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J Clin Microbiol. Sep 2011; 49(9): 3415–3417.
PMCID: PMC3165616

Hallucinations, Sensory Neuropathy, and Peripheral Visual Deficits in a Young Woman Infected with Bartonella koehlerae [down-pointing small open triangle]

Abstract

A young woman experiencing depression, anxiety, mood swings, severe headaches, muscle spasms, interphalangeal joint stiffness, decreased peripheral vision, diminished tactile sensation, and hallucinations was persistently Bartonella koehlerae seroreactive and bacteremic. Following antibiotic treatment, B. koehlerae antibodies and DNA were not detected and all symptoms resolved.

CASE REPORT

An 18-year-old female was sequentially examined by a neurologist, psychiatrist, neuro-ophthalmologist, and infectious disease physician because of a 4-year history of slowly progressive neurological and neurocognitive abnormalities. Biopsy-proven celiac disease was diagnosed in December 2004, following complaints of frequent stomach cramps. Despite dietary control of gastrointestinal symptoms, she developed intermittent joint pain, primarily involving the ankles. During 2005, the patient reported reduced tactile sensation in her hands and by 2007 frequent severe headaches, back pain, generalized muscle spasms, and an inability to extend her fingers due to stiffness in her proximal and distal interphalangeal joints. In 2008, she was referred to a neurologist for evaluation of depression, anxiety, mood swings, dizziness, auditory and visual hallucinations, and a progressive decrease in peripheral vision. No abnormalities were observed on a noncontrast magnetic resonance image (MRI) of the brain or an electroencephalogram. The hallucinations were initially infrequent; however, by fall 2008, the hallucinations became frequent, more intense, and at times were accompanied by 1- to 2-min dissociative episodes. The patient's psychiatrist addressed her anxiety with cognitive behavioral therapy and prescribed oxcarbazepine (300 mg twice daily) and quetiapine fumarate (300 mg in the evening), which reduced hallucination frequency to less than once daily.

In January 2009, at the request of the patient's parents, we performed PCR on aseptically obtained EDTA-anticoagulated blood and serum, inoculated EDTA blood into Bartonella-Alphaproteobacteria growth medium (BAPGM), and tested serum for immunofluorescent antibodies using cell culture-grown Bartonella vinsonii subsp. berkhoffii genotypes I, II, and III and Bartonella henselae antigens, as previously described (2, 5, 6, 11). At the time of her original testing, our research laboratory did not perform Bartonella koehlerae immunofluorescent-antibody (IFA) testing, and we had not yet developed a B. koehlerae-specific PCR assay. Therefore, her first samples were not seroreactive (IFA titer, ≥1:64) to any of the Bartonella sp. test antigens, and no amplicons were obtained with 16S-23S intergenic spacer (ITS) Bartonella genus primers from blood, serum, or the 7-day BAPGM enrichment blood culture (Table 1). However, a PCR amplicon was obtained from the 14-day BAPGM enrichment culture, suggesting Bartonella sp. growth following incubation for 14 days. Efforts to determine the Bartonella species by sequencing the amplicon were unsuccessful; therefore, serology and BAPGM enrichment blood cultures were repeated in March and May 2009. Repeat testing generated no additional serological or molecular evidence to support previous or current infection with a Bartonella sp.

Table 1.
Serological, BAPGM enrichment blood culture, and PCR/DNA sequencing test results for an 18-year-old woman with hallucinations and peripheral visual deficits

In March 2009, the patient was referred to a neuro-ophthalmologist because of decreased peripheral vision. The ophthalmologic examination was normal, with 20/20 visual acuity and no eye pain or redness. By formal perimetry, peripheral vision was reduced to the central 5 degrees bilaterally. The patient was advised to avoid driving a car and to repeat perimetry testing in a few weeks; however, the patient was noncompliant and was not reexamined until 20 months later.

In June 2009, her infectious-disease clinician initiated an 8-week course of doxycycline (100 mg twice daily) and rifampin (300 mg twice daily), due to ongoing symptoms and the January 2009 Bartonella genus PCR result in the 14-day enrichment culture. After starting antibiotics and while continuing cognitive behavioral therapy, oxcarbazepine, and quetiapine fumarate, the patient reported a further decrease (from daily to one episode every 2 weeks) in hallucination frequency. When the patient was reexamined at the conclusion of the antibiotic course, treatment duration was extended for an additional 6 weeks due to the patient's maladherence. Following completion of antibiotics, the patient regained the ability to extend her fingers and described improved tactile sensation. Her psychiatrist documented a further improvement, with her hallucinations changing from disturbing visual and auditory sensations, to nondisturbing episodes of hearing her name called, to simply a “white noise.” At the patient's request, the dose of oxcarbazepine was reduced.

By November 2009, the Intracellular Pathogens Research Laboratory (IPRL) had developed a B. koehlerae immunofluorescent-antibody assay, using an isolate derived from a sick cat (2, 5). Retrospective IFA testing of frozen serum samples (January, March, and May 2009) and prospective testing of serum obtained in November 2009 and February and June 2010 consistently detected B. koehlerae antibodies (Table 1). During the same time period, B. koehlerae species-specific 16S-23S ITS PCR primers repeatedly amplified organism-specific DNA sequences from the blood or BAPGM enrichment cultures. Specifically, amplification of the B. koehlerae ITS region was performed using oligonucleotides Bkoehl-1s (5′ CTT CTA AAA TAT CGC TTC TAA AAA TTG GCA TGC 3′) and Bkoehl1125as (5′ GCC TTT TTT GGT GAC AAG CAC TTT TCT TAA G 3′) as forward and reverse primers, respectively. Amplification was performed in a 25-μl final volume reaction mixture containing 12.5 μl of Tak-Ex Premix (Fisher Scientific), 0.1 μl of 100 μM each forward and reverse primer (IDT DNA Technology), 7.3 μl of molecular-grade water, and 5 μl of DNA from each sample tested.

With repeated PCR documentation of B. koehlerae bacteremia, the patient was treated with rifampin (300 mg twice daily) and azithromycin (250 mg/day) for an additional 4 months. Following this treatment regimen, her hallucinations stopped completely, and normal peripheral vision was confirmed by visual field perimetry in November 2010. The quetiapine fumarate dosage was gradually decreased, and hallucinations and dissociative episodes have not returned. B. koehlerae antibodies were not detected in August and September 2010 and January and March 2011 (Table 1). With the exception of a single 7-day BAPGM enrichment culture PCR result (January 2011), for which the amplicon could not be successfully sequenced, Bartonella sp. DNA was not amplified from blood, serum, or enrichment blood cultures (n = 31 independent PCRs) following the 4-month treatment regimen. During the 9-month posttreatment follow-up period, the patient has experienced no hallucinations, peripheral vision has remained normal, and tactile sensation has improved substantially. Family members reported that the patient was much improved and had returned to her preinfection baseline, both neurologically and psychiatrically.

Discussion.

Bartonella koehlerae was initially characterized from blood culture isolates obtained from two flea-infested healthy cats from northern California in the early 1990s (7, 8). In 2004, the bacterium was first reported as a human pathogen in a patient from Israel with aortic valve endocarditis (1). Investigators subsequently isolated B. koehlerae from flea-infested (Ctenocephalides felis) stray cats in Israel (1). In 2010, we reported B. koehlerae bacteremia in eight patients with variable symptoms (5). The diagnostic evaluation of the patient in this case report benefitted from development of a B. koehlerae serological and, subsequently, species-specific PCR assay (5). When first tested using Bartonella genus ITS primers in January 2009, only the 14-day BAPGM enrichment blood culture was PCR positive. As multiple attempts to sequence this amplicon were not successful, Bartonella species bacteremia was suspected but not confirmed. Subsequent serological and Bartonella genus ITS PCR (genus primers) testing of BAPGM enrichment blood cultures spanning a 17-month time period was consistently negative, whereas retrospective and prospective IFA testing consistently identified B. koehlerae antibodies, until after the third course of antibiotics, when the patient also became seronegative. Of serodiagnostic importance, there was no cross-reactivity to B. henselae or B. vinsonii subsp. berkhoffii antigens. Similarly, B. koehlerae DNA was repeatedly amplified and sequenced using species-specific primers until after the third antibiotic course. Assuming that the patient was not reexposed, treatment with doxycycline and rifampin for 14 weeks in 2009 did not eliminate B. koehlerae bacteremia. Lack of patient compliance may have contributed to the initial treatment failure but was not a factor during administration of the subsequent treatment regimens. Following the third course of antibiotics, the patient experienced clinical resolution of symptoms and a decrease in B. koehlerae antibody titers to a seronegative status, and whole-blood, serum, and BAPGM cultures were PCR negative, with one exception (5 January 2011). It is possible that her infection may not have been eliminated or that the patient was reinfected by animal or arthropod contact. Her pet cat and dog were seronegative and BAPGM PCR negative. Follow-up serological and BAPGM enrichment culture testing in March 2011 was negative.

In this study, all patient samples were processed in a biosafety cabinet with HEPA filtration, located in a limited access laboratory. To avoid DNA carryover, PCR sample preparation, DNA extraction, and PCR amplification and analysis were performed in three separate rooms with a unidirectional work flow. For PCR, Bartonella sp. negative controls were prepared using 5 μl of DNA from the blood of a healthy dog. As newly designed B. koehlerae species-specific PCR primers were used in this study, we purposely did not use a B. koehlerae positive control. To assess for potential contamination during processing of enrichment blood cultures, an uninoculated BAPGM culture flask was processed simultaneously and in an identical manner with each batch of patient blood and serum samples tested. For all components of the BAPGM blood culture enrichment platform (PCR from blood, serum, enrichment cultures, and subcultures), PCR negative controls remained negative throughout the course of the study. Based upon the results of this study, the B. koehlerae ITS species-specific primers were more sensitive than the Bartonella genus ITS primers. In order to successfully amplify Bartonella sp. DNA from as many patient samples as possible, the antisense primer used in the genus PCR was designed to amplify pathogenically relevant species, while avoiding nonspecific amplification of Mesorhizobium DNA (9). Thus, the design of this primer resulted in greater specificity but decreased sensitivity. The B. koehlerae species-specific antisense primer was designed to amplify only B. koehlerae, thus sensitivity was improved. As illustrated in the table, direct DNA extraction from blood and serum was repeatedly negative, whereas PCR from 7- or 14-day BAPGM enrichment cultures contained adequate bacterial numbers (ITS targets) to allow for successful amplification and DNA sequencing. Despite growth in the liquid-enrichment culture flasks, we were never able to obtain a B. koehlerae subculture isolate from this patient, which remains a technical problem with this genus of highly fastidious bacteria. Interestingly, there was no cross-reactivity to antigens of other Bartonella sp. (B. henselae) or subspecies (B. vinsonii subsp. berkhoffii genotypes I, II, and III).

Fatigue, insomnia, joint pain, headache, memory loss, and muscle pain were among frequent symptoms in eight patients with B. koehlerae bacteremia, of which four patients reported decreased tactile sensation or numbness and three reported blurred vision (5). B. koehlerae antibodies were not detected in 30 healthy individuals, who were concurrently PCR negative for all components of the BAPGM platform (5). Following suspected needlestick transmission of Bartonella vinsonii subsp. berkhoffii, a veterinarian reported frequent headaches, fatigue, and intermittent paresthesias in the left arm in focal, nondermatomal areas (11). Bartonella henselae infection was reported in a patient with distal axonal sensomotor polyneuropathy and Raynaud's phenomenon (13). Brachial plexus neuropathy was diagnosed in three patients with neuralgic amyotrophy (12, 13). Prospective studies are needed to evaluate B. koehlerae bacteremia in patients with unexplained fatigue, joint pain, sensory neuropathies, visual deficits, and hallucinations.

With the advent of B. henselae serology, PCR, and improved enrichment culture techniques, case studies are suggesting an important and expanding role for Bartonella sp. infection in patients with memory loss, expressive aphasia, word substitution errors, and impaired repetition (3, 4, 10). In our patient, there was a decrease in hallucination frequency following the initial course of antibiotics and total resolution of the hallucinations and visual field deficits following the third course of antibiotics while on a stable dose of antipsychotic medication. We conclude that this constellation of symptoms should raise the index of clinical suspicion for Bartonella infection.

Acknowledgments

This research was supported in part by a grant from the American College of Veterinary Internal Medicine Foundation, the Kindy French Foundation, the State of North Carolina, and Bayer Corporation.

We are grateful to Tonya Lee for editorial assistance.

In conjunction with Sushama Sontakke and North Carolina State University, E. B. Breitschwerdt holds U.S. patent no. 7,115,385, “Media and methods for cultivation of microorganisms,” which was issued 3 October 2006. He is the chief scientific officer for Galaxy Diagnostics, a newly formed company that provides diagnostic testing for the detection of Bartonella species infection in animals and in human patient samples. R. G. Maggi has led efforts to optimize the BAPGM platform and is the scientific technical advisor and laboratory director for Galaxy Diagnostics. The remaining authors have no potential conflicts of interest to declare.

Footnotes

[down-pointing small open triangle]Published ahead of print on 6 July 2011.

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