Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016

Clinical Protocol: Chronic Lyme-Like Syndrome Protocol PREAMBLE   

Patients with a diagnosis of “Chronic Lyme-Like Syndrome (CLLS) often suffer debilitating symptoms and disability. Our clinic is dedicated to helping this group, as well as other groups with complex syndromes. The diagnosis of CLLS includes patients who carry varying probabilities of Borrelia burgdorferi infection and those diagnosed in very different ways. For the purpose of individualizing care and identifying appropriate patients for future research, the following table outlines four categories which will be adopted by the Program:

 Patient Category Definitive Lyme Disease

Post-Treatment Chronic Lyme Syndrome (PTCLS) Alternatively Diagnosed Chronic Lyme-Like Syndrome (ADCLLS)

Chronic Lyme-Like Syndrome (CLLS)

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Basis for Diagnosis Diagnosed on clinical grounds in early disease or by reference laboratory testing in disseminated Lyme disease (1) Diagnosed as above but failing to experience complete symptom resolution after standard antibiotic therapy (2) Diagnosed on clinical grounds supported only by alternative tests, the validity of which is questioned by major reference laboratories and the CDC (3) Diagnosed on purely clinical grounds and early disease is excluded

A detailed discussion of testing for Lyme disease is beyond the scope of this protocol. The expertise for testing for Lyme disease resides with BCCDC. o http://www.bccdc.ca/health-info/diseases-conditions/lyme-disease-borrelia-burgdorferiinfection o The CCDP has also created a Lyme Testing Fact-Sheet available on our Web site Those with definitive Lyme disease, if not already treated fully, will be referred for treatment o http://www.bccdc.ca/dis-cond/a-z/_l/LymeDisease/default.htm A proportion of people who have had definitive Lyme disease continue to have symptoms following standard antibiotic treatment: Post-treatment Lyme Syndrome (PTCLS). We offer a broad array of treatment modalities based on these symptoms and aim to individualize treatment. In recent months, it has become very clear that those diagnosed by alternative “Lyme specialty labs” most frequently do not have Definitive Lyme disease or PTCLS. (4,5) However, symptoms experienced by these patients with ADCLS can be equally crippling. For these patients, we will first recheck their serology with definite and reliable testing. Then we will assess symptoms, searching for other plausible explanations or medical conditions. We will then offer an array of therapeutic approaches as outlined in these guidelines, similar to the approach for those who carry a clinical diagnosis of Chronic Lyme-Like Syndrome. Patients with ADCLLS are clinically similar to patients with Chronic Fatigue Syndrome (CFS). (6) Because many individuals with PTCLS have a similar symptom cluster, central sensitization may be a process mediating or exacerbating their sensory processing. (7) Virtually all of the patients with ADCLLS and CLLS seen in the CCDP so far also fulfill diagnostic criteria for CFS and/or Fibromyalgia (FM).

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The positive response to antibiotics reported by many patients with CLLS can be explained by mechanisms other than suppression of Borrelia: pain modulation, anti-inflammatory, and glial health. (8,9) The CCDP adheres to a “patient first” approach to care o Although we remain agnostic in areas where evidence is lacking, that should not be interpreted that we discourage or discount individual patient’s choices or experience. Patient preferences, values, and the weighting of risk vs. benefit are personal. We support patients with the tools and approaches we have to offer while patients continue or pursue other forms of treatment. The CCDP Clinical Advisory Committee has done a review of the evidence including the ILADS guidelines (10) and its source documents. o The committee concluded that there was insufficient evidence to recommend antibiotic treatment of CLLS outside of research protocols. o This is in keeping with practice guidelines from numerous North American and European medical societies who recommend against treating patients with prolonged or repeated courses of antibiotics. (11) Much of the evidence used in developing this protocol comes from the treatment of CFS and FM given the significant symptom overlap and the usual fulfillment of diagnostic criteria for CFS and/or FM by CLLS patients. The symptoms of CLLS can be broadly divided into 4 categories: o Fatigue (both physical and mental) o Pain o Unexplained (or unusual) symptoms (e.g., palpitations, temperature instability, etc.) o Sleep dysfunction No one treatment to date targets all 4 categories effectively The order and combination of treatments undertaken will depend on prior treatment, patient preference, costs, etc. Given the different mechanisms of action, patients often require two or more medications. Medications that benefit two or more problems are recommended: o For example, Selective Serotonin Reuptake Inhibitors (SSRIs) can benefit depression and anxiety. In addition, they reduce unexplained or unusual symptoms by 50% (on average). o Furthermore, SNRIs are also helpful in pain management. Patients with CLLS are often sensitive to medications and may need to be titrated slowly, and may not tolerate higher doses of medications. The treatments described within this document may occur through individual or group patient settings depending on resource availability. It is expected that physicians would educate themselves about medications beyond the outline provided within this document. Patients should be provided with the information/dose adjustment handout.

1. PATIENT EDUCATION    

Informed by Level A evidence (Please see Appendix A for further definition on Levels of Evidence) Provided through a variety of mechanisms (e.g. patient handouts, web-based resources) Incorporated into core group programming: “Living with Complex Chronic Diseases” Integrated into the “Family and Friends” evening interactive session

2. PHYSICAL ACTIVITY Page 2

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Informed by Level A evidence Includes Graded Exercise Therapy (GET) Offered in group setting: Physical Activity Group Tai-Chi and mild Yoga o Suggested to patients o Access through community-based providers, not within the CCDP itself

3. SLEEP  

Sleep disturbance is a major component of CLLS and pain disorders Refer to Sleep Protocol for details

4. DIET  

Informed by emerging evidence and data from available Randomized Control Trials (RCT) Offered in group setting o Topic specific “one-off” groups (one session)  General Nutrition and a Healthy Diet  Low-Inflammatory Diet o Included in disease specific groups (3 – 5 sessions)  e.g., Irritable Bowel Syndrome (IBS) Group

5. ALTERNATIVE AND COMPLEMENTARY THERAPIES 

Some agents have a strong theoretical rationale and early evidence o Co-enzyme, D-Ribose 5 g, magnesium Malate, NADH, Vitamin D

5.1 Co-enzyme Q  200 mg TID 5.2

D-Ribose  5 g TID

5.3 Magnesium Malate  250 mg QID 5.4 NADH  10 – 20 mg daily 5.5 Vitamin D  1000 IU daily

6. PSYCHOLOGICAL AND BEHAVIOURAL THERAPIES  

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Informed by Level A evidence Incorporated in core group: “Living with Complex Chronic Diseases” o Combines Education, Pacing, CBT &, Mindfulness o 12 week program o Includes a “Family and Friends” 2 hour session Incorporated in disease specific groups, e.g., IBS Group, Migraine Group Other optional groups available: Page 3

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016 o o

Physical Activity group Mindfulness group

7. INTERVENTIONS 7.1 Trigger Point Injection (TPI), etc.  Informed by emerging evidence and expert opinion  Maneuvers that resolve muscular trigger points, lengthen muscle contractures, and release painful scars and other connective tissue restrictions  For example: o Myofascial release o Trigger Point Injections o Nerve blocks o Currently available:  Internally:  Externally (outside referral):  Change Pain Clinic  Muscle MD  Community MDs  See TPI Protocol

7.2 Acupuncture  Informed by RCT data  See Acupuncture Protocol

8. MEDICATIONS 8.1 Iron  Informed by RCT data  Assists with fatigue in patients with Ferritin below 50  Watch for constipation (especially IBS-C)  May need to add PEG +/- Milk of Magnesia (see IBS protocol)  For patients unable to tolerate oral iron, intravenous (IV) iron replacement may be needed  The degree of intolerance matches the amount of bioavailable iron 8.1 A Ferrous fumarate  Available without prescription  High amount of iron  Very effective, but less well tolerated  300 mg (one capsule) daily; each capsule contains 100 mg elemental iron 8.1 B Ferrous gluconate  Available without prescription  Less iron than fumarate, and also spread over 3 doses  Effective, better tolerated than fumarate  300 mg (one tablet) TID; each tablet contains 35 mg elemental iron 8.1 C Iron polysaccharide Page 4

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016    

Available without prescription Contains the highest amount of elemental iron Well tolerated but often not as effective 150 mg daily (as elemental iron)

8.1 D Iron sucrose IV  IV iron, usually administered in a medical short stay unit  300 mg over 3 hrs x 3 doses (1 – 2 weeks between doses)  Ferritin falsely elevated (often above 100) for a few months

8.2 Modafinil  RCT data  Helps with mental alertness/brain fog  Risk of pushing patients beyond their energy envelope and causing crashes  Start 100 mg daily  May increase to 200 mg daily  Watch for anxiety, insomnia, and adrenergic side effects

8.3 Tricyclics  Used for pain  Also improves sleep architecture  Not generally used during the day  Watch for: o Dry mouth o Blurred vision o Urinary retention  May need to taper at higher doses when discontinuing 8.3 A Amitriptyline  Start 5 mg 2 hours before bed (or 12 hours before getting up in the morning)  Increase to 10 mg after 1 week  Increase by 5 mg increments at 2 week intervals  Increase to 70 mg as tolerated, depending on benefit & side effects  Many patients cannot tolerate more than 20-30 mg 8.3 B Cyclobenzaprine  Alternative to amitriptyline  Also helps muscle spasms  Start 5 mg 2 hours before bed (or 12 hours before getting up in the morning)  Increase by 5 mg increments at 2 week intervals  Increase to 20 mg as tolerated, depending on benefit and side effects  Not generally used during the day, but occasionally patients may benefit from 3 divided doses o 1/3 during the day and 2/3 2 hours before bed o e.g., 5 mg BID + 20 mg 2 hours before bed 8.3 C Nortriptyline  Alternative to amitriptyline

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Useful in patients who have tried amitriptyline in the past and didn’t tolerate it (usually because it was started at too high a dose) Generally less benefit for pain, but also fewer side effects Start 10 mg 2 hours before bed (or 12 hours before getting up in the morning) Increase by 10 mg increments at 2 week intervals Increase to 50-70 mg as tolerated, depending on benefit & side effects

8.4 Anticonvulsants  Used for pain  Also helps with sleep, anxiety, dysesthesia, and restless leg  Start with evening dosing and add during day later (1/3 day + 2/3 evening)  Watch for: o Sedation (common) o Cognitive dysfunction o Weight gain o Edema  Not a good choice in patients with obesity, metabolic syndrome, or fear of gaining weight  Topiramate may be an alternative in these populations, especially patients with migraine (see below)  Avoid abrupt withdrawal; need to taper  Balance pain relief (benefit) with day time somnolence (side effect)  Monitor weight  Follow Brief Pain Inventory 8.4 A Pregabalin (Lyrica)  Expensive $$$  Patient dosing schedule  Inform patients not to expect benefit until 100mg (prevent early discontinuation) AM

Evening 25 mg 50 mg 75 mg 100 mg Patient review at 100mg 25 mg 100 mg 50 mg 100 mg 1/3 + 2/3 Physician review for higher doses / multidrug regimens Maximum dose 450 mg / day  Increase dose at one (or more) week intervals depending on side effects  If unsure current dose is helping, trial of tapering warranted 8.4 B Gabapentin  Alternative to pregabalin if cost is a factor  Patient dosing schedule  Inform patients not to expect benefit until 600mg (prevent early discontinuation) AM

Afternoon

HS 100 mg 200 mg 300 mg 400 mg Page 6

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016 AM

Afternoon

HS 500 mg 600 mg Patient review at 600 mg 100 mg 600 mg 100 mg 100 mg 600 mg 100 mg 100 mg 700 mg 100 mg 100 mg 800 mg 100 mg 200 mg 800 mg 100 mg 200 mg 900 mg 200 mg 200 mg 900 mg Physician review for higher doses Maximum dose 3600 mg / day  Increase dose at one (or more) week intervals depending on side effects  If unsure current dose is helping, trial of tapering warranted 8.4 C Topiramate  No specific evidence for fibromyalgia  Strong evidence for other pain syndromes  May be useful when gabapentinoids can’t be used due to obesity, metabolic syndrome or fear of gaining weight  Used off-label as a weight loss drug  Also useful if patient has migraines  Watch for: o Drowsiness o Cognitive dysfunction o GI upset o Good water intake (prevent renal stones) o Weight loss  Check blood work at baseline; q month x 2, then q 6 months: o Lytes (metabolic acidosis) o Neutropenia o Elevated liver enzymes  Patients who benefit but have daytime somnolence may do better with just night time dosing  Patient dosing schedule o Inform patients not to expect benefit until 50mg BID (prevent early discontinuation) AM

Evening 12.5 mg 25 mg 50 mg 50 mg 50 mg 75 mg 75 mg 100mg 100 mg

25 mg 50 mg Patient review at 50 mg BID 50 mg 75 mg 75 mg 100 mg And so on… Maximum dose 200 mg BID  Increase dose at weekly (or more) intervals 8.5 Serotonin and norepinephrine reuptake inhibitors (SNRIs) Page 7

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Used for pain Also helps with comorbid depression or anxiety, and other somatic symptoms If patient is currently on SSRI, consider a trial of switching from SSRI to SNRI o Can switch from one day to the next o Use same relative dose of SNRI (e.g., 50% of maximum dose) Coming off SNRI more difficult than SSRI o Slower taper Tell patient to expect “transition” effects in the first 7-10 days o Otherwise patient will think these are side effects and discontinue drug o Patient may feel “off,” anxious, not like themselves, etc. Watch for: o Agitation, insomnia o Dyspepsia, and other GI side effects o Sexual dysfunction Monitor blood pressure

8.5 A Duloxetine (Cymbalta)  Expensive $$$  Inform patient not to expect benefit for 4-6 weeks (prevent premature discontinuation)  Start 30 mg daily (or q 2 days in drug sensitive patients)  Increase to 60 mg daily after 3 weeks if tolerated  Stay on 60 mg for at least 2 months before considering further dose increase  Physician review for doses above 60 mg daily  Above 60 mg go to BID dosing  Can increase to 90-120 mg daily in select patients who benefit o Usually decreased incremental benefit at higher doses and increased side effects 8.5 B Venlafaxine XR  Alternative to duloxetine if cost is a factor  Can also be tried in patients who did not tolerate duloxetine o Venlafaxine XR comes in much smaller incremental doses  Inform patient not to expect benefit for 4-6 weeks after reaching dose of 112.5 mg o Prevent premature discontinuation  Start 37.5 mg daily  Increase by 37.5 mg increments at q 2 week intervals  Reassess after 112.5 mg daily  Maximum dose 225 mg daily 8.6 Canabinoids  Used for pain  Also helpful for anxiety, nausea, appetite, and sleep  Can assist with opioid tapering 8.6 A Nabilone (Cesamat)  Expensive $$$ o Not covered by many drug plans o Cesamat 0.5 mg covered by Pharmacies o 0.25 mg not covered by Pharmacies  Watch for: o Drowsiness o Cognitive dysfunction o Dizziness Page 8

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016

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o Dry mouth o Weight gain Use with caution in patients with: o POTS (Postural Orthostatic Tachycardia Syndrome) o NMH (Neurally Mediated Hypotension) Patient dosing schedule o Can also be taken prn for breakthrough symptoms AM

Evening/Bedtime 0.25 mg

Patient may break open a 0.5 mg capsule and take half (if using 0.5 mg covered by Pharmacies)

0.5 mg 0.25 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.75 mg 0.75 mg 0.75 mg 0.75 mg 1 mg 1 mg 1mg Patient review at 1 mg BID Physician review for doses above 1 mg BID Consider TID dosing at higher doses Consider regular + prn dosing Maximum 6 mg daily (2 mg TID)  Dose can be increased every few days or at weekly intervals 8.7 Low Dose Naltrexone  Only 2 small RCTs  Used for pain  Not to be used for patients on opioids  May benefit patients with inflammation/inflammatory markers (e.g., co-infections)  Usually tried only if other meds have failed  Inexpensive drug but needs to be compounded o $$ o Compounding not usually covered  Few side effects at lower doses but watch for: o Headaches o Dizziness o GI sided effects  Follow inflammatory markers if elevated at baseline  Inform patients not to expect benefit until 4 mg daily (prevent early discontinuation)  Start 1 mg daily  Increase by 1 mg at weekly intervals  Target (max) dose: 4.5 mg daily as tolerated o Give new script for 4.5 mg dose 8.8 Nonsteroidal anti-inflammatory drugs (NSAIDs)  No evidence of efficacy in fibromyalgia (level 5D evidence)  May benefit patients with “peripheral pain generators” (e.g., OA, back pain, etc.)  Best used for short periods or prn  Long term use associated with GI, renal, and cardiac side effects  e.g., diclofenac 25-75 mg TID  May need to provide gastro-protection o Addition of PPI Page 9

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016  e.g., pantoprazole 40 mg daily Combination drugs  e.g., Arthrotec (diclofenac + misoprostol)  Expensive $$$; not covered  e.g., Vimovo (naproxen + esomeprazole)  Expensive $$$; not covered Toradol may be helpful in acute severe flares o

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8.9 Opioids   Tramadol (with or without acetaminophen) may be helpful in refractory cases  No evidence of efficacy for stronger opioids (level 5D evidence)  May benefit patients with “peripheral pain generators” (e.g., OA, back pain, etc.)  May want to get patients off opioids if other meds have not been tried  Tapentadol (opioid with norepinephrine reuptake inhibition) or buprenorphine patches (opioid partial agonist) may be of benefit  Other opioids generally avoided 8.9 A Tramadol  Expensive $$$  Tramadol 50-100 mg q6h; max 400 mg / day  Tramacet (Acetaminophen 325 mg and Tramadol 37.5 mg) o 1-2 tabs q6h o max 8 tablets / day 8.9 B Tapentadol  Expensive $$$  Tapentadol IR (immediate release) o For breakthrough pain o 50-100 mg q6h prn o Max 500 mg daily  Tapentadol ER (extended release) o Start 50 mg daily then BID o Max 500 mg daily 8.9 C Buprenorphine transdermal patch  Expensive $$$  Applied weekly  Comes in 5, 10, 15, and 20 mcg/hr patches

9. ASSESS AND TREAT COEXISTING CENTRAL SENSITIVITY SYNDROMES   

Informed by Level A evidence for most of these conditions May require referral out Central Sensitivity Syndromes include: o ME/CFS o Fibromyalgia o IBS o Migraine o Tension Type Headaches o POTS o Multiple Chemical Sensitivities Page 10

Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016 o o o o o o o

Interstitial Cystitis Pelvic Pain Syndromes Irritable Larynx Syndrome Restless Leg Syndrome Temporomandibular Disorders Myofascial Pain Syndrome PTSD

10. ASSESS AND TREAT FOR COEXISTING ANXIETY AND MOOD DISORDERS  

Informed by Level A evidence Referral to psychiatrist for selected patients

11. HORMONAL ISSUES 

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Testing o TSH is part of the screening blood work for new patients o AM cortisol can be ordered as a second-line test o Patients requiring anything beyond this, should be referred to endocrinology Non-Addison adrenal insufficiency o Currently there is no evidence that patients who do not demonstrate adrenal insufficiency by validated tests such as ACTH stimulation test, CRH stimulation test and Insulin Tolerance Test (ITT) would benefit from active glucocorticoid replacement. o The CCDP Clinical Advisory Committee believes that the potential harm would greatly outweigh any perceived benefit by patients. Patients with low TSH, low T3, and low T4 o These findings are analogous to those seen in “sick euthyroid” hospitalized patients. o Currently, there is no role for the administration of exogenous thyroxine to these patients. Extrapolating from this approach, CCDP patients with similar thyroid function test findings would similarly not be given thyroid replacement therapy. Growth Hormone o Lower levels of IGF-1 /GH have been reported in some patients with fibromyalgia. o Although growth hormone replacement has been explored in small series, the potential benefit of GH replacement long- term clearly is outweighed by the risks and cost. Hormone Replacement Therapy (HRT) for women o For women, HRT is currently indicated for symptomatic management of perimenopausal symptoms. Ongoing use of HRT is associated with increased cardiovascular risks, venous thromboembolism, and breast cancer. o The use of HRT should not be routine in perimenopausal women without a further assessment of patient risks from these sex-hormone replacement. o Further referral to subspecialists is required for these patients. Androgen replacement therapy (ART) in men o Androgen replacement therapy may be indicated for those with symptoms and who have a confirmed diagnosis of hypogonadism (decreased free testosterone levels below the normal values). o However, ongoing use of androgen replacement is similarly associated with the risk of cardiovascular disease and prostate disease.

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Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016 o

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The use of ART should not be routine in men with hypogonadism without a further assessment of patient risks from these sex-hormone replacement. o Further referral to subspecialists is required for these patients. Patient with diabetes insipidus-like symptoms o If patients are suspected to have diabetes insipidus based on a history of polyuria and polydipsia and the absence of diabetes of mellitus, they should be referred to an endocrinologist for consideration of a water deprivation test. o There is currently no logistic support at BC Women’s Hospital’s to safely perform a water-deprivation test. Melatonin assessment o The CCDP Clinical Advisory Committee Endocrinology panelist members are unaware on the implications of melatonin assessment on the health of patients.

Appendix A- Levels of Evidence Definition

GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group 2007 (modified by the EBM Guidelines Editorial Team) Code Quality of Evidence Definition A High Further research is very unlikely to change our confidence in the estimate of effect. Several high-quality studies with consistent results In special cases: one large, high-quality multi-centre trial B Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. One high-quality study Several studies with some limitations C Low Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. One or more studies with severe limitations D Very Low Any estimate of effect is very uncertain. Expert opinion No direct research evidence One or more studies with very severe limitations References 1. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-134.

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Chronic Lyme-Like Syndrome COMPLEX CHRONIC DISEASES PROGRAM Clinical Protocol Date: March 4, 2016 2. Feder HM, Jr., Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP, et al. A critical appraisal of "chronic Lyme disease". N Engl J Med. 2007;357(14):1422-30. 3. Caution while testing for Lyme disease. MMWR. 2005;54(5):125. 4. Fallon BA, Pavlicova M, Coffino SW, Brenner C. A comparison of lyme disease serologic test results from 4 laboratories in patients with persistent symptoms after antibiotic treatment. Clin Infect Dis. 2014;59(12):1705-10. 5. Dattwyler RJ, Arnaboldi PM. Editorial commentary: comparison of lyme disease serologic assays and lyme specialty laboratories. Clin Infect Dis. 2014;59(12):1711-3. 6. Patrick DM, Miller RR, Gardy JL, Parker SM, Morshed MG, Steiner TS, et al. Lyme Disease Diagnosed by Alternative Methods: A Phenotype Similar to That of Chronic Fatigue Syndrome. Clinical Infectious Diseases 2015. July. 7. Batheja S, Nields JA, Landa A, Fallon BA. Post-Treatment Lyme Syndrome and Central Sensitization. J Neuropsychiatry Clin Neurosci 25:3. 8. Bastos LF, Merlo LA, Rocha LT, Coelho MM. Characterization of the antinociceptive and antiinflammatory activities of doxycycline and minocycline in different experimental models. Eur J Pharmacol. 576(1-3):171-9, 2007 Dec 8. 9. Lazzarini M, Martin S, Mitkovski M, Vozari RR, Stuhmer W, Bel ED. Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model. Glia. 61(7):1084-100, 2013 Jul. 10. Cameron JJ, Johnson LB, Maloney EL. ILADS Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease (Review). Expert Rev Anti Infect Ther. 12(9):1103-35, 2014 Sep. 11. Lantos PM. Chronic Lyme Disease. Infect Dis Clin N Am 29 (2015) 325–340.

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