Two Opposing Camps Offer Insight Into Treatment of Neurologic Lyme Disease


Your patient has pain and numbness that extends from the shoulder to the hand. You suspect a herniated cervical disk, but the MRI scan comes back normal. What else could the culprit be?

Your patient has pain and numbness that extends from the shoulder to the hand. You suspect a herniated cervical disk, but the MRI scan comes back normal. What else could the culprit be? If the person has spent time in a tick-ridden area, the answer could be Lyme disease.

Radiculopathy, meningitis, and cranial nerve palsy are the classic neurologic manifestations of Lyme disease, according to John Halperin, MD, medical director of neuroscience for Atlantic Health System and director of the Atlantic Neuroscience Institute in Overlook, New Jersey. Halperin serves on the committees of the Infectious Diseases Society of America (IDSA) and the American Academy of Neurology (AAN), which are updating their respective Lyme disease practice guidelines (due in fall 2006 and early 2007, respectively). Other potential manifestations of Lyme disease are peripheral neuropathy, encephalopathy, and encephalomyelitis,1 which Halperin said can mimic a first episode of multiple sclerosis (MS). Together, these disorders occur in approximately 15% of patients with untreated Lyme disease.2 The good news is that most cases of Lyme disease are avoidable and treatment with antibiotics is usually effective.3

There is a minority view that Lyme disease can become chronic, leading to neurologic symptoms in a large percentage of patients. Raphael B. Stricker, MD, an immunologist at California Pacific Medical Center in San Francisco who worked on the practice guidelines for the International Lyme and Associated Diseases Society (ILADS), said that the 15% figure is accurate for early Lyme disease. But neurologic symptoms can affect 34% to 62% of patients with chronic Lyme disease4-a condition that the IDSA does not acknowledge. Stricker said that manifestations of Lyme dis-ease can include such neuropsychiatric conditions as psychosis, bipolar disorder, and even musical hallucinations; it also can cause symptoms that mimic amyotrophic lateral sclerosis (ALS) and Guillain-Barre syndrome.

Halperin said that although it was possible in rare circumstances to mistake Lyme disease for a condition such as ALS or Guillain-Barre syndrome, such cases could usually be resolved through standard testing. As for neuropsychiatric symptoms, he said that episodes of depression, bipolar disease, and other disorders are no more likely to occur in Lyme disease than in other prolonged inflammatory states and are more likely to co-occur with Lyme disease than be caused by it.


At total 19,804 cases of Lyme disease were reported to the CDC in 2004, down somewhat from a high of 23,763 in 2002.5 It is caused by Borrellia burgdorferi, which is carried by Ixodes scapularis or Ixodes pacificus ticks. The areas of the United States where these ticks are endemic are primarily the Northeast, Upper Midwest, and Northwest.3 The best way to avoid Lyme disease is to stay away from tick-infested areas. If this is not possible, outdoor enthusiasts should wear long pants tucked into their socks and a long-sleeved shirt tucked into their pants. When a tick is found attached to a person, it should be removed without delay by inserting tweezers between the tick and the skin and lifting gently. Ticks must be attached for at least 48 hours to transmit disease.6,7 Halperin said that when neurologic symptoms occur, they are probably triggered by the direct action of the bacterium and an immunologic reaction.


Although some physicians routinely administer antibiotics to a person who has been bitten by a tick or had a tick attached for more than 48 hours, the IDSA does not recommend this practice because most ticks do not carry infection. Instead, the group recommends monitoring these patients closely. The appearance of erythema migrans (which appears as an enlarging bull's-eye rash) at the site of the bite suggests Lyme disease, while a temperature of over 38 degrees C (100.4 degrees F) may indicate infection with another bacterium carried by ticks-specifically, ehrlichiosis or babesiosis.

The IDSA recommends that people who develop erythema migrans around the site of a tick bite should receive immediate treatment with doxycycline or amoxicillin for 2 to 3 weeks.


A neurologic evaluation is in order if a clinician suspects neurologic involvement in a patient with early Lyme disease. Lumbar puncture is helpful in diagnosing CNS Lyme infection, particularly Lyme meningitis that could co-occur with cranial nerve palsy or radiculopathy. Some IDSA panel members perform lumbar puncture on all patients with cranial nerve palsy; others reserve lumbar puncture for cases in which there is more clinical evidence of CNS involvement.

Halperin said that having a greater concentration of Lyme-specific antibody in cerebrospinal fluid than in blood is "the best diagnostic indicator of central nervous system Lyme." Cerebrospinal fluid also should be analyzed for cells and protein.

Peripheral neuropathy occurs frequently in untreated Lyme disease. The condition may present as a typical mononeuropathy multiplex, cranial neuropathy, radiculopathy, plexopathy, or as a confluent mononeuropathy multiplex mimicking a diffuse polyneuropathy, said Halperin. Making a diagnosis of peripheral neuropathy caused by Lyme disease requires objective evidence of peripheral nerve damage (clinically or by electromyography) and evidence of active Lyme disease.

An inflammatory illness such as Lyme disease can cause a mild confusional state, much like that seen in patients with lupus erythematosus or sepsis, Halperin explained. He emphasized that in almost all circumstances, this is a "toxic/metabolic" encephalopathy and does not reflect brain infection or brain damage. Rarely, this is due to mild encephalitis, in which case MRI and lumbar puncture will reveal abnormalities.

In those rare patients in whom Lyme disease causes encephalomyelitis, the disease may mimic a first episode of MS on clinical examination and MRI. In these cases, the cerebrospinal fluid should be examined for evidence of Lyme antibodies and compared against serum antibody levels.

Lyme disease could theoretically resemble ALS by causing spinal cord inflammation that affects both upper and lower motor neuron function, but MRI and lumbar puncture are usually able to differentiate between the 2 diseases, Halperin said. Guillain-Barre syndrome also may mimic Lyme disease, Halperin continued, but the electromyograms of patients with classic Guillain-Barre syndrome will show signs of a true demyelinating polyneuropathy that probably does not occur in Lyme disease. Also, the spinal fluid of patients with Guillain-Barre syndrome typically shows elevated protein in the absence of pleocytosis, whereas Lyme disease typically causes pleocytosis.

Halperin cautioned against performing tests for Lyme disease in persons who are unlikely to have been exposed to the disease. Although the assay is fairly accurate, he pointed out that, just as with any test, the positive predictive value is poor if used in circumstances where the likelihood of a true positive is small. "If you did a Lyme blood test on everybody in the country, you'd have 10 false positives for each true positive," he said.

The standard blood test for Lyme disease is a 2-stage test that starts with an enzyme-linked immunosorbent assay (ELISA). If the result on the ELISA is borderline or positive, Western blot testing is done. A positive result is 5 of 10 particular IgG bands or 2 of 3 particular IgM bands. The specificity of the test is very high, according to Halperin.

Stricker, on the other hand, maintained that commercial tests are very insensitive and miss about 50% to 60% of cases. "Only a handful of labs do a good job; unfortunately, the commercial tests for the disease are terrible," he asserted.

When asked whether it was possible that commercial laboratories were missing large numbers of cases, Halperin responded that this was "an unfortunate impression that those who've looked at it in a scientifically rigorous manner disagree with." In an effort to maintain high standards for Lyme disease testing, the CDC and the FDA issued a warning in 2005 against "using laboratories that conduct testing for Lyme disease by using assays whose accuracy and clinical usefulness have not been adequately established."8


Erythema migrans often goes unnoticed or does not occur at all, so when it comes to cases of suspected nervous system Lyme disease, the AAN allows immunologic evidence of B burgdorferi exposure or culture or histologic or polymerase chain reaction proof of its presence to support a diagnosis. As with the IDSA criteria for diagnosing Lyme disease, there must also be possible exposure to appropriate ticks in an area.

Patients with early Lyme disease who are showing signs of acute neurologic disease, such as radiculopathy or meningitis, will need antibiotic therapy for 2 to 4 weeks. The IDSA recommends intravenous ceftriaxone (Rocephin), penicillin, or cefotaxime (Claforan). People who are unable to take these medications can take oral doxycycline.

Antibiotics do not speed the resolution of cranial nerve palsy, but they should be used to prevent further complications. Patients with normal findings on a lumbar puncture should be given one of the 2- to 3-week antibiotic regimens recommended for persons with a rash, while those with clinical and laboratory signs of CNS infection should receive one of the 2- to 4-week regimens recommended above.

The IDSA also recommends antibiotics for late neurologic manifestations of Lyme disease, such as encephalomyelitis and neuropathy. Late disease can take weeks or months to resolve, but most patients eventually recover.

The ILADS guidelines take a far different approach. They recommend that "the duration of therapy should be guided by clinical response" and discourage the practice of discontinuing antibiotics before symptoms have resolved.4

"There are people who are on intravenous therapy for a year, 2 years," said Stricker. "Of course, you need to get out the smelling salts when you tell the IDSA people that." In defense of the practice, he pointed out that long-term antibiotics are the norm for tuberculosis and other chronic infections.

But Halperin maintained that there are no scientific data to show that long-term antibiotics are useful in Lyme disease. "It doesn't make much microbiologic sense, in terms of the behavior of this organism. He also pointed out that "in the few published studies that have looked at up to 3 months of treatment, there's no demonstrable difference between doing that and taking a placebo."9,10 Long-term antibiotic use is not innocuous, Halperin reminded. He pointed to the risk of colitis, diarrhea, lethal infections, kidney damage, liver damage, and an overall increase in antibiotic resistance.


Relapses are rare and can be treated with a 4-week regimen of antibiotics if they occur, said Halperin. The IDSA guidelines state that repeated treatment should be undertaken only if relapse is shown "by reliable, objective measures."3

Some people have persistent symptoms after treatment for Lyme disease. The ILADS considers these to be signs of continuing infection and refer to the phenomenon as "chronic Lyme disease." By contrast, the IDSA guidelines maintain that the idea of residual infection "has yet to be substantiated."3

"You have to ask yourself whether the symptoms are related to Lyme disease or if they're something else," said Halperin. "Sometimes they're related to Lyme disease, in which case you come back with 4 weeks of antibiotics. But often, it's something unrelated." Halperin said that the term "post-Lyme syndrome" could be used to describe lingering symptoms, although the cause of these symptoms remains to be determined.


Stricker argued that the IDSA approach, although standard, has not worked out for a large number of patients. "I like to call it the Lyme denialist approach," he said. Halperin, of course, sees things differently. He said that the IDSA guidelines are based on evidence, whereas the ILADS guidelines are based on conjecture, but he understands the desire to offer an alternative explanation for a devastating diagnosis such as ALS.

"Nobody wants to tell a human being that they have a disease that's going to kill them in 3 years. . . . The physician is desperate to come up with an alternative explanation." It is that desire, he said, that encourages physicians to diagnose Lyme disease-and begin a course of therapy that's unlikely to help.


1. Halperin JJ, Logigian EL, Finkel MF, Pearl RA. Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease). Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1996;46:619-627.

2. Steere AC. Lyme disease. N Engl J Med. 1989;321:586-596.

3. Wormser GP, Nadelman RB, Dattwyler RJ, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(suppl 1):1-14.

4. Cameron D, Gaito A, Harris N, et al; ILADS Working Group. Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther. 2004;2(1 suppl):S1-S13.

5. CDC Division of Infectious Vector-Borne Diseases. Number of Reported Cases of Lyme Disease by State, 1992-2004. Available at: Accessed July 27, 2006.

6. Piesman J. Dynamics of Borrelia burgdorferi transmission by nymphal Ixodes dammini ticks. J Infect Dis. 1993;167:1082-1085.

7. Ohnishi J, Piesman J, de Silva AM. Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. Proc Natl Acad Sci. 2001;98:670-675.

8. Notice to Readers: Caution Regarding Testing for Lyme Disease. MMWR. February 11, 2005.

9. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345:85-92.

10. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60:1923-1930.

DEVON SCHUYLER is a freelance medical news writer in Portland, Oregon.

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