Lyme disease overview

# Overview
Lyme disease is an emerging infectious disease caused by spirochete bacteria of the genus Borrelia. The vector of infection is typically the bite of an infected black-legged or deer tick(I. scapularis), but other carriers (including other ticks in the genus Ixodes) have been implicated. Borrelia burgdorferi is the predominant cause of Lyme disease in the US and Borrelia afzelii and Borrelia garinii are the predominant causes in Europe.
The disease's presentation varies widely, and may include 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.

# Historical Perspective
In 1883, Alfred Buchwald was the first to describe a condition associated with Lyme disease which is now known as acrodermatitis chronica atrophicans. Arvid Afzelius first observed ring-like lesions, now known as Erythema migrans, and associated the rash with tick bites. In the United States, Lyme disease was not recognized until 1975, when a cluster of cases was identified in three towns in Southeastern Connecticut (including towns Lyme and Old Lyme), which gave Lyme disease its popular name. In 1981, the infectious agent (a spirochete) was isolated by Willy Burgdorfer, a researcher  at the National Institutes of Health, from the midgut of Ixodes ticks. The spirochete was named Borrelia burgdorferi in honor of Willy Burgdorfer.

# Classification
Lyme disease can be classified into three stages. The first stage is localized Lyme disease, the second is disseminated Lyme disease, and the third is late disseminated Lyme disease. During stage 1, the patient can develop erythema migrans rash. Ten to twenty percent of the patients who have Lyme disease can develop post treatment Lyme disease syndrome. There are various genospecies of Borrelia burgdorferi sensu lato complex that can cause Lyme disease. A novel spirochete, Borrelia mayonii, has been recently discovered to be responsible for Lyme disease.

# Pathophysiology
Lyme disease is caused by Borrelia burgdorferi and is transmitted primarily by tick species Ixodes scapularis. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted. Very few people affected with Lyme disease recall a tick bite. B. burgdorferi has two morphological forms, a spiral form and a spheroplast form. Survival strategies of B. burgdorferi include: antigenic variation, physical sequestration, intracellular invasion, and immune system supression.

# Epidemiology and Demographics
Lyme disease is the most commonly reported vector-borne illness in the United States. In 2015, it was the sixth most common nationally notifiable disease. The number of people diagnosed with Lyme disease each year in the United States is around 30,000. This disease is concentrated heavily in the Northeast and upper Midwest. Lyme disease has a seasonal variation and incidence increases during the months of May to August.

# Causes
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 strain diversity than previously estimated.
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.

# Differentiating Lyme from other Disease
The differential diagnosis of Lyme disease includes babesiosis, leptospirosis, mononucleosis, viral meningitis, and chronic diseases such as SLE, fibromyalgia, and chronic fatigue syndrome. Lyme disease must be differentiated from other diseases that may cause arthralgia, fever, and skin manifestations and that are associated with a history of tick exposure. Lyme disease should also be differentiated from other causes of infectious arthritis as well as acute arthritis.

# Risk Factors
Because Lyme disease is a tick-borne disease, an individual is at a heightened risk of contracting it when traveling or residing within endemic regions. Risk within endemic regions is higher during the spring and summer months, with peaks in June and July. Other factors that may increase the risk of contracting Lyme disease include owning a domesticated animal such as a dog or cat, as both of these pets may be potential hosts for a blacklegged tick. In summary, individuals who spend much of their time outdoors and/or have pets that go outdoors and who live in endemic regions, are at a higher risk of contracting tick-borne diseases.

# Screening
There is insufficient evidence to recommend routine screening for Lyme disease.

# Natural History, Complications and Prognosis
Lyme disease may present as a red, expanding rash called  erythema migrans (EM) along with flu-like symptoms such as fatigue, arthralgia, myalgias, headache, fever and/or chills, stiff neck, anorexia, and regional lymphadenopathy. Erythema migrans resolves in approximately 28 days in untreated patients. Lyme disease is effectively managed by prompt treatment.
Untreated infection may spread from the site of the bite to other parts of the body, producing a range of symptoms including neurological, cardiac, and dermatological manifestations. Many of these symptoms will resolve over a period of weeks to months, even without treatment. However, lack of treatment can result in additional complications. Lyme arthritis is the most frequently presented symptom in late disseminated Lyme disease.
Prognosis is mainly affected by a failure to treat in a timely manner as well as simultaneous infections with other tick-borne diseases. Sometimes, patients with Lyme disease have symptoms that last months to years even after treatment with antibiotics. These symptoms includes muscle and joint pains, cognitive defects, sleep disturbance, or fatigue. The condition is referred to as post treatment Lyme disease syndrome (PTLDS).

# Diagnosis
Due to the difficulty in culturing Borrelia bacteria in the laboratory, diagnosis of  Lyme disease is typically based on clinical exam findings and a history of exposure to endemic  areas. The erythema migrans rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologies are negative. Serological testing can be useful, but is not diagnostic.
Clinicians who diagnose strictly based on the U.S. Centers for Disease Control (CDC) Case Definition for Lyme are in error, as the CDC explicitly states that this definition is intended for surveillance purposes only, and is "not intended to be used in clinical diagnosis."
It is important that 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 is difficult to diagnose using standard serological or intrathecal testing. Lyme is a deep tissue infection and by the time encephalopathy is established, few, if any CSF antibodies can be detected, and PCR is unreliable. Seronegative disease can occur for the same reason that this phenomenon occurs in neurosyphilis, with incomplete antibiotic treatment voiding 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. Resolve 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." Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS), or other autoimmune and neurodegenerative diseases.

## History and Symptoms
Lyme disease is divided into 3 stages and the symptoms are stage specific. Initial symptoms include bullseye rash called erythema migrans, with accompanying flu-like symptoms. Lyme disease can progress to cardiovascular, neurological, dermatological and/or musculoskeletal manifestations. Multiple erythema migrans develops as disease disseminates throughout the body. Most common neurological manifestation includes lymphocytic meningitis and cranial nerve palsies (usually facial nerve palsy). Dermatological manifestation includes borrelial lymphocytoma and acrodermatitis chronica atrophicans appearing in stage 2 and stage 3 Lyme disease respectively. Cardiac manifestation include Lyme carditis. Musculoskeletal manifestation include Lyme arthritis. There is a difference in clinical features of Lyme disease in patients living in different geographical regions depending on the genospecies of Borrelia burgdorferi sensu lato complex causing it.

## Physical Examination
The physical examination of Lyme disease is necessary for diagnosis. Erythema migrans and fever are commonly seen on physical examination in early disease. Disseminated disease is characterized by multiple erythema migrans, neurological, musculoskeletal, and cardiac symptoms.

## Laboratory Findings
Laboratory blood tests are helpful if used correctly and performed with validated methods. Laboratory tests are not recommended for patients who do not have symptoms typical of Lyme disease. The Centers for Disease Control recommends a two-tier testing protocol for Lyme disease. Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. Currently, PCR is the only means to detect the presence of organism. Identification and testing of the individual tick after removal is generally not useful.

## Electrocardiogram
There are no ECG findings associated with Lyme disease. However, an ECG may be helpful in the diagnosis of complications of Lyme disease, which include Lyme carditis. Most of the time, Lyme carditis symptoms are related to fluctuating degrees of atrioventricular block (first-degree block to complete heart block) including lightheadedness, palpitations, shortness of breath, chest pain, and syncope.

## X-ray
There are no X-ray findings associated with Lyme disease. However, an X-ray may be helpful in the diagnosis of complications of chronic Lyme arthritis.

## CT Scan
There are no CT scan findings associated with Lyme disease.

## MRI
MRI is not helpful in diagnosis of Lyme disease. However, an MRI may be helpful in diagnosing neurologic manifestations of early and late disseminated Lyme disease. MRI scan in patients with neurological Lyme disease may demonstrate increased intensity in white matter at multiple foci on T2-weighted images, suggesting demyelination or inflammatory changes. After antibiotic therapy, spontaneous resolution of MRI white matter hyper-intensities has been observed in Lyme disease.

## Ultrasound
There are no ultrasound findings associated with Lyme disease.

## Other Imaging Findings
Single photon emission computed tomography is one of the major other imaging modalities of Lyme disease. In Lyme patients, cerebral hypoperfusion of frontal subcortical and cortical structures has been found.

## Other Diagnostic Studies
There are no additional diagnostic findings associated with Lyme disease.

# Treatment

## Medical Therapy
The mainstay of therapy for Lyme disease is antimicrobial therapy. Antimicrobial therapy may include doxycycline, amoxicillin, cephalosporins, or macrolides. The choice of antimicrobial therapy depends on the stage of  Lyme disease. Individuals who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days.

## Surgery
Surgical intervention is not recommended for Lyme disease.

## Primary Prevention
Primary prevention of Lyme disease involves tick control and reducing exposure to ticks. The tick should be removed with proper technique so as to decrease the risk of infection. A Lyme disease vaccine used in the past is no longer available.

## Secondary Prevention
The secondary prevention of Lyme disease may include post exposure prophylaxis with doxycycline in select cases meeting criteria for chemoprophylaxis.

## Future or Investigational Therapies
Future and investigational therapies of Lyme disease are directed towards decreasing the pro-inflammatory immune process and decreasing Th1 upregulation. Studies have also been conducted to test the role of neurohormones in neuropsychiatric complications of Lyme disease. Other therapies including hyperbaric oxygen therapy, antifungal medications and use of bee venom are also under investigation.