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SAVE THE DATE!
2014 Lyme & Tick-Borne Diseases:
Medical, Neuropsychiatric & Public Health Implications

Providence Downtown Marriott

Providence, RI

May 3-4, 2014



Spinal Fluid and Brain Tests

a. Spinal Fluid

Patients with neurologic symptoms suggestive of central nervous system involvement should have a lumbar puncture with determination of opening pressure.   When the CSF is examined, the fluid should be sent for routine studies such as cell count, and protein and glucose levels.  In addition, the CSF should be sent for Bb PCR assay and paired serum and CSF should be sent for calculation of the intrathecal index.  Please note that the serum should be drawn on the same day as the spinal fluid for an optimal study. The index refers to the ratio of Bb antibodies in the CSF compared to the serum, corrected for immunoglobulin levels in each of those fluid compartments.  When the index is positive, that indicates that there is a preferential production of antibodies against Bb in the CSF – a finding strongly suggestive of central nervous system invasion by the agent of Lyme disease.  It is believed that the index may remain positive long after the initial infection has been treated due to immunologic memory.  If the CSF is being examined as part of the differential diagnosis with multiple sclerosis, the neurologist is also likely to order other tests, such as an assay for oligoclonal bands.   Unfortunately, patients may have neurologic Lyme disease but test negative on the Lyme index.  When positive however, the clinician can be confident that this particular individual has or has had central nervous system Lyme disease.

b. Imaging

a. MRI.  

1Unlike SPECT and PET images which assess brain function, MRI captures the physical structure of the brain.  Inflammatory abnormalities in the brain are also assessed with MRI scans.  In children with neurologic Lyme disease, the MRI may reveal white matter hyperintensities suggestive of inflammation or areas of demyelination.  Up to 40% of adults with Lyme disease may also have small white matter hyperintensities, but it should be noted that the number of hyperintensities increase with age – even among patients who do not have Lyme disease.  In addition, certain factors such as ischemic disease or a history of smoking may result in an increased number of hyperintense areas.

1The white matter hyperintensities are sometimes called UBOs or "unidentified bright objects". In some patients, antibiotic treatment results in a diminution or disappearance of these hyperintensities. Certain MRI sequences, such as FLAIR, are best able to detect hyperintensities. These MRI images in Lyme Disease may appear similar to the demyelinated areas seen in the "white matter" of the brain MRI of patients with multiple sclerosis.  The brain MRI of the young patient at the left revealed MS-like lesions in this individual with  a fully positive IgG Lyme Western blot indicating immune reactivity against the agent of Lyme disease.  Because an MRI scan uses a very powerful magnet, patients with pacemakers or other metallic implants should not get an MRI.

b. SPECT Imaging

Single Photon Emission Computerized Tomography (SPECT) is an imaging device that provides a picture of the functioning of the brain. The advantage of SPECT imaging is that it is widely available and relatively inexpensive (compared to PET imaging). SPECT machines with several "heads" allow for increased imaging sensitivity. In Lyme Disease, the most common finding is of heterogeneous hypoperfusion diffusely throughout the brain. This pattern cannot be distinguished from diseases with a similar pattern, such as Lupus, chronic cocaine abuse, or other vasculitic inflammatory disorders. This pattern of heterogeneously decreased perfusion is different from what one would see in patients with primary depression or Alzheimer's disease.  Approximately 70% of patients with chronic Lyme disease will have multiple areas of hypoperfusion.  1

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A. Alzheimer's disease
B. Cerebral Vasculitis


C1. Lyme Disease prior to treatment
C2. Lyme Disease with improvement following treatment


D1. Lyme Disease prior to treatment
D2. Lyme Disease with deterioration following treatment

Note: areas of yellow show normal cortical flow

Although the pattern looks like a vasculitis, such a pattern could be produced even if the blood vessels were normal if the nerve connections to the blood vessels were functioning abnormally. In other words, a SPECT scan cannot tell you whether the problem is due to your blood vessels or due to nerve cell dysfunction. SPECT scans also are limited in that the images obtained are rated relative to a part of the brain that is presumed to be working normally, such as the cerebellum or deep gray matter. This may not be true in Lyme Disease. This lack of "absolute quantification" limits the firmness with which one can draw conclusions regarding a SPECT image. Although SPECT imaging may be considered a helpful adjunctive tool in the differential diagnosis of Lyme Disease, it does not and cannot "make" the diagnosis of Lyme Disease.

SPECT imaging is also used to determine whether the heterogeneous hypoperfusion has diminished over time, perhaps due to treatment. Repeated SPECT scans should be done at the same medical center to allow for a fair comparison across images.

PET Imaging

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Positron Emission Tomography (PET), although primarily a research tool, has been used increasingly for clinical purposes. PET imaging can demonstrate biochemical or physiological processes involved in brain metabolism. The assumption behind all functional brain imaging (such as PET) is that there is a close relationship between local brain nerve activity, brain glucose metabolism, and brain blood flow. The advantage of PET (in comparison to SPECT) is that the images have enhanced resolution and, in research settings, with the use of an arterial line, absolute quantification of the metabolism and flow in different brain areas is possible. In other words, unlike SPECT which requires assumptions about normal and abnormal brain areas for interpretation, PET can provide a definitive absolute number regarding the amount of flow or metabolism in a particular area of the brain. Because a PET center requires a highly trained multi-disciplinary staff of physicists, chemists, computer and mathematical experts, technologists, and physicians as well as a cyclotron in the same building as the patient and the scanner to allow for production of the radiopharmaceuticals, PET scans are more expensive and far less widely available than SPECT scans.

1Different radiopharmaceuticals allows us to measure different aspects of brain function. For example, the most widely used "tracer" for measuring regional brain blood flow is 15O-labeled water.18F(fluorine) as fluorodeoxyglucose (FDG) is widely used to measure brain glucose metabolism, since the brain uses glucose to function. Because the radioactive tracer used for FDG PET scans is stable over many hours, PET scans in clinical settings typically assess metabolism directly (through monitoring of glucose function) rather than blood flow.  One way of determining whether the brain blood vessels are functioning normally is to conduct a 15O-PET before and after a carbon dioxide inhalation challenge. The patient is then asked to breathe through a tube that contains a slightly higher amount of carbon dioxide than the normal atmosphere. In a person with normal blood vessels, this should result in an expansion of blood flow throughout the brain. If certain areas have damaged blood vessels, then the expansion of flow in that area would be less. This is one way of determining whether the problem in a disease (such as Lyme encephalopathy) is due to inflamed or blocked small blood vessels or due to normal blood vessels with abnormal nerve input.  Because this carbon dioxide inhalation challenge however is not routinely available in the clinical setting, an approximation may be obtained by using the medicine acetazolamide.

At this point, it is unclear whether PET has an advantage over SPECT for clinical evaluation of a patient with possible Lyme Disease.  Recent reports from Dr. James Moeller of the Columbia Lyme Center however suggest that there is a specific neural circuit that can be measured using a PET scan that may be associated with intrathecal antibody production using the C6 ELISA assay.  If this finding is confirmed by further study, then PET scans make emerge as a very helpful clinical tool in differential diagnosis.

c. Neuropsychological Testing            

Comprehensive cognitive assessments are valuable for several reasons. First, they provide an objective measure of the person's cognitive functioning at a specific point in time. Second, by providing fully quantitative results, the testing is a very useful way to monitor change in response to treatment for patients with cognitive deficits. Third, neuropsychological tests may help to differentiate between organic or neurologic and psychiatric causes of cognitive problems. Fourth, an understanding of static deficits may help to guide the individual in the construction of alternate strategies to cope with cognitive deficits; for example, a person with auditory attention problems may do best with visually presented information.

Since subjective reports of cognitive difficulties, such as memory problems, do not always correlate with objective data, we cannot rely only on self-reported cognitive problems. A comprehensive selection of tests is administered, including measures of general intellectual functioning as well as specific areas of functioning such as verbal and visual memory and learning, attention/concentration, verbal fluency, processing speed, fine and gross motor functioning, and executive functioning is administered. The sensitivity of neuropsychological tests in identifying brain dysfunction is high, though the test deficits are not specific to Lyme Disease. Measures of psychopathology, particularly depression and anxiety are administered as well since affective states may affect cognitive performance .

Impairments in memory, working memory, attention and mental activation, language conceptual ability, and motor function have been documented in adults with LD. The most consistently identified deficits in adults with Lyme disease have been problems with verbal memory, verbal fluency and mental processing speed.  Verbal memory is typically assessed by a list-learning task such as the Buschke Selective Reminding Test or the California Verbal Learning Test.  Verbal fluency is often assessed through the Controlled Oral Word Association Test or through Category fluency tests.  Speed of processing is assessed through any of the timed tests, such as digit symbol.

Studies by Keilp, Kaplan, Krupp and others support the hypothesis that cognitive impairments are caused by CNS dysfunction and not secondary to a psychological response to chronic illness. Subjective memory impairments may however be higher in LD patients with comorbid depression, a finding which strengthens our recommendation that patients with depression should be monitored closely by a psychopharmacologist.

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