1 DIAGNOSING LYME WITH MS FEATURESSteven J. Harris, MD

2 Introduction Diagnosis Issues Particular to Lyme Case 1 Case 2 Case 3

3 Introduction Lyme disease has several neurologic features overlapping with MS. Not only is diagnosis challenging, but once the diagnosis is established, treatment strategies remain unclear. How do we create a best practices model to diagnose Lyme with MS features? Are there any new, useful treatment strategies to include in the various antibiotic regimens?

4 MS VS. LYME MS LYME Discreet episodes in space and time2 clinical attacks originating from separate lesions, lasting at least 24 hours. 3 months must separate the discreet attacks MRI 4 white matter areas of increased signal intensity at least 3mm diameter CSF oligoclonal IgG bands different from any such bands in serum Elevated IgG synthesis/index (90%) Elevated myelin basic protein (80%) Elevated neurofilament levels Normal aldolase levels Normal CSF lymphocyte levels (66%) Ab to oligodendrocyte-glycoprotein MS VS. LYME MS LYME Borrelia Burgdorferi IgM, IgG,IgA Ab Pleocytosis Elevated CSF protein Kynurenines Some matrix-metalloproteinases Dendritic cells-plasmacytoids Sources: Schmutzhard, Erich, Multiple Sclerosis and Lyme Borreliosis; Winer Klinische Wochenschrift; July 31, 2002 International MS Support Foundation

5 Lab Data + Tests Lyme MS IgG syntesis rate + +/- myelin basic proteinOligoclonal IgG Bands Anti-Neuronal Nuclear Antibody (ANNA), IFA/WB Lymphocytic pleocytosis Specific antibody DNA/antigen/organism detection CSF elevated protein + +/-

6 Problems With DiagnosisTest/Criteria Actual Practice/Assumptions CSF Lyme PCR Urine PCR probably more reliable CSF Lyme Antibody Often not present, despite literature MRI Changes over time/ rigid criteria not able to distinguish SPECT MRS Data lacking in Lyme What are the criteria to diagnose Lyme in the absence of Laboratory evidence?

7 Now on Ceftriaxone 2g qd X 10 months.TREATMENT SUMMARY Symptoms gone after Dr. Shantha program. Fatigue better. No neuropathy. Memory more precise. PLAN: Hold antibiotics. Zhang’s herbs if desired. Vitamins, diet, heat, rest and sunlight. In 3 mos ABX Challenge and urine LDA/PCR Oral antibiotics for for several months. IV for 10 days. Poor tolerance of IV. Presumed to be JH rxn. Pt 3 On Tegretol, refusing tinidazole or metronidazole; zithromax precluded. Intense fear over recurrence of seizures. Environmental allergy gone, spinal dysesthesia absent. Executive functioning now decaying again after a long course to resolution. Patients with features of MS, undergoing treatment for Lyme. Fighting Insurance companies for treatment. Pt 2 Now on Ceftriaxone 2g qd X 10 months. Pt 1 Hx Dr. Ling’s program. Doxy tid x 4 years and Biaxin 500 bid x 4 years. Plateau until one month ceftriax. All symptoms gone x 2 months. Insurance denial Incontinence recurred. Near syncope x several. Awaiting pregnancy. Restarting orals x 1 week.

8 Patient 1 History Pre-treatment Exam left foot edemaDeer tick San Diego Given Doxy x 1 week. 1 month later unable to walk; vision deteriorated Dx’d MS by MRI/neurologist 1996. Told no Lyme in California and offered hymenoptera shots. Diagnosed Lyme by Dr. Ling 1996 Presented 08/01 with incontinence, imbalance, syncope,fatigue, clumsiness, sweats, hair loss, heart palpitation Pre-treatment Exam left foot edema impaired finger/nose +romberg poor tandem gait speech slurring hypesthesia fingers/toes muscle twitching bilateral Lower extremity weakness Treated 4 years with zovirax, Doxy, Biaxin. Vision returned after 2 years. Plateaued. Off meds x 2 months in 2000. Previous gains diminishing Started on Ceftin and Flagyl (pulsed) x 9 months. Improved, then plateaued. Switched to Amox due to Ceftin cost. No change. Off meds x 3 months in 2001 8/01 Started Biaxin 500 BID, Ceftin 500 BID, Plaquenil 200 BID. Added 4 g Amox for 6 days monthly during Herx. Modest response. Started Ceftriaxone 2g/day 11/01. Flare 10 days later; then definite, progressive response. 12/01 returned to work, driving LUAT 152 7/00 WB 09/00 IgM 30,31, 58,66 IgG 30, 41, 58 urine pcr + 4/01 urine pcr + 6/02 Babesia serology neg Laboratory Post-treatment Exam Full strength all findings normal except slight tandem gait difficulty and slight sensory deficit in fingers

9 Plan: restart Tinidazole 500 tid. Continue Amox. Patient 1 Pt presented 10/02 with recurrence of venous lakes under eyes Recurrence of syncope, urinary incontinence right foot drop, +romberg, moderate sensory neuropathy left toes Tandem gait worse than pretreatment On Rocephin x 6 months, finishing 05/02. After 4 months on IV nearly all symptoms gone. No meds x 1 month. Felt fine. Urine PCR + 06/02. Amox restarted 875 qid. Plan: restart Tinidazole 500 tid. Continue Amox. In 2 weeks begin Biaxin 500 bid. In 6 weeks add plaquenil 200 bid. If no response in 10 weeks, or if worse, resume Rocephin x months. Counfounder: pt wants to get pregnant. Averse to more IV abx.

10 PATIENT 2 41 yo law enforcement officer. Questionable tick bite right hand 05/98 in Pasadena/Los Angeles . Diagnosed as ringworm. By 10/98 developed Bells palsy, visual disturbance, head pressure, vibratory sensation in spine, weakness, severe imbalance diplopia. Developed acral numbness and dysesthesia. Symptoms sporadic, coming and going every few days with variable severity. 11/98 joint pain, head numbness, brain fog, myoclonic jerks. 03/99 Started Tegretol 225 tid. Diagnosed probable remitting/relapsing MS and partial complex seizures 4/99. Brief trial of interferon-beta. No change. Diagnosed Lyme Disease 10/00. Declined IV Rocephin. Began Amox 1g tid 01/01. Within one week, neurological problems improved. Soon developed several round rashes on legs and hands and cramping in legs. Despite recommendations from her primary Lyme doctor and myself patient did not begin more intensive therapy (ie. Tinidazole). Developed tremendous environmental allergies and headaches. 03/02 Commenced Rocephin 1g bid (per patient request). Had significant flare in musculoskeletal symptoms lasting 6 weeks. Allergies improved. By 05/02 had vibration in arms, neck stiffness, light-headedness. 06/02 Biaxin added. Seizure-like activity resulted in discontinuation. Hospitalized for several days for spinal vibrational pain. With high dose magnesium, resolved in 1 day. 07/02 no further spine or peripheral nerve pain. Started experiencing monthly flares of myalgia, neck stiffness,muscle spasms. 09/02 spine tingling recurred. Food allergies recurred. However, muscle mass greatly increased. Overall looked stronger. 11/02 allergies recurred. Fatigue improved. Hypomanic. Severe cognitive decline in two months. Refusing to attempt zithromax, metronidazole, tinidazole or any other anti-seizure medicine. Fear of doctors and unable to follow advice.

11 PATIENT 2 Initially patient doing better on RocephinStarted Declining after 7 months. Recent (10/02) neuropsychological evaluation gave her a GAF of 4.5

12 PATIENT 2 LAB DATA 12/98 Lyme ELISA neg 05/99 Lyme ELISA pos10/00 LUAT (pos) 12/00 Lyme WB IgM 30, 39, 45, +/ IgG 30,41,45 (Igenex) 05/01 Lyme WB IgM 18,37,39,41,45,66; IgG 30,+/-39,41,45 08/01 Lyme ELISA pos x 2 08/01 Lyme WB IgM 18, 39,41,45 IgG 30,+/-39,41,45, +/-58,+/-66 (Igenex) 08/01 Lyme PCR whole blood neg x 2 08/01 LDA (urine) pos 2/3 PCR urine neg 01/02 Lyme WB IgM 41 IgG 41 (Stony Brook) 01/02 Lyme WB IgG neg IgM neg (FOCUS) 10/98 CSF protein 36 wbc % lymphs 13% monos Myelin Basic Protein (MBP) ug/L (wnl) IgG syn mg/d (hi) +oligoclonal bnds 01/99 CSF MBP 1.3 IgG syn oligoclonal bands 11/99 CSF MBP <0.5 IgG syn oligoclonal bnds negative Lyme Ab IgM IgG IFA neg 01/02 CSF protein 33 wbc 0 lymphs MBP 1.2 IgG syn oligoclonal bands 3-4

13 Patient 2 Lab Data Electrolytes consistently normalCBC consistently normal sed rate occasionally mildly elevated Babesia PCR neg, IgM equivocal x1; neg x 2, IgG equivocal x1;neg x1; pos x 1 HME IgM equivocal x1; IgG neg x1 Bartonella neg ANA neg anticardiolipin Ab negative >10 times

14 Patient 2 Radiology- MRI BRAIN10/98 increased signal intensity in white matter bilaterally 03/99 no change. “A few Multiple Sclerosis plaques are seen in the periventricular region” 01/00 a few small punctate areas. Less than previous exam 06/00 No increased signal intensity areas seen as evident on previous. 11/01 a few scattered periventricular white matter signal abnormalities 03/02 scattered periventricular white matter signal abnormalities consistent with demyelination 08/02 SPECT BRAIN moderately diminished perfusion in frontal/orbitofrontal regions as wellas at temporal lobe tips and left temporoparietal region 10/02 multiple periventricular signal abnormalities worse on left side. Worse over previous exam

15 Patient 2 MRI SPINE 08/99 lumbar L4 bulging disc. O/w normal07/01 cervical areas of increased T2 signal in cervical and thoracic spinal cord 11/01 thoracic patchy cord signal T3-T7 right side 03/02 cervical abnormal contrast enhancement C2-C5. Mild cord expansion. “Most likely etiology is MS” 09/02 cervical resolution of cord expansion at C2-C5. Less signal abnormality 09/02 thoracic minimally improved patchy signal changes

16 Patient 3 Initially diagnosed with depression. Placed on prozac. No change. Seen by neurology for r/o MS. 02/99 LP negative for protein, MLB, oligoclonal bands and Lyme antibodies. MRI negative. Found to have positive Lyme ELISA by Kaiser ID. Placed on Doxycyline 100 bid x 28d despite being told Lyme was doubtful “no Lyme in California”. Symptoms resolved until March, 2001 when she developed severe balance problems, memory loss, unilateral facial numbness and diplopia, sensory neuropathy in legs and feet. 27 yo female undefined bug bite on right thigh November, 1998 in San Fernando Valley (Los Angeles County). Two weeks later myalgias, fatigue, headaches, balance problems. Soon after developed tingling in arms, ear pain and visual disturbance.

17 Patient 3 Over next 6 weeks while off meds symptoms got gradually worse. Seen 2/02. Had hyperreflexia and left foot sensory neuropathy. Babesia serology, WA-1, Erlichea serology neg. Lyme IgG Bands 23-25, 28, 30, 31, 41. IgM Bands 18, 30, 45, 58, 93. Started Amox 875 tid x 4 months and Flagyl 6 weeks on 3 months off. Zithromax added 6/02. All symptoms resolved except memory. Dr. Zhang’s herbs x 2 months. August,2002 to Dr. Shantha x2 weeks. Currently all symptoms resolved, including memory. Repeat serology +Lyme. WB (AML-Kaiser) negative. Told she did not have Lyme, but placed on Amoxicillin x 2 weeks 12/01 and then Ceftriaxone, planned for 21 days. After 3 days, felt better. One week later, developed rash and fever, taken off Ceftriaxone and placed on Doxy for 1 week. Repeat LP negative.

18 Summary of Issues Patient 1 Patient 2 Patient 3 Risks of therapyCosts of therapy Long term outcomes unclear Next steps? MRI worse after treatment Treatment not complete Pt getting worse again, despite 10 months Rocephin. Presume cystic forms. How long to treat? Restart IV antibiotics now?

19 Towards a Best Practices Model in Diagnosing Lyme With MS FeaturesLyme Disease Laboratory, Radiological, Clinical Multiple Sclerosis

20 Towards a Best Practices Model in Treating Lyme With MS FeaturesLyme Disease Antibiotics Heat Hyperbaric O2 Intracellular Facilitators Diet/ Supplement Immune modulation Homeopathy energy work other... Symptom Resolution/Cure