eMedicine Specialties > Neurology > Neurological Infections

Lyme Disease

Author: Augusto A Miravalle, MD, Fellow, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School
Coauthor(s): R Philip Kinkel, MD, FAAN, Associate Professor of Neurology, Harvard Medical School; Director, Multiple Sclerosis Center, Beth Israel Deaconess Medical Center; Consultant Neurologist, Children's Hospital of Boston
Contributor Information and Disclosures

Updated: Jul 23, 2009

Introduction

Background

Lyme disease (LD) is a vector-borne, multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi sensu lato. It is transmitted to humans by infected ticks of the Ixodes genus. LD is endemic in North America, Europe, and Asia, and the distribution of the vectors directly affects the incidence of the disease. Ixodes scapularis is the principal vector found in Northeastern and Central United States and Canada, while Ixodes pacificus is more common on the Pacific coast. Ixodes ricinus is the principal vector in Europe. The vector in Asia is the taiga tick, Ixodes persulcatus.

Clinical Image Atlas Click to view clinical images on the features, causes, epidemiology, diagnosis, and treatment of Lyme disease.

The clinical manifestations of LD generally follow 3 stages of disease progression: early localized, early disseminated, and chronic disseminated. All are potentially curable with antibiotic therapy. The infection progresses to disseminated disease in approximately 50% of untreated patients.

Pathophysiology

The infectious cycle of B burgdorferi involves colonization, infection of Ixodes ticks, and transmission to broad a range of mammalian hosts, including humans. Variation in environmental and host conditions promotes different gene expression and changes in the composition of the membrane proteins of the spirochete. This adaptation is a critical step in the pathogenesis and transmission of LD.

The Ixodes tick progresses through 4 stages of development: egg, larva, nymph, and adult.

Ticks carry B burgdorferi organisms in their midgut. Disease is transmitted to humans as the spirochete is translocated from the gut to the salivary glands and then to the person at the site of the bite. B burgdorferi then invades the surrounding local tissue and undergoes hematogenous dissemination. The exact mechanisms involved in this process are poorly understood. Recently, an idea has been proposed that hematogenous dissemination follows a sequential series of stages, including tethering of the endothelial wall, dragging, stationary adhesion, and extravasation.¹

After entering the circulation, the organism invades the cutaneous, synovial, cardiac, and nervous systems. Spirochetes have also been demonstrated histologically in bone marrow, the spleen, lymph nodes, the liver, testes, and the placenta during early hematogenous dissemination. Animal studies suggested a primary role of astrocytes and microglial cells in the pathogenesis of neuroborreliosis. Interleukin 6 (IL-6) production by astrocytes and subsequent oligodendrocyte apoptosis were proposed mechanisms of cell injury.²

The effects of B burgdorferi infection in humans are related to direct invasion by the organism (eg, erythema migrans) or to a secondary inflammatory reaction. Antibodies against spirochetal protein membrane epitopes have been shown to cross-react with neural and connective tissues. This molecular mimicry possibly generates an autoimmune inflammatory reaction. The pathophysiology of early versus late manifestations of the disease is similar to that seen with syphilis.

Frequency

United States

LD is the fastest growing vector-borne disease in the United States. More than 27,000 cases were reported during 2007, yielding a national average of 9.1 cases per 100,000 persons. Most of the states in the United States have reported LD. The areas with higher incidences are northeastern (Massachusetts to Maryland), midwestern (Minnesota and Wisconsin), and western (Oregon and California) states. In the states where LD is most common, the average is 34.7 cases per 100,000 persons.³

More LD cases are probably being reported now because of enhanced physician awareness and sophisticated laboratory surveillance. In addition, urban expansion into formerly wooded habitats has increased the incidence of LD as more people than before are living near tick-infested fauna.

The incidence of LD-related neurologic manifestations is broadly described in the literature. One group reported the following frequencies of neurologic involvement: cranial neuritis in 50-60%, radiculoneuritis in 45%, and CNS involvement in 15-20%. The same group reported the following signs and symptoms in patients with meningitis: headache in 50%, fatigue in 40%, fever or myalgia in 30%, neck stiffness in 20%, and photophobia in 10%. Other sources report that cranial neuropathies occur in 5-10% of untreated patients with LD, whereas lymphocytic meningitis develops in 10-15%.⁴

International

Cases have been documented in eastern Ontario, Canada; Europe; Russia; China; Japan; and Australia. Infection most often occurs between May and November, with peak incidence in June and July. In a recent publication, the estimated incidence of LD was as high as 206 cases per 100,000 population in Slovenia and 135 cases per 100,000 population in Austria. Increases in prevalence have been also observed in Poland, Germany, Bulgaria, Norway, and Finland.

Mortality/Morbidity

• Approximately 80% of untreated or inadequately treated patients develop some manifestation of disseminated disease. Although such episodes are typically subacute and transient, infrequent cases of chronic, severe, and disabling disease have been described.
• Although 15-55% of patients with LD report chronic or intermittent symptoms persisting for months to years after adequate antimicrobial treatment, recent data do not support postulations of a poorly defined post-LD syndrome. Common symptoms that patients and their caregivers often attribute to previous LD include cognitive disturbances, fatigue, joint or muscle pain, headaches, hearing loss, vertigo, mood disturbances, paresthesias, and difficulty sleeping.
• Death is rarely, if ever, attributed to LD.

Sex

Although both genders are susceptible to tick bite, LD is most common among boys aged 5-19 years and persons aged 30 years or older.³

Age

LD can occur at any age; however, the age distribution is bimodal, with the highest incidence of infection occurring in patients aged 2-15 years and 30-55 years. In general, this pattern is related to increased levels of outdoor activity and environmental exposure in patients in these age groups.

Clinical

History

A history of environmental exposure in an area endemic for LD (particularly wooded, brushy, or grassy habitats) aids in recognizing the infection. Endemic areas can be defined as those with established populations of vector ticks and evidence of enzootic transmission of B burgdorferi between the tick and the resident animal population. In addition, current recommendations for antimicrobial prophylaxis require that the rate of infection of the ticks with B burgdorferi should be greater than 20%. Patients are generally unaware of a tick bite because ticks are extremely small and their bites are often painless.

The 3 stages of LD are as follows:

• Stage 1 - Early localized infection (1-30 d after the bite)
  • Most patients present with a characteristic expanding rash (ie, erythema migrans) at the site of the tick bite 7-14 days after the tick is removed.
  • Approximately 50% of patients describe flulike symptoms within days to 1 week of infection.
  • Symptoms include fatigue, myalgia, arthralgia, headache, fever, chills, and neck stiffness, which may resolve spontaneously even if specific therapy is not initiated.
• Stage 2 - Early disseminated LD (weeks to months after the bite)
  • Symptoms related to early disseminated LD occur in at least half of all untreated patients.
  • One or more organ systems become involved as hematologic or lymphatic spread disseminates spirochetes to distant sites. Musculoskeletal and neurologic symptoms are the most common; less common symptoms are cardiac disturbances such as dizziness, syncope, dyspnea, chest pain, and palpitations. The most common cardiac abnormality is atrioventricular block. Fibrinous pericarditis has also been described.
  • Skin involvement can be seen in 25% of cases. Multiple secondary erythema migrans, lymphocytoma, and acrodermatitis chronicum atrophicans (ACA) are some examples.
  • Neurologic involvement, also known as Lyme neuroborreliosis, is reported in 5-20% of cases. In the United States, cranial neuropathy is the most common manifestation of early neurologic LD. Other manifestations include diffuse or focal mononeuropathy multiplex (multifocal involvement of anatomically unrelated nerves), lymphocytic meningitis, plexopathy, and/or radiculoneuropathy. Less common presentations include myositis, pseudotumor cerebri, and cerebellitis.
• Stage 3 - Chronic LD (months to years after infection and may occur after a period of latency)
  • Musculoskeletal and neurologic systems are most commonly affected.
  • Neurologic abnormalities are apparent in both the CNS and peripheral nervous system.
  • Typical presentations of late-stage neurologic LD include subacute encephalopathy, chronic progressive encephalomyelitis, and late axonal neuropathies.
  • Progressive encephalomyelitis and ACA-associated neuropathy are more common in Europe.

Physical

• Dermatologic findings
  • As many as 90% of infected patients have a characteristic expanding rash (ie, erythema migrans) at the site of the tick bite.
  • An erythematous skin lesion present while an Ixodes tick is still attached is most likely a hypersensitivity reaction rather than erythema migrans. Hypersensitivity reactions also tend produce smaller (<5 cm) lesions, which typically begin to disappear in the first 2 days. In contrast, erythema migrans starts as a flat to slightly raised erythematous lesion at the site of the tick bite within days to weeks. Over days, the lesion spreads to a diameter of approximately 5-6 inches. The center of the bite may clear, giving this lesion its typical bull's-eye appearance. Erythema migrans can also manifest as a purpuric lesion with vesicles or pustules at the center of the primary lesion. Without therapy, erythema migrans typically fades within 3-4 weeks.
    
    

    

    Typical appearance of erythema migrans, the bull's-eye rash of Lyme disease.

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    Typical appearance of erythema migrans, the bull's-eye rash of Lyme disease.

    
    
    

    

    Lyme rash. Courtesy of M. Fergione, B. Tucker, and L. Zernel; Pfizer Laboratories.

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    Lyme rash. Courtesy of M. Fergione, B. Tucker, and L. Zernel; Pfizer Laboratories.

  • Several weeks to months after the initial event, multiple areas of erythema migrans occur in more than half of all untreated patients. These secondary cutaneous eruptions are similar to the initial erythematous lesions but typically are smaller, are not uniquely associated with the site of the tick bite, and are less migratory. In addition, they lack indurated centers. Secondary lesions tend to fade within 3-4 weeks. In less than 1% of patients, a small, reddish nodule or plaque (described as Borrelia lymphocytoma) may develop on the ear or nipple during stage 2 disease.
  • ACA is a relatively uncommon physical manifestation of chronic LD. This condition manifests as swelling and bluish-red discoloration of the skin on a distal extremity. Over time, the lesion typically becomes atrophic or sclerotic, appearing similar to scleroderma. One third of patients with acrodermatitis chronicum have an associated sensory polyneuropathy.
• Rheumatologic findings
  • Approximately 60% of all patients develop symptoms of intermittent migratory monoarthritis. Episodes last a mean of 3 months and almost universally affect the knee or temporomandibular joints.
  • Joint symptoms develop in approximately 80% of all untreated patients within 2 years of infection.
  • The severity of joint involvement can range from intermittent episodes of subjective pain to frank arthritis to chronic erosive synovitis.
  • The knee joints are commonly affected, although migratory oligoarthritis involving the small or large joints can occur. During the attacks, the joints are swollen, hot, and painful, but they are not usually red.
  • Although the percentage of patients with recurrent arthritic attacks decreases each year beyond infection, the duration of such episodes progressively lengthens.
  • Less than 10% of patients with arthritic sequelae develop pannus or erosion of cartilage and bone.
• Neurologic findings
  • Approximately 5-10% of untreated patient with LD have signs of cranial neuropathies, and up to 60% of patients with early neuroborreliosis develop cranial neuritis. It usually begins 3 weeks after infection. Seventh nerve palsy is by far the most common. Bilateral facial palsy can be seen in 35% of patients and is a unique characteristic that is useful for distinguishing it from idiopathic Bell palsy and other disorders. Typical associated findings depend on the nerve affected and can include visual or auditory disturbances, facial paresthesia, and/or vertigo. Multiple cranial neuropathies can occur.
  • Aseptic meningitis is relatively common, occurring in as many as 15% of untreated patients bitten by the Ixodes tick and in 30% of LD cases. Symptoms usually occur 2-10 weeks following infection. Headache, neck pain or stiffness, and photophobia typically indicate meningeal irritation. Meningitis may be accompanied by cranial or peripheral radiculoneuropathy.
  • Borrelia encephalopathy most commonly manifests as a mild confusional state accompanied by disturbances in memory, concentration, mood, sleep, personality, and/or language occurring months to years after the infection. Depression and irritability are also common. The results of cerebrospinal fluid (CSF) analysis and neuropsychiatric testing usually confirm the diagnosis. Evaluation of the CSF usually yields normal results, but some cases of elevated protein concentrations and evidence of intrathecal antibody production have been reported.
  • Borrelia encephalomyelitis is a rare but severe and slowly progressive syndrome that occurs in late disseminated disease. Symptoms can progress gradually or in a relapsing-remitting pattern, with partial improvement after the attacks. The most common clinical manifestations are hemiparesis, ataxia, seizures, cognitive impairment, bladder dysfunction, and hearing loss. Myelitis is present in 50% of patients with late neuroborreliosis. Progressive spastic paraparesis or quadriparesis is common.
  • Acute radiculoneuritis is reported in 50-85% of cases. Acute onset of motor deficits, severe radicular pain, and sensory loss are commonly seen after 2-4 weeks of infection. Multifocal asymmetric weakness is a common presentation. Although the presentation of inflammatory radiculoneuropathy is often indistinguishable from that of spinal-root compression, involvement of the thorax of multiple dermatomes and a lack of a precipitating injury can aid in diagnosis.
  • For peripheral neuropathy, patients usually report intermittent paresthesias. The most frequent finding upon examination is decreased vibratory sensation of the distal lower extremities. A "stocking glove" distribution of epicritic sensory deficits is also a common finding.
  • With late axonal neuropathy, patients can report intermittent distal limb paresthesias months to years after infection. It is distinct from the neuropathy of early LD because the symptoms are less severe. ACA-associated neuropathy is common in Europe and manifests as neuropathic pain, paresthesias, and muscle cramps.
  • In Europe, common manifestations of Garin-Boujadoux-Bannwarth syndrome (Bannwarth syndrome) include neuritic pain, cranial neuritis without headache, and lymphocytic pleocytosis. Bannwarth syndrome has also been called tick-borne meningopolyneuritis, lymphocytic meningoradiculitis, and chronic lymphocytic meningitis.
  • Neuropsychiatric findings are controversial and include manifestations of late-stage disease or post-LD syndrome, including depression, anxiety, schizophrenialike psychosis, bipolar disorder, and dementia.
• Cardiac findings
  • Approximately 8% of untreated patients have acute-onset atrioventricular conduction abnormalities.
  • Cardiac involvement ranges from atrial or ventricular arrhythmias to transient heart block or myopericarditis.
  • Most attacks are isolated and transient, lasting less than a week. In rare instances, patients with heart block require electrical pacing.
• Ophthalmic findings: Less than 5% of untreated patients have ophthalmic manifestations such as iritis, keratitis, retinal vasculitis, or optic neuritis.

Causes

• LD is caused by infection with the spirochete B burgdorferi sensu lato, which is transmitted to the host by the bite of Ixodes ticks after exposure to areas likely to harbor ticks (eg, woody, brushy, or grassy outdoor habitats).
• B burgdorferi sensu lato is a broad category of closely related but genetically distinct genospecies. These subspecies are associated with different clinical presentations, probably due to genomic variation.
  • B burgdorferi sensu stricto mainly is present in the United States, and infection with this organism has a particular predilection to affect joints.
  • Borrelia garinii is present in Europe and is responsible for many of the neurological manifestations.
  • Borrelia afzelii is present in Europe and commonly causes cutaneous manifestations, including ACA.
• Patients with HLA haplotype DR4 or DR2 and antibodies to OspA and OspB proteins in their joint fluid may be more susceptible to long-term arthritis than persons without these characteristics. The presence of these genes is related to the development of autoimmunity in the joint, which can lead to persistent inflammation even after the spirochete is apparently eradicated.

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