Lyme disease: differential diagnosis

Information to assist with differentiating Lyme disease from other causes of rash, neurological or non-specific symptoms.

Skin rashes

The diagnosis of Lyme disease with an erythema migrans rash is usually straightforward, and the condition should be treated on clinical grounds. The rash can have a variety of appearances and a library of pictures is available in the NICE Lyme disease guideline.

It takes at least 3 days after being bitten by an infected tick for an erythema migrans rash 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 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 two 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 PHE Rare & Imported Pathogens Laboratory (RIPL) during working hours. Note that 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)
PHE, Manor Farm Road
Porton Down


Telephone 01980 612348 (available 9am to 5pm, Monday to Friday)

DX address DX 6930400, Salisbury 92 SP

Published 31 July 2018