a) EARLY LOCALIZED: Stage 1 begins with a distinct skin lesion, erythema migrans at the site of the bite, which may be accompanied by flu-like or meningitis-like symptoms including fatigue, fever, headache, stiff neck, arthralgia and myalgias. Onset is 3 to 32 days post exposure. CNS involvement or infection at this stage is very unlikely.
b) EARLY DISSEMINATED: Stage 2 includes neurologic or cardiac abnormalities that develop weeks to months after the onset of illness. Neurologic effects include lymphocytic meningitis, cranial neuritis (especially facial palsy) radiculoneuropathy, and rarely encephalomyelitis. Cardiac effects include atrioventricular conduction defects and myocarditis. Tachycardia or bradycardia develop in more than 50% of patients with cardiac involvement. Carditis is fairly common in untreated patients (4% to 10%); principle manifestations are conduction and rhythm disturbances (most often AV block); congestive cardiomyopathy, chest pain, myocarditis, and other dysrhythmias develop less often. Conjunctivitis and sore throat are common early in the course. Mild hepatomegaly and elevations in hepatic enzymes are common. Cough is common early in the course, dyspnea may also develop. ARDS is a rare complication.
c) LATE STAGE: Stage 3 occurs months or years after the acute illness, with the development of arthritis in one or more large joints. Chronic neurological syndromes including encephalopathy, axonal polyneuropathy, and leukoencephalopathy can also occur.

a) Finding in about 5% of cases. It may be associated with mild liver enzyme abnormalities suggesting hepatic inflammation (Steere et al, 1983a).

a) Hepatitis (often subclinical) associated with Lyme disease has been reported, and may be the result of direct tissue invasion by the spirochete (Chavanet, 1987)( Goellner, 1988) (Agger et al, 1991; Kazakoff et al, 1993). About 10% of patients have symptoms suggestive of hepatitis, including anorexia, nausea, and vomiting (Steere et al, 1983a).
b) Elevated liver enzymes indicating subclinical hepatitis may provide a clue to the diagnosis when erythema migrans lesion is absent and patients remain ill. In one series, liver enzyme abnormalities were detected in about 25% of patients with erythema migrans who had not been treated with antibiotics; elevated GGT was the most common finding (25%), followed by elevations of ALT, alkaline phosphatase, and AST; bilirubin levels usually were normal (Kazakoff et al, 1993).
c) Another series found one abnormal liver enzymes in 40% of patients with erythema migrans and more than one in 27%. Elevations of GGT (28%) and ALT (27%) were most common, with bilirubin elevated in only 3%. Most elevations were mild, not associated with symptoms, and improved or resolved within 3 weeks of antibiotic treatment (Horowitz et al, 1996).

a) TESTICULAR EDEMA: Occurs in 2% of males with Lyme disease, but the significance of this finding is uncertain (Steere et al, 1983a).

a) May be part of neuroborreliosis or due to direct invasion of the urinary tract by the spirochete. Urinary urgency, frequency, and nocturia are the most frequent symptoms; urinary retention may also occur (Chancellor et al, 1993).
b) Mild proteinuria has occasionally been noted in patients with hematuria. Resolution occurs within one to two weeks (Steere et al, 1983a).

a) Rarely, microscopic hematuria for one to two weeks, sometimes associated with mild proteinuria, may be present (Steere et al, 1983a).

a) Tachycardia (HR greater than 100 beats/min) or bradycardia is the most common clue to cardiac involvement, occurring in over 50% of involved patients. Otherwise, increased heart rate is appropriate for the degree of temperature elevation (Steere et al, 1980b).
b) Nonsustained ventricular tachycardia has been reported (Vlay et al, 1991; McAllister et al, 1989).

a) Over 50% of patients with cardiac involvement exhibit either bradycardia (HR less than 55 beats/min) or tachycardia (Steere et al, 1980b).

a) Severe hypotension manifesting as dizziness or syncope may occur in patients with high degree heart block (Steere et al, 1980b).

a) LD also may cause chronic congestive cardiomyopathy, with resultant dyspnea and exercise intolerance (Faul et al, 1999).

a) Cardiac abnormalities (ie carditis) occur in approximately 4% to 10% of untreated patients, with manifestations developing 4 to 83 (median 21) days after onset of EM (Stage II). Over 75% of these patients still have skin lesions and 50% are febrile. Concurrent CNS or joint involvement is common (Steere et al, 1980b; Asch et al, 1994; Sigal, 1995).
b) Symptoms suggestive of cardiac involvement include: dizziness, syncope, shortness of breath, pleuritic chest pain increased by lying down, and palpitations (Forrester & Mead, 2014). Tachycardia or bradycardia is the most common sign of cardiac involvement (Steere et al, 1980b).
c) Myopericardial involvement may result in conduction disturbances, ventricular dysfunction, dysrhythmias, or cardiomegaly. Most abnormalities resolve within three to six weeks (Steere et al, 1980b).
d) Carditis develops in 4% to 10% of untreated persons with erythema migrans; occurs much less frequently in patients who have received treatment for early LD (Evans, 1998). There appears to be a male predominance in Lyme carditis, despite generally equal gender distribution of LD (Sigal, 1995). May include atrioventricular block, myopericarditis, and left ventricular dysfunction; conduction and rhythm disturbances are noted most frequently (Nadelman & Wormser, 1998; Bachman & Srivastava, 1998; Evans, 1998; Spach et al, 1993; Steere et al, 1980b; Reznick et al, 1986; Woolf et al, 1991; McAllister et al, 1989; van der Linde MR, 1991; Agger et al, 1991; Levine et al, 1991).

a) Most common cardiac complication; 90% of patients with cardiac involvement have AV block, and about 50% of these patients display high-degree blocks. May be presenting and main clinical problem (Rosenfeld et al, 1999; Spach et al, 1993; van der Linde MR, 1991; Kimball et al, 1989; Clesham et al, 1994; Steere et al, 1980b).
b) The heart block can fluctuate rapidly. Shifting from first degree to complete block and vice versa can occur in minutes, so that patients with complete heart block also often have first and second degree (Wenckebach) blocks; the block is most often proximal to the bundle of His, although both bundle branch and fascicular block have been described (Weissman et al, 1999; Steere et al, 1980b; McAllister et al, 1989; van der Linde MR, 1991; Sigal, 1995; Huff et al, 1995).
c) Patients with high-degree AV block often complain of syncope, dizziness, shortness of breath, palpitations, and substernal chest pain. Most also have either tachycardia or bradycardia at some point, and a loud S3 gallop rhythm may be noted(Rosenfeld et al, 1999; Evans, 1998; Steere et al, 1980b; Olson et al, 1986; Kishaba et al, 1988; Vlay, 1986; van der Linde MR, 1991; Kimball et al, 1989; de Koning et al, 1989).
d) POPULATION AT RISK: Young male patients appear to be at greater risk to develop features of Lyme carditis. Of all cases of lyme disease, males account for just over 50% of cases; however, the male to female ratio is 3:1 among patients developing lyme carditis. Males also develop more cases of third-degree heart block and it occurs at a predominantly younger age (10 to 45 years). The exact cause for more episodes of heart block and third-degree heart block is unknown (Forrester & Mead, 2014).
e) CASE REPORT: One case reported frightening dreams and seizure-like symptoms or "spells" while the patient was in complete heart block with periods of ventricular asystole. The combination of heart block and meningitis (lymphocytic cerebrospinal fluid) pleocytosis led to the diagnosis of Lyme disease (Weissman et al, 1999).
f) Cardiac evaluation for evidence of myocarditis should be included in the evaluation of children with Lyme disease, even in the absence of clinically apparent heart disease. Children with cardiac involvement frequently are asymptomatic but may have abnormal ECGs; in one series, almost 30% of children with definite or probable LD had abnormal ECG findings, most commonly first degree heart block (Woolf et al, 1991).
g) Hospitalization and continuous monitoring is required for patients with high-degree heart block or a PR interval greater than 0.3 seconds (Evans, 1998; McAllister et al, 1989). Temporary pacemaker insertion may be necessary (Huff et al, 1995). Prognosis usually is excellent, with resolution of complete block seen within 10 to 14 days (McAllister et al, 1989; van der Linde MR, 1991; Clesham et al, 1994). Rarely, heart damage may result in permanent pacemaker insertion (Artigao et al, 1991; de Koning et al, 1989; McAllister et al, 1989).

a) Chest pain, described as stabbing, occurs early in the course in about 4% of patients. It is quite brief, lasting only seconds at a time, and is increased with lying down (Steere et al, 1983a).

a) Syncope suggests cardiac involvement and may be related to transient bradycardia or heart block that compromises cardiac output (Steere et al, 1980b).

a) Palpitations suggest cardiac involvement. A heart rate greater than 100 beats/minute may be noted in over 50% of affected patients (Steere et al, 1980b).

a) Invasion of the myocardium by B burgdorferi has been demonstrated (van der Linde MR, 1991; de Koning et al, 1989). Manifestations include T wave flattening or inversion, intraventricular conduction defects, PVCs, transient and reversible depression of left ventricular function, cardiomegaly, flow murmurs, mitral regurgitation murmurs, and pericardial effusions. Severe cardiac dysfunction or fulminant heart failure is rare (Evans, 1998).

a) Premature ventricular contractions: Three of 20 patients with cardiac involvement had intraventricular conduction delays and accompanying PVCs; the PVCs resolved without treatment as the conduction delay normalized (Steere et al, 1980b). Intraventricular conduction delays are usually asymptomatic, but may be associated with PVCs (Steere et al, 1980b).
b) Atrial fibrillation with a ventricular response of 120 beats/minute occurred in an otherwise healthy patient. First-degree heart block developed after resolution of the atrial fibrillation. During remission, EKG and exercise thallium-201 perfusion scan were normal (Steere et al, 1980b).

a) Nonproductive cough is a symptom in 5% of patients (Steere et al, 1983a).

a) Patients with early disseminated LD may complain of shortness of breath due to cardiac involvement or phrenic nerve palsy (Faul et al, 1999). Symptoms of dyspnea and palpitations are seen in patients with high-degree heart block (Olson et al, 1986) and heart failure. LD also may cause chronic congestive cardiomyopathy, with resultant dyspnea and exercise intolerance (Faul et al, 1999).

a) CASE REPORT: Fatal ARDS in a patient with Lyme disease has been reported. The patient presented initially with a dry cough, fever, generalized maculopapular rash, and myositis; she also had markedly abnormal liver enzymes results. Her condition remained refractory to treatment, and she ultimately developed ARDS (Kirsch et al, 1988).

a) The Quality Standards Subcommittee of the American Academy of Neurology has proposed the following guidelines. The diagnosis of definite nervous system LD requires (QSSAAN, 1996; (Halperin et al, 1996):
b) Possible exposure to appropriate ticks in an endemic area.
c) One or more of the following:
d) Occurrence of one or more of the neurologic disorders described below, after exclusion of other potential etiologies:
e) CLINICAL MANIFESTATIONS (Nadelman & Wormser, 1998; Steere, 1989; Sigal, 1992; Coyle, 1993):

a) May occur as part of the early symptom complex of LD (about 2/3 of cases) or may indicate meningitis (Steere et al, 1983a; Moscatello et al, 1991). Present in about 40% of both adults and children with early localized LD (Nadelman et al, 1996; Gerber et al, 1996a).
b) When headache occurs as an indication of meningitis, it is usually accompanied by focal neurologic and/or cognitive abnormalities; headache as the sole manifestation of Lyme meningitis has been reported, but appears to be rare (Scelsa, 1995).
c) The headache associated with meningitis typically fluctuates in intensity. It can be excruciating or, at times, mild or absent. The location is usually frontal or occipital but may be bitemporal, global, or very low, almost in the neck (Pachner & Steere, 1985) 1995).
d) In one study, 22 (32%) of the 69 patients with Lyme disease developed headache (Petersen et al, 2015).

a) Most common cranial neurologic manifestation of Lyme disease, occurring in about 10% of both children and adults and in 1/3 to 1/2 of patients with neurologic findings (Dressler, 1994; Reik et al, 1979; Pachner & Steere, 1985) Clark, 1985; (Asch et al, 1994)Bingham, 1995;(Gerber et al, 1996a; Smouha et al, 1997).
b) Most common infectious cause of facial palsy (Robert, 1991; Christen, 1990; (Bjerkhoel et al, 1989). One Swedish study found LD accounted for 6% of all facial palsies; among patients with facial palsy, LD was a more common cause in children than in adults (Engervall, 1995).
c) Occurs early, often while erythema migrans is still present. The mean time from onset of erythema migrans to facial palsy is 20 days (Clark, 1985).
d) Bilateral in about 25% of cases. May be the only presenting sign and may occur without an antecedent rash; arthritis may accompany or follow the facial palsy (Clark, 1985; Bingham, 1995). The weakness may be preceded or accompanied by a sensation of numbness and tingling on the affected side of the face, but a clear sensory abnormality is not present. Patients often report pain around the ear or jaw (Pachner & Steere, 1985) Olsson, 1988; (Lesser, 1995). May be preceded by nontender facial edema and erythema of varying severity (Markley, 1989).
e) In endemic areas, facial nerve palsy may be a marker of occult meningitis (Belman, 1997). Accompanied by aseptic meningitis in one third to one half of Lyme disease cases in children (Williams et al, 1990)(Bingham, 1995).
f) Lyme disease should be considered in patients presenting with idiopathic facial paralysis that is bilateral, occurs in the summer months in an endemic area, and/or is associated with facial erythema and induration (Bachman & Srivastava, 1998) Clark, 1985; (Caruso, 1985) Olsson, 1988; (Markby, 1989; Lesser, 1995; Smouha et al, 1997). However, prior erythema migrans or concurrent clinical signs are often absent (Smouha et al, 1997).
g) The combination of acute facial palsy, particularly bilaterally, and CSF pleocytosis suggests the second stage of Lyme disease (Lewis, 1986; Clark, 1985; Christen, 1990; (Smouha et al, 1997). The facial paralysis itself has an excellent prognosis. May last for weeks, but there usually is no or only minimal residual weakness (Pachner & Steere, 1985) Clark, 1985; (Lesser, 1995; Moscatello et al, 1991); Bingham, 1995).
h) In one study, 36 (52%) of the 69 patients with Lyme disease developed facial palsy. Monosymptomatic facial palsy was observed in one patient. Older age group had a significantly lower risk of facial palsy without radicular symptoms (Petersen et al, 2015).

a) Shoulder girdle neuritis is the most common motor radiculopathy in Lyme disease. Onset may be 3 weeks to 6 months after the acute illness; it begins with shoulder pain, followed one to two days later by motor weakness. The deltoid, supraspinatus, infraspinatus, biceps, and triceps may all be involved. There is corresponding diminution of deep tendon reflexes (Reik et al, 1979).
b) In one series, bilateral shoulder weakness was reported in two patients, and one also had hypesthesia of the axillary nerve (Reik et al, 1979).
c) Radiculoneuritis, usually characterized by a "belt-like" tightness with sharp or burning pain radiating along one or two adjacent dermatomal segments from T5 to T11, is a relatively common manifestation of neuroborreliosis and may persist for 6 to 8 weeks with gradual decrease in pain. Radicular pain rarely begins within the dermatomal distribution of the tick bite (Reik et al, 1979; Halperin et al, 1996).
d) Painful radiculoneuritis may accompany meningitis in stage II LD (Halperin et al, 1996)). Chronic radiculoneuropathy occurs in up to 30% of patients with other systemic findings of stage II LD and may not be associated with CNS infection (p 505; Halperin et al, 1996).
e) NEURITIS, CRANIAL: 40% to 50% of patients with neurologic abnormalities develop cranial neuritis, primarily unilateral or bilateral facial (7th nerve) palsy (Reik et al, 1979; Pachner & Steere, 1985) Clark, 1985; Olsson, 1988; (Lesser, 1995; Asch et al, 1994). Involvement of other cranial nerves is unusual; 6th, 9th, and 10th nerve palsies have been observed (Pachner & Steere, 1985; Lesser, 1995).
f) NEURITIS, PERIPHERAL: Approximately one third of patients with neurologic manifestations developed peripheral nervous system involvement, including thoracic sensory radiculitis, motor radiculitis in extremities, brachial plexitis, mononeuritis, and mononeuritis multiplex (Pachner & Steere, 1985; Reik et al, 1986; Finkel, 1988). Patients with extremity involvement generally have severe radicular pain, dysesthesias, subtle sensory loss, focal weakness, and loss of reflexes. Thoracic radiculitis may be experienced as intense pain or pressure within the distribution of a few dermatomes (Pachner & Steere, 1985) (Sindic, 1987) (Reik, 1987) (Finkel, 1988).
g) NEURITIS, OPTIC: Uncommon complication; appears to result from direct tissue invasion by spirochete with immune-mediated inflammation (Schechter, 1986; Farris & Webb, 1988; Gustafson et al, 1988; Bertuch et al, 1988; Lesser, 1995) .

a) Focal meningoencephalitis in which the initial symptom was acute hemiparesis has been reported (Wilke, 2000) (Feder et al, 1988).

a) Ataxia or broad-based gait has been reported in several cases of Lyme neuroborreliosis and is usually accompanied by other neurologic findings. Symptoms may be typical of cerebellitis or mimic those of a localized mass lesion (Mario-Ubaldo, 1995) (Curless, 1996).

a) INCIDENCE: Up to 80% of patients complain of fatigue(Steere et al, 1983a; Gerber et al, 1996a). It is often a constant symptom, contrary to other early manifestations that are intermittent and changing over a period of weeks. Persistent general fatigue is common and is predictive of late complications or relapse (Steere et al, 1980b; Asch et al, 1994)(Shadick, 1994). A feeling of constant lethargy is reported by up to 80% of patients (Steere et al, 1983a).

a) Up to 80% of patients will complain of malaise (Steere et al, 1983a; Moscatello et al, 1991).

a) Aseptic meningitis occurs in less than 10% of cases (Bowen & Griffin, 1984; Agger et al, 1991). It may occur while erythema migrans is still present or, more typically, several weeks later (Reik et al, 1979; Pachner & Steere, 1985; Huppertz & Sticht-Groh, 1989).
b) Headache, neck stiffness, nausea, vomiting, and photophobia are common and recur over months. Neck stiffness is usually noted only on extreme neck flexion; Kernig and Brudzinski signs are absent (Nadelman & Wormser, 1998; Pachner & Steere, 1985; Coyle, 1993).
c) When headache occurs as an indication of meningitis, it is usually accompanied by focal neurologic and/or cognitive abnormalities; headache as the sole manifestation of Lyme meningitis has been reported but appears to be rare (Scelsa, 1995). The headache associated with meningitis typically fluctuates in intensity. It can be excruciating or, at times, mild or absent. The location is usually frontal or occipital but may be bitemporal, global, or very low, almost in the neck (Pachner & Steere, 1985).
d) In children, it should be suspected in the presence of facial palsy and any neck complaints; facial palsy is accompanied by aseptic meningitis in 1/3 to 1/2 of cases (Belman, 1997)(Williams et al, 1990)(Bingham, 1995).
e) Seropositive patients with aseptic meningitis and without initial signs of an infectious etiology should be suspected of having neuroborreliosis even when first LP is negative (Millner, 1989).
f) CASE REPORT: One case reported frightening dreams and seizure-like symptoms or "spells" while the patient was in complete heart block with periods of ventricular asystole. The combination of heart block and meningitis (lymphocytic cerebrospinal fluid) pleocytosis led to the diagnosis of Lyme disease (Weissman et al, 1999).

a) Chronic Lyme disease commonly is associated with subtle difficulty with concentration and memory; may represent either a vasculitis or encephalitis. Encephalitis probably occurs in about 0.1% of LD patients (Halperin, 1989 (Halperin et al, 1996).
b) Patients may experience subtle neuropsychiatric symptoms months to years after initial infection, including somnolence, emotional lability, depression, memory loss or difficulty concentrating, and behavior changes (Pachner & Steere, 1985) 1995). Other reported manifestations include choreiform movements (Reik et al, 1979) and diffuse encephalopathy with seizures (Reik, 1985).
c) Focal encephalitis in a young woman six years after the onset of untreated Lyme disease and abrupt onset of focal symptoms suggesting brain stem tumor in a teenager 7 years after diagnosis of Lyme arthritis have been described (Broderick et al, 1987) Curless, 1996).
d) Marked chronic CNS involvement without any alteration of peripheral nerves has also been reported (Kohler, 1988). Symptoms usually fluctuate over months, but most patients are able to resume normal activities, including return to work or school (Halperin, 1990 (Halperin et al, 1996).
e) Children may develop neurocognitive symptoms concurrently for months after classic manifestations of LD, possibly representing an infectious or postinfectious encephalopathy related to B burgdorferi infection (Bloom, 1998).

a) Adults with previous LD have a higher prevalence of neurocognitive impairment compared with those without a history of LD; characterized by verbal memory deficits occasionally associated with headache or decreased concentration. These sequelae appear to correlate with a longer duration of infection (Pollina, 1999) (Shadick, 1994) (Asch et al, 1995; Bujak et al, 1996).
b) A subgroup of adults treated for LD but with continuing symptoms of arthralgia, fatigue, and memory impairment had decreased attention/concentration scores, decreased verbal memory, and increased depressive symptomatology when compared with a matched group of patients without persistent complaints (Bujak et al, 1996).
c) Children appropriately diagnosed and treated for LD have an excellent prognosis for unimpaired cognitive functioning (Wang, 1998; Adams, 1999, 1994). However, children may develop neurocognitive symptoms along with or months after classic manifestations of LD, possibly representing an infectious or postinfectious encephalopathy related to B burgdorferi infection (Bloom, 1998).
d) Post-Lyme syndrome and chronic fatigue syndrome (CFS) share many features, including symptoms of severe fatigue and cognitive difficulty. However, despite this symptom overlap, patients with post-Lyme syndrome show greater cognitive deficits than those with CFS (Gaudino et al, 1997).

a) Rare complication of neuroborreliosis; may present with headache, alteration of consciousness, seizures, and/or focal signs (Uldrey, 1987) (Brogan et al, 1990).

a) Studies of nonhuman primates indicate that involvement of the CNS reproducibly occurs by one month post-inoculation and is preceded by a brief spirochetemia (Pachner, 1995) 1995a).

a) About 10% of patients have symptoms suggestive of hepatitis, including anorexia (Steere et al, 1983a). In one series, anorexia was present in about 30% of patients but was not significantly associated with abnormal liver enzymes (Horowitz et al, 1996).

a) Nausea and vomiting, suggestive of hepatitis, occur in about 10% of patients (Steere et al, 1983a). In one series, nausea and vomiting were present in about 30% of patients but was not significantly associated with abnormal liver enzymes (Horowitz et al, 1996).
b) May be more common in children; in one series 20% of children with stage I and 1/3 of those with stage II LD complained of nausea (Gerber et al, 1996a).
c) In one study, 7 (10%) of the 69 patients with Lyme disease developed nausea (Petersen et al, 2015).

a) Right upper quadrant pain accompanied by nausea and vomiting, suggestive of hepatitis, is present in about 10% of patients (Steere et al, 1983a).
b) May be more common in children; in one series abdominal pain was present in about 20% of children with stage I or stage II LD (Gerber et al, 1996a).

a) In one study, about 10% of patients reported weight loss (up to 10 kg) (Steere et al, 1983a).

a) Noted in approximately 5% of cases. Its significance is undetermined (Steere et al, 1983a).

a) About 2% of patients will experience diarrhea (Steere et al, 1983a), which may be more common in children. In one series, 15% of children with stage I and 20% of those with Stage II LD complained of diarrhea (Gerber et al, 1996a).

a) WBC count ranges from 4600 to 14,100/mm(3). The WBC count is elevated above 10,000/mm(3) in about 8% of patients and above 12,000/mm(3) in about 5% (Steere et al, 1983a; Nadelman et al, 1996).
b) In one study, 8 of 20 patients with cardiac involvement had elevated WBC counts ranging from 6600 to 18,000/mm(3) (median, 9100/mm(3)) (Steere et al, 1980b).

a) A case of early LD presenting with leukopenia and thrombocytopenia has been reported. Also suggests coinfection with Ehrlichia or Babesia (Gunthard et al, 1996).

a) Polymorphonuclear counts ranging from 39 to 83/mm(3) (median, 68) have been reported in patients with cardiac involvement. Band forms ranged from 0 to 13% (median, 4%) (Steere et al, 1980b).

a) Peripheral eosinophilia has been described with borrelial fasciitis (Granter et al, 1996).

a) HEMATOCRIT, DECREASED: In one study, anemia was present in about 12% of patients on initial presentation. During remission, the hematocrit value usually returns to normal (Steere et al, 1983a).
b) Another study found an incidence of only 3% among culture-confirmed cases (Nadelman et al, 1996).
c) In one series, no patient had depressed haptoglobin level suggestive of intravascular hemolysis (Steere et al, 1983a).
d) Four of 20 patients with cardiac involvement in the above series had anemia; hematocrit values ranged from 31% to 48% (median, 40%) (Steere et al, 1983a).

a) An elevated ESR (greater than 30 mm/hr) is the most common laboratory abnormality noted: 25% to 50% of patients (Steere et al, 1983a; Agger et al, 1991; Nadelman et al, 1996).
b) While EM was present, the ESR was found to be elevated (4 to 46 mm/hr) in a small subset of patients who subsequently developed arthritis, but it was normal in patients in whom arthritis did not develop (Steere et al, 1977a).
c) The ESR in patients with chronic arthritis ranges from 4 to 54 mm/hr (median, 24 mm/hr)(Steere et al, 1979a).
d) In patients with cardiac involvement, the ESR ranges from 3 to 74 mm/hr (median, 47 mm/hr) (Steere et al, 1980b).
e) ESRs ranging from 2 to 46 mm/hr (median, 22 mm/hr) have been reported in patients with neurologic complications (Reik et al, 1979).

a) Coexistent thrombocytopenia and LD has been reported. In endemic areas, LD should be suspected in patients who present with flu-like symptoms and thrombocytopenia, particularly in absence of EM (Ballard et al, 1994; Gunthard et al, 1996).
b) In one series, thrombocytopenia was present in only 1.5% of culture confirmed cases of EM (Nadelman et al, 1996). Platelet count normalizes shortly following antibiotic therapy (Ballard et al, 1994). Also suggests coinfection with Ehrlichia or Babesia.

a) ERYTHEMA MIGRANS (EM): Hallmark of early localized LD, present in 70% to 80% of patients (Bacon et al, 2008). Distinctive erythematous, maculopapular, commonly round or oval, expanding, annular skin lesion greater than 5 cm in diameter occurring 3 to 32 days (median 7 to 10 days) after (and at the site of) the tick bite (Weissman et al, 1999; Edlow, 1999; Sigal, 1998; Nadelman & Wormser, 1998). Not present in late disease, although patients may recall a prior rash compatible with EM (Bachman & Srivastava, 1998; CDC, 1991; Agger et al, 1991; Steere, 1989; Levine et al, 1991; Williams et al, 1990; Asch et al, 1994; Wormser et al, 1997).
b) HYPESTHESIA: Approximately 25% of patients with EM or arthritis have intermittent periods of regional or generalized hypesthesia, described as an unpleasant increased awareness or sensitivity of the skin to touch or temperature. The scalp is most commonly affected (Steere et al, 1977a).
c) LYMPHOCYTOMA, BORRELIA: A red to dark bluish-red nodule or swelling a few centimeters in diameter is a rare manifestation of LD in Europe. Most common site is on the ear lobe in children and on the nipple in adults; also may occur on nose, scrotum, upper arm, shoulder. May be painful to touch (Pohl-Koppe et al, 1998; Strle et al, 1996c; Strle et al, 1992; Gautier et al, 1995; Albrecht et al, 1991). A tick-associated EM-like rash illness caused by an agent other than B burgdorferi has been reported in southern US; suspected agent is carried by A americanum ticks and may be a spirochete (Kirkland et al, 1997).
d) ACRODERMATITIS CHRONICA ATROPHICANS: Chronic progressive skin disorder that occurs as a late manifestation of untreated cutaneous Lyme disease; occurs most commonly in elderly patients, with predominance in females (Asbrink, 1991; Kaufman et al, 1989; Patmas, 1993). Characterized in initial stages by edematous infiltration with bluish-red discoloration that progresses over years to atrophic lesions resembling localized scleroderma. Lesions often develop slowly and insidiously (Asbrink, 1991).

a) Arthralgia noted early in the course in 33% to 80% of cases (Williams & Rolles, 1986; Steere et al, 1987; Cristofaro et al, 1987; Agger et al, 1991; Moscatello et al, 1991; Asch et al, 1994; Gerber et al, 1996a). Frank arthritis, typically the last manifestation, is found as an early sign in up to 40% of patients (Asch et al, 1994); may be sole presenting sign, especially in children (Steere, 1995).
b) Usually develops 4 weeks following erythema migrans rash but ranges from several days to years. Only about 50% of children with arthralgia have a history of erythema migrans or other rash (Eichenfield et al, 1986)(Culp, 1987).
c) Chronic arthritis develops in about 10% of patients. Chronic or recurrent arthritis appears to be more common in those with HLA-DR2, -DR3, or -DR4 specificity (Shapiro, 1995; Steere, 1995).
d) Arthralgias are typically migratory, usually affecting one location at a time. Arthritis is usually monarticular or oligoarticular but is occasionally migratory; usually affects the knees, shoulders, elbows, ankles, wrists, and temporomandibular joints. When chronic arthritis occurs, it commonly affects one or both knees. In children, more than 90% of arthritis occurs in the knee (Shapiro, 1995)( Huppertz, 1995)(Asch et al, 1994)(Steere, 1983)(Steere et al, 1987).
e) Warmth and swelling of involved joints will be noted in patients with arthritis (Steere et al, 1977b). Onset of arthritis is typically sudden, with involvement of one or more large joints, particularly the knees; small joints of the fingers and toes may also be involved.

a) JOINT EDEMA: Physical examination of patients with arthritis reveals a swollen, often warm, but rarely erythematous joint (Steere et al, 1977a). Onset of arthritis is typically sudden, with involvement of one or more large joints, particularly the knees; small joints of the fingers and toes may also be involved. Childhood presentation is usually subacute swelling of knee joint (Shapiro, 1995).

a) Early symptom in about 50% of patients. Some patients have only generalized aching and stiffness, while others have severe cramping, particularly in the thighs, calves, and back (Steere et al, 1983a; Cristofaro et al, 1987; Moscatello et al, 1991).
b) The muscle pain is typically migratory, usually affecting one location at a time, and lasts only hours in a given location (Steere et al, 1983a).
c) Tenderness in the muscles of the calves, thighs, and back may be noted (Steere et al, 1983a).

a) TENDON PAIN: Typically migratory, usually affects only one location at a time, and lasts hours in a given location (Steere et al, 1983a).

a) May occur during the febrile ("flu") syndrome, simultaneously with or immediately after the onset of EM (Bowen & Griffin, 1984). The pain is generally migratory, although only one location is affected at a time, and lasts only for hours in a given location (Steere et al, 1983a).
b) Diffuse fasciitis characterized by pain and stiffness in an extremity associated with thickening of skin and subcutaneous tissue has been reported as an expression of LD (Granter et al, 1996).
c) Stiff hand is occasionally a manifestation of Lyme disease (Steere et al, 1983a).

a) Subacute multiple-site osteomyelitis caused by B burgdorferi has been reported. Presence of the spirochetes in bone was documented both by culture and PCR (Oksi et al, 1994). Postulated that the spirochetes enter the bone via the hematogenous route and cause multiple lesions in the highly vascularized metaphyses of long bones (Oksi et al, 1994).

a) Characterized by severe proximal muscular pain and weakness accompanied by increased CK levels and EMG alterations (Schoenen, 1989; Kengen, 1989; Atlas, 1988; (Horowitz et al, 1994; Ilowite, 1995). Also has been associated with new onset of dermatomyositis(Horowitz et al, 1994).
b) May occur early or late in course of LD; improvement may take months. Usually occurs near involved joint or peripheral nerve (Schoenen, 1989; Kengen, 1989; Atlas, 1988; (Horowitz et al, 1994; Ilowite, 1995).
c) Muscle biopsy is diagnostic. Gallium-67 imaging shows abnormal skeletal muscle uptake (Kengen, 1989).
d) Diffuse fasciitis characterized by pain and stiffness in an extremity associated with thickening of skin and subcutaneous tissue has been reported (Granter et al, 1996).

a) May occur following antibiotic treatment of LD. Does not represent ongoing infection with B burgdorferi (Hsu et al, 1993) (Sigal, 1993) (Dinerman & Steere, 1992).

a) ARTHRITIS, LYME: Most common manifestation of deep-tissue dysfunction, occurring in 40% to 50% of early disseminated cases and in up to 100% of late disease (Steere, 1998)( Aggar, 1991)(Asch et al, 1994).
b) Spectrum ranges from recurrent episodes of joint, periarticular, or musculoskeletal pain (20%), to intermittent attacks of monarticular or oligoarticular arthritis in large joints (50%), to chronic erosive disease (10%); about 20% of untreated patients have no subsequent manifestations of Lyme disease (Steere, 1998; Steere, 1989; Steere, 1989; Steere et al, 1987; Asch et al, 1994).
c) Almost all patients who develop arthritis have a prodrome of headache, neck stiffness, chills, fever, and malaise. Arthritis as the sole presenting sign of LD appears to be more common in children than adults. Physical examination reveals a very swollen, often hot, joint that is rarely erythematous.
d) In children, the usual presentation is a subacute effusion of the knee. Arthritis appears to be milder and of shorter duration in younger versus older children (Steere, 1998; Steere, 1989; Steere et al, 1977a)(Steere, 1995)(Culp, 1988)(Eichenfield et al, 1986; Cristofaro et al, 1987; Agger et al, 1991; Levine et al, 1991; Asch et al, 1994; Shapiro, 1995).
e) Temporomandibular joint arthritis may be chronic or recurrent over years.

a) NECK PAIN: Present as an early symptom in 40% to 50% of patients (Steere et al, 1983a; Agger et al, 1991; Moscatello et al, 1991). Nuchal rigidity may occur early in nearly 50% of patients. Patients with neck stiffness at the onset of illness have fewer late complications (Steere et al, 1983a). On physical examination, almost all patients with meningitis have mild stiffness on extreme neck flexion, but Kernig and Brudzinski signs are usually absent (Pachner & Steere, 1985).

a) Diagnosis of LD is usually clinical; patients with an erythema migrans rash can be diagnosed clinically. Laboratory studies should be used to confirm the diagnosis. Patients may be seronegative and have LD during the early stage of disease or patients may be seropositive and not have active disease (ie, past infection).
b) GENERAL laboratory studies: CBC, erythrocyte sedimentation rate (ESR) and liver enzymes are generally unnecessary, depending on patient's presentation. However, it is common that ESR may be elevated and hepatic transaminases may be mildly elevated.
c) Laboratory support of diagnosis is essential in suspected extracutaneous LD. Confirmation of late disease requires objective evidence of a clinical manifestation of disseminated disease plus laboratory evidence of infection.
d) CULTURE: Requires special techniques; low yield from blood/CSF; organism (B burgdorferi) may be cultured from skin biopsy or aspirate of erythema migrans lesion.
e) SEROLOGY: Serologic testing is insensitive during the first few weeks of infection. The presence of an erythema migrans rash can be diagnostic. A single positive serologic test cannot distinguish between active and past infection, due to antibody persistence. It also cannot be used to measure treatment response.
f) ANTIBODIES: Demonstration of diagnostic IgM or IgG antibodies to B burgdorferi in serum or CSF. CDC currently recommends a two-test approach using a sensitive enzyme immunoassay (EIA) or immunofluorescence antibody (IFA) (rarely used) followed by Western blot is recommended. If the first step is negative, no further testing of the specimen is recommended. If the first step is positive or equivocal the second step should be an immunoblot test (usually a "Western blot"). The results are only considered positive if the EIA/IFA and the immunoblot are both positive. It is recommended that the 2-steps are done together (Centers for Disease Control and Prevention (CDC), 2011).
g) If a patient has been ill for more than a month, only IgG testing should be performed and not the IgM (ie, it is not sufficient to diagnose current disease). Both the EIA and IFA tests have low specificity and may yield false-positive results and can cross react with other antibodies (Centers for Disease Control and Prevention, 2014).

a) Culture is not feasible in most practice settings (Sood, 1999). Although B burgdorferi grows well in the laboratory, it is not easily recovered from clinical specimens other than biopsy samples of EM lesions (60% to 80%) (Am Coll Physicians, 1997; Tugwell et al, 1997). Culture yield also is high from blood in early disseminated LD but is very low from CSF and almost negligible from synovial fluid (Sood, 1999).
b) EXAMINATION, CEREBROSPINAL FLUID
c) PROTEIN, CEREBROSPINAL FLUID, INCREASED
d) GLUCOSE, CEREBROSPINAL FLUID
e) ENZYME-LINKED IMMUNOSORBENT ASSAY, CEREBROSPINAL FLUID
f) WHITE BLOOD CELLS, SYNOVIAL FLUID, INCREASED

1) ACUTE ARTHRITIS: Should be obtained routinely. Although Lyme arthritis does not typically display bone or joint changes early in the course, mimicking arthritides may be distinguishable.
2) CHRONIC ARTHRITIS: All patients with chronic arthritis; in one series, abnormalities were noted in 20 of 24 patients with chronic knee arthritis (Lawson & Steere, 1985).
3) FINDINGS:

1) Confirmation of clinically diagnosed radiculitis was obtained by electromyography in three patients with Lyme disease.
2) They had neuropathic abnormalities in muscles innervated by one or more roots, but nerve conduction velocities were near normal.
3) Of two patients with a clinical picture suggestive of mononeuritis multiplex, one had marked slowing of nerve conduction velocities in multiple nerves (Pachner & Steere, 1985).

1) Isolation of the spirochete from specimens obtained with a punch biopsy of the outside edge or advancing margin of the rash often is possible, particularly in patients with primary or secondary EM (Berger, 1992; Mitchell, 1993; Melski, 1993; Nadelman, 1996).
2) Aids definitive diagnosis of LD in patients with only primary EM who often lack constitutional symptoms, have nondiagnostic lesions, or who are seronegative (Melski, 1993).

1) A small amount of subcutaneous tissue fluid is aspirated with 3 back-and-forth passes beneath the edge of the lesions using an 18- or 20-g needle on a 3-mL syringe; no saline is injected.
2) The needle and syringe are then flushed with 1 to 2 mL of fresh BSK-II media. After incubation, dark-field microscopy is done weekly for 4 weeks.

1) Examination of synovium may demonstrate hypertrophy or pannus formation, vascular proliferation, and heavy mononuclear cell infiltrates. This is indistinguishable from the histologic picture seen with rheumatoid arthritis (Steere, 1977).
2) B burgdorferi DNA can be detected in the synovial tissue of most patients with Lyme arthritis using PCR techniques (Jaulhac, 1996).

1) WBC COUNT:
2) CRYOGLOBULIN:
3) RHEUMATOID FACTOR: Rheumatoid factor is absent from joint fluid.

1) All patients with meningeal signs. The presentation of Lyme meningoencephalitis can mimic that of bacterial infections, and CSF analysis is necessary for differentiation.
2) Patients with a facial palsy may have a CSF pleocytosis even in the absence of meningeal signs; the need for LP in all patients with facial palsy is controversial (Rahn & Malawista, 1991; Pachner, 1995).

1) WBC COUNT:
2) PROTEIN: Elevated protein levels are commonly found in CSF. A mean level of 79 mg/dL (range 8 to 400) was found in patients with Lyme meningitis (Pachner & Steere, 1985).
3) GLUCOSE: CSF glucose levels are generally normal in patients with Lyme meningitis. A mean value of 49 mg/dL (range 33 to 61) was found in 38 patients studied (Pachner & Steere, 1985).
4) OPENING PRESSURE: The opening CSF pressure of patients with Lyme meningitis is generally normal (Pachner & Steere, 1985).
5) CSF ANTIBODY: Antibodies to B burgdorferi should be measured in the CSF, if testing is available. Increased levels of CSF antibodies relative to the sera strongly suggest Lyme-related meningitis (Rahn & Malawista, 1991).

1) Highly specific and sensitive assay but is not available for routine use (Segal, 1998; (Rosa & Schwan, 1989) Stiernstedt, 1991). Advantages include rapidity (2 d), positive results early in disease, and avoidance of difficulties of identify the organism by culture or immunohistochemistry (Sigal, 1994b) (Goodman, 1995) (Magnarelli, 1995).
2) Can help in making sound clinical judgments when interpreted with knowledge of the clinical context and limitation of the technique (Sigal, 1994b).
3) May prove to be particularly useful for diagnosis early in disease when serology is negative, in neuroborreliosis, and for monitoring response to therapy (Kruger & Pulz, 1991; Keller et al, 1992) (Jaulhac, 1991) (Pachner & Delaney, 1993) (Goodman, 1995) (Schmidt, 1996) (Mouritsen, 1996).
4) Can detect B burgdorferi in synovial fluid, although in one study, detection was more efficient in synovial tissue samples; may be able to show whether Lyme arthritis that persists after antibiotic treatment is due to persistence of the spirochete (Nocton, 1994; Jaulhac, 1996).

1) Overall specificity is 96.4%, but sensitivity depends on body fluid tested (76.7% overall; 100% for CSF and urine; 80% to 85% for synovial fluid; 59% for serum); 3.6% false-positive rate (Liebling, 1993). Concordance between laboratories and primer probe sets remains limited (Nocton, 1996).
2) Can detect DNA from as few as 1 to 5 organisms, even those that are nonviable; however, contamination by even a single organism at any stage can cause a false-positive result. A positive result can suggest previous B burgdorferi infection and diagnosis of LD but is not proof of persistent infection (Sigal, 1994b; Magnarelli, 1995).
3) A negative test does not rule out Lyme neuroborreliosis (Pachner & Delaney, 1993; Huppertz et al, 1993) (Nocton, 1996).
4) False-negative results may occur because of the presence of polymerase "inhibitors" (e.g., hemoglobin) or because of paucity of organisms (Sigal, 1994b).
5) Combined culture-PCR test is more rapid and specific than culture alone (Schwartz, 1993).

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

a) Remove the offending tick if it is still on the animal. If none can be found, consider an insecticidal dip, especially with large animals, to remove ticks.

a) AIRWAY - Maintain a patent airway via endotracheal tube or tracheostomy.
b) EPINEPHRINE - For severe reactions.
c) FLUID THERAPY -
d) ANTIHISTAMINES - Administer doxylamine succinate (1 to 2.2 milligram/kilogram subcutaneously or intramuscularly every 8 to 12 hours).
e) STEROIDS - Administer dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisone (1 to 5 milligram/kilogram intravenously every 1 to 6 hours).

a) A Lyme disease vaccine is now available for dogs (Prod Info, 1992).

a) AIRWAY - Maintain a patent airway via endotracheal tube or tracheostomy.
b) FLUIDS -
c) EPINEPHRINE -

1) Remove the patient and other animals from the tick infested area.
2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
4) ANIMAL POISON CONTROL CENTERS

1) GENERAL TREATMENT