How will research on neurologic Lyme disease need to change to identify better treatments?
Research must distinguish between clinical constructs.
Four clinical constructs are commonly attributed to nervous system Lyme disease, but only one of these actually represents nervous system infection with Borrelia burgdorferi, also known as neuroborreliosis. However, there are legitimate and important research questions regarding each of the four.
Neuroborreliosis manifests as lymphocytic meningitis, multifocal inflammation of nerves and nerve roots (including cranial neuritis, radiculoneuritis, and mononeuropathy multiplex), and – very rarely – multifocal inflammation of the central nervous system. This is probably the only one of these four constructs in which animal models, primarily nonhuman primates, can be informative.
Although antibiotics are curative for neuroborreliosis, it is virtually impossible (except in meningitis) to demonstrate spirochetes in involved tissue. Immune activation and amplification appear to play key roles in pathogenesis, but their mechanisms require clarification. Are there specific markers – such as cytokine responses, human leukocyte antigen type, prior host immune exposures, the site of the bite, spirochete genotype, blood culture positivity, or particular Western blot bands, to name just a few –that predict which patients will develop neuroborreliosis and its particular form? Are there predictors of the rate or completeness of antimicrobial response? Do similarities between host and spirochete antigens cause antispirochete antibodies to attack the host?
Current diagnostic tools for neuroborreliosis are excellent. However, the sensitivity and specificity of cerebrospinal fluid (CSF) antibody measurement and polymerase chain reaction should be explored in well-defined populations with CNS infection. Measures of treatment response need improvement, be they nonspecific or specific. Although the currently recommended parenteral antibiotic regimens are highly effective, several European studies indicate that oral doxycycline is as effective as parenteral antibiotics for all but parenchymal CNS disease (Neurology 2007;69:91-102). This requires confirmation in U.S. patients.
A second clinical entity, referred to as Lyme encephalopathy, manifests as altered cognitive function in the setting of extraneurologic (but usually not nervous system) infection. Like patients with many other systemic inflammatory states, individuals with active Lyme disease often describe cognitive and memory difficulties, in the absence of CNS infection. An understanding of this disorder, which presumably is mediated by cytokines or other soluble molecules that are produced systemically and diffuse into the CNS, may well provide broad insights into the delirium seen in many other systemic infections. Studies should focus on the range of neuroimmunomodulators that are present in the serum and CSF of such patients, as well as microorganism characteristics. Informed by these studies, researchers can explore more specific therapeutic interventions.
Posttreatment Lyme disease syndrome (PLDS) manifests typically as fatigue, perceived cognitive and memory difficulty, widespread pain, sleep disorders, and other symptoms overlapping extensively with chronic fatigue syndrome, fibromyalgia, and similar states. These symptoms occur and persist for many months following usually curative treatment of patients with clear-cut Lyme disease. Identical symptoms have been observed following other infectious or inflammatory states.
Larger prospective studies are needed to establish whether PLDS occurs more frequently after Lyme disease than in control populations. If so, understanding its pathophysiology may be informative both for this state and for a broader range of similar, postinfectious states. Additional studies should focus on both who is affected and why. Work to date indicates that PLDS is not caused by ongoing infection, but rather appears to relate to pre-illness traits. Recovery seems to correlate best with patients’ emotional resilience (Am. J. Med. 2009;122:843-50) and only inconsistently with psychiatric comorbidities such as depression or anxiety.
Assays of markers of innate and acquired immunity both in serum and CSF could be performed to test whether or not there is ongoing immune stimulation in PLDS. A possible role of coinfections with other tick-borne infections such as flaviviruses can be assessed as well. The role of learned behavioral responses to stressors can be assessed by prospective studies using neuropsychological metrics and brain functional MRI or possibly PET scans. Treatment recommendations would follow from the demonstrated pathophysiology.
In other instances, individuals are diagnosed with and treated for "chronic Lyme disease" despite the absence of any evidence for their ever having had this infection. These symptoms are identical to PLDS and significantly impact quality of life in an estimated 2% of the general population (Med. Care 2005;43:1078-86), but often do not have an identifiable cause. Future studies should compare these patients to individuals believed to have PLDS to determine if there are any biological differences between the two populations. The tools described above for PLDS should then be used to study the pathophysiology of this far more prevalent disorder.
Dr. Halperin is a professor of neurology at the Mount Sinai School of Medicine, New York, and is medical director of the Atlantic Neuroscience Institute and chair of the department of neurosciences at Overlook Hospital in Summit, N.J. He has served as an expert witness defending physicians accused of failure to diagnose nervous system Lyme disease.
