolinska Institute in Sweden, believed that many skin conditions were caused by spirochetes. Karolinska Institutet (often translated from Swedish into English as the Karolinska Institute, and in older texts often as the Royal Caroline In 1948, he used a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM. [155] 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. [156] In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarth's syndrome were recognized throughout Europe leading to the widespread use of penicillin for treatment in Europe. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections [157][158]
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. Wisconsin ( or wɪˈskɑnsɨn (French Ouisconsin) is one of the fifty United States of America, located in the north central part of the United States This was the first documented case of EM in the United States. Based on the European literature, he treated the patient with penicillin. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections [159]
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. In Medicine and Psychology, the term syndrome refers to the association of several clinically recognizable features signs (observed by a physician This article does not deal with the more general topic of Childhood arthritis. Connecticut ( is a state located in the New England region of the northeastern United States of America. Lyme is a town in New London County, Connecticut, United States. Old Lyme is a town in New London County, Connecticut, United States. [160] This was investigated by Dr David Snydman and Dr Allen Steere of the Epidemic Intelligence Service, and by others from Yale University. Allen C Steere is a professor of Rheumatology at Harvard University and previously at Yale University. The Epidemic Intelligence Service is a program of the United States' Centers for Disease Control and Prevention. 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. [161]
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. Montauk is a hamlet (and Census-designated place) in Suffolk County, New York on the South Shore of Long Island. Since 1976 the disease is most often referred to as Lyme disease,[162][163] Lyme borreliosis or simply borreliosis.
In 1980 Steere, et al, began to test antibiotic regimens in adult patients with Lyme disease[164] 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. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa Spirochaetes is a phylum of distinctive Gram-negative bacteria, which have long helically coiled cells 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. Jorge Benach is a medical researcher at the State University of New York (SUNY at Stony Brook in New York state State University of New York at Stony Brook, commonly known as Stony Brook University, is a public research university located in Stony Brook, New York Willy Burgdorfer, an American scientist born and educated in Basel, Switzerland, is an international leader in the field of medical entomology "NIH" redirects here For other meanings of NIH see NIH (disambiguation. Rickettsia is a Genus of motile, Gram-negative, non-sporeforming, highly Pleomorphic bacteria that can present 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. Tetracyclines are a group of Broad-spectrum antibiotics whose general usefulness has been reduced with the onset of bacterial resistance Amoxicillin ( INN) or amoxycillin ( BAN) is a moderate-spectrum bacteriolytic β-lactam antibiotic used to treat Bacterial Infections Cefuroxime is a second-generation Cephalosporin Antibiotic that has been widely available in the USA as Ceftin since 1977 Ceftriaxone ( INN) (ˌsɛftraɪˈæksoʊn/ /ˌkɛf- is a third-generation Cephalosporin Antibiotic. [165][166] 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. [167]
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External links
- General
- Compilation of academic literature and electron micrographs on the existence and basis of chronic Lyme infection
- Lyme disease at the Open Directory Project
- CDC Lyme disease page
- Columbia University - Overview of Neuropsychiatric Lyme Disease
- Eurosurveillance: Lyme disease in Europe
- Lyme Disease The Merck Manual
- US Army Factsheet on Lyme Disease (CHPPM's Entomological Sciences Program)
- National Institute for Occupational Safety and Health - Lyme Disease Page
- Images
- Collection of micrographs and academic literature on the 'spore' form of Lyme
- Factsheet on Lyme Disease (Hardin MD/Univ of Iowa)
- Interactive Image of Ixodes scapularis, Deer Tick or Blacklegged Tick (CHPPM's Entomological Sciences Program)
- Professional societies, foundations, advocacy
- Lyme disease organizations at the Open Directory Project
- National Research Fund of Tick-Borne Diseases
- Lyme Disease Research Foundation of Maryland
- Other
- Lyme.startpagina.nl: Professional link-site with 100+ links to Lyme-sites
- Lyme Disease Medical Literature Summaries
- Lyme Disease Research Database
- Prehistoric Lyme - (The History of Lyme Disease) Lymenet Newsletter Volume: 1 Issue: 24 25-Oct-93
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