LYME DISEASE T HE DI SE ASE I N YOUR BACK YARD Kevin I. - - PowerPoint PPT Presentation

T HE DI SE ASE I N YOUR BACK YARD

LYME DISEASE

Kevin I. Young, MD

Free copy of full slide presentation available on request at kevin@plymouthfamilypractice.com

LYME DISEASE INSTRUCTIONS TO PATIENTS Rules:

1.Don’t get it in the first place. 2.If you do get it, treat it early! 3.Know the “red flags” for the disease. 4.If you don’t treat it early, study both national guidelines about diagnosis and treatment. (They don’t agree.) 5.Never trust the lab test (completely). 6.If there is any possibility of Lyme disease, never take a steroid (or immunosuppressant).

LYME DISEASE TAKE HOME INFORMATION

• 1. Avo ida nc e a nd pro phyla xis
• 2. E

rythe ma mig ra ns

• 3. Se c o nda ry dise a se

L yme a rthritis Be lls pa lsy

• 4. Po st L

yme syndro me / Chro nic Ne uro lo g ic L yme dise a se

• 5. L

yme se ro lo g y

E L I SA We ste rn b lo t

• 6. T

re a tme nt pro to c o ls

HIGH RISK BEHAVIOR: BRUSHING AGAINST LEAVES

• De finitio n o f e nde mic e xpo sure to L

yme dise a se is a ny b e ha vio r tha t re sults in b rushing a g a inst le a fy ve g e ta tio n in a re g io n o f mo de ra te o r hig h tic k infe c tio n ra te .

PROBLEM WITH TICK BITE PROPHYLAXIS

T ic k bite

Only 14- 32% of pa tie nts with L yme dise a se re c a ll a tic k bite .

Othe r me tho ds o f tra nsmissio n:

• Ve rtic a l tra nsmissio n fro m mo the r to fe tus
• L

a c ta tio n

• Blo o d tra nsfusio n
• Se xua l tra nsmissio n
• 1. Nadelman RB; Wormser GP. Erythema migrans and early Lyme disease. American Journal of

Medicine, 98(4A):15S-23S.

• 2. Gardner, T. 2001. Lyme disease, pp. 519-641. In J. S. Remington and J.O. Klein (eds.), Infectious

Diseases of the Fetus and New Born Infant. W. B. Saunders Co., Philadelphia, PA.

• 4. Stricker, R.B., D.H. Moore, and E.E. Winger. 2004. Clinical and immunologic evidence of

transmission of Lyme disease through intimate human contact. J. Invest. Med. 52, S151.

NEW HAMPSHIRE TICKS

Deer tick (Ixodes scapularis), the species of black legged tick native to NH, carry Lyme, Borrelia, Bartonella (cat scratch fever), Babesia (North American “malaria”), Ehrlichia, Mycoplasma fermentans, Mycoplasma pneumoniae Lone star tick (Amblyomma americanum), is known to transmit ehrlichiosis, tularemia, and southern tick-associated rash illness. American dog tick (Dermacentor viriabilis), carries Ricketsia and tularemia.

DEER TICK

BLACK LEGGED TICK IXODES SCAPULARIS

Scutum = hard shield Black is bad—black scutum, black legs

TICK IDENTIFICATION

SIZE VS. APPEARANCE Dog tic k De e r tic k (All pictures are of adult ticks.)

L

• ne Sta r tic k

DEER TICK

BLACK LEGGED TICK

TICK SIZE

varies by stage

IXODES SCAPULARIS (MALE AND FEMALE)

Deer tick, adult— Female and male (July-November)

Dog tick, adult Dear tick nymph— Female and male (March – June)

Dog Tick

TICK SIZE

DEER TICK VECTOR

• Nymphs tra nsmit 85% of c a se s.
• Nymphs a re a c tive in la te spr

ing thr

• ug h the summe r.
• Adult de e r tic ks a re most c ommon tic k bite in the fa ll.
• More then 50% of the ticks from Lee and Durham and more then

70% from the Concord sample infected with Lyme causing

• bacteria. Alan Eaton, UNH, 2008.
• T

ic k e xposure ra te s inc re a se with we t we a the r, dro p o ff

sig nific a ntly with dry we a the r.

• T

ic ks hide in fissure s in b a rk during dry we a the r to a vo id dying

• f de hydra tio n
• T

ic ks re ma in a c tive until the te mpe ra ture is <28 de g re e s.

TAKE HOME MESSAGES:

DON’T FEED THE TICKS!

• Ne w Ha mpshire ha s the 2nd hig he st inc ide nc e o f

L yme dise a se pe r c a pita in the US (2012).

INCIDENCE OF LYME DISEASE (NEW HAMPSHIRE)

DEET

• DE

E T = N,N-die thyl-me ta -to lua mide

• Mo st c o mmo n inse c t re pe lle nt sinc e 1946
• Adva nta g e : e ffe c tive
• (E

me rg ing re sista nc e —in mo sq uito , thro ug h g e ne tic muta tio n o f inse c t re c e pto r , I r40a re c e pto r in a nte nna e )

• Disa dva nta g e s
• Sme ll
• Ne e d to re a pply e ve ry 30 min (5% so ln) to 5 hrs (50% so ln)
• Disso lve s synthe tic fa b ric s, type s o f pla stic , pa inte d surfa c e s
• We a k a nti-c ho line ste ra se inhib ito r
• E

xtre me ly ra re inc ide nc e o f se izure s in c hildre n up to a g e 6

PERMETHRIN

• Spra ye d o n c lo thing . No n-to xic whe n dry.
• 1 a pplic a tio n la sts up to 6 wa shing s whe n se lf a pplie d,

75 wa shing s whe n c o mme rc ia lly a pplie d

• Odo rle ss a fte r a pplic a tio n.
• 3 o z is pro pe r a mo unt fo r shirt-pa nts-so c ks.
• Pe rspira tio n a nd e xpo sure to wa te r do e s no t de c re a se

e ffic a c y.

• Ava ila b le a t Wa lma rt (se a so na lly), E

MS, Ca b e lla s, e tc .

TAKE HOME MESSAGES:

AVOIDANCE

• Hig h risk b e ha vio r = any be havio r that le ads to brushing

against le afy ve ge tatio n in e nde mic are a

• Ne w Ha mpshire ha s the 2nd hig he st inc ide nc e o f L

yme dise a se pe r c a pita in the US (2012).

• 50-70% o f de e r tic ks te ste d in Co nc o rd a re infe c te d.
• Do g tic ks do no t tra nsmit infe c tio n to huma ns.
• De e r tic k (b la c k le g g e d tic k)s, b la c k shie ld o n uppe r

b a c k, sma ll size

• Nymph = Ma rc h-July = “po ppy se e d size ”=hig he st risk o f tra nsmitting

infe c tio n

• Adult = mo st c o mmo n tic k o n huma ns in Oc to b e r , b ig g e r, e a sie r

to se e a nd re mo ve

• Pre ve nt with DE

E T(o n skin) o r pe rme thrin (o n c lo the s).

TICK BITE PROPHYLAXIS

• I

ndic a tio ns fo r pro phyla xis:

• De e r tic k b ite in e nde mic a re a
• Atta c hme nt g re a te r tha n 36 ho urs (? )
• Sta rting a ntib io tic with 72 ho urs o f finding tic k.
• No o ne with a do g tic k b ite ne e ds a ntib io tic

pro phyla xis fo r L yme dise a se .

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis. Warshafsky S; Francois LK, Nowakowski J, Nadelman RB, Wormser GP, The Journal Of Antimicrobial Chemotherapy [J Antimicrob Chemother] 2010 Jun; Vol. 65 (6), pp. 1137-44. Date of Electronic Publication: 2010 Apr 09

Meta-analysis of 4 placebo-controlled clinical trials, 1082 subjects Placebo risk of Lyme disease 2.2%, compared with 0.2% in antibiotic treated group (p=0.0037) 3 of the 4 studies involved 10 day course of antibiotics (PCN, amox, amox+TCN), 4th study used doxycycline 200 mg dose, study ended at 6 wks, outcome measure EM 1 case of Lyme prevented for every 50 people treated (depending on case definition).

TRANSMISSION RATE

• 14-32% o f pe o ple with L

yme dise a se re me mb e r a tic k b ite .

• T

ra nsmissio n usually o c c urs a t the e nd o f the 48 ho ur me a l.

Ma tusc hka F R,Spie lma n A. Risk if infe c tio n fro m a nd tre a tme nt o f tic k b ite s. L a nc e t 1993;342;8870:529-30. Na de lma n RB,Wo rmse r GP.Re c o g nitio n a nd tre a tme nt o f e rythe ma Ann I nte rn Me d. 2002 Ma r 19;136(6):477- 9.mig ra ns: a re we o ff ta rg e t?

Atta c hme nt T ra nsmission

24 hr 5% 48 hr 38% 72 hr 92%

• Spiroc he te , de sig ne d to tra ve l
• E

a sily pa sse s throug h me mbra ne s

• L

ive s in both intra c e llula r a nd e xtra c e llula r e nvironme nts

• F

la g e lla is built into the spiroc he te sha pe

• Proka ryotic
• Ha s up to 23 pla smids
• Some pla smids re quire d for virule nc e
• Ha s hype r- va ria ble DNA re g ions

tha t c ode s for isome r s of immunog e nic surfa c e prote ins

• Ca n e limina te surfa c e prote ins

(L

• form or c yst form)
• L

ive s in biofilms

• Use s ma ng a ne se ra the r tha n iron

Borre lia burg dorfe ri

L-FORM

• L
• form la c ks

immunog e nic surfa c e prote ins

• Adva nta g e :
• Minima l a ntig e nic

stimula tion

• Re sista nt to ma ny c e ll

wa ll a ntibiotic s.

• Disa dva nta g e :
• L
• se s its motility
• Stric tly intra c e llula r

CYST FORM

• If the ba c te ria is stre sse d by c ytokine s, hig h oxyg e n

le ve ls, a ntibiotic s, e tc ., it will pa c ka g e its DNA in a sma ll “c yst”.

• Cysts show minima l me ta bolic a c tivity.
• T

he c yst form ha s ve ry fe w immunog e nic surfa c e prote ins.

• Afte r a pe riod of up to 3 we e ks, e a c h c yst c a n

tra nsform itse lf ba c k into a c omple te spiroc he te .

BLEB

• Purpose of ble b: unknown
• Spe c ulatio n: sourc e of “a uto- immunity” ?

Ble b form 1.T he L yme ba c te ria ma ke s thousa nds or short strips of DNA, pa c ka g e s the m, a nd e xtrude s the m a s a “ble b” throug h e xoc ytosis. 2.T his DNA e nte rs huma n c e lls, a nd is c opie d into the huma n DNA throug h re ve rse DNA tra nsc ripta se . Spe c ula tion:

• T

he huma n c e ll the n ma ke s prote ins from this ba c te ria l DNA.

• T

he n the prote in is e xpre sse d on the surfa c e of the c e ll, the immune syste m will a tta c k the huma n c e ll.

• T

he immune syste m c a nnot te ll “frie nd from foe ” be c a use both c onta in fore ig n ba c te ria l surfa c e prote ins.

REASONS FOR PERSISTENT INFECTION

• Bo rre lia do e s no t de ve lo p a ntib io tic re sista nc e .
• Bo rre lia do e s e va de the immune syste m:
• Hide s in intra c e llula r e nviro nme nt a s L
• fo rm
• Cha ng e s into c yst fo rm
• De ve lo ps re se vo irs in le ss va sc ula r tissue s
• T

e ndo ns (c o lla g e n = g ro wth fa c to r); b o ne

• De ve lo ps iso me rs o f surfa c e me mb ra ne pro te ins
• L

ive s in b io films

• Bo rre lia a tta c ks the immune syste m:
• Surfa c e pro te ins a re 500X mo re a ntig e nic tha n E

c o li a nd o the r usua l b a c te ria

• Re sult: o ve rstimula tio n o f T

h1 syste m (“c yto kine “sto rm”), unde r-stimula tio n o f T h2 syste m (minima l a ntib o dy re spo nse )

CLINICAL SYNDROME

LYME DISEASE

STAGES

Primary disease Secondary disease Tertiary disease

• r post infection

Skin “Flu like” illness Joints Nerves Meninges Heart muscle Chronic CNS and/or immune problems

Erythema migrans

Arthritis Bell’s palsy, radiculitis Meningitis Carditis Erythema migrans Lymphocytoma

Chronic neurologic Lyme disease / Post-Lyme syndrome

PRIMARY DISEASE

IDENTIFYING ERYTHEMA MIGRANS

• Clinical characteristics:
• Red rash
• Gradually expanding day to day
• Central clearing—or not.
• Flat—or slightly raised.
• Slightly warmer than surrounding skin.
• Usually no discomfort—or very occasionally

mild stinging or itch

• Starts 4‐27 days after the bite
• Disappears , even without treatment, after 3‐

12 days

• Sometimes associated with flu‐like symptoms

(body aches, fatigue, headache)

ERYTHEMA MIGRANS— NOT THAT SIMPLE

• Homog e ne ous re d skin

59%

• Da rke r c e nte r

32%

• Ce ntra l bump pre se n

31%

• Ce ntra l c le a ring bullse ye

9%

• Bliste r or ulc e r

7%

ERYTHEMA MIGRANS

OTHER RASHES NOT LYME DISEASE

• RI

NGWORM

• Ra ise d, so me time s

wa rm

• SPI

DE R BI T E

• Pa inful, so me time s

ne c ro tic c e nte r

PRIMARY DISEASE

E rythe ma mig ra ns (ide ntifie d in 30- 70% of L yme c a se s) F lu- like illne ss (inc ide nc e : “some time s”): Symptoms: fe ve r, c hills, ma la ise , he a da c he , stiff ne c k, a rthra lg ia s a nd mya lg ia s E xa m: lympha de nopa thy +/ - sple nome g a lly

• 45% o f pa tie nts with e rythe ma mig ra ns ha d

b a c te re mia (po sitive b lo o d PCR fo r Bo rre lia b urg do rfe ri) a t time o f dia g no sis.

• Qua ntita tio n o f c e ll-a sso c ia te d b o rre lia l DNA in the b lo o d o f L

yme dise a se pa tie nts with e rythe ma mig ra ns. D. L ive ris & I . Sc hwa rtz & D. Mc K e nna & J. No wa ko wski & R. B. Na de lma n & J. De Ma rc o & R. I ye r & M. E . Co x & D. Ho lmg re n & G. P. Wo rmse r, E ur J Clin Mic ro b io l I nfe c t Dis, DOI 10.1007/ s10096-011-1376

SEROLOGY

• DO NOT

g e t la b s to de c ide whe the r a ra sh is

e rythe ma mig ra ns!

• I

mmuno g lo b ulins me a sure d b y a n E L I SA o r We ste rn b lo t do to a ppe a r in the se rum fo r 3-12 we e ks a fte r e xpo sure .

• E

rythe ma mig ra ns is a c linic a l dia g no sis!

2ND STAGE OF DISEASE

• Lyme arthritis
• Bell’s palsy, radiculitis
• Meningitis
• Carditis
• Lymphocytoma
• Erythema migrans

LYME ARTHRITIS

MIGRATORY PAUCIARTICULAR ARTHRALGIAS

• Mo st c o mmo n pre se nta tio n o f L

yme dise a se a fte r e rythe ma mig ra ns.

• I

nitia lly a rthra lg ia, la te r a rthritis

• Usua lly pa uc ia rtic ula r
• Jo ints a ffe c te d:
• Kne e s mo st c o mmo n
• Othe r c o mmo n a re a s: a nkle s, lo w b a c k, ne c k,

sho ulde rs, e lb o ws, wrists

• Unc o mmo n: fing e rs.
• L

e a st c o mmo n: hips

• Mig ra tory.
• Off- a nd- on pa in a nd swe lling .
• Gra dua lly prog re ssive
• L

a te r e piso de s mo re pro lo ng e d a nd se ve re .

• F

re q ue ntly trig g e re d by minor injury

• F

irst a tta c k usua lly 3 mo nths a fte r initia l b ite (ra ng e 1-6 mo nths)

FINDINGS (LYME ARTHRITIS)

• Joint e xa m:
• No rma l (c o mmo n)
• Re d, wa rm
• E

ffusion without pe ria rtic ula r swe lling

• Blood te sts:
• Blo o d c o unt (CBC) no rma l
• E

SR no rma l; no rma l se nsitivity CRP no rma l o r mo de ra te ly e le va te d

• RF

ne g a tive , ANA no rma l o r mo de ra te ly po sitive

• Joint a spira te te sts:
• White b lo o d c o unt mo de ra te ly e le va te d
• Culture fo r b a c te ria ne g a tive , inc luding Bo re lia c ulture
• DNA po lyme ra se po sitive 50-80% o f the time
• No re a so n to g e t a We ste rn b lo t o n jo int a spira te
• Xra y:
• Usua lly no rma l (unle ss se c o nda ry d e g e ne ra tive c ha ng e s)

• Sudde n we a kne ss o r pa ra lysis o f o ne side o f the

fa c e , due to infe c tio n o f the 7th c ra nia l ne rve .

Bell’s Palsy

Bell’s (idiopathic) 38% Lyme 4% (Beth Israel) 25% (Suffolk Co. NY) Varicella zoster Cancer Surgery, injury

Etiology, diagnosis, and management of facial palsy: 2000 patients at a facial nerve

• center. Hohman MH; Hadlock TA, The Laryngoscope [Laryngoscope], ISSN: 1531-

4995, 2013 Nov 27; Publisher: Wiley-Blackwell; PMID: 24431233. Lyme borreliosis in Bell's palsy. Long Island Neuroborreliosis Collaborative Study Group. Halperin JJ; Department of Neurology, State University of New York, Stony Brook. Halperin JJ; Golightly M, Neurology [Neurology], ISSN: 0028-3878, 1992 Jul; Vol. 42 (7), pp. 1268-70; Publisher: Lippincott Williams & Wilkins; PMID: 1620330.

ALWAYS EVENTS

(OPPOSITE OF NEVER EVENTS)

• T

HI NK OF L YME DI SE ASE :

• E

rythe ma mig ra ns

• Re d a re a e nla rg e s e ve ry da y, the n disa ppe a rs o n its o wn
• No t pa inful, o c c a sio na lly slig htly itc hy
• Do NOT

use se ro lo g y fo r dia g no sis.

• Artha lg ia s
• Prima ry c a re pre se nta tio n: mig ra to ry pa uc ia rtic ula r a rthra lg ia s,

g ra dua lly pro g re ssive

• E

R, o rtho pre se nta tio n: jo int pa in a nd infla mma tio n tha t is mo re pe rsiste nt o r mo re inte nse tha n e xpe c te d a fte r a n injury

• Be ll’s pa lsy

2 NATIONAL GUIDELINES CLINICAL SYNDROME

CHRONIC LYME DISEASE

• POST LYME SYNDROME

LYME DISEASE

STAGES

Primary disease Secondary disease

Skin rash “Flu like” illness Joints Nerves Meninges Cardiac muscle Chronic brain and immune problems

Erythema migrans

Lyme arthritis Bell’s palsy, radiculitis Meningitis Carditis Lymphocytoma Erythema migrans

Chronic neurologic Lyme disease (neuroborelliosis)

Tertiary disease Autoimmune disease

Post-Lyme syndrome

IDSA VS ILADS

CONTROVERSIES

IDSA

Infectious Disease Society of America

Both ILADS

International Lyme & Associated Disease Society

Definitions

Persistent Recurrent Refractory Chronic = persistent (> 30 days) despite appropriate antibiotics

(Older literature = symptoms duration> 1 yr, treated or untreated)

Diagnoses

Post Lyme Syndrome

Erythema migrans Lyme arthritis Bell’s palsy, radiculitis Meningitis Carditis Lymphocytoma (Acrodermatitis chronica atrophicans)

Chronic neurologic Lyme disease (accounts for 18-29% of Lyme diagnosed by ILADS criteria?)

Medical model

(Neurologic sequellae) Autoimmune disease Active infection (cytokine model)

Serology

ELI SA, then Western blot: CDC surveillance criteria

(IDSA: Specificity 99%)

Western blot, including bands 31 and 34, “high risk band” criteria

(ILADS: Sensitivity 85%)

Treatment

Antibiotics: maximum 6 weeks Antibiotics: single or in combination until symptoms to “baseline intensity” for 2 months

POST LYME SYNDROME

(IDSA CRITERIA—LEVEL III EVIDENCE)

• 2000 I

DSA g uide line s:

• Autoimmune pro b le m tha t pe rsists a fte r a c tive

infe c tio n

• Ra re
• “Late neurologic lyme disease is a very rare event.

Collectively, only one patient over the past five years was diagnosed by panel members.” I

DSA g uide line s (2000)

• Rx: wa it it out
• “The good news is that pa tie nts with Po st T

re a tme nt L yme Dise a se Syndro me a lmo st a lwa ys g e t b e tte r with time ; the bad news is that it can take months to feel

completely well.” I

DSA g uid e line s (2000)

POST LYME SYNDROME

(IDSA CRITERIA—LEVEL III EVIDENCE)

• 2006 I

DSA g uide line s

• T

he syndro me pro b a b ly e xists, b ut ha s no c le a rly de fine d dia g no stic c rite ria .

• T

re a tme nt:

• No c o mme nt, e xc e pt a void a ntibiotic s
• Conc e ntra te on dia g nostic issue s:
• L

yme re -e xpo sure (ra te ~18%)

• Misdia g no sis
• Psyc hia tric illne ss (de pre ssio n, a nxie ty, b ipo la r, c o nve rsio n diso rde r)
• Infla mma tory a rthritis
• F

ibromya lg ia , c hronic fa tig ue syndrome

:

ILADS SUMMARY: CHRONIC NEUROLOGIC LYME DISEASE

PREDICTIVE MODEL

CL I NI CAL PRE SE NT AT I ON

• History of e nde mic e xposure
• Symptom c luste rs:
• No n-re sto ra tive fa tig ue
• Rhe uma to id sympto ms
• Allo dynia (hype ra lg e sia )
• Co g nitive / ne uro lo g ic de fic its
• E

mo tio na l dysre g ula tio n

• Positive se rolog y
• We ste rn b lo t po sitive fo r 1-2 hig h

risk b a nds a nd/ o r po sitive PCR a nd/ o r po sitive urine do t b lo t

• Clinic a l prog re ssion c o nsiste nt with

L yme dise a se

• Re vie w o f e xha ustive diffe re ntia l

dia g nosis

TREATMENT RESPONSE

–Flare in original symptoms (Herxheimer reaction), usually within 4‐27 days of initiation –Pattern of flare and remission (classically 1 week on, 3 weeks

• ff) developing by the 4th month

–Symptom intensity decreasing monthly, but persisting for 4‐15+ months.

NON-RESTORATIVE FATIGUE

“NEVER FULLY AWAKE, NEVER FULLY ASLEEP.”

• Non- re stora tive fa tig ue (le ve l I

I e vide nc e )—

• Mo de ra te ly o r se ve re ly disa b ling , sig nific a nt dura tio n
• No n-re sto ra tive :
• No t impro ve d with sle e p, de spite a de q ua te sle e p time a nd a b se nc e o f
• the r sle e p diso rde rs (i.e ., sle e p a pne a ).
• Co nsiste ntly a g g ra va te d b y e xe rc ise , se ve re inte nsity, dura tio n ho urs to

2 da ys fo llo wing a c tivitie s.

• Hype rsomnia / insomnia (le ve l I

I e vide nc e )—

• Be st me a sure is to ta l ho urs o f sle e p pe r 24, sho wing ma jo r c ha ng e

fro m prio r b a se line .

• Sle e p study: a b no rma l, no nspe c ific , fre q ue nt a ro usa ls witho ut

hypo pne a , ma jo r de c re a se in sta g e 3 sle e p; va ria b le sle e p la te nc y; a b no rma l o nse t o f RE M (c o nfo unde d b y hig h ra te o f a ntide pre ssa nt usa g e )

Steere AC; BartenhagenNH; Craft JE; Hutchinson GJ et all, The early clinical manifestations of Lyme disease, Annals of Int Med, 99(1):76-82, 1983. Steere AC; Malawista SE et al, Yle Journal of Biology and Medicine, 57(4):453-64. 1984. Coyle PK; Schutzer SE. Neurologic presentations in Lyme disease. Hospital Practice, 26(11):55-66, 1991. Greenberg HE, Newy G, Scharf SM, Ravdin L, Hilton E, Sleep quality in Lyme disease. Sleep, 18(10):912-6, 1995.

RHEUMATOID SYMPTOMS

Rhe uma to id sympto ms—

• Cla ssic a lly mig ra to ry po lya rthra lg ia s, g ra dua lly

pro g re ssive o ve r time .

• K

ne e s mo st c o mmo n, a lso a nkle s, b a c k, ne c k, sho ulde rs, e lb o ws, wrists

• Unusua l in hips, le ss c o mmo n in sma ll jo ints

ALLODYNIA (HYPERALGESIA)

• F

ib ro mya lg ia sympto ms, b ut b o th a xia l a nd e xtre mity musc le te nde rne ss, mo re diffuse a nd (so me time s) le ss inte nse tha n c la ssic trig g e r po ints

• “F

lu-like ” b o dy a c he s

• He a da c he syndro me s, sta nda rd pre se nta tio ns
• Se nso ry issue s (pho to pho b ia , pho no pho b ia ,

hype re sthe sia s, e tc ., with irrita b ility)

Steere AC; BartenhagenNH; Craft JE; Hutchinson GJ et all, The early clinical manifestations of Lyme disease, Annals of Int Med, 99(1):76-82, 1983. Brinck T, Hansen K, Olesen J, Headache resembling tension-type headache as the single manifestation of neuroborreliosis. Cephalalgia, 13(3):207-9. 1993. Smith RP, Schoen RT, Rahan DW et al, Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med, 136(6):421-8, 2002. Mikkila HO, Seppala IJ et all. The expanding clinical spectrum of ocular Lyme borreliosis. Ophthalmology, 107(3):581-7, 2000.

COGNITIVE/NEUROLOGIC

• Cog nitive sympto ms a re wide ly va ria b le , b ut c ha ra c te ristic is on-off

patte r n

• “ Bra in fog”
• De lirium
• Word se a rc h, re a ding c o mpre he nsio n pro b le ms, dysc a lc ulia
• Ve ry slow proc e ssing spe e ds, c a n’ t ke e p up, hype r-fo c a liza tio n
• Me mo ry pro b le ms fre q ue ntly pre se nt b ut mo re mino r
• E

xe c utive func tion skills fre q ue ntly pro mine nt

• Co nc e ntra tio n, a tte ntio n; ina b ility to tra nsfe r a tte ntio n, multita sk
• Org a niza tio n, pla nning : ma jo r inc re a se in no n-purpo se ful b e ha vio rs

(“I wo rk a nd I do n’ t g e t a nything do ne .”)

• Ne urolog ic —se nsor

y, CNS; motor ra re ly (unle ss lo ng tra c t o r

ra dic ula r)

• Ra dic ulitis—CN a nd spina l, no n-va sc ulitic mo no ne uritis multiple x;

e le c tro physio lo g ic te sting = se nso rimo to r a xo n lo ss

WAIS‐III and WMS‐III performance in chronic Lyme disease. Keilp JG et al. Journal Of The International Neuropsychological Society: JINS, ISSN: 1355‐6177, 2006 Jan; Vol 12(1), pp. 119‐29. Memory and executive functions in adolescents with posttreatment Lyme disease. mcAuliffe P, Brassard MR, Fallon B. Appl Neuropsychol, 2008; 15(3):208‐19.

• Prctice parameter treatment of nervous system Lyme disease (an evidence‐basedreview), report of the Quality Standards Subcommittee of the American Academy of
• Neurology. (eng) By Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, Krupp L, Gronseth G, Bever CT Jr, Quality Standards Subcommittee of the

American Academy of Neurology, Neurology [Neurology], ISSN: 1526‐632X, 2007 Jul 3; Vol. 69 (1), pp. 91‐102; PMID: 17522387

EMOTIONAL DYSREGULATION

• “Mig ra to ry” mo o d sympto ms
• Anxie ty, usua lly inte nse a nd disa b ling (a vo ida nc e

b e ha vio rs)

• I

rrita b ility

• De pre ssio n
• Ha ppy
• Disa b ling inte nsity, la b ile with o n-o ff patte rn
• Diffe re nt fro m prio r b a se line , tra nsitio n so me time s

a b rupt

Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. NEMJ, 22;323(21):1438-44, 1990 Fallon BA, Nielfds JA, Liegner K, DelBene D, Liebowitz MR, The neuropsychiatric manifestations of Lyme borreliosis. Psychiatric Quarterly, 63(1):95-117, 1992. Sherr VT Panic attacks may reveal previously unsuspeced chronic disseminated Lyme disease. J Psych Pract, 6(6):352-356, 2000.

CHRONIC LYME INCIDENCE (ILADS)

• Chronic neurologic Lyme disease occurs in 18-29% of patients with Lyme

disease

• Risk of disease is predicted by:
• Autoimmune markers (HLA b27, HLA Dr4);
• Delay of more than 2 months between onset of symptoms and start of

initial antibiotic;

• Use of steroids between onset of symptoms and start of initial antibiotic.

THE LONG-TERM CLINICAL OUTCOMES OF LYME

• DISEASE. A POPULATION-BASED RETROSPECTIVE

COHORT STUDY.

SHADICK NA; PHILLIPS CB; LOGIGIAN EL; STEERE AC; KAPLAN RF; BERARDI VP; DURAY PH; LARSON MG; WRIGHT EA; GINSBURG KS; KATZ JN; LIANG MH. DEPARTMENT OF RHEUMATOLOGY-IMMUNOLOGY, BRIGHAM & WOMEN'S HOSPITAL, BOSTON, MA 02115.[ANN INTERN MED] 1994 OCT 15; VOL. 121 (8), PP. 560-7.

• Se tting : c o a sta l re g io n

e nde mic fo r L yme

• Da ta c o lle c te d me a n o f 6.2

ye a rs fro m dise a se o nse t

• 34% o f study g ro up ha d

a rthritis/ re c urre nt a rthra lg ia s, c o g nitive impa irme nt, o r ne uro pa thy/ mye lo pa thy.

• Pa tie nts with lo ng -te rm

se q ue la e re c e ive d tre a tme nt la te r (p<0.0001).

Lyme Control

P value

N

43 38

Arthralgias

61% 16%

0.0001

Sleep difficulty

47% 16%

0.003

Fatigue

26% 4%

0.04

Emotional lability

18% 5%

0.05

Concentration problems

16% 2%

0.03

Paresthesias

16% 2%

0.03

Persistent depression

8% 5%

NS

INTENSITY OF ILLNESS

NIH trials validate the severity of the symptoms of chronic Lyme disease Fallon NIH trial, Neurology 2008 “Pain was similar to those of post-surgery patients” “Fatigue was similar to that of patients with multiple sclerosis.” “Limitations in physical functioning were comparable with those of patients with congestive heart failure.”

COST OF CLD-POST LYME SYNDROME

The cost of CLD calculated by investigators from: CDC, University of Maryland , Eason Health Plan (Maryland)

• $1,310 – Average annual cost for early LD
• $16,199 - Average annual cost for chronic

Lyme disease

• 88% of cost of CLD – indirect, non-medical and

productivity losses

Zhang et al. Economic cost of Lyme disease. 2006 Emerg Infec Dis

DI AGNOST I C CRI T E RI A AND T RE AT ME NT GUI DE L I NE S

LYME SEROLOGY

“The most dangerous test result in microbiology is a false negative.” TRUE OR FALSE?

Answer?:

It depends (on how much the clinician bases his diagnosis upon the test result--and the risk of untreated infection).

6 of the 7 clinical syndromes mentioned in both the IDSA and ILADS guidelines are highly dependent on lyme serology results.

SEROLOGIC TESTING

IDSA

• T

wo tie re d te sting:

• L

yme E L I SA,

• I

f E L I SA po sitive , the n L yme We ste rn Blo t

• I

nte rpre ta tio n c rite ria : use CDC surve illa nc e

• I

g M: c he c k

• Che c k 3 b a nds
• 2 = po sitive
• within 30 d o f sympto m o nse t
• I

g G:

• Che c k 10 b a nds
• 5 = po sitive

IL ADS

• We ste rn blot only
• I

nte rpre ta tio n c rite ria : use CDC surve illa nc e c rite ria o r

• Mo difie d I

Ge ne X c rite ria :

• I

g M o r I g G

• Che c k 6 “hig h-spe c ific ity” b a nds
• 1 = po ssib le
• 2 = po sitive

ELISA LYME IGG AND IGM SENSITIVITY AND SPECIFICITY IN COMMERCIAL LABS

INTERLABORATORY COMPARISON OF TEST RESULTS FOR DETECTION OF LYME DISEASE BY 516 PARTICIPANTS IN THE WISCONSIN STATE LABORATORY OF HYGIENE/COLLEGE OF AMERICAN PATHOLOGISTS PROFICIENCY TESTING PROGRAM. BAKKEN LL, CALLISTER SM, WAND PJ, SCHELL RF, JOURNAL OF CLINICAL MICROBIOLOGY [J CLIN MICROBIOL], ISSN: 0095-1137, 1997 MAR; VOL. 35 (3), PP. 537- 43; PMID

• Appro xima te ly 500 pa rtic ipa nts
• E

a c h pa rtic ipa nt a na lyze d 50 sa mple s o ve r a 3 ye a r pe rio d

• 28 po sitive a c c o rding to CDC c a se de finitio n
• 22 no e vide nc e o f lyme
• Spe c ific ity: 81%
• Sa mple a ppro pria te ? (Pre te st pro b a b ility a ffe c ts

spe c ific ity.)

• 1 sa mple T

re po ne ma pa llidum po sitive re po rte d po sitive b y 70% o f pa rtic ipa nts

• Se nsitivity 75- 93%
• de pe nding upo n the c o njug a te use d b y the

la b o ra to ry

EVIDENCE: ELISA sensitivity: 62.8% IgM, 47.3% IgG combined specificity 81-94%, sensitivity 70-93% depending on reagents and lab quality IDSA: negative Elisa = “You do not have Lyme disease.” ILADS: (does not recommend Elisa testing)

ELISA SUMMARY

COLLEGE OF AMERICAN PATHOLOGY (CAP)

2-TIERED APPROACH TO LYME SEROLOGIC TESTING

Studie s c o nduc te d b y the g ro up re spo nsib le fo r L yme Dise a se pro fic ie nc y te sting fo r the Co lle g e

• f Ame ric a n Pa tho lo g ists (CAP) c o nc lude d tha t

the c urre ntly a va ila b le E L I SA a ssa ys fo r L yme Dise a se do no t ha ve a de q ua te se nsitivity to b e pa rt o f the two -tie re d a ppro a c h o f the CDC/ ASHL D, whe re b y o nly E L I SA-po sitive sa mple s c a n b e te ste d b y We ste rn b lo tting .

I nte r-la b o ra to ry c o mpa riso n o f te st re sults o f de te c ting L yme dise a se b y 516 pa rtic ipa nts in the Wisc o nsin Sta te L a b o ra to ry o f Hyg ie ne Co lle g e o f Ame ric a n Pa tho lo g ists pro fic ie nc y te sting Pro g ra m. J Clin Mic ro b io l. 1997 537- 543.

WESTERN BLOT (FDA-approved kits)

CDC IgG (5 = pos)

• 18 kDa
• 23-25 kDa (Osp C)
• 28 kDa
• 30 kDa
• 39kDa
• 41 kDa (Flagella)
• 45 kDa
• 58 kDa
• 66kDa
• 83-93 kDa

CDC IgM (2 = pos)

• 23-25 kDa (Osp C))
• 39 kDa
• 41 kDa (Flagella)

Interpretation criteria:

• IgM: 2 positive out of 3

bands,

• IgG: 5 positive out of 10

bands

WESTERN BLOT (ILADS)

IGeneX IgM or IgG (2 = pos)

• 23-25 kDa (Osp C)
• 31 kDa (Osp A)
• 34 kDa (Osp B)
• 39 kDa
• 41 kDa (Flagella)
• 83 - 93 kDa

ILADS:

• Use only 5 “high specificity

bands” + band 41

• IgM: 2 out of 6 = positive

IgG: 2 out of 6 = positive

• Include bands 31 and 34

QUALITY vs QUANTITY

Bar graph of probability of Lyme bands in Lyme patients and control population

Lyme + Control Band

41

87% 43% Band

39

83% 1.3%

Western Blot Pattern: Special Role of Osp A (31 kDa) in Chronic Disease

Sensitivity: Band 31 shows a higher incidence in patients with chronic neurologic symptoms: IGeneX study on sera from 30 well defined late Lyme patients:

Sera from 29 of the 30 reacted with 30-31 kDA antigens. All 10 negative samples were negative.

Specificity: Band 31 98% Band 34 98% Sensitivity: Band 31 13% Band 34 15% Bands 31 and 34 were excluded from FDA approved Western blot kits since the Lymerix vaccination turned these bands positive.

Lyme Western Blot Assay (n=165)

Western Blots CDC criteria IGeneX criteria IgG

Specificity Sensitivity 100% 38%

5/10 bands (18,23-25, 28, 30, 39, 41, 45, 66 and 83-93 kDA)

96% 63.3%

2/6 bands (23-25, 31, 34, 39, 41 and 83-93 kDA)

IgM

Specificity Sensitivity 99% 58.3%

2/3 bands (23-25, 39 and 41 kDA)

96% 73.3%

2/6 bands (23-25,31, 34, 39, 41 and 83-93 kDA)

IgG+ IgM Specificity* Sensitivity* 99% 70% 96% 85%

* Actual sensitivity and specificity results will vary (slightly?) based upon Borrelia strain and sample characteristics (i.e., pretest probability

• f disease within study sample)

Serum Sample Types 37 Lyme positive patients (CDC LD Panel) 23 Lyme positive patients confirmed by PCR 60 Tick-borne disease negative patients 45 Lyme negative, other tick-borne disease positive patients

CLINICAL JUDGMENT: WHICH IS BETTER?

A 99% spe c ific ity a nd 70% se nsitivity (I DSA)

• r

A 96% spe c ific ity a nd 85% se nsitivity (I L ADS)

Diffe re nt bia s

• IDSA: minimize risk of unne c e ssa ry a ntibiotic s (ba se d on fa lse positive s)
• IL

ADS: minimize risk of untre a te d infe c tion (ba se d on fa lse ne g a tive s)

Additio na l issue : Hig he r pic kup o f po st L yme syndro me / c hro nic L yme dise a se with b a nds 31 a nd 34?

TREATMENT GUIDELINES

DI AGNOST I C CRI T E RI A AND T RE AT ME NT GUI DE L I NE S

TREATMENT—ERYTHEMA MIGRANS

• Prima ry dise a se : E

rythe ma mig ra ns

• Dura tio n o f a ntib io tic : 3 we e ks
• Antib io tic c ho ic e s:
• Do xyc yc line

100 mg 2x/ da y

• Amo xic illin

500 mg 3x/ da y

• Ce furo xime a xe til

500 mg 2x/ da y

• NOT

ma c ro lide s

Drug o f c ho ic e : DOXYCL

INE

• NOT

in c hildre n unde r a g e 8, pre g na nt o r la c ta ting wo me n

• T

re a ts c o infe c tio n: Ana pla sma pha g o c yto philum

• Be st CNS pe ne tra tio n
• Pho to se nsitivity!

Ce llulitis vs E M—a mo xic illin-c la vulina te

TREATMENT—SECONDARY DISEASE

• Se c o nda ry dise a se
• T

re a tme nt dura tio n: 4 we e ks

• F

a c ia l pa lsy: Do xyc yc line 100 b id

• Me ning itis:

Ce ftria xo ne 2g / d

• Arthritis:

Do xyc yc line 100 b id o r Amo xic illin 500 tid

TREATMENT—TERTIARY DISEASE

• T

e rtia ry dise a se

• I

DSA: sympto m tre a tme nt o nly

• I

L ADS: 4 tre a tme nt o ptio ns

• T

e tra c yc line s

• Cla rithro myc in + hydro xyc hlo ro q uin
• Be ta la c ta ms (a mo xic illin o r c e furo xime a xe til)
• Misc e lla ne o us (usua lly a s “a dd-o ns”)
• Dura tio n: until sympto m le ve l to pa tie nt b a se line x 2

mo nths

THANK YOU

kevin@plymouthfamilypractice.com