The neurological complications of Lyme disease are caused worldwide by Borrelia burgdorferi (B. burgdorferi), the vector of Lyme disease in North America. Central nervous system (CNS) manifestations result from involvement of the brain and spinal cord that presents as meningitis, encephalitis, and encephalopathy. Peripheral nerve system (PNS) manifestations result from involvement of large caliber, named peripheral nerves that present as cranial neuritis, radiculoneuritis, mononeuritis multiplex (MNM), distal demyelinating or axonal polyneuropathy (DPN), and a non-length-depending neuropathy. Small fiber involvement in Lyme disease often occurs in concert with autonomic nervous system (ANS) disturbances, leading to disturbed vasomotor tone with alterations in systolic blood pressure (SBP) and heart rate (HR) which may result from predilection of the infectious or immune response toward sensory and autonomic neurons that reside in ganglia. Orthostatic intolerance (OI) is the commonest presentation and most easily demonstrated finding of acquired dysautonomia. Orthostatic hypotension (OH) differs from postural orthostatic tachycardia syndrome (POTS) by the finding of a non-compensatory HR response to tilting in the former, and an inordinately increased HR to postural changes or minimal exertion in the latter. There is increasing aware of the likelihood of polymicrobial tick-borne infection manifested as co-infections which require concomitant treatment, and the emergence of new species of pathogenic Borrelia.
Even before recognition of the responsible spirochete, European investigators described erythema chronicum migrans (EM) in 1922, and, a year later, the neurological triad of meningitis, cranial neuritis, and painful radiculitis. European physicians familiar with the disorder emphasized both neurological and rheumatic involvement and routinely treated it with penicillin. In 1977, EM rash was later described in the United States in conjunction with childhood arthritis in near epidemic proportions in towns surrounding Lyme, Connecticut. Detailed epidemiological studies demonstrated that the disorder occurred in children with a history of Ixodes tick bites and EM. Two years later, a triad of neurological sequel was described similar to those in Europe years before. Subsequent studies in the United States and Europe led to the isolation and identification of the causative Borrelia spirochete and the neurological sequel thereof.
With an incidence of 1 in 2719 persons, and a prevalence of nervous system involvement of 12 to 15% of individuals infected by B. burgdorferi in the United States, reported cases of Lyme disease have been rising steadily for the past three decades. This underreported disease has a 15-year mean annual rate for all states ranging from less than .01 cases per 100,000 persons of Montana and Colorado, to 74 cases per 100,000 in Connecticut. The vast majority of statistically affected individuals are children age <15 years, and adults of either gender of >30 years of age. Since the responsible spirochete is transmitted almost exclusively by the bite of infected hard-shell back legged Ixodes ticks that occur in specific locations in which appropriate hosts are available, residence in or visitation to endemic areas during the spring and summer months are useful in determining the likelihood of contracting the illness.
The life cycle of the causative Borrelia spirochete is well understood. Larval ticks transmitted by the bite of infected Ixodes ticks hatch uninfected and feed upon small mammals such as white-footed field mice, catbirds, squirrels, opossum, and other small mammals, and then mature into nymphs. If the initial host is infected so will be the nymph tick, which can transmit the disease. For the second host, perhaps human, two other conditions must be met before contraction of the disease. First, spirochetes must proliferate in the tick gut, prompted by ingestion of blood with subsequent dissemination to tick salivary glands. Second, the infected tick must attach to the host for a relatively prolonged period, typically 24 to 48 hours. Endemic cycles have been established in discrete areas of North America, Europe, and Asia. Along the eastern coast of the United States from Maryland to Massachusetts, infected Ixodes scapularis ticks, known colloquially as “deer ticks” for the preferred host of the adult forms, are widely prevalent. The same ticks are also found in Minnesota and Wisconsin where they are known as “bear ticks.” In general, causative ticks live where animal hosts are widespread, habitats both in underdeveloped areas to wealthy exurban regions beyond the suburbs of a city. Some mammalian species are poor Lyme disease hosts because they infect few of the ticks that bite them, or kill the ticks when they groom their fur. Habitats high in biodiversity lead to an overall reduced risk of Lyme disease to its inhabitants because ticks feed both upon efficient hosts such as field mice and less efficient ones such as squirrels and opossum. One thing is clear, effective management of Lyme disease starts at home by preserving biodiversity so that infected mice are minimized and the surrounding property around your home is well kept.
Although the causative pathogen has only been characterized within the past forty years, many of the clinical disorders it causes have been well known for much longer. After acute exposure via prolonged tick attachment, most but not all patients develop a characteristic EM rash. This slowly enlarging rash, which may reach many inches in diameter, typically develops over days to weeks at the site of the tick bite and attachment, which may be unapparent. In some patients the spirochetes disseminate early and cause multifocal EM. There is often concomitant fever, arthralgia, malaise, and flu-like illness but not so in the sense of a typical upper respiratory or gastrointestinal infection. However, as both the tick bite and rash may be asymptomatic and occur on parts of the body not easily seen, affected patients may be unaware of either. Three neurological disorders clearly attributed to Lyme disease are lymphocytic meningitis, painful meningoradiculoneuritis, and encephalomyelitis. Lymphocytic meningitis is clinically indistinguishable from viral or aseptic meningitis, occurs several weeks after the skin rash, and is characterized by varying degrees of headache, neck stiffness, and photophobia. Radicular involvement, especially evident in painful polyradiculoneuritis, is typically asymmetric, of sudden onset, and localized close to the bite with burning quality and nocturnal exacerbation. Weakness appears over several days with cranial nerve involvement, especially the facial nerve, although this may occur as part of the PNS disorder in the absence of meningitis, and tendon reflexes, which may be reduced or absent. Lyme encephalomyelitis, which occurs in 0.1% or fewer of untreated patients in North America, presents with symptoms and signs appropriate to the site of inflammatory focal white matter brain and spinal cord involvement, typically manifesting focal cerebral deficits or progressive gait disorder with sphincter dysfunction and altered vital signs. Distal symmetrical demyelinating and axonal polyneuropathies which can occur at any time, including months to years after infectious exposure, appear to be closely tied to acquired cellular and humoral immunity.
The systematic approach to the investigation of the CNS, PNS, and ANS function in neurological Lyme disease starts include the two-tier approach to active disease and previous infection with demonstration of significant changes in IgM and IgG antibody responses to B. burgdorferi in paired acute and convalescent-phase serum samples, including diagnostic levels of IgM and IgG antibodies, and isolation of B. burgdorferi from cerebrospinal fluid (CSF). First-tier screening is performed by an enzyme-linked immunoassay (ELISA), which should be performed in all suspected patients that becomes informative 3 to 4 weeks after initial exposure, when Lyme-specific IgM serology is also detectable. This is followed months later by a Lyme-specific IgG response. During the early phase of exposure, serological testing may be uninformative and falsely negative. Second-tier confirmatory Lyme IgM and IgG Western blots (WB) should absolutely be obtained in borderline and reactive first-tier test results. The Lyme IgM WB response is the first to appear after initial exposure to B. burgdorferi and is comprised of specific and non-specific bands. This is followed by the Lyme IgG WB response of specific and non-specific band reactivity months later. Consensus criteria have been developed for WB confirmation which have very high specificity, wherein a positive Lyme WB IgG provides compelling confirmation that an acute disorder may indeed be due to B. burgdorferi infection, while a positive Lyme WB IgG provides strong support of more long-standing infection. However, neither IgM nor IgG have very high sensitivity. Early treatment may lead to falsely negative serological test results as may also occur in immune-compromised individuals and immune competent patients with true infection that are tested before a Lyme IgM WB immune response is mounted. Baseline serology at the onset of antibiotic treatment may provide documentation of a favorable response to therapy with improvement in the number of specific reactive bands.
A spinal tap for CSF studies should be considered in all patients with CNS involvement for routine studies and paired serum for B. burgdorferi serology, including diagnostic levels intrathecal Lyme specific IgM and IgG antibodies, and isolation studies for B. burgdorferi culture by DNA using a polymerase chain reaction (PCR) methodology with comparison to a paired serum specimen. Common CSF findings in neurological Lyme disease include elevated protein content, normal glucose, lymphocytic pleocytosis, and humoral immune response composed of intrathecal immunoglobulins that depend upon the stage and activity of the disorder.
Brain neuroimaging including magnetic resonance imaging (MRI) of the brain and spinal cord should be considered in all patients with suspected neurological Lyme disease employing T1- and T2-weighted sequences to quantify the structural integrity of the brain. Conventional MRI may shows subcortical WMC that are indistinguishable from multiple sclerosis (MS) in T2 and fluid-attenuated inversion recovery (FLAIR) imaging. Functional neuroimaging has become useful in the management of neurological Lyme disease. High-field 3-D 1H-MR spectroscopy (MRS), coupled with metabolic analysis to calculate whole brain N-acetyl aspartate (NAA) levels, experimentally showed difference between the WMC due to neurological Lyme disease and MS. Nuclear medicine cerebral perfusion with single photon emission computed tomography (SPECT) reveals various patterns of potentially reversible cortical hypo perfusion in various stages of CNS Lyme disease and encephalopathy. Metabolic analysis of the brain employing FDG position emission tomography (PET), coupled with contrast MRI, adds additional valuable information when encephalopathy or overt dementia is suspected.
Nerve conduction studies (NCS) and electromyography (EMG) of the affected limbs and regions employing standard techniques should be considered in clinically symptomatic patients to investigate large nerve fiber function. Such studies can discern the type, duration, severity, and likely histological basis of the underlying neuropathic disorder from among the likely disorders associated with neurological Lyme disease including radiculopathy, MNM, and DPN that typically presents with patchy radicular and distal sensory disturbances characterized as stiffness, numbness, tingling, prickling, aching, or jabbing sensations, with little or minimal frank motor involvement. ENF analysis via 3 mm punch biopsy of the thigh and calf documents the density of small fibers responsible for disturbed heat-pain sensations. Beat-to-beat BP and HR responses to a 5 minute head-up tilt, deep breathing, and Valsalva maneuver, screens for ANS dysfunction, the symptoms of which typically consist of palpitation, dizziness, headache, and lightheadedness in association with OI and POTS. Such disturbances, are closely linked with SFN making ENF indispensable in ANS disturbances.
While screening metabolic, autoimmune and infectious serology are widely employed and probably overused in a given patient, their value cannot be overemphasized as Lyme disease in planning antimicrobial therapy, or in the detection of a coincidental or related condition that requires separate treatment.
The mechanisms of the etiopathogenesis of nervous system damage in neurological Lyme disease are not well understood but are likely related to aspects of the infectious process and post-infectious autoimmune host factors; however the two processes may overlap in a given patient. The factors that influence the infectious process include tropism of the B. burgdorferi pathogen for particular areas of the CNS and PNS, the duration of tick attachment, dose of spirochete inoculum, the particular organism strain, and persistent atypical cystic and granular spirochete forms. The factors that influence the host response to B. burgdorferi infection include a prior history of infection, the status of host immune competence, the innate host major histocompatibility complex, (MHC) or human leukocyte antigen (HLA) system that resides on chromosome 6, encoding antigen-presenting proteins and other essential elements of the cell-mediated and humoral immune host response. Moreover there may be associated tick-borne co-infections, and concomitant viral and parasitic infection. The possible mechanisms of inflammation related to acquired humoral and cell-mediated, post-infectious immunity, likely impact and gain access to the nervous system disrupting the blood-brain, blood-CSF and blood-nerve barriers.
NEUROLOGICAL LYME DISEASE TREATMENT
In general, once the suspected diagnosis of B. burgdorferi infection is ascertained in an affected patient, antibiotics therapy should commence. For those with objective brain and spinal cord involvement, there is good evidence and consensus that parenteral antibiotics are safe and effective. For patients without brain or spinal cord involvement there is good evidence and consensus that oral doxycycline is probably safe and effective but this medication should not be used in children under the age of eight or in pregnant women. Recommendations of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) include treatment with parenteral antibiotics for syndromes associated with meningitis, encephalomyelitis, encephalopathy, and any neurological syndrome with CSF pleocytosis. Similarly, severe neuropathic disease syndromes, particularly those deemed oral antibiotic treatment failures, warrant treatment with parenteral therapy, including peripheral nerve radiculopathy, diffuse neuropathy, MNM, and cranial neuropathy. Doctors treating Lyme disease, and any concomitant tick-borne, viral and parasitic illness, must choose from a wide variety of available therapies, recognizing that the inherent toxicities, anticipated complications, and risks of suppressing innate bacterial flora. The injudicious use of agents by a single treating physician can often be tempered by the collective input of other physicians, each with his or her experience, collaborating in a team effort for each patient. Various forms of immunotherapy have become mainstream in providing immune competence to those with deficient or overactive immune systems. Those forms of therapy, including intravenous and subcutaneous immune globulin (Ig), should be performed by physicians with a unique competence in that field.
Lyme disease, a spirochete that has been the subject of extensive study in the past forty years, frequently affects the CNS and PNS, and ANS, with aspects related to the infectious and post-infectious autoimmunity. The abrupt onset of acute meningoradiculoneuritis with CSF pleocytosis and a triad of meningitis, radiculitis, and cranial neuritis in an affected patient, weeks to months after a spreading rash, should prompt a vigorous search for the causative agent, B. burgdorferi. Occasional patients present with chronic CNS involvement, including encephalopathy long after initial treatment has been given.