This patient—a police officer, 35 years old at the time of his initial visit in October 1995—reported he had had around, uniformly red rash on his upper inner right leg just below the knee, roughly the size of a lemon, sometime 5–10 years earlier. It was thought to be a ‘spider bite’ and no treatment was given. He developed hip pain in 1992 with anxiety, panic attacks, and palpitations. In summer 1994, extreme fatigue developed, and by fall 1994 he was feverishness, with malaise and flu-like symptoms, chills, mild unrelenting headache, and a stiff neck. In December 1994, disorientation, memory and speech difficulties developed.
He was active out of doors for work and recreation in Rockland County, New York. He hiked extensively in the lower Hudson River Valley and had an indoor/outdoor dog.
A physician treated him with amoxicillin for two weeks with improvement, but symptoms recurred following cessation of the drug. The second course of amoxicillin of four weeks duration likewise improved his symptoms, but they relapsed the following cessation of the agent. The treating physician advised the patient that he suspected him to have Lyme disease and he was referred to an infectious disease specialist, who did not agree with the diagnosis, as serologic tests were negative. Neurological consultation was obtained. An MRI of the brain with and without gadolinium was normal in May 1995, as was spinal fluid. Although Lyme disease was not able to be confirmed by laboratory methods, the neurologist advised the patient that it had not been ruled out. In June 1995 he was treated for six weeks with IV ceftriaxone, with the initial intensification of joint symptoms, but with subsequent marked overall improvement. By the fall of 1995, he experienced a relapse of symptoms, feeling ‘hungover’ and also a sense of breathlessness. A pulmonary evaluation was obtained. The angiotensin-converting-enzyme was elevated but pulmonary evaluation did not sustain a diagnosis of sarcoidosis.
The brain single-photon emission computed tomography SPECT at Columbia Presbyterian Medical Center in November 1995 showed diffuse heterogeneous cerebral hypoperfusion, with decreased uptake in the white matter. A Lyme ELISA at the State University of New York at Stony Brook was negative, and a Western blot showed no bands on IgM but 39 and 41 kiloDalton (kDa) bands on IgG .
He experienced multi-system symptoms, including headaches, stiff neck, chills, photosensitivity, swollen glands that accompanied his cycling symptoms, mood swings, sleep disturbance, joint pain, debilitating fatigue, cognitive and balance difficulties, and diminished libido, among others.
Aware of his cognitive difficulties, the patient often found himself in situations that could involve split-second decisions on resorting to deadly force. He sought and received medical leave from duty in the fall of 1995.
Formal detailed neuropsychological testing in May 1996 demonstrated impairments in practical reasoning, social judgment, auditory processing speed, primary visuospatial processing, and visual memory—areas of particular premorbid strength. These objective findings corroborated the patient’s subjective sense of cognitive difficulties and buttressed the administrative decision to grant medical leave.
From November 1995 to February 1996 he was treated with high dose amoxicillin (maximum dose was 3.5 g of amoxicillin Q 8 h, along with probenecid) aimed at CNS Lyme disease, achieving a peak amoxicillin blood level of 20.6 mcg/mL (therapeutic for CNS = 15–25 mcg/mL) . Treatment was combined with clarithromycin in doses as high as 1.5 g PO Q 12 h. Despite this, he was getting lost while driving in familiar areas, had difficulty expressing himself, and experienced intolerable anxiety. Minocycline was substituted for clarithromycin.
In January 1996, a Lyme Western blot at the State University of New York at Stony Brook showed 30, 39, and 93 kiloDalton bands on IgM and 41, 45, and 58 kDa bands on IgG [53,54].
In March 1996, oral amoxicillin was discontinued, and IV ceftriaxone (2 g/day) was initiated and continued, with some hiatuses, until October 1996, when it was suspended due to the development of asymptomatic pseudocholelithiasis. Imipenem/cilastatin (1 g IV Q 8 h) was substituted until December 1996, and then cefotaxime (2 g IV Q 8 h) was administered until February 1997, when this drug was discontinued due to leukopenia. Oral minocycline was continued until October 1996, when clarithromycin was resumed and minocycline stopped. Altogether, treatment with IV antibiotics had continued for the bulk of the eleven months from March 1996 to February 1997, with occasional hiatuses.
During this treatment period, the patient reported improved mental sharpness, with easier word retrieval and facility of speech, diminished depression and anxiety, and improved sleep quality and libido.
Repeat brain SPECTs at Columbia Presbyterian Medical Center in October 1996 and April 1997 showed interval improvements, with progressive improvement in cortical heterogeneous and white matter hypoperfusion, however, the pattern did not return to normality.
Oral antimicrobial therapy, with high dose amoxicillin and probenecid, combined with clarithromycin, was resumed in March 1997.
In April 1997, the patient was able to resume work on a limited schedule. The patient felt he had improved to about 65–70% of his normal ‘pre-morbid’ status and felt he was still making gains on oral antimicrobial therapy, although he experienced stiffness about his hips and deep bone pain in his thighs. Oral antibiotics were changed to cefuroxime (1 g) and azithromycin (0.5 g PO Q 12 h).
In May 1997 at the State University of New York at Stony Brook, a Western blot showed 37 and 41 kDa bands in IgM and 18, 39, 41, and 93 kDa bands on IgG [53,54,55].
In late May 1997, the patient’s psychiatrist added donepezil, which resulted in improved word-finding and confidence with speech. The patient felt psychologically improved and felt his condition was ‘holding’ on oral antimicrobial therapy.
In July 1997, on his own advice, he adopted a ‘pulse’ approach to oral antibiotic usage, partly due to loose bowels when on intensive treatment, despite ample probiotics. Diarrhea remitted. He felt at “75%” of his pre-morbid status and was able to resume full-time police work by fall 1997. Oral azithromycin was discontinued and instead, cefuroxime (2 g PO Q 12 h) was combined with doxycycline (150 mg PO Q 12 h) . In December 1997, monotherapy with azithromycin (500 mg PO Q 12 h) was begun, to which cefuroxime was added in January 1998. He was maintaining his ground on oral antimicrobial therapy.
In February 1998, the patient sustained an Achilles tendon rupture while playing sports, and surgical repair was undertaken. He had never received any treatment with quinolone antimicrobials.
In July 1998, the patient was doing well on a rotating schedule of single antimicrobial agents, which included cefuroxime, doxycycline, amoxicillin, and clarithromycin, sequentially. In October 1998 the patient was feeling well and he suspended all antibiotic treatment. In April 1999, he was working hard, full time, occasionally doing ‘double shifts’. In July 1999, he noted spells of feeling ‘sick’ with malaise, sinusitis-like symptoms, stiffness about his hips, and some decrease inarticulateness. In November 1999, he took a two-week course of left-over cefuroxime (1 g Q 12 h). In an exam, in December 1999 he was noted to exhibit mild ataxia on tandem gait with eyes closed. Over the prior spring, summer, and fall, he had been hiking, including ‘bushwacking’, through dense brush in Harriman State Park and the Shawangunk Mountains—heavily tick-infested areas—but he was unaware of any known tick attachments.
In February 2000, he reported experiencing monthly flares of symptoms, which had been absent since the prior spring but had begun to resurface in the summer and fall of 1999. High dose amoxicillin was resumed but then discontinued from March to August of 2000. Modest doses of amoxicillin were resumed until October 2000, then discontinued, as the patient was unclear as to the cause of his symptoms or the efficacy of amoxicillin. He modified his habits, with more rest, and avoidance of alcohol and caffeine. Nonetheless, right hip pain severe enough to interfere with sleep, dull head pressure, anxiety, and panic attacks, and feeling ‘at a loss’ for words recurred. He suspected that Lyme disease was responsible. In January 2001 he resumed left-over doxycycline, using up to 400 mg/day, and noted that his hip pain resolved within a few days . Further doxycycline was prescribed for a few months.
In September 2001, he developed fatigue so severe he could barely get out of bed, along with muscle and joint pain and stiffness, and he resumed left-over doxycycline. By November 2001, he was feeling relatively well once again. He reported hiking in Harriman State Park several times per month until the fall of 2001, again, without known tick attachments.
In November 2001, a Western blot at the State University of New York at Stony Brook showed band 23 on IgM and bands 23 and 41 on IgG.
Doxycycline was continued until January 2002, when it was discontinued by the patient, who was feeling relatively well. Within one month of discontinuing the drug, muscle and joint stiffness recurred. Doxycycline was resumed but after one additional month, it did not seem to be conferring a benefit. He had a deep aching in his thigh muscles ‘close to the bone’, diminished stamina, bilateral Achilles tendon pain, and recurrent cognitive symptoms. Treatment was changed to cefuroxime, combined with clarithromycin, and by June 2002 the patient was feeling remarkably better.
A decision was made to treat ‘episodically’ as seemed necessary, and discontinue when a satisfactory status was achieved, with the option to resume treatment if needed.
The patient remained relatively well off antibiotic therapy from June 2002 until January 2004, when sinusitis-like symptoms occurred. He was treated for sinusitis by a physician, with amoxicillin/clavulanate for 10 days, and felt better for several weeks. Sinusitis-like symptoms recurred, along with fatigue, leg pain, heaviness, stiffness, and weakness. He reconsulted the physician he had seen and was re-treated with the same regimen. All symptoms responded. The patient began to suspect Lyme disease once again because of the recurrence of this familiar constellation of symptoms. He used a friend’s left-over cefuroxime (1 g Q 12) for some three months and felt better.
He was feeling fairly well and able to function. He had had no known tick attachments but had been in the woods a lot with his dog at Harriman State Park, in June 2004. After the outing, he removed some 20 ticks from the animal.
In late August 2004, off antimicrobials, a dry cough developed that lasted six weeks, which was resolved with cefuroxime but recurred 3 weeks later. This resolved with amoxicillin, which he acquired from a friend.
He commented that sinusitis had been a prominent symptom with the onset of his illness in 1994 and that an annoying ‘dry’ cough was a frequent symptom that responded to antibiotic therapy. He averred that on antibiotic therapy he generally would feel well, his anxiety would decrease, and his libido would improve.
With recurring symptoms of Lyme disease, and ongoing exposure risk, a laboratory re-assessment for tick-borne infection was undertaken in December 2004, which revealed a positive Lyme ELISA at the State University of New York at Stony Brook, with an optical density of +0.206 and a positive cut-off of 0.152, but a concurrent Western blot showed only band 41 on IgM and IgG. Empiric re-treatment with cefuroxime and clarithromycin was instituted and continued until February 2005. With this, he felt better and suspended further treatment.
In March 2005 right elbow pain and right knee pain developed, which required three-four weeks to resolve, and which flared again in early June 2005, along with a dry cough and some anxiety. He resumed left-over cefuroxime and clarithromycin—the joint pain improved within several days of resumption of antibiotics and the cough and anxiety resolved.
In February 2006, he returned for care, reporting significant stiffness since the prior November, interfering with his functioning and quality of life. He was also experiencing loss of words and, once again, difficulty with his sense of direction, and expressed that he was living a ‘diminished’ life. Oral amoxicillin was prescribed at 3500 mg PO Q 12 h, and he remained on this between February and October 2006, feeling relatively well.
He retired from the police department after 20 years of service in August 2006.
In late February 2007, he developed a mild fever and chills, worse with exertion, which lasted 10 days. Once again, he began to consider Lyme disease. During 2007, he resorted to short courses of azithromycin, doxycycline, or amoxicillin when symptoms which he interpreted as denoting Lyme disease (sinusitis, right knee and left Achilles tendon pain, anxiety) recurred, achieving temporary surcease and returning to a sense of relative well-being.
In late 2007 and early 2008, the patient experienced periodic ‘flares’ of symptoms he attributed to Lyme disease, with sinusitis-like symptoms, excessive somnolence, headache, feverishness, and a stiff neck. In May 2008, minocycline was prescribed.
His psychiatrist prescribed duloxetine, which was tried without benefit.
A Lyme ELISA at the State University of New York at Stony Brook, March 2008 was positive, with an optical density of 0.239 and a positive cut-off of 0.140, with a 41 kDa band on the IgM Western blot but no bands on the IgG blot. A Western blot at IGeneX in May 2008 showed the presence of 31, 34, and 41 kDa bands on the IgM Western blot .
A brain SPECT in April 2008 at Columbia Presbyterian Medical Center showed moderate global cortical hypoperfusion and heterogeneity, which had worsened compared to the prior study of April 1997.
In May 2008, otolaryngology was consulted in view of recurring sinusitis-like symptoms. An MRI of the sinuses was clear of any anatomical features typical of sinusitis, despite the patient’s symptoms.
In September 2008, despite treatment with minocycline, the patient reported a worsened cognitive status, with poor comprehension and a sense of direction and an inability to read, which he usually enjoyed.
IV ceftriaxone was instituted in April 2009 and continued, with some hiatuses related to difficulties with vascular access during the spring and summer of 2009, for a total of 28 administered doses. Parenteral treatment was combined with oral clarithromycin.
Around this time, serologies returned positive for exposure to Babesia duncani from several different laboratories, including the Public Health Laboratory of the County of Sonoma, California. Treatment aimed at babesia piroplasms was instituted for the first time, using atovaquone/proguanil.
The parenteral and oral treatment was discontinued in September 2009, with greatly improved symptoms, including the resolution of cognitive difficulties, with the patient feeling generally well.
In November 2009, following a hike in Harriman State Park, he removed a fully engorged tick from his skin. A 50 cent piece-sized area of inflammation developed around the tick bite site, and a one-month course of doxycycline was taken.
In December 2009, chills, fatigue, and difficulty regulating his body temperature occurred, and the patient took leftover amoxicillin, up to 5.25 g PO Q 12 h, with no impact on his chills. Ceftriaxone was resumed until March 2010 with atovaquone/proguanil, chills subsided, and he was feeling well.
In May 2010, he was on azithromycin and atovaquone liquid and feeling well with no further chills or a sense of ‘air hunger’. Artemisinin was added (150 mg PO BID), and by September 2010 he reported feeling the best he had in a year .
From November 2011 to April 2014, the patient was under the care of a practitioner who utilized benzathine penicillin, atovaquone, clarithromycin, and sulfamethoxazole/trimethoprim for his treatment.
In November 2013, he had sustained a new, engorged deer tick attachment, for which doxycycline was prescribed for 21 days.
In December 2013, serology for exposure to Babesia duncani was reactive from one commercial reference lab, and in March 2014 this was confirmed at a second commercial lab.
A Lyme PCR in whole blood was positive for the detection of the OspA plasmid target, at IGeneX, April 2014, confirmed by southern dot blot. A Lyme Western blot at the same lab showed the presence of a 39 kDa band and faint bands at 31 and 41 kDa on IgM and 41 and 58 kDa bands on IgG, with a faint band at 23 kDa.
Benzathine penicillin was discontinued in May 2014, and the patient was treated with intramuscular ceftriaxone, initially at 1 g in a regimen of two days on and one day off (per the patient’s preference), along with a regimen of oral treatment mostly consisting of azithromycin (0.5–1 g PO QD), atovaquone (250 mg) and proguanil (100 mg PO X 2 BID), as well as liquid atovaquone (ranging from 750–2250, mg twice daily), but orals were usually limited to five consecutive days per week (again, per the patient’s preference).
Due to inadequate control of symptoms, ceftriaxone was increased to 2 X 1 g IM, two days on and one day off, September 2014.
Treatment was changed to IV ceftriaxone between December 2015 and February 2016. At that point, an attempt to transition from parenteral ceftriaxone with oral azithromycin and atovaquone to oral minocycline or doxycycline with artemether/lumefantrine proved unsuccessful. All treatment was suspended in March 2016, but a return of the symptoms of tick-borne infection required the reinstitution of atovaquone with azithromycin . A fully implanted vascular access device was placed, and the patient was treated with IV ceftriaxone (2 g/day) from May 2016 until August 2016. From August 2016 to January 2018, the patient was treated with IM ceftriaxone (1 g X 2), two days on and one day off. Attempts at the cessation of treatment with azithromycin and atovaquone resulted in the onset of drenching night sweats.
The patient was advised of the impact of treatment with disulfiram in the patients described in Cases 1 and 2, and after due consideration, including a discussion of its potential risks and its uncertain utility in the treatment of human Lyme disease, he requested a trial of treatment with that agent. Correspondence was held with his treating psychiatrist before treatment was initiated.
Disulfiram (250 mg tablets, 1–2 per day) was prescribed, and the patient-initiated treatment in mid-January 2018, discontinuing all other antimicrobial treatment.
Disulfiram resulted in profound fatigue that interfered with functioning, and initially, the patient was unable to tolerate more than 125 mg of disulfiram every other day. The dose was gradually increased from January to April, when he was able to tolerate 500 mg/day for about the last two months of treatment (ending in late May 2018). Periodic surveillance laboratory testing was satisfactory. Notable to the patient was that, despite the discontinuance of azithromycin and atovaquone in mid-January of 2018, he experienced no recurrence of night sweats, even shortly after initiating only low dose disulfiram. He remained clinically well on no antimicrobial treatment until December 2018. He noted improved libido following the course of disulfiram. In retrospect, he opined that the debilitating initial effects of disulfiram seemed most consistent with Jarisch–Herxheimer-like effects, which he had experienced with the application of conventional antibiotics during his course of care.
In November 2018, he requested interval testing for tick-borne diseases stating, however, that he remained clinically well. Surprisingly, Lyme PCR for the detection of the plasmid target in the serum returned positive. Babesia duncani antibodies at the County of Sonoma Public Health Laboratory also returned reactive, at 1:256. Babesia microti antibodies were negative, as were direct detection for B. microti and B. duncani by PCR and F.I.S.H at IGeneX.
During December 2018 and January and February of 2019, the patient experienced left Achilles tendon and right hip pain, the latter interfering with sleep and reminiscent of past relapses of Lyme disease. On his own advice, he administered a five-day course of IM ceftriaxone, with left-over supplies that he had on hand. The course, from 12 February 2019 to 16 February 2019, reduced musculoskeletal pain by some 60%, by his estimation.
The second course of disulfiram was initiated on 19 February 2019, starting slowly with 0.5 X 250 mg every other day, with the intention to ramp the dose up over several weeks to 750 mg/day, remain at that dose for 90 days, and then discontinue the agent for a period of observation.