Donta, Sam T. MD*; Noto, Richard B. MD†; Vento, John A. MD‡
From the *Department of Medicine (Infectious Diseases), Boston University Medical Center, Boston, MA; †Department of Diagnostic Imaging (Nuclear Medicine), Rhode Island Hospital, and The Warren Alpert Medical School of Brown University, Providence, RI; and ‡Department of Diagnostic Imaging and Therapeutics (Nuclear Medicine), University of Connecticut School of Medicine, Farmington, CT.
Received for publication January 25, 2011; and revision accepted April 23, 2012.
Dr Donta is currently with the Department of Medicine (Infectious Diseases), Falmouth Hospital, Falmouth, Mass.
Some of the results included here were reported in preliminary fashion at the 43rd Annual ICAAC Meeting, Chicago, Ill, September 14–17, 2003.
Conflicts of interest and sources of funding: none declared.
Reprints: Sam T. Donta, MD, Donta Infectious Disease, PO Box 944, Falmouth, MA 02541. E-mail: email@example.com.
Objectives: Lyme disease is an infectious disease that frequently involves the central nervous system, leading to cognitive and/or mood dysfunction. The basis for these symptoms remains to be defined but may be the result of a vasculitis or metabolic abnormality secondary to the infection. SPECT scans of the brain might provide an objective measure of abnormalities present in patients with otherwise difficult to objectify clinical findings. The objective of this study was to determine the frequency, location, and severity of abnormalities in SPECT scans of the brain of patients with chronic Lyme disease.
Methods: A total of 183 individuals who met the clinical definition of chronic Lyme disease underwent SPECT scanning of the brain using 99mTc and standard nuclear imagine techniques. Abnormalities of perfusion to affected areas of the brain were defined as mild, moderate, or severe.
Results: Of all patients, 75% demonstrated abnormalities in perfusion to various areas of the brain, most notably the frontal, temporal, and parietal lobes. Patients considered to be seropositive and those considered seronegative had similar rates, types, and severity of perfusion defects. Abnormalities of MRI of the brain were seen in 14% of patients. Treatment with antibiotics, especially those with intracellular-penetrating activity, resulted in resolution or improvement of abnormalities in 70% of patients over a 1- to 2-year period.
Conclusions: Brain SPECT scans are abnormal in most patients with chronic Lyme disease, and these scans can be used to provide objective evidence in support of the clinical diagnosis. The use of certain antibiotic regimens seems to provide improvement in both clinical status and SPECT scans.
Lyme disease is the result of infection with Borrelia burgdorferi, and the nervous system seems to be the primary target of the infection.1 The central nervous system, the peripheral nervous system, and the autonomic nervous system can all be affected by the infection. Central nervous system involvement may be manifested as meningitis, meningoencephalitis, or encephalopathy. The encephalopathy usually involves changes in cognitive and/or mood function that can persist for long periods and can create diagnostic problems for the physician. Abnormalities in both MRI and SPECT scans of the brain have been previously noted in small numbers of patients,2–5 with the MRI typically showing some areas of T2 hyperintense signal, and the SPECT scan showing perfusion defects, typically in the temporal and/or frontal lobes that are involved in cognitive and mood function, respectively. The underlying basis for the SPECT findings remains to be delineated but may involve a mild vasculitis.1–3
This report details the results of SPECT scans of the brains of 183 patients with chronic Lyme disease seen and evaluated over a 5-year period. The results support the utility of SPECT scans of the brain in the diagnosis and management of patients with the chronic form of the disease.
Patients were considered to have chronic Lyme disease if they lived or were exposed to deer ticks in an endemic area for Lyme disease and had symptoms (2/3) of otherwise unexplained fatigue, musculoskeletal pain, and/or neurocognitive dysfunction persisting for more than 6 months, a definition similar to that of chronic fatigue syndrome.6 Patients given the diagnosis of chronic fatigue syndrome or fibromyalgia were not excluded from the analyses. All patients included in the study had serologic testing. Patients who had one or more reactions against proteins highly-specific for B. burgdorferi on Western immunoblots were considered seropositive patients (110 patients, 60%), and those without any such reactions were considered seronegative patients (73 patients, 40%).1 Patients selected for SPECT examinations of the brain were those who reported neurocognitive and/or mood dysfunction that impaired their daily living activities. Patients who had a history of head trauma or ongoing use of narcotics for pain control were excluded from the study. Many patients had cerebrospinal fluid examinations with normal results, and they were not excluded from the study.
Brain SPECT scans were performed using dual-head gamma cameras, either the Picker Prism 2000 or the ADAC Genesys camera. Matrix size was 128 × 128, pixel size was 3.23 × 3.23 (width by height), and camera rotation was 360 degrees. Attenuation correction, center of rotation, and high count flood uniformity corrections were routinely performed. Each patient received 20 mCi of 99mTc-ethyl cysteinate dimer or HMPAO for their scan. After administration of radiopharmaceutical agents, patients were kept in a quiet, dark environment for 45 to 60 minutes before imaging. SPECT acquisition was performed for approximately 30 minutes and reconstructed using standard filtered back-projection algorithms done with a Butterworth filter. Abnormalities were graded as mild, moderate, or severe, as well as localized or diffuse. Each scan was interpreted by a single observer—a fellowship-trained nuclear medicine physicians with more than 5 years of experience in interpreting SPECT scans of the brain. Cortical activity was based on the intensity of uptake relative to the cerebellum (which was assumed to be unaffected by the disease process and normal unless focal defects were present). In equivocal cases, a region-of-interest analysis was performed with regions manually placed on the cerebellum and the cortical regions of interest, looking for a reduction in cortical activity below 70% of the cerebellar activity. No statistical tests were used because interpretations of these scans were deemed to be qualitative. Scans were generally repeated at 1-year intervals, and correlations were made with the patient’s clinical status.
Most patients were treated with courses of intracellular-penetrating antibiotics, either tetracycline itself, 1500 mg/d, or the combination of clarithromycin (1000 mg/d) and hydroxychloroquine (400 mg/d) over at least a 3-month period, usually 6 months—a regimen that seems to result in resolution of sustainable improvement in patient symptoms.11,12
A total of 183 patients who met the inclusion and exclusion criteria underwent SPECT scanning of the brain between 1995 and 2001. Of both seropositive and seronegative patients, 75% had discernible abnormalities on their initial scans, with no differences in the incidence or severity of abnormalities between the 2 groups (data not shown). The temporal, frontal, and parietal lobes were the areas most often affected, often involving only 1 lobe (temporal lobe alone, 46%; frontal lobe alone, 40%; parietal lobe alone, 33%), with the combination of temporal and frontal lobes seen in 27%; temporal, frontal, and parietal lobes in 15%; temporal and parietal lobes in 7%; and frontal and parietal lobes in 6%. The severity of abnormalities is displayed in Figure 1.
There were no differences in the incidence or severity of abnormalities according to sex or age (data not shown). Patients with symptoms for up to 1 year were less likely to have abnormalities than those with symptoms for greater than 2 years, and abnormalities tended to be more severe in patients with symptoms for more than 5 years (Table 1). There were no differences in the distribution or severity of SPECT scan abnormalities between patients who were seropositive and those who were seronegative (data not shown).
Abnormalities of brain MRI were found in 14% of 62 patients who had both MRI and SPECT scans of the brain (Table 2). These were typically T2 hyperintense signals that were present in different locations of the brain, some with periventricular predominance. There seemed to be no correlation between the severity of the SPECT scan results and the presence or absence of abnormalities in the MR images.
Seventy percent of treated patients with abnormalities on the SPECT scans of their brains showed improvement or clearing of all perfusion defects after antibiotic treatment of their chronic Lyme disease (Table 3). Compared with untreated patients (16/88, 18%), patients treated with intracellular-penetrating antibiotics, that is, tetracycline (8/19, 42%), or the combination of clarithromycin and hydroxychloroquine (8/11, 72%) had greater normalization of their scans than did patients treated with IV ceftriaxone (4/26, 15%) or other β-lactam antibiotics (eg, oral amoxicillin) or doxycycline (10/38, 26%; data not shown). An example of a SPECT scan of the brain in a patient with moderately severe changes before and after treatment is shown in Figure 2. Persisting abnormalities were demonstrated in 30% of patients, with results correlating with their lack of clinical improvement.
Patients with Lyme disease often develop abnormalities of cognitive function, including short-term memory deficits, inability to concentrate, and problems with retrieval of words and numbers, especially those with ongoing or recurring symptoms of Lyme disease. Problems with mood function can occur as well, leading to panic, anxiety, depression, hallucinations, or bipolar disorder.7 It is unclear how infection with the causative agent, B. burgdorferi, results in the symptoms, but there is evidence that the bacteria can infect the central nervous system.8,9 Whether the symptoms and/or the changes in the SPECT scans of the brain seen in patients with chronic Lyme disease are secondary to the effects of a neurotoxin found in B. burgdorferi10 or due to other nonspecific effects remains to be determined. Regardless, it does seem reasonable to assume that the consequences of infection, especially involving the temporal and frontal lobes, correlate with deficits in function associated with those parts of the brain, that is, cognitive and mood, respectively. The results of the SPECT scans of the brain reported here, as well as previous reports,2–5 are consistent with that assumption.
The reversibility of the abnormalities in the SPECT scans of the brain using antibiotic therapy supports the hypothesis that the abnormalities are secondary to persisting infection. Reversal of the abnormalities seems to require a number of months, results consistent with clinical observations.1,4,5,11,12 Although no controlled clinical trials have been conducted to evaluate the comparative abilities of various antibiotics to improve central nervous system function, including abnormalities in the SPECT scans of the brain, our findings support the hypothesis that intracellular-type antibiotics (eg, tetracycline, clarithromycin combined with hydroxychloroquine) are more effective than IV β-lactam antibiotics in resolving the abnormalities. These results also discount any role of the blood-brain barrier in determining the type of antibiotic required to result in improved function.13
The abnormalities seen on SPECT scan are not specific for Lyme disease. Other causes include head trauma, ischemia, use of narcotics, and, in 1 study, a violent offender.14–16 Similar abnormalities have been noted in chronic fatigue syndrome,17–19 although involvement of the occipital lobe was found more frequently in 1 study.19 Ichise et al19 noted SPECT abnormalities involving the frontal lobe in 63%, the temporal lobe in 35%, parietal lobe in 53%, occipital lobe in 38%, and basal ganglia in 40% of 60 Canadian patients with chronic fatigue syndrome. In limited studies, perfusion deficits involving the frontal and left temporal lobes have also been described in patients with multiple sclerosis.20 Most patients in our series demonstrated perfusion deficits involving the temporal, frontal, and parietal lobes—patterns that have been previously noted. But there were also changes involving periventricular areas, basal ganglia, and the corpus callosum. The specificity of these abnormalities for Lyme disease remains to be established, but their reversibility with antibiotic treatment supports a relationship to the underlying Lyme disease. These abnormalities are not seen in normal individuals, nor are they part of any day-to-day variation. Therefore, in patients with a clinical picture compatible with chronic Lyme disease, the presence of abnormalities in the SPECT scan of the brain provides objective evidence supporting the clinical diagnosis. And the ability to reverse the abnormalities with certain antibiotic therapies provides additional objective evidence, along with reason for optimism that the clinical symptoms can be reversed.
There did not seem to be a good correlation between the results of SPECT studies of the brain and abnormalities noted on MR images of the brain. Abnormalities in the MR images were noted in only 14% of patients but, when present, could be considered as additional objective evidence in support of the clinical diagnosis. Abnormalities in the MR images have been an important component of the diagnosis of multiple sclerosis, but the overlap between abnormalities in the MR images seen in patients with Lyme disease and those seen in patients with multiple sclerosis has often created difficulties in the differential diagnosis of these 2 entities.
There were several limitations to this study. SPECT data were interpreted by a single reader, albeit by faculty with more than 5 years of experience with such scans. Quantitative analyses were performed in some scans, but there was not 1 coherent quantitative program that was used by each institution because there is no standard quantitative analysis program for SPECT scans of the brain that is widely used across institutions. Instead, there are a wide variety of methods for doing quantitative analysis, and there has been no firm conclusion that quantitative analysis makes for improved interpretations. As with other radiologic procedures, experience is needed for the appropriate interpretation of changes in the SPECT scans of the brain, especially when perfusion deficits are mild. The most important point of our study is that SPECT scans can provide much needed adjunctive evidence to affirming that patients with persisting neurocognitive symptoms of Lyme disease actually have some objective evidence for making an otherwise difficult clinical diagnosis and that these changes are reversible with effective antibiotic treatment.
Additional studies will be needed to determine the mechanisms underlying the abnormalities seen on SPECT scans of the brain. The comparative utility of SPECT and PET scans is also an area of future interest. Newberg et al21 used PET scans and observed decreased metabolic activity in 17 of 23 patients with Lyme disease, and mild, diffuse changes involving the frontal and parietal lobes in 7 of 17 patients—results essentially similar to those found in SPECT studies. Most recently, Fallon et al22 compared SPECT and PET scans in patients with persistent encephalopathy and demonstrated abnormalities by both techniques. A registry of patients would also be useful for eventual correlation of SPECT scan findings and anatomic or molecular localization of bacteria or their products.
The authors thank Amanda Green for converting the figures to the Journal’s specifications.
1. Donta ST. Chronic and late Lyme disease. Med Clin North Am. 2002; 86: 341–349.
2. Fallon BA, Das S, Plutchok JJ, et al.. Functional brain imaging and neuropsychological testing in Lyme disease. Clin Infect Dis. 1997; 25: S57–S63.
3. Silbersweig DA, Stern E. Symptom localization in neuropsychiatry. A functional neuroimaging approach. Ann N Y Acad Sci. 1997; 835: 410–420.
4. Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis. 1999; 180: 377–383.
5. Logigian EL, Johnson KA, Kijewski MF, et al.. Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurology. 1997; 49: 1661–1670.
6. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003; 60: 221–226.
7. Fallon B, Nields JA. Lyme disease: a neuropsychiatric illness. Am J Psychiatry. 1994; 141: 1571–1583.
8. Preac-Mursic V, Weber K, Pfister HW, et al.. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection. 1989; 17: 6.
9. Cadavid D, O’Neill T, Schaefer H, et al.. Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of Lyme disease. Lab Invest. 2000; 80: 1043–1054.
10. Donta ST. A Novel Neurotoxin of B. burgdorferi. VIII International Congress on Lyme Borreliosis. Munich, Germany; 1999.
11. Donta ST. Tetracycline therapy of chronic Lyme disease. Clin Infect Dis. 1997; 25: S52–56.
12. Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit. 2003; 9: 136–142.
13. Coyle PK. Lyme disease. Curr Neurol Neurosci Rep. 2002; 2: 479–487.
14. Abdel-Dayem HM, Abu-Judeh H, Kumar M, et al.. SPECT brain perfusion abnormalities in mild or moderate traumatic brain injury. Clin Nucl Med. 1998; 23: 309–317.
15. Browndyke JN, Tucker KA, Woods SP, et al.. Examining the effect of cerebral perfusion abnormality magnitude on cognitive performance in recently abstinent chronic cocaine abuser. J Neuroimaging. 2004; 14: 162–169.
16. Soderstrom H, Hultin L, Tullberg M, et al.. Reduced frontotemporal perfusion in psychopathic personality. Psychiatry Res. 2002; 114: 81–1194.
17. Schwartz RB, Garada BM, Komaroff AL, et al.. Detection of cranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. AJR Am J Roentgenol. 1994; 162: 934–941.
18. Schmaling KB, Lewis DH, Fiedelak JI, et al.. Single-photon emission computer tomography and neurocognitive function in patients with chronic fatigue syndrome. Psychosom Med. 2003; 65: 129–136.
19. Ichise M, Salit IE, Abbey SE, et al.. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun. 1992; 13: 767–772.
20. Pozzilli C, Passaflume D, Bernardi S, et al.. SPECT, MRI, and cognitive function in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1991; 54: 110–115.
21. Newberg A, Hassan A, Alavi A. Cerebral metabolic changes associated with Lyme disease. Nuc Med Commun. 2002; 23: 773–777.
22. Fallon BA, Lipkin RB, Corbera KM, et al.. Regional cerebral blood flow and metabolic rate in persistent Lyme encephalopathy. Arch Gen Psychiatry. 2009; 66: 554–563.
© 2012 Lippincott Williams & Wilkins, Inc.