Lyme Disease

This disease was formally described following the investigation of a collection of patients with rashes and swollen joints occurring in Lyme, Connecticut in 1975, and acquired the name "Lyme disease" (Lyme arthritis) in 1977.¹ The various rashes however had been recognised many years previously, as had their association with neurological problems.

Lyme disease is caused by a tick-borne spirochaete, Borrelia burgdorferi² and others. The infectious spirochetes are transmitted to humans through the bite of certain Ixodes spp. ticks.

The disease is caused by the infection and the body's immune response to infection. Different strains of Borrelia spp. cause different clinical manifestations of Lyme disease and this explains differences between the disease in Europe and the disease in the United States.

Although there is a rising incidence this is likely to be due to better detection and surveillance.³ It is still a rare disease.

The spirochete responsible is transmitted from host to host by Ixodes spp. or deer ticks. Understanding the life cycle of these organisms gives better understanding of the epidemiology and other clinical aspects of Lyme disease and prevention of Lyme disease.
The Ixodes tick:

• Is made up of different species, found in different areas of the world. For example:
  Ixodes persulcatus and Ixodes ricinus (European ticks), Ixodes scapularis, Ixodes pacificus.
• Emerges in a larval form in the summer and feeds just once on a host animal (often a mouse).
• In the spring the larva becomes a nymph and feeds, again only once, from similar animal host. Humans can be victims in the nymph stage (85% of tick bites in humans occur at this time in spring and early summer).
• In the autumn the adult tick finally emerges to feed on deer, again just once. Humans can be hosts at this stage (15% of tick bites in humans are at this stage and occur in the autumn).

The spirochete responsible:

• Is transmitted by the tick. The tick must have fed on a host significantly infected with spirochete to pass on the infection to man.
• Once it infects the tick has to go through a particular cycle of multiplication and dissemination to salivary glands within the tick before it can be passed on to the animal victim. Hence a tick must be attached for 2-3 days to a person before infection can be passed on.

Once the spirochete infects the host there may be one of several consequences:

• The infection is cleared by host defences. This means the person will have had no clinical manifestations, be asymptomatic but seropositive.
• The organism spreads by direct invasion. This is believed to be a feature in early disease. For example erythema migrans is thought to result from the inflammatory response to direct invasion of the organism in the skin.
• The organism excites an immune response in the host which causes a variety of clinical manifestations around the body. In such cases there is no evidence of direct bacterial invasion. Host factors (immunological and genetic) are associated with development of disease in this form. For example HLA- DR4 and HLA- DR2 are associated with such disease. The manifestations of Lyme disease are also related to the particular Borrelia spp. strain involved. Particular strains are found in different countries. For example:
  • B. burgdorferi garnii found in Europe is associated with neurological disease.
  • B. burgdorferi afzelii from Europe is associated with acrodermatitis chronica atrophicans.
  • B. burgdorferi sensu stricto is found on the East Coast of the United States.
  • B. burgdorferi predominates in the USA⁴ with an associated pattern of musculoskeletal complications.
  • B. valaisiana has a relatively high prevalence in British ticks, and does not appear to be associated with manifestations of disseminated borreliosis, which may explain the low incidence of Lyme borreliosis in the UK.
  • Lyme disease is now becoming global and mixed infections are becoming recognised.

• In the UK, areas where infection is acquired include:
  • Exmoor
  • The New Forest
  • The South Downs
  • Parts of Wiltshire and Berkshire
  • Thetford Forest
  • The Lake District
  • The Yorkshire moors
  • The Scottish Highlands
• About 20% of confirmed cases are reported to have been acquired abroad:³
  • The United States
  • France
  • Germany
  • Austria
  • Scandinavia
  • Eastern Europe
• Laboratory-confirmed reports of Lyme borreliosis have risen steadily since reporting began in 1986. Several factors have contributed to the observed increase, including increased awareness of the disease, access to diagnostic facilities, more sensitive diagnostic methods, the enhanced surveillance scheme (introduced in 1996) and since 2000, more complete reporting of cases.³ Other possible factors producing a real increase include changes in the geographical ranges of I. ricinus both in the UK and Europe (successive mild winters), more recreational travel to high endemic areas and the increasing popularity of activity holidays (walking, trekking and mountain biking).³
• Over 3,000 reports of Lyme borreliosis have been received since 1986, almost 2,800 of which have been reported since the introduction of enhanced surveillance in 1997.³
• Mean annual incidence rates for laboratory-confirmed cases have risen from 0.06 per 100,000 total population for the period 1986 to 1992, to 0.64 cases per 100,000 total population in 2002, to 1.1 cases per 100,000 total population in 2005.³ The highest rates in the United States are 69.9 cases per 100,000 persons in Connecticut.
• Lyme disease occurs in temperate regions of North America, Europe, and Asia.
• In some countries of Europe, the incidence of Lyme disease has been estimated to be over 100 per 100,000 people a year.
• Lyme disease infection has occurred in northern forested regions of Russia, in China, and in Japan.
• It has not been found in tropical areas or in the southern hemisphere.
• Risk of infection is greater if the tick is attached for more than 24 hours.
• There is a rise in reported cases in autumn, but the peak occurs in spring and summer.
• It is not possible to separate false-positive antibody tests from asymptomatic infection. In endemic areas as many as 10% of the population may have positive serology without any history of symptoms.
• Cases of Lyme disease are lowest in urban areas in the eastern states of the United States.
• In the United States there are peaks in incidence in the 5-9 year age group and the 50-54 year age group.

It should be remembered that some infected people will have no symptoms. In Europe as many as 64% of patients with Lyme disease do not remember being bitten by the often innocuous tick. The presentation depends on the stage of disease at the time of presentation. For example:

• Early Lyme Disease (Stage 1 or localised disease):
  • The characteristic manifestation is erythema migrans:
    • A circular rash at the site of the infectious tick attachment that radiates from the bite, within 2 - 40 days.
    • It expands over a period of days to weeks in 80-90% of people with Lyme disease.
    • It may be the only manifestation of disease in one third of patients.
    • In most patients there is only one episode of erythema migrans but in about 20% there are recurrent episodes.
    • About 40% of patients have multiple lesions (not the result of multiple bites).
  • Pyrexia, arthritis, musculoskeletal symptoms and local lymphadenopathy may occur in about two thirds of patients but one third of patients will develop no further symptoms.
  
• Disseminated Lyme disease (or stage 2 disease ). This disseminated stage is still considered to be early infection and occurs weeks to months later, with:
  • Flu-like illness, oligoarthralgia (60%). Typically with myalgia, multiple erythema migrans and sometimes systemic upset. Malaise and fatigue are very marked (particularly in the United States where 80% of patients are affected- about double that recorded in Europe).
  • Intermittent inflammatory arthritis:
    • This is more common in the United States.
    • In Europe joint pains are less often associated with inflammation.
    • Untreated episodes last about a week.
    • Most patients have at least 2 or 3 episodes and even untreated these resolve over a a few years.
  • Central nervous system disorders (15%):
    • These include facial (and other cranial nerve) palsies. These are the most common neurological manifestations in Europe and the United States.
    • Meningism and meningitis may occur alone or with other neurological manifestations. It is usually at the mild end of the spectrum but can be more severe.
    • Mild encephalitis producing malaise and fatigue.
    • Peripheral mononeuritis
    • Lymphocytic meningoradiculitis (or Bannwarth's Syndrome which is more common in Europe than the United States).
  • Cardiovascular problems (10%):
    • This usually presents with syncopal episodes associated with fever.
    • Manifestations include transient atrioventricular block, myocarditis, or chronic dilated cardiomyopathy.
  • Occasionally hepatitis, orchitis, uveitis and panophthalmitis.
  • Lymphocytomas:
    • These are bluish-red nodular lesions infiltrated with lymphocytes.
    • They typically appear on earlobe or nipple.
    • They occur in Europe but not the United States.
• Late manifestations of Lyme disease (or stage 3 disease):
  Untreated or inadequately treated Lyme disease can cause late disseminated manifestations weeks to months after infection. These late manifestations typically include prolonged arthritis, polyneuropathy, encephalopathy and symptoms consistent with fibromyalgia.
  • Chronic lyme arthritis - a chronic erosive arthropathy typically involving knees.
  • Acrodermatitis chronica atrophicans . This is a blueish discolouration (usually lower leg over extensor surfaces) signifying epidermal atrophy usually with mild sensory neuropathy and myalgia. It is generally seen in Europe not the United States.
  • Chronic neurological syndromes . Generally these appear to be more common in Europe. These include chronic neuropathies (usually with paraesthesia and occasionally with pain but not with motor deficit). They may even present as chronic fatigue syndromes, spastic paraparesis or depression.

Chronic Lyme disease can be indistinguishable from fibromyalgia and chronic fatigue syndrome and in the assessment of these illnesses Borrelia burgdorferi infection should be considered.

• Non-infectious:
  • Urticaria
  • Gout
  • Psoriatic arthritis
  • Thyroid disease
  • Degenerative arthritis
  • Metabolic disorders (vitamin B12 deficiency, diabetes)
  • Heavy metal toxicity
  • Vasculitis
  • Systemic lupus erythematosus
  • Psychiatric disorders
• Localised infections:
  • Gonococcal arthritis
  • Meningitis
• Infections which can mimic certain aspects of the typical multisystem illness seen in chronic Lyme disease include:
  • Viral infections, for example:
    • Parvovirus B19
    • West Nile virus infection
  • Bacterial infections, for example:
    • Relapsing fever
    • Syphilis
    • Leptospirosis
    • Mycoplasma
    • Infective endocarditis

There is currently no definitive test. Lyme disease is a clinical diagnosis and tests should be used to support clinical judgement. The most useful tests are antibody detection tests. The only national guidelines for testing come from the US Centers for Disease Control and Prevention (CDC).⁵ They recommend a 2 step testing process:

1. Lyme disease symptoms (other than erythema migrans)- antibody titre (total or IgG and IgM).
2. Confirm positive titres with a Western blot.

Antibody testing in patients with erythema migrans is unhelpful because the rash develops before the antibodies.

• Serology:
  • Serology may help in cases of endemic exposure who have clinical features suggestive of disseminated disease.³
  • Serology (ELISA) remains negative for several weeks in the initial phase, but is usually positive in serum and CSF in disseminated stage. False positives may occur with other spirochaete infections.
• Polymerase chain reaction (PCR) may identify very small numbers of spirochaetes in samples, and may influence decisions about whether to treat asymptomatic individuals with positive serology. Usually however PCR techniques are not helpful because of the uncertain correlation between positive results and the presence of live organisms in biological fluids.

Management at a glance: Tick bite- remove tick and consider single dose oral antibiotic in high risk cases (not recommended routinely in UK acquired tick bites)3 Skin manifestations- oral regimen for 30 days Arthritis- oral regimen for 30 days, repeated IV if oral course unsuccessful Neuroborreliosis-oral regimen 30 days for all except encephalitis and encephalopathy Encephalitis/ encephalopathy- IV regimen 28 days Fibromyalgia- no evidence from trials of benefit with oral or IV treatment

• The early use of antibiotics (for example doxycycline) can prevent persistent, recurrent, and refractory Lyme disease. Antibiotics shorten clinical course and progression. The duration of therapy should be guided by clinical response, rather than by an arbitrary treatment course. Long courses of antibiotics may be required (2-4 weeks or longer).
• Jarisch-Herxheimer reaction may occur soon after treatment is initiated.
• First-line drug therapies for Lyme disease include oral doxycycline (and tetracycline), amoxicillin, azithromycin, cefuroxime, and clarithromycin. These antibiotics have similar favourable results in studies. For many Lyme disease patients, there is no clear advantage of parenteral therapy.
• Intravenous antibiotics are used in severe cases (for example encephalitis, meningitis, optic neuritis, joint effusions, and heart block); or where there is failure of oral medications - in patients with persistent, recurrent, or refractory Lyme disease. Ceftriaxone, cefotaxime, and penicillin are commonly used intravenous antibiotics. The precise regime will depend on the individual situation but high doses of antibiotics, combination of antibiotics, sequential regimes and prolonged duration (one month or longer) are advocated.
• Surgical synovectomy should be reserved for knee pain failing antibiotic treatment. Intra-articular steroid injection may be useful for persistent knee pain but runs the risk of masking persistent infection.
• Treatment of Lyme arthritis - Cefotaxime, ceftriaxone, doxycycline and amoxicillin plus probenecid are all effective.
• Treatment of late neurological Lyme disease - Cefotaxime has been shown to improve neuropathy in patients with late Lyme disease. Intravenous ceftriaxone has been shown to be effective in Lyme encephalopathy.⁶ Other studies have shown no benefit of antibiotic for late neurological Lyme disease.
• Temporary pacemaker may be required where there is carditis and conduction defects.

Prophylactic treatment of tick bite

Prophylactic antibiotics after Ixodes scapularis tick bites in Lyme disease endemic areas in North America have been shown to reduce the risk of developing clinical Lyme disease.⁷ This article in the New England Journal of Medicine suggests that a single dose of 200 mg of doxycycline within 72 hours of tick removal can prevent Lyme disease developing. The risk in the UK is such that use of prophylactic antibiotics is not recommended. It might be considered in very exceptional circumstances, for example when a person travelling from an endemic area discovers a tick which has been attached for more than 48 hours.

• Lyme disease is rarely fatal.
• However, untreated Lyme disease can result in arthritis (50% of untreated people), meningitis or neuropathies (15% of untreated people), carditis (5-10% of untreated people with erythema migrans) and, rarely, encephalopathy. Over 90% of facial palsies due to Lyme disease resolve spontaneously, and most cases of Lyme carditis resolve without sequelae.⁸
• The natural disease course of European borreliosis is not well defined and the effect of antibiotic treatment is unclear.⁹ There are no UK studies on the outcome of treatment.
• Long term sequelae also include poor concentration and fatigue.⁸
• Recovery is often incomplete if disease presents late.

Measures to reduce infection in areas associated with ticks:

• Wear long hair under a hat.
• Keep to the middle of paths and avoid unnecessary brushes with foliage where ticks loiter waiting for the next passing mammal.
• Avoid wooded areas where possible. Mowed grass areas are less likely to have ticks in them.
• Keep legs and arms covered (wear trousers inside socks).
• Use insect repellent for humans.
• Use tick collars for pets (they can get Lyme disease) and inspect for (and remove) any ticks.
• Inspect skin regularly during day in at risk area (especially groin, axillae and hairline). Remember ticks are unlikely to transmit Lyme disease until attached for several days.