The importance of early diagnosis in Lyme disease

A thorough history and recognition of the erythema migrans rash will aid identification. By Dr Sara Ritchie

The incidence of Lyme disease is increasing. The disease is passed to humans via tick bites from infected animals such as deer. Preventive measures to prevent tick bites in endemic areas and early removal of ticks will reduce the risk of transmission. Prompt diagnosis of the disease is key because patients who are treated in the early stages usually recover rapidly and completely.

Key words
Erythema migrans, Lyme disease, ticks, zoonosis

Lyme disease is a tick-borne zoonosis caused by the spirochaete Borrelia burgdorferi. It occurs in endemic foci at temperate latitudes of the northern hemisphere. In Europe, it is endemic from southern Scandinavia into northern Italy, Spain and Greece. In the US, highly endemic areas are the north-eastern and north-central US.1 Transmission of the disease has not been documented in the tropics.
Most cases occur in the summer, coinciding with tick activity, although they can present throughout the year.2
The reported incidence of Lyme disease is increasing, with more than 950 cases reported in the UK in 2011.3 In 2013, the US Centers for Disease Control and Prevention issued a press release to state that the true number of annual new cases in the US is likely to be 10-fold higher than previously thought, at approximately 300,000 annually.4
Many species of mammals can be infected and deer are an important reservoir. Transmission occurs via the bite of infected Ixodes ticks. Ticks can attach to any part of the body, but are often found in hard-to-see areas, such as the groin, armpits and scalp.
The bite is usually painless and even engorged ticks may go unnoticed by the affected individual. Infection rarely occurs during the first 24 hours of feeding,5 so if a tick can be removed promptly, the risk of transmission is low.

Clinical features

Lyme disease can affect the skin, joints, heart and nervous system. The clinical symptoms have been considered in three stages – early localised, early disseminated and late disease – although these are not clear-cut phases.

Erythema migrans
Acute symptoms include fever, headache, fatigue, arthralgia, myalgia and often a characteristic skin rash at or near the site of the bite, known as erythema migrans (figure 1). This rash usually develops within the usual incubation period of three to 30 days.
Data suggest, however, that 20-30% of those infected do not develop the rash at all.6 Classic erythema migrans is an erythematous patch which slowly expands over days, with or without central clearing.
The appearance of the rash can vary, however. Oedema, vesicles and crusting can occur (figure 2), and multiple lesions may appear, as a result of haematogenous dissemination.7

Figures 1 and 2: erythema migrans may appear after three to 30 days and can involve the development of vesicles and oedema (Photographs: Dr Sara Ritchie)

Borrelial lymphocytoma
A borrelial lymphocytoma is a manifestation of early disseminated Lyme disease, which has been reported only in Europe, occurring in <1% of cases.
This is a bluish-red nodular swelling that can occur on the earlobe, nipple areola, nose, scrotum or extremities. It can be mistaken for a cutaneous lymphoma because it has an intense lymphocytic infiltrate on histology, but resolves following antimicrobial treatment.

An estimated 10-15% of patients diagnosed with Lyme disease develop CNS involvement (neuroborreliosis).
Neurological symptoms usually take months to develop, but can also occur early in the infection – within weeks.
Cranial nerve palsies, radiculopathies, a transverse myelitis, meningitis, encephalomyelitis, a ‘glove and stocking’ pattern of peripheral neuropathy, or a motor polyradiculopathy can occur.
Neuroborreliosis may be confused clinically with MS, Guillain-Barré syndrome or amyotrophic lateral sclerosis.8

Lyme arthritis
Lyme arthritis is a rare complication in the UK, but is more common in the US and central Europe. It may develop a few years after the original infection, and is usually a mono- or oligoarthritis affecting the knee or other large joints. Effusion is often a striking presenting feature.9

Lyme carditis
Lyme carditis is extremely rare, but may present with AV conduction defects, such as heart block.10 Renal involvement is also rare, but an early postborrelial immune-mediated glomerulonephritis has been known to occur in some patients.11

Acrodermatitis chronica atrophicans
Acrodermatitis chronica atrophicans is a cutaneous feature of late-stage Lyme disease, occurring in about 1% of infections, only in Europe.
It occurs at acral sites on extensor surfaces of the hands, feet, knees and elbows. Early on, erythematous or violaceous patches occur. It is important to be aware of this appearance, because if the patient has a history of outdoor activities in endemic areas, confirmation of positive serology for Borrelia at this stage can lead to resolution of the symptoms with doxycycline treatment for four weeks.12
Later, atrophic changes are seen, with scaling and thinness of the skin (often described as ‘cigarette paper’ skin), visible superficial veins and sometimes a peripheral neuropathy. The later stages are difficult to treat.


Laboratory confirmation is unnecessary with a clinical diagnosis of erythema migrans. However, in all other circumstances, laboratory confirmation is required for diagnosis. A screening ELISA is used first and if this is positive, it should be followed by a confirmatory western blot (immunoblot).
IgM antibodies are only significant during the first four weeks of illness, but are more likely to cross-react and give false positive results, so testing at this stage is problematic. IgG antibodies are more reliable, but can take from four to six weeks to become detectable.
In suspected neuroborreliosis, testing CSF is mandatory and can exclude the infection with a high degree of certainty.13 A clinical encephalopathy identical to that seen in many systemic inflammatory diseases can occur during active infection and is not evidence of CNS infection.
PCR is available and may be useful in testing joint fluid and biopsies of rashes. However, there are still problems with the sensitivity and specificity of PCR on blood,14 and both PCR and culture have poor sensitivity on CSF, where antibody detection is the preferred first-line test.
Seropositivity in serum usually gradually declines in treated patients, although strongly seropositive patients may remain seropositive – even in the CSF – for decades, despite resolution of symptoms. Untreated patients who remain seronegative despite continuing symptoms are unlikely to have active infection with Borrelia burgdorferi.15


Borrelia burgdorferi is highly antibiotic-sensitive, and patients with Lyme disease who are treated in the early stages usually recover rapidly and completely.
However, those who are more systemically ill at the time of diagnosis seem to take longer to have a complete response to therapy. For adults, doxycycline 100mg twice daily is first-line, then amoxicillin 500mg three times daily or cefuroxime 500mg twice daily.
For young children, amoxicillin 50mg per kg per day in three divided doses, or cefuroxime 30mg per kg per day in two divided doses, is recommended.16
If the child is aged eight years or over, doxycycline 4mg per kg per day in two divided doses is recommended.16
Recent evidence suggests doxycycline does not cause adverse fetal effects in the first trimester, but its use is still best avoided in pregnancy if other options are available.17
There is still controversy regarding the optimal duration of antibiotic regimens, however, and Infectious Diseases Society of America (IDSA), European Federation of Neurological Societies, American Academy of Neurology, and International Lyme and Associated Diseases Society (ILADS) guidelines differ.
The IDSA guidelines recommend 14-day courses for adult patients with early localised or early disseminated Lyme disease, in the absence of neurological or cardiac manifestations.16 The IDSA states that less than 10% of individuals do not respond overall and courses can be given up to 21 days.16 The ILADS recommends not less than 21 days of treatment.18
For neuroborreliosis, oral doxycycline or IV ceftriaxone is recommended for up to 28 days. For Lyme arthritis, oral treatment for 28 days is recommended. For patients who have persistent symptoms of Lyme arthritis, retreatment with another 28 days of oral antibiotics, or two to four weeks of IV ceftriaxone, is recommended.
For neuroborreliosis with peripheral nervous system involvement, treatment with IV ceftriaxone and oral doxycycline is considered equally effective. However, for neuroborreliosis with confirmed CNS involvement, current US and European guidelines advocate IV ceftriaxone.16,19
Despite historic preferences for parenteral treatment in CNS neuroborreliosis, oral doxycycline is well absorbed, and a 2014 retrospective study on CSF sampling has shown that this form of the infection may also be highly responsive to oral doxycycline.20
A double-blind randomised prospective trial is now required, however, to establish whether IV and oral regimens are equivalent in CNS neuroborreliosis.21

Chronic sequelae

Up to 10-20% of patients treated for Lyme disease can develop chronic symptoms, known as post-treatment Lyme disease syndrome, despite adequate treatment.
These symptoms can include profound fatigue, pain, joint or muscle aches, or impaired cognitive function. In some cases, these symptoms can last for more than six months, although their cause is still unknown. Patients with post-treatment Lyme disease syndrome usually recover with time, but this process can take several months.

Classic erythema migrans slowly expands over a period of days (Photograph: Dr Sara Ritchie)

Prevention and prophylaxis

Single-dose prophylaxis within 72 hours of a tick bite is sometimes mentioned in the literature. However, this regimen is not currently recommended by ILADS because the data come from a single trial with methodological problems, and this strategy may contribute to the development of antibiotic resistance.18
Box 1 outlines some basic measures that can be recommended to prevent tick bites in endemic areas.  

 Box 1: Measures to prevent tick bites

Wear appropriate clothing

Long trousers should be tucked into socks, and shirts tucked into trousers. Permethrin-treated clothing can also help to improve this protection

Apply insect repellents to the skin

Lemon eucalyptus oil has been shown to be highly repellent against ticks,22 and N,N-diethyl-meta-toluamide (DEET) is also effective

Check for ticks at least daily

If ticks are found, they should be removed promptly by pulling steadily (without twisting or jerking), grasping as close to the skin as possible with fine-tipped tweezers or a commercial tick removal device. There is no evidence that other methods, such as using petroleum jelly or placing a lit match near the tick, are effective

  • Dr Sara Ritchie is an honorary clinical fellow in tropical dermatology, University College London Hospitals NHS Foundation Trust

Competing interests: None declared

1. Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease – United States, 1992-2006
2. Public Health England. Lyme borreliosis epidemiology and surveillance. 1 May 2013.
3. Dubrey SW, Bhatia A, Woodham S et al. Lyme disease in the United Kingdom. Postgrad Med J 2014; 90(1059): 33-42.
4. Centers for Disease Control and Prevention press release. CDC provides estimate of Americans diagnosed with Lyme disease each year. August 19, 2013. 
5. Radolf JD, Caimano MJ, Stevenson B et al. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol 2012; 10(2): 87-99.
6. Public Health England. Lyme disease: guidance, data and analysis. 6 July 2014.
7. Nadelman RB, Nowakowski J, Forseter G et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med 1996; 100(5): 502-8.
8. Burakgazi AZ. Lyme disease-induced polyradiculopathy mimicking amyotrophic lateral sclerosis. Int J Neurosci 2014; 124(11): 859-62.
9. British Infection Association. The epidemiology, prevention, investigation and treatment of Lyme borreliosis in United Kingdom patients: a position statement by the British Infection Association. J Infect 2011; 62(5): 329-38.
10. Forrester JD, Mead P. Third-degree heart block associated with lyme carditis: review of published cases. Clin Infect Dis 2014; 59(7): 996-1000.
11. Littman MP. Lyme nephritis. J Vet Emerg Crit Care 2013; 23(2): 163-73.
12. Aberer E, Breier F, Stanek G et al. Success and failure in the treatment of acrodermatitis chronica atrophicans. Infection 1996; 24(1): 85-7.
13. Lautner R, Zetterberg H, Blennow K. Laboratory testing for lyme neuroborreliosis. JAMA Neurol 2015; 72(1): 125-6.
14. Dunaj J, Moniuszko A, Zajkowska J et al. The role of PCR diagnostics of Lyme borreliosis. Przegl Epidemiol 2013; 67(1): 35-9.
15. Halperin JJ, Baker P, Wormser GP. Common misconceptions about Lyme disease. Am J Med 2013; 126(3): 264.e1-7.
16. Wormser GP, Dattwyler RJ, Shapiro ED et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43(9): 1089-134.
17. UK Teratology Information Service. Use of doxycycline in pregnancy. August 2012.
18. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther 2014; 12(9): 1103-35.
19. Mygland A, Ljostad U, Fingerie V et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 2010; 17: 8-16.
20. Bremell D, Dotevall L. Oral doxycycline for Lyme neuroborreliosis with ?symptoms of encephalitis, myelitis, vasculitis or intracranial hypertension. Eur J Neurol 2014; 21(9): 1162-7.
21. Halperin JJ. Oral treatment of parenchymal central nervous system neuroborreliosis: are we there yet? Eur J Neurol 2014; 21(9): 1147-8.
22. Due C, Fox W, Medlock JM et al. Tick bite prevention and tick removal. BMJ 2013; 347: f7123.

Lyme disease is a tick-borne zoonosis that is endemic from southern Scandinavia into northern Italy, Spain and Greece. In the US, highly endemic areas are the north-eastern and north-central US
The bite is usually painless and even engorged ticks may go unnoticed by the affected individual. Infection rarely occurs during the first 24 hours, so if a tick can be removed promptly, the risk of transmission is low
The disease can affect the skin, the joints, the heart and the nervous system
The clinical symptoms have been considered in three stages: early localised, early disseminated and late disease
Acute symptoms include fever, headache, fatigue, arthralgia, myalgia and often a characteristic skin rash at or near the site of the bite, known as erythema migrans

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