1 Aim: What is Lyme disease and how is it transmitted?Do Now: What do you know about lyme disease currently?

2 LYME DISEASE Epidemiology Clinical ManifestationsDifferential Diagnosis Diagnosis Treatment Prevention

3 EPIDEMIOLOGY Caused by spirochete Borrelia burgdorferiTransmitted by Ixodes ticks Nymph-stage ticks feed on humans May through July - transmit spirochete Endemic areas Northeastern coastal states Wisconsin & Minnesota Coast of Oregon & northern California

4 Ixodes scapularis ticksThe percentage of nymphs infected with the spirochete is only half that of adult ticks. Nonetheless, 90% or more of cases of Lyme disease are spread by nymphs because adults are less abundant, larger (found and removed more quickly and easily), and active at a time when fewer people are outside. The tick takes 24 hours or longer to attach. During that time B. burgdorferi lies dormant on the inner aspect of the tick's midgut. As the blood meal reaches the midgut, spirochetes proliferate and escape the gut, ultimately reaching the tick's salivary glands, where the excess water of the blood meal is passed back into the host along with the spirochete. (Courtesy of Leonard Sigal.)

5 Larva, nymph, and adult female and male Ixodes dammini ticksFigure Larva, nymph, and adult female and male Ixodes dammini ticks (from right to left). The larva (far left) is approximately 1 mm in diameter. I. dammini is the principal vector for transmission of Lyme disease in the eastern and midwestern United States. (From Rahn [51]; courtesy of Marge Anderson, Pfitzer Central Research, Groton, CT.)

6 EPIDEMIOLOGY (cont) Deer ticks carry diseaseRising frequency attributed to enlarging deer population & concurrent suburbanization High risk areas - wooded or brushy, unkempt grassy areas & fringe of these areas Lower risk on lawns that are mowed

7 MAJOR RISK FACTORS Geographical Occupational RecreationalNortheast, north-central (Wisconsin, Minnesota) coastal regions of California & Oregon Occupational Landscaper, forester, outdoor Recreational hiking, camping, fishing, hunting

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13 CLINICAL MANIFESTATIONSStage 1 - Acute, localized disease Stage 2 - Subacute, disseminated disease Stage 3 - Chronic or late persistent infection

14 ACUTE INFECTION Tick must have been feeding for at least 24-48 hrsrash develops 1 to 4 weeks after bite Without treatment rash clears within 3 to 4 weeks About 50% of pts will also c/o flulike illness - fever, H/A, chills, fatigue

15 Erythema migrans Erythema migrans

16 DISSEMINATED DISEASE May develop in wks to mos in untreated ptsSymptoms usually involve skin, CNS, musculoskeletal system, & CVS Dermatological manifestations new skin lesions, smaller and less migratory than initial

17 AIM: How do the clinical stages of Lyme Disease compare?Do Now: Compare the terms acute and disseminated as it relates to disease.

18 DISSEMINATED (cont) Neurologic complicationsOccurs wks to mos later in about 15% to 20% of untreated Symptoms Lyme meningitis – member 1 mild encephalopathy – member 2 Unilateral/bilateral Bell’s palsy – member 3 peripheral neuritis – member 4

19 Left facial palsy (Bell's palsy) in early Lyme diseaseFigure Left facial palsy (Bell's palsy) in early Lyme disease. The left facial droop reflects a seventh nerve palsy (Bell's palsy), an early neurologic manifestation of Lyme disease, and one that may be bilateral. Other neurologic manifestations include lymphocytic meningitis or meningoencephalitis and other cranial or peripheral neuritis. They typically occur 2 to 8 weeks after infection. (From Klempner [52]; with permission.)

20 DISSEMINATED (cont) Musculoskeletal symptomsSymptoms evolve into frank arthritis in up to 60% of untreated pts Onset averages 6 mos from initial infection Symptoms migratory joint, muscle, & tendon pain knee most common site no more than 3 joints involved during course lasts several days to few weeks then joint returns to normal

21 DISSEMINATED (cont) Cardiac involvementNoted in about 5% to 10% beginning several wks after infection Transient heart block may be consequence Range from asymptomatic to first-degree heart block to complete Cardiac phase lasts from 3 to 6 wks

22 CHRONIC - LATE PERSISTENTFollows latent period of several mos to a yr after initial infection 60% to 80% will have musculoskeletal complaints Most common; arthritis of knee - may also occur in ankle, elbow, hip, shoulder

23 CHRONIC (cont) Neurologic impairment distal paresthesiasradicular pain memory loss fatigue

24 Aim: How do the different stages of Lyme disease vary?Do Now: What is a known vector for the transmission of lyme disease? What is a common symptom of early stage lyme disease?

25 NATURAL HISTORY Without treatment will see disseminated disease in about 80% of pts Oligoarthritis - 60% to 80% Chronic neurologic & persistent joint symptoms - 5% to 10%

26 Clinical stages of Lyme diseaseStage III or the chronic stage is also referred to as the "late neurologic stage." This stage is characterized by chronic or late persistent infection of the nervous system. Syndromes included in this stage are encephalopathy, encephalomyelopathy, and polyneuropathy. The encephalopathy is characterized by memory and other cognitive dysfunction. The encephalomyelopathic signs are combined with progressive long tract signs and optic nerve involvement. White matter lesions may be visible on magnetic resonance imaging of the brain. The late polyneuropathy is primarily sensory. (Adapted from Davis [229].)

27 CONCURRENT INFECTIONSHuman babesiosis fever, chills, sweats, arthralgias, headache, lassitude pts with both appear to have more severe Lyme disease Ehrlichiosis described as “rashless Lyme disease” high fever & chills & may become prostrate in day or two

28 DIFFERENTIAL DIAGNOSISAcute & early disseminated stages Rocky Mountain spotted fever human babiosis summertime viral illnesses viral encephalitis bacterial meningitis

29 DIFFERENTIAL (cont) Late disseminated & chronic stages gout pseudogoutReiter’s syndrome, psoriatic arthritis, ankylosing spondylitis rheumatoid arthritis depression fibromyalgia chronic fatigue syndrome

30 DIAGNOSIS Clues to early disease EPIDEMIOLOGICtravel or residence in endemic area within past month h/o tick bite (especially within past 2 weeks) late spring or early summer (June, July, August)

31 EARLY DISEASE (cont) RASHexpanding lesion over days (rather than hours or stable over months) central clearing or target appearance minimal pruritis or tenderness central papular erythema, pigmentation, or scaling at sit of tick bite lack of scaling location at sites unusual for bacterial cellulitis (usually axillae, popliteal fossae, groin, waist

32 Erythema (chronicum) migransFigure Erythema (chronicum) migrans. Erythema migrans (EM), the pathognomonic skin lesion of Lyme disease, appears as an expanding erythematous lesion, often with central clearing, around the site of the tick bite. Rare lesions of EM can have erythematous and indurated centers resembling streptococcal cellulitis or vesicular and necrotic centers. EM is reported in 60% to 80% of patients. Common sites are the thigh, groin, trunk, and axilla. (From Steere et al. [51]; with permission.)

33 Single erythema migransAn example of single erythema migrans is shown on the back with the appearance of a "bull's eye." The lesion occurred at the site of a tick bite and slowly spread over the course of a few days. (Courtesy of Leonard Sigal.)

34 EARLY DISEASE (cont) ASSOCIATED SYMPTOMS fatigue myalgia/arthralgiaheadache fever and/or chills stiff neck respiratory & GI complaints are infrequent

35 Aim: How do we continue to test for Lyme disease?Do Now: What are some symptoms of early and late disease of lyme disease?

36 EARLY DISEASE (cont) PHYSICAL EXAM Regional lymphadenopathyMultiple erythema migrans lesion Fever

37 DISSEMINATED DISEASE Clinical presentation can make diagnosisepidemiological inquiry review of key historic features physical findings serum for antibody testing spinal tap

38 LATE DISEASE Careful attention to musculoskeletal & neurologic symptoms Differentiating Lyme from fibromyalgia & CFS oligoarticular musculoskeletal complaints that include signs of joint inflammation limited & specific neuro deficits abnormalities of CFS absence of disturbed sleep, chronic H/A, depression, tender points

39 ANTIBODY TESTING Testing with ELISA is not required to confirm diagnosis Pts with objective clinical signs have high pretest probability of disease Tests are not sensitive in very early disease Should not use in pt without subjective symptoms of Lyme

40 TESTING(cont) A + test in person with low probability of disease risks false + rather than true + Test when pts fall between these two extremes pt with lesion or symptoms without known endemic exposure (new area) pretest probability now has high sensitivity & specificity

41 TESTING (cont) For a positive or equivocal ELISA or IFA CDC recommends Western blot Testing cannot determine cure as pt remains antibody + PCR is being developed - still considered investigational

42 TREATMENT Early Lyme disease doxycycline, 100 mg BID for 21 to 18 daysamoxicillin, 500 mg TID for 21 to 28 days cefuroxime, 500 mg BID for 21 days

43 PREVENTION Wear light-colored clothes - easier to spot tickWear long pants, long sleeves Use tick repellent, such as permethrin, on clothes Use DEET on skin Check for ticks after being outside Remove ticks immediately by head

44 VACCINATION NO LONGER AVAILABLE

45 Aim: What other kinds of infectious diseases are humans constantly exposed to but don’t realize?Do Now: What insect is this? What disease(s) do they carry?

46 WEST NILE VIRUS Summer first detected in NYC & Western hemisphere 59 hospitalized - epicenter Queens - 7 died Summer epicenter Staten Island - 19 hospitalized - 2 died For states, 3737 confirmed cases, 214 deaths

47 INFECTIOUS AGENT Member of family FilaviviridaeBelongs to Japanese encephalitis(brain encephalitis) complex Before 1999 outbreaks seen only in Africa, Asia, Middle East, rarely Europe Reservoir & Mode of transmission wild birds primary reservoir & Culex spp. major mosquito vector

48 INCUBATION PERIOD/SYMPTOMSIncubation usually 6 days (range 3-15) Symptoms milder: fever, headache, myalgias(muscle), arthralgias(joint), lymphadenopathy(lymph nodes), maculopapular(flat red) or roseolar rash affecting trunk & extremities occasionally reported: pancreatitis, hepatitis, myocarditis(inflammation heart muscle) CNS involvement rare & usually in elderly

49 TREATMENT No known effective antiviral therapy or vaccineIntensive supportive in more severe cases

50 DIFFERENTIAL DIAGNOSISEnteroviruses Herpes simplex virus Varicella

51 TESTING Lab conformation based on following criteria:isolating West Nile virus from or demonstrating viral antigen or genomic sequences in tissue, blood, CSF, or other body fluid demonstrating IgM antibody to West Nile virus in CSF by ELISA demonstrating 4-fold serial change in plaque reduction neutralization test (PRNT) antibody to West Nile virus in paired, acute & convalescent serum samples demonstrating both West Nile virus-specific IgM & IgG antibody in single serum specimen using ELISA & PRNT

52 Must report suspected cases of West Nile to the NYC Department of HealthDuring business hours call Communicable Disease Program (212) At all other times call Poison Control Center - (212)

53 INFECTIOUS MONONUCLEOSISInfectious mononucleosis - designates the clinical syndrome of prolonged fever, pharyngitis, lymphadenopathy Epstein-Barr virus-associated infectious mononucleosis (EBV-IM) non Epstein-Barr virus-associated infectious mononucleosis (non-EBV-IM) approximately 10-20% have

54 EPIDEMIOLOGY >90% of adults have serologic evidence of prior EBV infection Mean age of infection varies In US 50% of 5-year-old children & 50-70% of first-year college students have evidence of prior infection Infection in children most prevalent amongst lower socioeconomic peak rate of EBV-IM

55 Chance of acute EBV infection leading to IM  with ageGood sanitation & uncrowded living conditions  risk of EBV-IM

56 OTHER CAUSES OF IM CMV Human herpesvirus 6 HIV Adenovirus ToxoCorynebacterium diptheriae Hep A Rubella Coxiella burnetii

57 CLINICAL MANIFESTIONSClassic triad - fever, pharyngitis, lymphadenopathy Prodrome- malaise, anorexia, fatigue, headache, fever Symptoms usually peak 7 days after onset &  over next 1-3 wks Splenic enlargement %

58 Less common clinical featuresupper airway compromise abdominal pain rash (ampicillin  risk of) hepatomegaly jaundice eyelid edema

59 DIAGNOSTIC TESTING Serologic test for heterophil antibodiesPercentage with antibodies higher > 4yrs old % of persons who are + at 1 week varies with test (1 study - 69% + at 1 wk; 80% + by 3 wks) False +s rare

60 If heterophil antibody continues neg & still suspect;serum for viral capsis antigen (VCA) IgG & IgM & for EBV nuclear antigen (EBNA) IgG VCA antibodies + in many at onset

61 LABORATORY ABNORMALITIESTotal leukocyte count  usually > 50% of total leukocytes consist of lymphocytes possible mild thrombocytopenia  LFTs fold abnormalities on UA

62 IM IN OLDER ADULTS 3-10% of persons >40 are susceptiblePresenting S & S different Fever present but few have pharyngitis & lymphadenopathy Jaundice in >20% R/O; hepatobiliary disease, neoplasms, collagen vascular diseases, bacterial infections

63 MANAGEMENT Supportive NSAIDs or tylenol - no ASABedrest during febrile stage If have splenomegaly avoid vigorous activity for 3-4 wks No evidence that steroids or antivirals are of benefit

64 CHRONIC FATIGUE SYNDROMEHas been called: chronic EBV syndrome, postviral fatigue syndrome, “yuppie flu” 1988 CDC convened researchers & clinicians to define & classify CFS 1994 international group proposed guidelines for CFS CDC reported prevalence of 4-11 cases/100,000 population In US most cases occur in young to middle-aged white women

65 ETIOLOGY No cause identified Postulated infective neuromuscularimmunologic neurologic psychiatric

66 DIAGNOSTIC CRITERIA (PER CDC)Fatigue criteria Must not be lifelong Must be persistent, relapsing & unexplained Must not be result of ongoing exertion & cannot be relieved by rest

67 Symptom Criteria Sore throatShort-term memory or concentration impairment Tender cervical or axillary lymph nodes Headaches of a new type, pattern, or severity Unrefreshing sleep Postexertional malaise lasting > 24 hrs Multijoint pain without joint swelling or inflammation Muscle pain

68 Exclusion Criteria Past or current diagnosis of major depression with psychotic or melancholic features, bipolar disorder, schizophrenia, delusional disorders, dementia, bulimia nervosa, anorexia nervosa Active medical conditions Previously diagnosed conditions with unclear resolution (malignancies, hepatitis B or C) Alcohol or substance abuse within 2 yrs of onset of fatigue Severe obesity (BMI  45)

69 Detailed medical history Complete physical LabsCBC ESR TSH UA Serum chem for electrolytes, BUN, cr, glucose, calcium, phosphorus, alk phos, total protein, albumen, globulin, LFTs

70 MANAGEMENT Goal: Restore pts occupational & social functioning & prevent further disability. Guidelines Establish diagnosis Prevent further disability If indicated, start medication ASAP Warn about unproven therapies Initiate psychological intervention

71 PHARMACOTHERAPY Antivirals Immunomodulators Psychotropic agentsPain medications Antiallergy medications Acetylcholinesterase inhibitors Agents used in alternative medicine

72 NONPHARMACOLOGIC TREATMENTExercise Cognitive behavior therapy Self-help groups Work as therapeutic modality

73 DIFFERENTIAL Fibromyalgia Endocrine Chronic viral infectionsMalignancy Sleep disorders causing fatigue Connective tissue diseases Body weight changes Side effects of medications Other illnesses

74 PSYCHIATRIC CONDITIONS EXCLUDING CFS DIAGNOSISMajor depressive episodes Anxiety disorders Delusional disorders Bipolar disorder Schizophrenia Eating disorders Dementias Sleep disorders Substance use disorders

75 HERPES ZOSTER Represents reactivation of varicell-zoster virusLatently resides in a dorsal root or cranial nervie ganglia Multiple erythematous plaques with clustered vesicles Vesicles begin to dry & crust in 7-10 days, clear within 2-3 wks, new may continue to appear for up to 1 wk

76 COMMON DISTRIBUTION Thoracic dermatome 50% Cervical dermatome 20%Trigeminal dermatome 15% Lumbosacral dermatome 10%

77 PRESENTATION/DIAGNOSISProdrome Vesicular rash Diagnosis - presentation

78 Herpes zoster Figure Herpes zoster. Reoccurrence of the varicella virus. Vesicles usually appear in a dermatomal distribution.

79 Acute herpes zoster ophthalmicusFigure Acute herpes zoster ophthalmicus. An elderly woman presented with tingling and subsequent pain on the left side of her forehead. She developed vesicular lesions over the distribution of the ophthalmic branch of the trigeminal nerve. The involvement of the tip of her nose (Hutchinson's sign) suggests involvement of the nasociliary nerve, a nerve that also supplies the cornea. In this case, the cornea has become inflamed, the eye is red, and there is a danger that glaucoma will develop. Patients with acute herpes zoster ophthalmicus should be treated with acyclovir, 800 mg five times a day for 5 days, beginning within 72 hours of the onset of symptoms; this reduces the incidence of ocular involvement, but it does not alter the course of postherpetic neuralgia.

80 POTENTIAL COMPLICATIONSTrigeminal dermatome may affect second branch associated with involvement of eye keratitis, uveitis, secondary glaucoma, iridocyclitis Ramsay-Hunt syndrome affects facial & auditory nerves facial palsy with cutaneous zoster of external ear or TM, with associated tinnitus, vertigo, &/or hearing loss

81 TREATMENT Early treatment Acyclovir (Zovirax) Valacyclovir (Valtrex)within hrs Acyclovir (Zovirax) 800mg 3x/day Valacyclovir (Valtrex) 1,000mg 3x/day Famciclovir (Famvir) 500mg 3x/day

82 POSTHERPETIC NEURALGIAFamvir and Valtrex  incidence Capsaicin cream (Zostrix 0.025% & Zostrix HP 0.075%) 4x/day Amitriptyline Gabapentin Often remits spontaneously after 6 months Pain referral