Introduction

Lyme neuroborreliosis designates neurologic involvement during systemic infection with the spirochete Borrelia burgdorferi . Individuals become infected with B. burgdorferi by the bite of an infected Ixodes tick. Lyme disease, like syphilis (another spirochetal infection), is thought to have three stages: acute localized disease (i.e., erythema migrans), early disseminated disease, and late disseminated disease. The organism can affect many organ systems, typically with the skin being the primary site of inoculation in about 80% of infected individuals. Subsequent joint involvement is also common, followed by the nervous system, which can be affected in 10%–15% of individuals infected with Lyme disease. The neurologic manifestations are discussed in detail in this chapter and can range from lymphocytic meningitis to cranial neuropathies to radiculoneuritis. Additional manifestations, including post-Lyme disease syndrome and chronic Lyme disease, are also discussed in this chapter.

This chapter aims to discuss both the pharmacologic and nonpharmacologic treatment strategies for neuropathic pain secondary to neuroborreliosis. A brief discussion of antimicrobial therapy and evidence for the duration of therapy are presented later in the chapter. This is followed by a discussion of the evidence for treatment of acute neurologic manifestations of Lyme disease, followed by the treatment of late neurologic manifestations. Initial focus on antimicrobial therapy followed by a discussion of evidence for the treatment of neuropathic pain from neuroborreliosis is presented.

Pathophysiology

Individuals become infected with B. burgdorferi by the bite of an infected Ixodes tick. Most of the available evidence attributes the pathogenesis of Lyme neuroborreliosis to the invasion of the central and peripheral nervous system by B. burgdorferi . Symptoms of Lyme neuroborreliosis are due to multifocal inflammatory involvement, predominantly in the subarachnoid space and perineural tissue, with common features of a subacute course over weeks to months after initial presentation of skin lesions (i.e., erythema migrans, which occurs in about 40% of individuals) (see Fig. 13.1 ).

Rash of erythema chronicum migrans on the leg in Lyme disease.

From Goering R, Dockrell H, Zuckerman M, Roitt I, Chiodini P. Vector-borne infections. In: Mims’ Medical Microbiology , 5th ed. Elsevier Saunders; 2013; with permission.

Neurologic Manifestations of Lyme Disease

By definition, nervous system involvement occurs only in the disseminated form of Lyme disease. Lymphocytic meningitis, cranial neuropathy (especially facial palsy), and radiculoneuritis (which may involve either sensory or motor nerves) constitute the triad of early and acute Lyme neuroborreliosis. Symptoms of a painful disseminated polyneuropathy reflect a more indolent onset and protracted time course.

Central nervous system (CNS) involvement in Lyme disease most commonly presents with lymphocytic meningitis and rarely with inflammation of the actual parenchyma (an encephalomyelitis) ( Box 13.1 ). Lyme meningitis is indistinguishable from viral meningitis presenting with headache, fever, neck stiffness, and systemic symptoms. Cerebrospinal fluid analysis is critical in establishing an accurate diagnosis, with particular attention to the percentage of mononuclear cells along with clinical evidence of cranial neuropathies. Lyme encephalomyelitis may present with segmental spinal cord involvement (at the level of the affected nerve root). Magnetic resonance imaging of the brain and spinal cord may reveal inflammatory changes involving the brain parenchyma, and cerebrospinal fluid analysis may show an elevated total immunoglobulin level and oligoclonal bands. Lyme encephalomyelitis is responsive to the appropriate antimicrobial therapy, although sequelae of neurologic injury may persist despite treatment, including neuropathic pain, intracranial hypertension, and encephalopathy.

Peripheral nervous system involvement in neuroborreliosis is typically a multifocal axonal inflammatory process, although the pathophysiology remains poorly understood. There are various suggested mechanisms, including a possible immunologic cross-reactivity, which may be responsible for the damage to the nerve axons. No evidence of spirochetes is present on peripheral nerve analysis, with a few spirochetes identified in the dorsal root ganglia in experimental studies on monkeys. Typical peripheral nervous system manifestations of Lyme disease include cranial neuropathies and radiculoneuritis, although some individuals may develop mononeuropathies, such as mononeuritis multiplex.

Cranial neuropathies occur in 8% of individuals with confirmed Lyme disease, as diagnosed with a positive anti- B. burgdorferi IgM antibody in the peripheral blood. They occur early in the disease course and most commonly involve the facial nerve. Other cranial nerves that can be involved include the vestibulocochlear, the lower division of the trigeminal, and the optic nerve, which can present as swelling of the optic nerve head (caused by increased intracranial pressure), inflammation of the optic nerve, or papillitis. About 3% of individuals with confirmed Lyme disease may also develop radiculoneuritis, which is an inflammation of the spinal nerve or nerve roots. Pain is the most prominent presentation, often mimicking mechanical radicular pain in one or several dermatomes. In addition, early in the course of neuroborreliosis, individuals may experience brachial or lumbosacral plexopathies and mononeuropathies. If the infection is left untreated, patients can develop a distal polyneuropathy clinically, which is thought to be due to a confluent mononeuropathy multiplex involving multiple smaller nerve branches.

Post-Lyme Disease Syndrome

Some patients, despite therapy with the recommended 10–21 day course of antibiotics, may continue to have vague residual chronic symptoms, which are referred to as post-Lyme syndrome (PLS), post-Lyme disease syndrome, post-treatment chronic Lyme disease, or chronic Lyme disease. Post-Lyme disease syndrome is often used to describe nonspecific symptoms that may persist even months after antimicrobial therapy for Lyme disease, including headache, fatigue, and diffuse arthralgias. According to the Infectious Diseases Society of America, criteria for the diagnosis of post-Lyme disease syndrome includes:

• 1.
  

  A prior history of Lyme disease treated with an accepted regimen, with subsequent resolution or stabilization of the manifestations of the disease

  
  
• 2.
  

  Onset of subjective symptoms (i.e., fatigue, diffuse musculoskeletal pain, or cognitive difficulties), which occur within 6 months of diagnosis of Lyme disease and are persistent for at least 6 months after completion of antimicrobial therapy.

This disease entity remains controversial, and its etiology remains unclear. The proportion of patients who develop post-Lyme disease syndrome is small.

The American Academy of Neurology (AAN) parameters present some data, although controversial, for post-Lyme disease therapy. The controversy largely lies in the question of whether PLS is a form of active infection, wherein the organism is too difficult to eradicate, or is perhaps a postinfectious or noninfectious chronic syndrome (with no active infection). In addition, the symptoms of PLS (i.e., cognitive difficulties, fatigue) are difficult to objectively evaluate with physical examination or laboratory analysis (especially if compared with those symptoms of patients with untreated Lyme disease). Data argue against persistent infection in those who have undergone curative courses of the recommended antimicrobial therapy, as there is no known antibiotic resistance to Borrelia , there is no correlate of persistent symptoms with any objective measures on examination or laboratory studies, and usually, there is undetectable antibody to B. burgdorferi (despite persistent symptoms).

Overview of Antimicrobial Therapy

The best available method for preventing infection with B. burgdorferi is to avoid exposure to vector ticks. The 2006 Infectious Disease Society of America updated guidelines for the treatment and prevention of Lyme disease state there is no recommendation for antimicrobial prophylaxis or serologic testing for the prevention of Lyme disease after a recognized tick bite. A single dose of doxycycline may be offered for adult patients and children over the age of 8 years (200 mg for adults, 4 mg/kg up to maximum 200 mg for children). This regimen is contraindicated in pregnant women and children less than 8 years of age.

Depending on the stage of infection, the Infectious Disease Society has specific antimicrobial recommendations as noted in Table 13.1 . Specifically, for early evidence of disease, such as erythema migrans, the recommended therapy is a 10–21 day course of doxycycline 100 mg twice per day, amoxicillin 500 mg three times per day, or cefuroxime 500 mg twice per day. The AAN published practice parameters for the treatment of CNS Lyme disease in 2007. Specific recommendations for antimicrobial therapy are noted in Table 13.1 . The AAN practice parameters note that evidence for antimicrobial therapy in neuroborreliosis is currently without placebo-controlled trials given the presence of residual symptoms (after therapy for erythema migrans). The initial literature in the 1980s noted that 12 patients treated with high-dose intravenous (IV) penicillin had a more rapid resolution of Lyme meningitis as compared with those who did not receive penicillin (with the untreated group later exposed to IV penicillin therapy with good recovery and fewer relapses). Additional studies of antimicrobial therapy in facial nerve palsies secondary to Lyme disease did not show hastening of the palsy’s resolution but did help prevent further sequelae. Studies subsequently showed comparison efficacy of various regimens presented in Table 13.1 . The AAN put forth the following recommendations in 2007:

• 1.
  

  Parenteral penicillin, ceftriaxone, and cefotaxime are probably safe and effective treatments for peripheral nervous system Lyme disease and CNS Lyme disease with or without parenchymal involvement.

  
  
• 2.
  

  Oral doxycycline is probably a safe and effective treatment for peripheral nervous system Lyme disease and for CNS Lyme disease without parenchymal involvement, with supporting data presently lacking for amoxicillin and cefuroxime as alternate therapy.

Table 13.1

Antimicrobial Therapy in Lyme Disease

Indication	Adult Regimen	Pediatric Regimen (Age < 8 years)
Erythema migrans	• PO doxycycline 100 mg BID for 14 days • PO amoxicillin 500 mg TID for 14 days • PO cefuroxime 500 mg BID for 14 days	• PO amoxicillin 50 mg/kg per day in 3 div doses (max 500 mg per dose) for 14 days • PO cefuroxime 30 mg/kg per day in 2 div doses (max 500 mg per dose) for 14 days • If < 8 yo—doxycycline 4 mg/kg per day in 2 div doses (max 100 mg per dose) for 14 days
Early Manifestations (Therapy Duration Range 10–21 days in the Literature)
Cranial neuropathy	• Ceftriaxone 2 g IV daily for 14 days • Cefotaxime 2 g IV every 8 h for 14 days • Penicillin G 18–24 million U/day (div doses every 4 h) for 14 days	• Ceftriaxone 50–75 mg/kg per day IV (max 2 g per day) for 14 days • Cefotaxime 150–200 mg/kg per day in 3–4 IV doses per day (max 6 g/day) for 14 days • Penicillin G 200,000–400,000 U/kg per day in 4 div doses (max 18–24 million U/day) for 14 days
Lyme meningitis
Radiculopathy
Late Manifestations
Lyme arthritis without CNS manifestations	• PO doxycycline 100 mg BID for 28 days • PO amoxicillin 500 mg TID for 28 days • PO cefuroxime 500 mg BID for 28 days	• PO amoxicillin 50 mg/kg per day in 3 div doses (max 500 mg per dose) for 28 days • PO cefuroxime 30 mg/kg per day in 2 div doses (max 500 mg per dose) for 28 days • If > 8 yo, PO doxycycline 4 mg/kg per day in 2 div doses (max 100 mg per dose) for 28 days
Lyme arthritis with CNS manifestations	• Ceftriaxone 2 g IV daily for 2–4 weeks • Cefotaxime 2 g IV every 8 h for 2–4 weeks • Penicillin G 18–24 million U/day (div doses every 4 h) for 2–4 weeks	• Ceftriaxone 50–75 mg/kg per day IV (max 2 g/day) for 2–4 weeks • Cefotaxime 150–200 mg/kg per day in 3–4 IV doses per day (max 6 g/day) for 2–4 weeks • Penicillin G 200,000–400,000 U/kg per day in 4 div doses (max 18–24 million U/day) for 2–4 weeks
Peripheral neuropathy	• PO doxycycline 100 mg BID for 28 days
Mononeuritis multiplex
Encephalomyelitis	• Ceftriaxone 2 g IV daily for 28 days • Cefotaxime 2 g IV every 8 h for 28 days • Penicillin G 18–24 million U/day (div doses every 4 h) for 28 days
Encephalopathy

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