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.[1] 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.[4] 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.[5] 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.[6] 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.
1. Coyle
PK: Neurologic Lyme disease update. 12th International Conference on Lyme
Disease and Other Spirochetal and Tick-Borne Disorders, New York, NY, 1999.
2. Coyle
PK, Schutzer SE, Deng Z, et al: Detection of Bb-specific antigen in
antibody-negative cerebrospinal fluid in neurologic Lyme disease. Neurology
45:2010-2015, 1995.
3. Coyle
PK, Deng Z, ,Schutzer SE, et al: Detection of Bb antigens in cerebrospinal
fluid. Neurology 43:1093-97, 1993.
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.
5. Logigian
EL, Johnson KA, Kijewski MF, et al: Reversible cerebral hypoperfusion in Lyme
encephalopathy. Neurology 49:1661-1670, 1997.
6. Fallon
BA, Das S, Plutchok JJ, et al: Functional brain imaging and neuropsychological
testing in Lyme Disease. Clin Infectious Disease 25(s):57-63, 1997.