Lyme disease: differential diagnosis
Information to assist with differentiating Lyme disease from other causes of rash, neurological or non-specific symptoms.
Skin rashes
A spreading, red erythema migrans (or bullseye) rash that typically appears between 1 to 4 weeks after a tick bite but may take up to 3 months to develop, is pathognomonic of Lyme disease. The rash can have a variety of appearances and a library of pictures is available in the NICE Lyme disease guideline. In the UK the rash occurs in about two-thirds of case.
The diagnosis of Lyme disease with an erythema migrans rash is usually straightforward. The condition should be treated on clinical grounds and laboratory tests are not necessary.
It takes at least 3 days after being bitten by an infected tick for an erythema migrans rash to start to develop. A reaction that develops and recedes within 48 hours from the time of the tick bite, and which may be hot, itchy or painful, is likely to be a reaction to the bite itself.
Other common causes of rashes that can be mistaken for erythema migrans include:
- reaction to an insect bite
- cellulitis
- tinea corporis (ringworm)
- granuloma annulare
- erythema multiforme (if multiple lesions)
- nummular eczema
Persistent rashes should be reviewed by a dermatologist if no clear diagnosis can be made.
Neurological symptoms
Neurological symptoms can be a feature of both early and late disseminated Lyme disease, and in a proportion of cases may be the primary or sole manifestation of the infection.
Early neurological Lyme disease, with symptoms of less than 6 months duration, can present with painful local radiculopathy (Bannwarth’s syndrome) or localised nerve palsies.
Central nervous system involvement is rare, but can result in meningo-encephalitis or myelitis, and can be associated with myoclonus, cognitive impairment, ataxia and confusion.
Facial nerve palsy is a common presentation of Lyme disease in children, but Lyme disease is not the main cause of facial palsy in the UK.
Early neurological Lyme disease frequently self-limits, but early treatment is recommended.
Late neurological Lyme disease is defined as symptoms of more than six months duration, and may include peripheral and central symptoms and signs, with a wide range of presentations. As many of the symptoms can result from other causes, both infectious and non-infectious, assessment by a neurologist or infectious diseases specialist is recommended.
It is particularly important to ensure that tumours, multiple sclerosis and motor neuron disease are not misdiagnosed as Lyme disease.
The diagnosis of neurological Lyme disease can only be confirmed by examination of the cerebrospinal fluid (CSF) to demonstrate both intrathecal synthesis of Borrelia-specific antibodies and the presence of a pleocytosis (usually predominantly lymphocytes).
CSF samples must be tested in parallel with a contemporaneous serum sample, and protein and immunoglobulin (IgM and IgG) levels compared between the 2 sample types to produce a meaningful result.
Persistent non-specific systemic symptoms
The differential diagnosis for persistent non-specific systemic symptoms is very wide, depending on the predominant symptoms and their presentation. Some examples to consider are:
- CMV
- EBV
- hepatitis B or C
- HIV
- syphilis
- toxoplasmosis
- unusual infections such as anaplasma, rickettsia, tick-borne encephalitis, Q fever
- auto-immune diseases including rheumatoid arthritis
- malignancy
- primary psychiatric disorders
- chronic fatigue syndrome, myalgic encephalomyelitis or fibromyalgia
For less common complications of Lyme disease including cardiac disease (such as heart block or pericarditis), eye conditions (such as uveitis or keratitis), or unusual rashes suspected to be lymphocytoma or acrodermatitis chronica atrophicans, referral to the appropriate specialist is advised.
Similarly, for more general issues, patients with predominantly joint or muscle pains should see a rheumatologist if additional investigation is required. For other presentations, a neurologist, a general or infectious disease physician may be appropriate. Further information can be found in the NICE Lyme disease guideline.
Other infections associated with tick bites
Ticks can carry a number of other bacterial and viral infectious agents, sometimes at the same time as the Lyme disease organisms. In the eastern part of the United States, babesiosis and ehrlichiosis may occur independently or with Lyme disease after tick bites.
Transmission of more than one agent in Europe and the UK is rare, with only a handful of cases reported with definite evidence of co-infection.
In other parts of the world, viruses such as tick-borne encephalitis virus can cause infections that may be mistaken for Lyme disease. Depending on where the patient was exposed, other infections may also give rise to symptoms similar to Lyme disease.
Contact details
Clinicians may seek advice on these diseases and their diagnosis from the UK Health Security Agency (UKHSA) Rare and Imported Pathogens Laboratory (RIPL) during working hours. Note, RIPL does not accept calls directly from patients. A patient concerned about infection following a tick bite should contact their GP, who can call RIPL if necessary.
Lyme disease diagnostic service
Rare and Imported Pathogens Laboratory (RIPL)
UKHSA, Manor Farm Road
Porton Down
Wiltshire
SP4 0JG
Email lyme.ripl@phe.gov.uk
Telephone 01980 612348 (available 9am to 5pm, Monday to Friday)
DX address DX 6930400, Salisbury 92 SP
Neurological Lyme disease: laboratory investigations and diagnosis
Accessible text version of the flowchart
If neurological Lyme disease is suspected by a specialist doctor:
- offer a test for intrathecal antibody production
- take a paired serum and CSF sample (each greater than or equal to 500 µL)
Send the paired serum and CSF sample to the UKHSA Lyme disease service along with (if known):
- the CSF cell count
- the serum total albumin and IgG
- the CSF total albumin and IgG
If not known, the UKHSA Lyme disease service will measure these last 2 parameters.
The UKHSA Lyme service will carry out an IgG immunoblot test on the CSF and appropriately diluted paired serum.
If there is a positive IgG immunoblot result, this is indicative of intrathecal production of antibodies to Borrelia spp. If the symptoms are compatible with neurological Lyme disease and/or there is evidence of pleocytosis in the CSF, treat.
If there is no positive IgG immunoblot result, offer a polymerase chain reaction (PCR) test on the CSF if symptoms are less than or equal to 6 weeks in duration and there is enough CSF.
If the PCR result is positive it means Borrelia spp DNA has been detected in the CSF, which is diagnostic of neurological Lyme disease, and the patient must be treated.
If the PCR result is negative, consider an alternative diagnosis. If Lyme remains a possibility, offer a screening ELISA test on serum in 6 weeks.
Updates to this page
Last updated 20 April 2022 + show all updates
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Updated skin rashes section and added text version of laboratory investigation flowchart.
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First published.