Lyme disease is the most commonly reported vector-borne illness in the United States. The Centers for Disease Control estimates more than 300,000 cases annually. More than eighty countries have reported Lyme disease cases and the earliest reports of the disease come from Europe, not the United States.
Lyme disease is caused by the pathogen Borrelia burgdorferi, a spirochete or spiral-shaped bacterium that infects humans through a tick bite. During the initial blood meal by the tick, the Borrelia bacteria are injected into the skin.
This usually causes an inflammatory reaction that leads to the development of an expanding red rash around the tick bite which is known as erythema migrans. This rash usually develops 2-4 weeks after the infecting tick bite. It is typically a round or oval shaped solid rash which expands over time and sometimes resembles a bull’s eye with a central clearing. The early stage of the disease is usually accompanied by flu-like symptoms and the erythema migrans.
When the Borrelia burgdorferi spirochete spreads locally within the skin it may enter the bloodstream. It gets distributed widely throughout the body and the spirochete infects whichever organ or tissue it has reached such as collagen tissue, joints, muscles, brain, peripheral nerves and the heart. The initial immune response to the organism can lead to a wide range of symptoms such as fever, joint pain and swelling, muscle pain, fatigue, headaches, stiff neck, nerve pain, irritability, cognitive problems, cranial nerve palsy, meningitis and cardiac inflammation.
Some patients don’t develop or see the rash and only have mild symptoms and don’t seek medical attention. In patients in whom the infection goes unnoticed and untreated Lyme disease can remain quiescent for months or years and result much later in arthritic or neurologic illness.
Lyme disease can involve many different organ systems and because it is a spirochete it has been compared with Syphilis, which also causes complex and chronic symptoms. In the twentieth century Syphilis was called “The Great Imitator”. “He who knows Syphilis knows medicine.” Today the same holds true for Lyme disease.
2. Signs and symptoms
Lyme disease is transmitted when an infected tick attaches to a human and injects Borrelia burgdorferi, the spirochetal bacteria that cause Lyme disease, into the skin. It usually takes 24-36 hours of attachment for the tick to infect a human.
The different manifestations of Lyme disease are grouped into multiple stages based on average time of onset but these stages are somewhat arbitrary in that there is often considerable variability as to when signs and symptoms appear.
Table of symptoms
- 70% gets a skin rash 7-14 days after the infection (some say only 30% get a skin rash)
- May be accompanied with flu-like symptoms (but it’s not a requirement)
- Skin rash can differ from the bull’s-eye shape or doesn’t appear at all
- Monoarthritis of major joints (preference for the knee)
- Lymphocytic meningitis (self-limiting)
- Bell’s palsy
- Meningoradiculitis (Bannwarth syndrome)
- Meningoencephalitis (Cerebellar syndrome)
- Peripheral neuropathy
- Vasculitis, stroke
- Psychiatric manifestations (psychosis, paranoia, anxiety, depression)
- Encephalitis (subtle)
- Chronic encephalopathy
- Encephalomyelitis (mimics MS and movement disorders like Parkinson’s) (Will be coded under 8A45.0Y in the upcoming ICD11 revision)
- Dementia (Will be coded under 6D85.Y in the upcoming ICD11 revision)
In the early stage of Lyme disease the skin at the site of the tick bite becomes infected with Borrelia burgdorferi bacteria which usually causes a typical round or oval skin rash that expands slowly around the bite. This skin rash is called erythema migrans. This means chronic migrating redness. It can appear from one day to one month after the tick bite.
As the rash grows it may develop a central clearing or a “bull’s eye” appearance. In most cases the rash will be uniformly red. Alternatively, the rash may have a dark bluish-red center, a raised or blistery central region or another atypical appearance. The shape of the rash varies from oblong, oval, linear or even triangular. Only 20-30% of the rashes will have a classical bull’s eye presentation and 20% of all the patients don’t develop a rash at all.
This high prevalence of symptoms without a rash is not widely recognized as a manifestation of Lyme disease because only externally verifiable signs of the disease are included in the CDC’s epidemiologic surveillance criteria. These common flu-like symptoms can be ignored by doctors or patients leading to an unrecognized and untreated illness.
A red rash occurring within several hours of a tick bite represents a hypersensitivity reaction rather than a Lyme rash. These reactions are usually less than two inches in diameter. They begin to disappear within 24-36 hours after removal of the tick. An early primary Lyme rash usually increases in size over time and appears days to weeks later.
Flu-like symptoms reflect the body’s immune response to the Borrelia burgdorferi bacteria. Many patients will experience moderate to severe systemic symptoms during the early phase of infection. Symptoms include achiness, chills, fever, sweats, fatigue, malaise, headache, stiff neck, sore muscles, joint pain, swollen lymph nodes and sore throat. The combination of the erythema migrans and the flu-like symptoms are the primary manifestations of the early stage of Lyme disease.
When the erythema migrans is not present in the early stage of the illness patients may not go to a physician and Lyme disease may not be recognized until the more debilitating and more severe manifestations of the infection present themselves. Flu-like symptoms in the absence of a cough, runny nose, vomiting or diarrhea in a Lyme endemic area during the spring and summer months should raise suspicion for possible Lyme disease.
Early disseminated infection
Borrelia burgdorferi can disseminate quickly beyond the initial localized skin infection. When Borrelia burgdorferi enters the blood vessels or the lymphatic system it has the potential to infect every tissue of the body from where it rapidly makes its way into the tissues. The spirochete may infect the skin, nerves, brain, hearts, joints, tendons and every organ system in the body. This usually triggers a local inflammatory response.
Sometimes patients develop multiple satellite rashes that are far removed from the initial tick bite. These rashes may take on different appearance such as smaller red spots that may not resemble the original skin rash.
Patients often experience joint and muscle pain during the initial phase of the infection. When it disseminates beyond the skin to the joints, swelling and tenderness may occur typically in the large joints and often migrates from one joint to another. Because a majority of patients does not develop joint inflammation until about six months after the initial infection, arthritis is grouped into the late disseminated stage. However, joint inflammation and swelling can occur as early as four days after the initial infection.
When Borrelia burgdorferi infects the nervous system multiple conditions may develop. The diagnosis of neurologic Lyme disease can be challenging because some patients don’t have abnormal spinal fluid test results. In Europe, when Borrelia afzelii infects the nervous system, patients don’t usually meet the criteria for neurologic Lyme disease.
Meningitis is an inflammation of the membranes covering the brain and spinal cord and is often characterized by mild to severe headaches. Additional symptoms include neck stiffness, nausea, vomiting, light/sound sensitivity and fever. The symptoms of Lyme meningitis are usually less severe and their onset less abrupt as with other bacterial causes of meningitis. It may therefore be mistaken for viral meningitis.
Cerebrospinal fluid will show an elevated number of lymphocytes (a type of white blood cell) but the increased number of lymphocytes is often lower than seen in other bacterial infections. There may also be elevated protein and Borrelia burgdorferi specific antibodies in the spinal fluid.
Some patients have only mild symptoms of neurologic Lyme disease and if no spinal fluid is performed these cases will go undetected. Many patients with Lyme meningitis also have other symptoms and signs of Lyme disease.
Another neurological presentation is called Lyme encephalitis. In this condition brain tissue itself is inflamed. Encephalitis was not included in the CDC case definition of Lyme disease which means there is no agreed-upon definition.
Encephalitis caused symptoms such as fatigue/sleepiness, decreased level of consciousness, mood disturbance such as irritability, tearfulness, confusion, depression, anxiety and adjustment problems, personality and behavioral changes, memory loss, word-finding difficulties, cognitive problems and sleep problems and seizures.
An electroencephalogram, which tests brain function, may show mild slowing. MRI of the brain may show focal abnormalities suggesting inflammation, often affecting the white matter more than the grey matter. Functional brain imaging with PET scans show regions of increased metabolism or blood flow. The spinal fluid may show oligo clonal bands and the synthesis of Borrelia burgdorferi specific antibodies.
Cranial neuritis is an inflammation of a cranial nerve. This can cause a variety of sensory and motor problems.
Facial Palsy (sometimes referred to as Bell ’s palsy) may be the first sign of Lyme disease. Facial drooping indicates weakness or paralysis of the facial nerve. The weakness often comes on rapidly over one to two days. Typical symptoms include problems with lip movement, eye closure and forehead wrinkling. Also common are pain behind the ear or an altered sense of taste. Sometimes patients also develop increased sound sensitivity.
When a patient develops weakness or paralysis of the face in Lyme endemic area, Lyme disease should be suspected. If both sides of the face are affected this suspicion should be even stronger. Other cranial nerves may also be involved.
Patients can develop optic neuritis causing changes in vision, abnormalities of facial sensation, facial pain, double vision and or hearing loss or tinnitus.
Pseudotumor cerebri is characterized by an increase in intracranial pressure that if left untreated can lead to compression of the optic nerve and potential visual loss. Rarely, this condition is caused by Lyme disease. A neurologic exam will show swelling of the optic disc. The most common symptom is headache followed by blurred vision or double vision. Very rarely, blindness may occur if the condition is not detected or treated.
Radiculoneuritis refers to nerve dysfunction that stems from inflammation of the roots of the spinal nerve. Motor and/or sensory symptoms may occur. The sensory symptoms may include numbness or tingling on one or both sides of the body. There may be increased sensitivity to painful stimuli in affected areas. Radicular pain may be experienced as sharp, stabbing, burning or shooting pains that radiate down along the nerves into the limbs or across the trunk.
Rarely patients may present with symptoms typical of Guillain-Barre syndrome in which there is a rapid progressive weakness and sensory changes starting in the lower extremities and progressing up. When severe certain muscles cannot be used at all and the person may become almost totally paralyzed. Respiratory muscles may be involved. This requires immediate medical attention.
These neuropathic complications are mediated by immunologically driven attacks on the nerves and require treatment with immunoglobulin or steroids in addition to antibiotics.
Lyme disease may infect the heart and cause conduction abnormalities and/or muscular inflammation. This usually occurs within weeks to months after the initial infection. When the heart’s conduction system is involved the transmission of electrical signals that control the heart rate and rhythm is disrupted. This is referred to as AV block.
Electrocardiogram (ECG) can show and differentiate between the degrees of AV block. Third degree AV block is the most severe and patients may need emergency treatment including but not limited to a pacemaker. The AV block can cause a very slow heart rate that puts the patient in risk of passing out, dizziness, chest pain and shortness of breath.
When the cardiac muscle tissue is infected and inflamed there may be a decrease in the ability of the heart to pump with sufficient strength. This is sometimes referred to as myocarditis. When the membrane surrounding the heart is affected it is called pericarditis.
Symptoms may be mild or life threatening. Common symptoms include lightheadedness, fainting, dizziness, chest pain, shortness of breath and palpitations. Because cardiac Lyme disease can be fatal a rapid recognition is essential because treatment with antibiotics is effective.
Joint swelling can be temporary or chronic. It usually emerges six months after initial infection but can happen as early as four days and as late as two years after the tick bite. The joint pain can be severe and often affects the large joints, most often the knees. Swelling may also occur without pain.
Multiple joints can be involved such as the ankle, shoulder, elbow or wrist. Fever is usually absent. The pain and swelling may resolve on its own but can recur intermittently over time. It can also be chronic and persistent.
It is most often abrupt in onset rather than gradual and is more often shorter in duration rather than chronic. Treatment may require up to 90 days of antibiotics. Some patients will develop ongoing symptoms despite treatment. Most doctors attribute it to inflammatory immune activity and not to active infection.
The infecting strain and genetic profile of the patient contribute to the development of this chronic joint inflammation. Researchers think the infection induces an auto-immune process.
Late Lyme disease
In some patients the infection goes undetected. The bacteria can remain quiescent in tissues without causing disease. Months or years later the Borrelia burgdorferi spirochetes can become active and cause Lyme disease symptoms. In this late stage the joints and the nervous system are often affected. Joint pain and swelling, fatigue, cognitive problems, sleep disturbance, irritability, and hypersensitivity to sensory stimuli.
Patients that have been left untreated for months or ears will develop less common neurological problems. These include encephalopathy, sensory polyneuropathy, dementia, encephalomyelitis or strokes. Lyme disease can affect memory, word finding problems and speed of thinking in this stage. Patients can develop depression, somnolence, headache, irritability and hearing changes.
Patients with encephalomyelitis will have inflammation of the brain and spinal cord. Symptoms include confusion, cognitive impairment, somnolence and severe psychiatric symptoms such as hallucinations, paranoia and mania.
It can also cause weakness in the extremities with sensory loss, abnormal body movements, impaired coordination and seizures. There may be autonomic nervous system involvement.
Encephalomyelitis caused by Lyme disease is often not relapsing remitting as in multiple sclerosis. Rare cases of progressive form of Lyme encephalomyelitis show a worsening over months or years that may be hard to differentiate from multiple sclerosis.
Cerebral vasculitis or stroke may present as an ischemic infarction or intracranial bleed. The symptom profile may be diverse, ranging from sudden onset to slowly evolving cognitive impairment with confusion and speech difficulties.
Dementia due to Lyme disease is rare but reported. Cerebrospinal fluid markets for other causes of dementia were not found in this group. Lyme disease can also exacerbate an already existing neuro-degenerative disease.
Intermittent tingling, numbness of the extremities can also be seen in late Lyme disease. The sensory symptoms may involve the arms and/or legs. Radicular pain may also occur. On physical examination the clinician may note a reduction in vibration sensitivity and weakness and/or decreased reflexes.
The neuropsychiatric symptoms may be caused by inflammation due to active infection or past infection, altered brain metabolism or perfusion, abnormal activation of neural pathways or changes in neurotransmitter function in the brain.
It is also possible that molecular mimicry is contributing to the onset of neuropsychiatric symptoms accompanying infection with Borrelia burgdorferi. In this model antibodies that are generated against portions of the Lyme disease spirochete might be mistakenly targeting the host’s own tissue.
Anxiety and depression can develop as a biological response to neurological invasion or inflammation as a result of Lyme disease but they may also manifest as a secondary reaction to loss of income due to medical expense and/or inability to work, interpersonal tensions because of inability to keep up with responsibilities and the stress of having been undiagnosed for a long time while living with terrifying, bizarre, painful, progressive and unexplained symptoms. Many patients develop trauma as the result of having one’s symptoms constantly discounted.
Rarely patients with neuro-psychiatric Lyme disease will develop paranoia, hallucinations, mania and or obsessive-compulsive symptoms. Uncommonly these neuropsychiatric symptoms may occur with few musculoskeletal signs or symptoms making it hard to distinguish Lyme disease from a normal psychiatric disorder. In these cases the psychiatric symptoms may be followed weeks to months later with other features such as radicular pain and migrating joint- and muscle pain.
If you want to learn more about Lyme disease and psychiatric disorders you can read the article written by psychiatrist Robert Bransfield.
Because symptoms and signs of Lyme disease can be diverse and blood tests are not 100 percent reliable, diagnosis is based on clinical history obtained from the patient and a thorough physical exam, supplemented by blood test results.
Physicians will ask the patient questions about tick bites, duration of tick attachment, expanding rashes, flu-like symptoms in the spring and summer, residence in or travel to Lyme endemic areas, a history of other tick-borne infection in themselves, close family members or neighbors and activities like golfing, gardening, hiking in the woods, hunting or working in the forest because they can increase the risk of exposure to Lyme disease.
Blood tests look at whether the body makes antibodies against the Borrelia burgdorferi spirochete. Antibodies can be measured with ELISA and Western Blot test methods. These antibody tests are not sufficiently sensitive at all stages of the disease and a person may have Lyme disease but test negative.
If the red expanding rash is present blood tests are not needed as at this stage antibody tests are unlikely to be positive and the red expanding rash is diagnostic of Lyme disease without the need of confirmatory blood tests.
Limitations of serological tests
Serological tests do not become positive until an infected individual has had time to develop antibodies. This means that early acute Lyme disease, often characterized by an erythema migrans at the site of a tick bite, cannot be diagnosed by serology.
Not all patients develop an erythema migrans. In these patients the serological tests will not be able to confirm an infection for at least 4 weeks after becoming ill. There is an increased chance of persistent symptoms in patients with a delayed diagnosis.
Another problem is that serological tests cannot confirm a cure. Antibodies persist after the infection is gone. This means that your blood will continue to test positive months or years after treatment. In cases were symptoms return or persist despite earlier antibiotic therapy these tests are not useful to determine whether there is treatment failure.
Reinfected patients will already have antibodies against Borrelia burgdorferi. It can be difficult to use serological tests to confirm the reinfection. This is especially difficult when the patient does not remember having a tick bite or an erythema migrans but does present with symptoms that suggest disseminated infection.
In treatment failure and reinfection it might be useful to use serial Western Blots to document a rise in antibodies.
Accuracy of serological tests
A two-tiered protocol is recommended by the CDC. The first step involves ordering an ELISA test. If this test is negative, no further testing is recommended. If the ELISA is positive or equivocal, the next step is to order a Western Blot.
The reliability of the CDC two-tiered protocol is controversial. This testing protocol is particularly problematic in Europe and other countries because there are several genospecies of Borrelia burgdorferi in Europe that vary in their surface proteins and therefore may not be detected by these tests.
The ELISA and Western Blot have additional problems with sensitivity, the ability of the test to correctly identify those who have the disease. The two-tiered approach enhances specificity at the expense of sensitivity, especially in early Lyme disease.
Multiple studies have been performed to assess the two-tier testing strategy. All studies agree that in early Lyme disease the sensitivity of the testing protocol is poor. Only 29-45% of the patients will test positive. In acute neurologic Lyme disease the sensitivity is improved but still problematic because 72-87% of patients will test positive. In Lyme arthritis the sensitivity is excellent picking up 97-100% of the patients.
Blood or tissue can be placed in a growth medium to see if Borrelia burgdorferi will grow. Culture is the ‘gold standard’ for diagnosis of most infections but Lyme disease is difficult to grow in the laboratory and therefor it is rarely used except in the research setting. The test results may not come back for 8-16 weeks and that is far too long to be helpful. It is also not useful once the infection has disseminated outside the bloodstream.
A polymerase chain reaction detects genetic material of the Borrelia spirochete itself. This is considered to be a direct test of active infection. Genetic material does not linger in the body for long after the infection is gone and it is therefore suggestive of current infection. The results can be acquired immediately when infection first appears. In skin biopsy samples from erythema migrans patients this test has a sensitivity of 64%. In synovial fluid specimens of patients with Lyme arthritis it has a sensitivity of 83%.
PCR of the blood from patients with early Lyme disease is only able to detect the disease in 18-26% of the blood samples. PCR of the cerebrospinal fluid of patients with neurologic Lyme disease PCR has sensitivities of 38% in acute neurologic Lyme disease and 25% in late neurologic Lyme disease.
One of the newer approaches looks at the cell mediated immune response to Borrelia burgdorferi infection. When the infection is current or recent the blood will show a stronger release of specific immune mediators when exposed to stimulation by Borrelia protein than when the infection has resolved. This is because the immune cells will have been primed by recent exposure to the Borrelia spirochete. These tests are indirect markers of infection.
Most of these tests are still in the validation phase but they do provide the promise of a test that serves as a marker of active infection at any stage of the disease. This brings us closer to the goal of finding a test that is positive early in infection and becomes negative after the infection is resolved.
Patients with symptoms that suggest neurological Lyme disease should have a lumbar puncture. The cerebrospinal fluid obtained in this test is sent for routine studies including cell count as well as protein and glucose levels. In addition the cerebrospinal fluid is tested for Borrelia burgdorferi specific antibodies and DNA by PCR.
When the spinal fluid is collected it is equally important to collect serum from the patient. This allows for comparison of the relative levels of antibodies in the cerebrospinal fluid compared to the serum. This can be used to calculate the intrathecal index. A positive index indicates that more antibodies are produced in the cerebrospinal fluid which that the spirochete has invaded the central nervous system.
The chemokine CXCL13 has also been reported in studies to be highly sensitive and specific for early neurologic Lyme disease. This chemokine however has also been found elevated in patients with neurosyphilis, B-cell lymphoma and in patients with NMDA-receptor encephalitis. Therefor it may be a sensitive marker of active infection in neurological Lyme disease but it is not 100% specific.
MRI is an imaging technique that uses magnetic fields to show the anatomy of the brain without using radiation. MRI is able to detect abnormalities that may be seen in some patients with neurological Lyme disease. Most findings on an MRI are not unique to Lyme disease and can occur for a wide variety of other reasons such as old age, stroke, multiple sclerosis and smoking. MRI is therefore informative but cannot be used to make a diagnosis of Lyme disease.
A single-photon emission computerized tomography enables an examination of how the brain is actually functioning. In Lyme disease the most common finding is “heterogeneous hypo perfusion” diffusely throughout the brain. Decreased blood flow can occur as a result of decreased demand of brain tissue. Studies at Columbia University have shown that Lyme patients have deficits in metabolic demand and blood flow.
SPECT has limitations and the results do not provide a diagnosis but it may be a helpful tool to clarify whether or not the blood flow in the brain appears normal or abnormal in someone with neurological symptoms.
Electromyography & skin biopsy
Electromyography and nerve conduction studies assess the function of muscles and nerves. It allows the neurologist to distinguish between muscle and nerve disease and to identify which muscle is involved. These studies inform about the integrity of sensory and motor nerves.
Electrical stimulation is applied to the skin to enable a recording of the speed of conduction and the amplitude of the electrical impulse traveling through a nerve. These studies assist in the diagnosis of demyelinating neuropathy and nerve root compressions.
Lyme disease can cause neuropathy and damage that results in burning, tingling and numbness. These abnormalities may be due to damage to tiny nerve fibers in the skin. To detect small fiber damage skin biopsies are performed.
An electrocardiogram may be useful in the diagnosis of complications such as Lyme carditis. Though findings such as heat block or carditis are not specific to Lyme disease alone they are useful in detecting potential damage that may be caused by the infection.
Guidelines for the treatment of Lyme disease have been developed by organizations such as the Infectious Disease Society of America (IDSA) and International Lyme and Associated Diseases Society (ILADS). The IDSA guidelines and the ILADS guidelines differ considerably.
There are controversies about treatment of Lyme disease and particularly when it comes with chronic persistent symptoms. The IDSA guidelines state that current treatments are sufficient and successful in treating Lyme disease while the ILADs guidelines state that current treatments are sometimes insufficient and at times fail to eradicate Borrelia burgdorferi.
These persistent symptoms after antibiotic treatment are called Post Treatment Lyme Disease Syndrome. It is currently unknown what causes it. The IDSA is of the opinion that PTLDS is uncommon and not helped by repeated antibiotics. The ILADS authors find that PTLDS is not uncommon and can benefit from additional antibiotic treatment. You can read our article about the concept of chronic Lyme disease to learn more about these different views on the disease.
Because some individuals do not experience a full remission of symptoms after standard treatment, clinical treatment of the individual patient needs to be personalized.
Treatment of early Lyme disease
Patients that present with early Lyme disease and erythema migrans are usually given 14-21 days of doxycycline, cefuroxime or amoxicillin. However not all cases result in a cure. There might be early central nervous system seeding for example. Some patients may develop later-stage disease and/or persistent symptoms despite antibiotic therapy.
The ILADS guidelines recommend at least 21 days of antibiotic therapy for the initial erythema migrans and recommend repeated courses of antibiotics in those patients that do not experience a full remission of symptoms.
Treatment of Lyme arthritis
Patients that present with Lyme arthritis without neurologic or cardiac involvement can be given 28 days of doxycycline, cefuroxime or amoxicillin. If joint swelling and pain persists additional antibiotic therapy is recommended with either 28 days of oral antibiotics or 14-28 days of intravenous ceftriaxone. It may take several months for the inflammation to resolve after treatment.
ILADS recommends a combination of azithromycine and amoxicilline or cefuroxime with or without the addition of hydroxychloroquine for a longer period if the initial 90 days of antibiotic treatment was unsuccessful in resolving joint swelling and pain.
Treatment of neurologic Lyme disease
Acute neurologic Lyme disease such as meningitis, radiculopathy, facial nerve palsy and cardiac symptoms are generally treated with 14-28 days of intravenous ceftriaxone. For encephalomyelitis 28 days of intravenous ceftriaxone is recommended. Not all patients recover after an initial course of antibiotics. Some studies suggest up to 50% of patients will have persistent symptoms.
In the case of neurologic Lyme disease ILADS recommends repeated or longer courses with intravenous ceftriaxone. Some patients do well on higher doses of doxycycline (200mg 2x daily) with or without the addition of hydroxychloroquine.
Patients who are given antibiotics and steroids do worse on follow-up than patients receiving antibiotics alone. Therefor steroids are contra-indicated.
Treatment of cardiac Lyme disease
The treatment of cardiac Lyme disease has not been studied adequately but intravenous or oral antibiotic therapy is recommended. Because the risk of life-threatening complications hospitalization for continued monitoring and treatment is recommended for symptomatic patients with second-or third-degree AV block.
Intravenous immunoglobulins contain IgG antibodies from the plasma of thousand blood donors. Immunoglobulin products are given intravenously. It is considered a relatively safe and effective treatment for neuropathies that are associated with autoimmune diseases. It decreases the inflammatory response and can play a role in immunomodulation of suppressing autoimmune diseases.
Although there are reports of the effectiveness of IVIG for small fiber neuropathy there are no randomized controlled trials that allow conclusions to be drawn about the true effectiveness. Neurologists are beginning to investigate how to best help patients with Borrelia burgdorferi induced peripheral neuropathy which causes tingling, burning and stabbing sensations in the limbs.
In 2009 Katz and Berkley presented results on the use of IVIG in patients with neuropathic symptoms and a history of Lyme disease. After six months of treatment with IVIG patients had objective improvement in small fiber nerve density as well as subjective improvement of clinical symptoms. This provides preliminary evidence in support of IVIG as a potentially effective treatment for Borrelia burgdorferi induced peripheral neuropathy.
Risk and benefits of antibiotics
Antibiotic therapy also carries risks that have to be discussed with the patient. All antibiotics carry risk of triggering allergic reactions or damage the gastrointestinal flora leading to dangerous colitis in some cases.
Doxycycline can cause sensitivity of the skin to sunlight, nausea, vomiting, diarrhea, yeast infection and rarely more serious problems such as liver damage and esophageal irritation.
Minocycline can cause immune-mediated lupus-like reactions with symptoms such as arthralgias, lymphadenopathy, rash and fever.
Azithromycin and clarithromycin can lead to gastric distress with diarrhea, nausea and abdominal pain, headaches and dizziness, tinnitus, reversible hearing loss, liver damage and fatal cardiac arrhythmias.
Ceftriaxone can lead to gall bladder disease and rarely hemolytic anemia and pancreatitis. The use of intravenous catheters can increase the risk of life-threatening staphylococcus infections and thrombus formation.
The fluoroquinolone antibiotics can cause gastric distress, mild headache and dizziness, and toxicity reactions such as tendonitis and tendon rupture or neurologic effects such as neuropathy and a range of neuropsychiatric symptoms.
Another risk of antibiotics is the development of drug-resistant microbes that no longer respond to available antibiotics. This stems from both the use in humans and in agriculture or as growth promoting drugs for food animals.
Treatment relapse or poor response to initial antibiotic treatment for Lyme disease has been well documented. Isolated case reports have been published that document persistent infection despite prior antibiotic treatment. These studies provide proof that persistent infection needs to be included as a possibility for persistent symptoms.
Lyme disease bacteria produce different morphological forms in the laboratory and in animal models that might require different treatment strategies. Richard Horowitz has reported success with a combination of doxycycline, rifampin and Dapsone for the treatment of Lyme disease patients with chronic symptoms despite prior treatment with antibiotics.
Read more about persistent infection and chronic Lyme disease in our article ‘Does chronic Lyme disease exist?’.
After starting antibiotic therapy for Lyme disease you can experience a Jarisch-Herxheimer reaction. This is a reaction to endotoxin-like products released by the death of harmful bacteria during antibiotic treatment. The release of these bacterial toxins results in a systemic inflammatory response. A Jarisch Herxheimer reaction is usually not life-threatening
A Jarisch-Herxheimer reaction usually starts between 24-72 hours after the start of antibiotic therapy for Lyme disease and can cause fever, chills, stiffness/rigor, muscle pain, hypotension, headache, heart palpitations, hyperventilation and anxiety. The intensity of the reaction indicates the severity of the inflammation.
The reaction is associated with the treatment of syphilis, leptospirosis, Lyme disease and relapsing fever. There have been reports of a Jarisch-Herxheimer reaction accompanying treatment of infections such as Q-fever, bartonellosis and brucellosis.
Ibuprofen, aspirin or acetaminophen can be taken to minimize the reaction. Drinking enough fluids and taking rest are also recommended.
The prognosis of Lyme disease patients is usually good when the disease is diagnosed and treated in the early stage of the infection. Unfortunately still 10-20% of patients have persistent symptoms of fatigue, headache, muscle aches and fogginess of the brain. What causes these ongoing symptoms is not understood. Because there is no test that can tell your doctor whether all bacteria are killed some doctors prescribe the antibiotics for a little longer or repeat the course of antibiotics when these symptoms persist.
In a small group of patients that developed Lyme arthritis, the swelling of the joints persists after oral and intravenous antibiotics apparently eliminated the bacteria. The complication is thought to result from the development of autoimmunity in affected joints. This condition is called antibiotic refractory Lyme arthritis and is treated by most doctors with anti-inflammatory medications or disease-modifying anti rheumatic drugs.
Patients that develop late stage neurological Lyme disease are most at risk of developing severe and chronic symptoms that persist after treatment. This condition can be severe and debilitating and is called post treatment Lyme disease syndrome (PTLDS). The cause of these persistent symptoms is currently unknown.
In addition to the Borrelia burgdorferi spirochete ticks may carry many other microbes – including other bacteria, viruses and parasites. Infection by one of these tick-borne infections may lead to a spectrum of illness ranging from mild that resolves without treatment to more severe illness leading to death. Some of these coinfections are relatively common in ticks from Lyme endemic areas.
The presence of coinfections in the patient is of clinical relevance. First the patient might have developed a chronic illness after the tick bite but test negative for Lyme disease. One possibility is that the test is insensitive but another possibility is that the patient got sick from another tick-borne infection that requires different testing and treatment.
Some patients may experience a more severe illness if they have been co-infected by more than one tick-borne infection. This has been supported by a study that demonstrated that individuals who were co-infected with both Lyme disease and Babesiosis had a more prolonged illness and experienced more severe symptoms.
In certain regions of the United States and Europe co-infections are common. In 192 residents from the northeastern United States 39% carried at least two tick-borne infections at the same time.
Similarly 30% of ticks collected from Lyme endemic areas were shown to carry more than one disease causing microbe.
Babesia and Bartonella infections in particular can be challenging to diagnose and might resist or persist the treatments that are given for Lyme disease. Since the discovery of Lyme disease in 1981, researchers found over 15 tick-borne infections that were unknown before.
6. Prevention of Lyme disease
Many areas of the United States are at high risk for Lyme disease. People who live/work/recreate in Lyme-endemic areas or tick habitat may be exposed to ticks in a variety of settings – campsites, parks, golf courses, sports fields, and their own back yards. Spending time outside gardening, hiking, walking your dog or hunting can increase your risk of encountering ticks. Pet ownership is associated with an increased risk of Lyme disease.
Ticks occur year-round but they are most active during spring, summer and early fall (April-September) but adult female ticks can also infect individuals during the winter. Ticks live in grassy and brushy and wooded areas and on animals. The best way to ensure you don’t get bitten is by eliminating close encounters.
1. Avoid wooded areas with high grass and leaf litter. Walk in the center of trials.
2. Wear long sleeved shirts.
3. Wear white or light colored clothing to make it easier to spot ticks.
4. Spray tick repellent on clothes and shoes before entering the woods.
5. Wear long pants and tuck your socks in your pants.
6. Wear closed footwear.
Maintain your yard
By reducing the tick population around the home, one can minimize the risk that family members or friends will be bitten by a tick.
You can place a deer fence high enough to prevent deer and small animals from entering your yard. If this is impractical you can remove plants and trees that attract deer to your yard. Deer are almost always infested with feeding ticks. These ticks drop off deer wherever they happen to be, whether in flower beds or lawns.
The majority of ticks found on a property are located in close proximity to a lawn’s perimeter with woodlands, stone walls, perennial beds and garden plantings. Pesticide spraying of these particular areas can help prevent getting tick bites in your own yard. The most common pesticides used for tick control are permethrin, befenthrin and cyfluthrin.
Keep the grass in your yard short and create low risk zones for dining and recreational use. Homeowners should also eliminate heavy brush and ground cover close to home and replace it with mulch and other less dense alternatives. Also read our article about how to keep your yard tick free.
7. History of Lyme disease
Ticks and Lyme disease have been around for thousands of years. Autopsy on a 5,300 year old mummy indicated the presence of bacteria which causes Lyme disease. Alfred Buchwald first described the skin rash characteristic of Lyme disease in 1883 in Europe but the first descriptions of Lyme disease in the United States are from the 1970’s.
In the early 1970’s there was a group of children and adults in the town Old Lyme, Connecticut, and the surrounding areas that suffered from mysterious and debilitating health issues. Their symptoms included swollen knees, neurological illness, skin rashes, headaches, severe chronic fatigue and cardiac abnormalities.
The mysterious disease outbreak was brought to the attention of Connecticut public health officials and clinical investigators at Yale University by two mothers who were very troubled by the strange epidemic in their town. The Connecticut Department of Health asked the CDC to investigate a mysterious outbreak of juvenile arthritis.
Allen Steere was asked by the Connecticut Department of Health to investigate a mysterious outbreak of juvenile arthritis. He noticed that some of the patients he studied also presented with a red circular rash with central clearing. This rash was later referred to as erythema migrans. The onset of this mysterious disease seemed to be during spring, summer or early fall. Because of the clustering in specific areas and the seasonal onset of the disease, Steere suspected that the disease was spread through an arthropod insect, probably a tick.
In Europe a similar disease was reported. After a tick bite European scientists described the same chronic skin rash that was accompanied by a long list of strange symptoms involving the heart, skin, joints and central nervous system. In Europe they suspected that this disease was caused by a spirochete because the early stage of this disease responded to treatment with antibiotics. Allen Steere was not convinced. The disease in Connecticut was characterized by arthritis, a relatively unusual phenomenon in European patients.
Steere’s findings emerged rapidly. In 1977 he reported in Annals of Internal Medicine that the disease had an ‘enlarging clinical spectrum’. Arthritis was only one of several possible outcomes after the rash and no longer a strict criterion for the disease. He described a broad spectrum of symptoms: malaise, fatigue, chills and fever, headache, stiff neck, back pain, muscle aches, nausea and vomiting. Within this broad spectrum of symptoms, he identified what he regarded as the most specific signs of the disease: migratory joint pains and neurological and cardiac abnormalities.
While a group of doctors had good results with treating their Lyme patients with antibiotics, the group at Yale held back. Steere thought it was more than justified to ignore the European studies in favor of his clinical observations at Yale. Eight Yale patients had received antibiotics for their erythema migrans before they were admitted to the study at Yale and despite the antibiotics they developed joint pains, neurological abnormalities and cardiac symptoms. That is why Steere thought that antibiotics would not help.
In 1981, while Steere and his team were looking for a virus that could be the possible cause of Lyme disease, microbiologist Willy Burgdorfer was involved in a collaboration with the State of New York in the search for ticks that contained Rocky Mountain Spotted Fever. In October, Jorge Benach and Edward Bosler went to Shelter Island to find ticks containing the pathogen. They collected a batch of Ixodes ticks and sent them to Burgdorfer who would dissect the ticks.
Burgdorfer found no evidence of the bacterium that caused Rocky Mountain Spotted Fever but he did discover that there were spirochetes in the gut of the tick. While observing these micro-organisms he knew he had discovered the cause of Lyme disease.
Steere’s first belief that Lyme was viral – and therefore not susceptible to antibiotics – affected the first results that showed that two weeks of antibiotic treatment made almost no difference. In 1981 the discovery of Burgdorfer would shake things up. Lyme disease was a bacterial infectious disease and Steere could no longer ignore it: he could no longer claim antibiotics were ineffective in treating Lyme disease.
One of the most important advances was the demonstration that antibiotic therapy was effective in treating Lyme disease, particularly when it was initiated early in the course of infection. Early studies recommended penicillin and tetracycline. Subsequent studies demonstrated that amoxicillin and doxycycline were more effective for early Lyme disease and that intravenous ceftriaxone was more effective than penicillin for late Lyme disease.
A major shift in the understanding of Lyme disease occurred when a mouse study showed that Lyme disease spirochetes could persist after antibiotic treatment. This study was intriguing because the bacteria could not be identified by standard mechanisms – such as blood testing – but by allowing a laboratory raised uninfected tick to feed on the treated mice and then testing the tick. It showed that Lyme disease could survive antibiotic treatment which was previously thought to be lethal and sterilizing. This was followed by other studies that also demonstrated persistent infection despite antibiotics in monkeys. This had rocked the foundation of the long-standing conviction that repeated antibiotic treatment made no sense because the infection did not persist after antibiotics.
While concerns were raised about research methodology that might have led to misleading results these concerns were addressed in subsequent research. What is clear is that researchers from different institutions using different animal models and different methods have come to the same conclusion that Borrelia spirochetes can persist after antibiotic therapy. Researchers were surprised but treating clinicians felt vindicated: their clinical experience with patients resonated with the animal model studies.
Other interesting articles
- Lyme disease in children
- How acurate are Lyme disease tests?
- Does chronic Lyme disease exist?
- Can Lyme patients be blood donors?
- Worldwide presence of Lyme disease
- Diminished Epidermal Nerve Fiber Density in Patients with Antibodies to Outer Surface Protein A (OspA) of B. burgdorferi Improves with Intravenous Immunoglobulin Therapy. Katz A, Berkley, JM. Neurology 2009;72(S3):A55
- Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. Krause PJ et al. 1996 Jun 5;275(21):1657-60.
- Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Krause PJ et al. Clin Infect Dis.2002 May 1;34(9):1184-91. Epub 2002 Apr 4.
- Assessment of polymicrobial infections in ticks in New York state. Tokarz R. Vector Borne Zoonotic Dis.2010 Apr;10(3):217-21.
Neurological Lyme disease
- The neuropsychiatric manifestations of Lyme borreliosis. Fallon et al. Psychiatr Q.1992 Spring;63(1):95-117.
- Lyme disease: a neuropsychiatric illness. Fallon et al. Am J Psychiatry.1994 Nov;151(11):1571-83.
- Lyme encephalopathy: a neuropsychological perspective. Kaplan RF. Semin Neurol.1997 Mar;17(1):31-7.
- Chronic or Late Lyme Neuroborreliosis: Present and Future. Miklossy & Donta. Open Neurol J. 2012; 6: 78.
- Cerebrovascular Manifestations of Lyme Neuroborreliosis-A Systematic Review of Published Cases. Front Neurol.2017 Apr 20;8:146.
- Chronic neurologic manifestations of Lyme disease. N Engl J Med.1990 Nov 22;323(21):1438-44.
- Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis.2004 Dec;6(6):639-49; discussion 673-81.
Cardiac Lyme disease
- Lyme borreliosis as a cause of myocarditis and heart muscle disease. Eur Heart J.1991 Aug;12 Suppl D:73-5.