Neuroborreliosis

Neuroborreliosis is a complication of Lyme Disease that affects the nervous system. 10 - 15% of patients with Lyme Disease develop Neuroborreliosis if left untreated.^[1] Neuroborreliosis is caused by a Borrelia bacteria-infected tick bite.

Neuroborreliosis
Other names	Lyme neuroborreliosis (LNB)
Specialty	Infectious diseases
Symptoms	stiff neck (meningitis), facial nerve palsy, and radiculoneuritis

History

• 1922 – Two French physicians, Drs. Garin and Bujadoux describe a patient presenting with meningorediculitis, after an erythema migrans following a tick bite^[2]
• A few years later (date unspecified), a German physician, Dr. Bannwarth encounters patients with similar symptoms^[2]
• 1976 – Lyme Disease was recognized as an independent condition, following reports of a group of children in Lyme, Connecticut, presenting with what appeared like juvenile rheumatoid arthritis^[3]
• 1981 – The bacteria responsible for eliciting Lyme Disease infection in the United States, Borrelia burgdorferi, is isolated^[4]

Epidemiology and Demographics

United States: Lyme Disease cases are highly concentrated in the Northeast and Midwest regions, with a single strain of Borrelia bacteria – B. burgdorferi – causing infection.^[5]

Europe: The highest incidences of Lyme Disease are found in Scandinavian countries, such as Sweden and Norway, as well as central Europe, including Germany, Poland, and Austria.^[5] Multiple strains of Borrelia bacteria drive infection here, including B. garinii, B. afzelii, B. burgdorferi, B. spielmanii, and B. bavariensis.

South America: Lyme Disease cases have been reported in Argentina, Brazil, and Chile.^[6]

Asia: Lyme Disease cases have been reported in China, Japan, and Malaysia^[7]

*Research is lacking on prevalence and Borrelia strains responsible for transmitting the disease in South America and Asia.

Africa: Lyme Disease infection is rare in Africa (restricted to countries bordering the Mediterranean Sea and Indian Ocean coastlines).^[8]

Australia: Lyme Disease is essentially absent in Australia.^[9]

The risk of developing Lyme Disease is directly related to time spent outdoors, in or near areas with tick-infested woods or vegetation.^[4] In the Northern Hemisphere, Lyme Disease cases peak during July.^[4] In the Southern Hemisphere, the tick life cycle is not as well documented, but infection primarily occurs during the warmer months.

Lyme Disease infection follows a bimodal age distribution: infection incidence is greatest between ages 5 – 9 and 50 – 55. There is a slight male dominance (56%) and the majority (90%) of individuals infected are white.^[10]

Mechanism of Nervous System Invasion

Source:^[1]

• Borrelia bacteria multiply locally at site of infected tick bite
• Bacteria spreads to other parts of the body (including the central and peripheral nervous systems) via the blood stream and lymphatic system^[11]
• Borrelia bacteria enters the central nervous system via passage through the blood-brain barrier or blood-spinal cord barrier^[11][12]
  • This occurs via three mechanisms:
    • Paracellular transport
    • Transcellular transport
    • Trojan-horse mechanism

Nervous System Damage

Once in the nervous system, Borrelia bacteria utilize a multifocal inflammatory process to elicit damage. Borrelia bacteria attract local immune cells, like monocytes or macrophages, that produce proinflammatory cytokines (IL-6, IL-12, TNF-α) or chemokines (CXCL13, CXCL12) upon recognition of the foreign material, promoting inflammation.^[13] This inflammation induces oxidative stress and activates various apoptotic signaling pathways (caspases, FASL, TNFR1), promoting neuronal cell death.^[14] Additionally, Borrelia bacteria possess indirect and direct mechanisms of cytotoxicity, both of which damage neurons. Lastly, Borrelia bacteria elicit an autoimmune-like response by “molecular mimicry”, whereby antigens for the bacteria share structural similarities to the host tissue, thereby producing cross-reactivity and the production of autoantibodies which attack the host tissues.^[15] In addition to cell death mechanisms, Borrelia bacteria degrade tight junction proteins in the BBB and BSCB^[16] allowing greater amounts of the bacteria to pass into the central nervous system.

Types

PNS Neuroborreliosis: PNS Neuroborreliosis occurs in 5 – 10% of patients with Lyme Disease and strictly affects the peripheral nervous system.^[1] Both cranial and peripheral nerves are targeted for cell death via inflammatory or cytotoxic mechanisms.^[2]

Extra-parenchymal CNS Neuroborreliosis: Extra-parenchymal CNS Neuroborreliosis occurs in 10% of patients with Lyme Disease and affects the areas around the brain, such as the meninges, rather than the brain itself.^[1] Infection here elicits inflammation of the meninges.

Parenchymal CNS Neuroborreliosis: Parenchymal CNS Neuroborreliosis occurs in 7 – 14% of patients with Lyme Disease and affects the brain and spinal cord.^[17][1] Neurons and glial cells are damaged here via inflammatory, cytotoxic (indirect and direct), and autoimmune mechanisms.

Stages

Neuroborreliosis can be subdivided into two stages, dependent upon the amount of time following infection.^[1]

Early Neuroborreliosis: 2 – 18 weeks after infection

Late Neuroborreliosis: months or years after infection

Both stages can possess one or all classifications of Neuroborreliosis (PNS, extra-parenchymal CNS, parenchymal CNS), however, infection strictly affecting the PNS often occurs first, followed by the other types as the infection must spread and travel to the CNS from the affected area. Therefore, extra-parenchymal CNS and parenchymal CNS Neuroborreliosis often occur during later stages of the disease.

Symptoms

Neuroborreliosis is often preceded by the typical symptoms of Lyme disease, which include erythema migrans and flu-like symptoms such as fever and muscle aches.

Early Neuroborreliosis symptoms:^[1][5]

• Peripheral Neuropathy – peripheral nerve damage
• Radiculitis – inflammation of the nerve roots
• Cranial Neuritis – inflammation of the cranial nerves (often results in unilateral or bilateral facial palsy)
• Meningitis – inflammation of the meninges

Late Neuroborreliosis symptoms:^[5][4]

• Chronic meningitis – long-lasting inflammation of the meninges
• Polyneuropathy – damage to multiple peripheral nerves
• Encephalitis – inflammation of the brain
• Myelitis – inflammation of the spinal cord

Diagnosis

Microbiological Diagnosis:

Microbiological diagnostics aim to directly measure the presence of the microorganism, in this case, Borrelia bacteria, in the body.^[18] One way this is accomplished is through cerebral spinal fluid (CSF) measurement via lumbar puncture.

Serological Diagnosis:

Serological tests detect antibodies of the microorganism of interest (Borrelia bacteria) and are the most common technique used for diagnosis of Neuroborreliosis.^[19] Serological assessments are effective in the diagnosis of both Early and Late Neuroborreliosis, as it detects the inflammatory response elicited by the bacteria, which occurs early in the disease progression. The CDC recommends a two-tier approach, such that individuals first undergo an initial sensitivity screening test (typically an ELISA), then upon a positive result undergo a confirmatory immunoblot assessment.

Prognosis and Treatment

The prognosis for Neuroborreliosis is generally excellent, considering that treatment is administered in a timely manner. Most patients exhibit complete or near-complete reversal of symptoms. The standard treatment for Neuroborreliosis consists of 2 (Early Neuroborreliosis) – 3 (Late Neuroborreliosis) weeks of antibiotic therapy.^[5] The most commonly used antibiotics are doxycycline (oral), amoxicillin (oral), cefuroxime (oral), and ceftriaxone (intravenous).^[20] Oral antibiotics are used in the treatment of Lyme disease (without neurological manifestations) and Early Neuroborreliosis, while intravenous antibiotics are reserved for Late Neuroborreliosis.

In their fast-growing form, all Borrelia bacteria strains respond similarly to antibiotic treatment.^[21] However, Borrelia bacteria can form slow growing, metabolically inactive cells called persister cells, that are more resistant to antibiotic treatment.^[22] One study showed in a mouse model of Lyme Arthritis that infection with Borrelia burgdorferi persister cells did not respond to standard antibiotic treatment but instead required a “three-antibiotic cocktail” to eradicate the infection.^[23]