Lyme disease, caused by the tick-borne pathogen, Borrelia burgdorferi (Bb), is the major human spirochetal infection in the United States and Europe. Neurologic involvement occurs in up to 40% of symptomatic infections. Two presentations today outlined some of the complexities of this illness and described new tools to assist in diagnosing cases of central nervous system (CNS) Lyme Disease.
Dr. Patricia Coyle, of the State University of New York at Stony Brook, described the typical neurologic presentations in Lyme disease, as well as some of the atypical ones. Lyme disease may be categorized into three stages: early localized infection, early disseminated infection, and late disseminated infection. Early localized infection is characterized by the erythema migrans (EM) rash, although in some cases the infection is no longer localized as a result of CNS seeding that may occur even before the EM rash appears. Early disseminated infection may result in meningitis, cranial nerve palsy, or acute radiculoneuritis.
Late disseminated infection may result in encephalopathy (the most common manifestation of chronic neurologic Lyme disease), encephalomyelitis (which at times may appear similar to multiple sclerosis but most often without the cerebrospinal fluid production of oligoclonal bands), and polyradiculoneuropathy. The pathology of CNS Lyme disease is most notable for a lack of tissue destruction, signifying that the pathophysiology has less to do with direct damage and more to do with a provoked immune or inflammatory response. Immunomodulatory therapies, therefore, may have a role in the treatment of neurologic Lyme disease. Steroid treatment, however, should be avoided as it may exacerbate the illness.
The gaps in our understanding of CNS Lyme disease stem from several factors. First, we lack a definitive assay to demonstrate active infection. Second, Bb infection can be occult, resulting in long periods of latency before symptoms are manifest. Third, Bb can disseminate to sequestered compartments where antibiotic penetration is difficult and immune surveillance is lacking. Fourth, Bb is known to have considerable strain heterogeneity. This strain heterogeneity may result in different levels of virulence and different organotropism. For example, some strains may be more likely to result in arthritic or skin disease whereas others may target the nervous system.
Fifth, the antigenic variability of Bb is known to result in different antigen expression in different locales. In the tick, outer surface protein (Osp) A is expressed, whereas in the human it is upregulated to Osp C (prior to transfer to the host by the tick). However, Osp A may be preferentially expressed in the CSF compartment, as the studies at Stony Brook have demonstrated. CSF studies at Stony Brook also have demonstrated a strong immunoglobulin M response, the presence of immune complexes, and a prominent TH1 proinflammatory cytokine response. Sixth, the significance of coinfection with other tick-borne organisms such as Babesia is not fully understood. Such co-infection may be misdiagnosed as being only Lyme disease and result in more severe and refractory cases of Lyme disease.
Finally, although there are well-characterized neurologic syndromes associated with early and late stage infection, the full spectrum of neurologic Lyme Disease has not yet been fully described. Patients with new onset Bb infection may develop an acute CNS demyelinated disease that looks much like multiple sclerosis; although rare, these cases do occur and do respond well to intravenous antibiotic therapy. Stroke-like syndromes and CNS vasculitis have also been induced by CNS infection with Bb.
The optimal treatment of neurologic Lyme disease is not yet known. Intravenous antibiotic therapy with Ceftriaxone or Cefotaxime is the accepted standard because these drugs more effectively penetrate the blood-brain-barrier. In studies of Lyme arthritis in which patients were treated with oral antibiotics, the treatment failures often showed signs of neurologic involvement, suggesting that oral antibiotics may be insufficient to eradicate infection that may already be sequestered in the CNS compartment.
Dr. Coyle presented preliminary results from a study of children and adults being conducted at the University Hospital at Stony Brook. Of the adult patients, the sample was primarily early Lyme disease: 40% had EM; 22% had a Bell's Palsy; and 17% had multifocal EM. Of this sample of 18 adults, although 47% had evidence of Bb antibody in the CSF, only 12% had evidence of intrathecal antibody production. In the 12 children with early-disseminated Lyme disease, 67% had a facial nerve palsy and 25% had multiple EM; of these, only 17% had evidence of intrathecal antibody production.
These findings were reinforced by earlier work done by the SUNY group in collaboration with Dr. Steven Schutzer and others in which immune complex dissociation enabled the disentangling of immune complexes and therefore the detection of Osp antigen and Bb antibodies.[2,3] Dr. Coyle emphasized that, unlike European Lyme disease, North American neurologic Lyme disease does not commonly demonstrate intrathecal antibody production. Therefore, the absence of intrathecal antibody production cannot rule out the presence of active neurologic Lyme disease, as in most cases such intrathecal production does not occur. The most common symptoms in the adults were fatigue, stiff neck, headache, and cognitive problems, whereas the most common symptoms in the children were headaches, sleep problems, fatigue and mood disturbances -- but not memory problems. Dr. Coyle concluded by noting that adults with neurologic Lyme disease appear to be more symptomatic than children.
Dr. Ronald Van Heertum, of the Columbia University College of Physicians and Surgeons, addressed the role of functional brain imaging in the diagnosis of chronic CNS Lyme disease. The need for such adjunctive diagnostic tools stems from the often nonspecific neurobehavioral symptoms presented by patients with chronic Lyme disease.
CT and MRI scans often may not reveal abnormalities in these patients. But functional brain imaging, particularly SPECT imaging, shows promise as a contributory adjunctive diagnostic technique, based on the assumption that brain blood and metabolism are tightly coupled. The most up-to-date SPECT scans use a triple-headed machine, but Dr. Van Heertum suggested that dual-headed machines also may produce useful images.
In about 70% of chronic Lyme disease patients with cogntive symptoms, brain SPECT scans typically reveal a pattern of global hypoperfusion in a heterogeneous distribution through the white matter. This pattern is not specific for Lyme disease; it can also be seen in other CNS syndromes such as HIV encephalopathy, viral encephalopathy, chronic cocaine use, and vasculitides. However, this pattern is different from what one would see with normal controls, patients with primary depression, patients with Alzheimer's disease, and patients with focal brain damage as in stroke.
Dr. Van Heertum presented a recent study from Columbia University, conducted with Drs. Lestor Johnson and Vitale Furman, of 20 patients with chronic Lyme disease and 7 normal controls whose brain SPECT scans were subjected to an SPM analysis. This quantitative approach to the evaluation of a SPECT image allows comparison of the blood flow in small areas or pixels of brain. Remarkably, the Lyme patients as a group (and each Lyme patient individually) had significantly reduced uptake of radioactive tracer (perfusion), primarily in the white matter. These results suggest that the primary pathology in Lyme disease is related to white matter dysfunction.
In conclusion, Dr. Van Heertum emphasized that SPECT imaging can have a role in Lyme disease by helping to demonstrate diffuse CNS involvement, differentiating Lyme disease from other syndromes that do not cause a diffuse process, and in monitoring the course of treatment.
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4. Heertum RV: Functional brain imaging in the diagnosis of chronic CNS Lyme disaese. 12th International Conference on Lyme Disease and Other Spirochetal and Tick-Borne Disorders, New York, NY, 1999.
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