By Greg Gargiulo
Reported cases of Lyme disease have been rising steadily over the past 30 years, but its diagnosis can be challenging. Left untreated, patients with Lyme disease can go on to develop neurological symptoms, including those that are characteristic of peripheral neuropathy.
Francis Bean, DPM, has been experiencing neurological symptoms in his lower extremities for more than six months. When they arise, he feels a tingling in his hallux, his heels go numb, and he develops a hypersensitivity to temperature and touch that leads to a painful burning sensation. On paper, these sound like common symptoms of diabetic peripheral neuropathy—a condition with which Bean, as a podiatrist, is quite familiar.
But Bean doesn’t have diabetes. His peripheral neuropathy developed as a result of Lyme disease, and in the US, he’s one of a growing number of people with similar complications.
Lyme borreliosis, or Lyme disease, is a multisystem infectious disease caused in the US by the spirochete Borrelia burgdorferi (Bb), which is transmitted almost exclusively through tick bites.1,2 Though cases are concentrated primarily in limited geographic areas where the tick is endemic, Lyme disease is the most commonly reported vector-borne infection in the country, and reported cases of its occurrence have been rising steadily over the past 30 years.3,4
Early diagnosis and treatment are extremely important to stop the progression of Lyme disease, and most patients treated appropriately in the acute phase recover without any residual effects; however, if left untreated, Lyme can go on to cause neurological symptoms, including those that are characteristic of peripheral neuropathy.5-7
Delayed diagnosis occurs because many adults don’t recall being bitten by a tick, don’t develop a rash (erythema migrans, often in a bulls-eye pattern) from the bite, or do develop a rash but don’t notice it.8 About 10% to 15% of untreated patients will develop Lyme neuroborreliosis, in which Lyme leads to neurological involvement.4
Lyme neuroborreliosis can manifest as a number of complications—including meningitis, radiculopathy, and encephalitis, as well as peripheral neuropathy—and symptoms may appear weeks or months after the tick bite.7,9,10 Unfortunately, managing Lyme neuroborreliosis presents a clinical challenge far greater than treating acute Lyme. Confirming a diagnosis can be difficult, and often neurological symptoms don’t resolve immediately after treatment with typical antibiotic therapy.11,12
“Early treatment can prevent most neurological complications in the majority of cases, and most patients can be treated early if they have the rash,” said Arthur Weinstein, MD, director of rheumatology and associate chair of the Department of Medicine at MedStar Washington Hospital Center in Hyattsville, MD, who has clinical research experience with Lyme. “But if patients don’t have the rash or they don’t receive early treatment, effective management can become quite problematic.”
In the US, the Bb spirochete is predominantly transmitted by the bite of hard-shelled Ixodes scapularis ticks.3,11 Infection requires the tick to be attached for at least 24 to 48 hours, during which time ingested blood triggers spirochete proliferation within the tick, followed by injection into the human host.11
The progression of Lyme disease is generally broken down into three stages. Stage 1 occurs three to 30 days after the bite and is characterized by fever, malaise, muscle or joint pain, and flu-like symptoms. The presence of erythema migrans may also appear and is useful for identifying Lyme, but statistics for rash appearance vary widely, and its incidence has been reported to be as low as 40% of affected adults.13,14
Stage 2, the neuroborreliosis stage, arises about one to six months after stage 1 and usually includes arthritis with associated muscle pain and swollen lymph nodes. It’s also during stage 2 that neurological symptoms like peripheral neuropathy may begin to develop in untreated Lyme patients. If it continues to progress, stage 3 Lyme disease can occur many months or even years after exposure. It indicates chronic neurological involvement and often includes chronic arthritis in large joints, especially the knee.5,15
The prevalence of Lyme varies greatly based on geographic location and season. More than 93% of cases are reported in highly endemic areas, which are mainly the mid-Atlantic and northeastern states from Maryland to Maine, as well as Michigan, Minnesota, and Wisconsin.3,11 Lyme disease also occurs in a bimodal age distribution, with peaks between ages 0 to 10 years and 40 to 70 years. Seasonal peaks are seen during summer months, when ticks are most prevalent and people and their pets are most likely to engage in outdoor activity.3,16
Approximately 30,000 cases of Lyme disease are reported to the Centers for Disease Control and Prevention (CDC) every year, though the actual number of diagnosed cases is much higher.17 This results in a mean annual national incidence of 9.7 cases per 100,000, but in highly endemic Connecticut, that figure is 74 per 100,000.2,4 Whether through increased awareness, incidence, or reporting, the annual number of reported cases of Lyme has more than doubled since 1991.3,4
“It’s possible that with the publicity surrounding Lyme, and physicians and patients being more aware of it, it may just be getting diagnosed more frequently because it’s being looked for more,” said David Simpson, MD, professor of neurology and director of the Clinical Neurophysiology Laboratories at the Icahn School of Medicine at Mt. Sinai in New York, NY .
When patients fail to receive appropriate treatment for Lyme, Bb may persist by evading the immune system and spreading infection further.18,19 This can occur in any part of the body, but Bb has a general tendency to affect the joints and the nervous system.20
“Lyme disease itself is a neuropathic disease as far as I’m concerned, because the bacterium penetrates into the nervous system and that’s how it moves through the body. The difficulty is that it tends to mutate between at least three identified forms, possibly four,” said Francis Bean, the Lyme patient described earlier, who has a podiatry practice at the Foot & Ankle Center of Mooresville in
Once Lyme neuroborreliosis develops, it can affect the central and peripheral nervous systems in a number of ways that span the entire anatomic spectrum of possibilities.11 But, according to Weinstein, the three major neurologic features of Lyme are meningitis, radiculopathy, and cranial neuropathy, which most often mimics Bell’s palsy.
While those are generally regarded as the most common manifestations of Lyme neuroborreliosis, other neurological complications may also arise, including encephalopathy, polyneuropathy, myelopathy, and motor neuron disease.10,11 Though firm figures are hard to come by, peripheral nerve involvement has been estimated to occur in approximately 25% of untreated patients.21,22 Richard Rhee, MD, a neurologist at Jersey Shore Neurology Associates in Neptune, NJ, who specializes in neurological Lyme disease, estimates that about 30% of patients who develop neurological complications will have peripheral neuropathic symptoms.
Only a small fraction of cases of peripheral neuropathy are related to Lyme disease. Of the more than 20 million Americans with peripheral neuropathy, about 30% of cases are due to diabetes, another 30% are idiopathic, and the remaining 40% are unevenly divided among other disorders and conditions, including Lyme.23
“On a histogram of peripheral neuropathy causes, you’d have diabetes as the major one, alcoholism as a small one in second place, and maybe twenty to thirty extremely uncommon other possible causes,” said David Armstrong, MD, PhD, director of the Southern Arizona Limb Salvage Alliance and professor of surgery at University of Arizona in Tucson, who has experience treating Lyme patients. “Lyme would be in one of those categories, and there’s so little literature on its prevalence because it’s so unusual.”
Symptoms of peripheral neuropathy from Lyme tend to be primarily sensory, occurring in a stocking-glove pattern, but patchy paresthesia may also occur. Though some of its characteristic symptoms overlap with those of diabetic peripheral neuropathy, others are unique to Lyme patients.11
“When it’s advanced, whether the peripheral neuropathy is from diabetes or Lyme, the symptoms are the same: numbness, tingling sensation, and loss of strength of muscle and control of the foot,” Rhee said.
But, in Weinstein’s experience, Lyme-related peripheral neuropathy can have a somewhat different presentation.
“It’s not chronic stocking-glove diabetic peripheral neuropathy, and it’s not associated with leg ulceration, which is mainly due to vascular problems,” he said. ”You can also get a mononeuritis multiplex, which is much more rare and affects individual motor or sensory nerves.”
Bean noted that a number of his symptoms are not typical of diabetic peripheral neuropathy. For example, he sometimes experiences hypersensitivity rather than a loss of sensation, and at other times his heels will feel numb while sensation in the forefoot is preserved—neither of which is typically seen in a patient with diabetes.
When symptoms indicate that Lyme may be present, the CDC recommends a two-tiered systematic approach that measures changes in IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies along with evidence of possible exposure to confirm diagnosis. But, because Lyme neuroborreliosis frequently has clinical overlap with other illnesses, there are many obstacles to securing a diagnosis with laboratory confirmation.12,24
First-tier screening is an enzyme-linked immunoassay (ELISA), which should be performed in all suspected patients three to four weeks after initial exposure; however, serological test results may be falsely negative and misleading during the early phase of exposure due to a lag between infection and serum antibody changes.4,25 Therefore, borderline and reactive first-tier test results should prompt second-tier confirmatory Lyme IgM and IgG Western Blot tests.4
This two-tier testing system is generally accepted as reliable when interpreted properly, but some believe the process is in need of an update.2,11
“Most of the standard assays that the CDC uses are grossly outdated and they don’t find any active antibodies for the bacteria that are hidden in the body,” Bean said. “The Western Blot is more accurate, but even that will often show a lot of false negatives because it’s not sensitive enough.”
When Lyme disease is confirmed, a spinal tap or brain magnetic resonance imaging (MRI) should be considered when there is suspected central nervous system involvement.4 To make a diagnosis of Lyme-related peripheral neuropathy, objective evidence of peripheral nerve damage, either obtained clinically or through electromyography (EMG), is needed.26
“You have to confirm the neuropathy with EMG and nerve conduction studies first to document the diagnosis and eliminate other causes of neuropathy,” Rhee said.
According to John Halperin, MD, a neurologist at Overlook Medical Center in Summit, NJ, who has authored numerous papers on Lyme and the nervous system, “Standard care is oral antibiotics and if that fails you go to IV antibiotics. The three most common are doxycycline, amoxicillin, and cefuroxime axetil.”
For Lyme neuroborreliosis without brain or spinal cord involvement, including peripheral neuropathy, there is evidence and consensus that oral doxycycline (100-200 mg twice a day) or amoxicillin (500 mg three times a day) for three to four weeks are both safe and highly effective.4,11,25 Parenteral IV antibiotic therapy, if needed, can be done with ceftriaxone, cefotaxime, or high-dose penicillin.4,10,11
Although nonpharmaceutical treatments for Lyme-related peripheral neuropathy have not been studied in the medical literature, anecdotally a number of therapies have been found to be helpful for symptom management.
“Physical therapy is important, especially soaking and massaging, and I also recommend vitamin B6 and B12 supplements, which provide nutrition to damaged nerves,” Rhee said.
Ilkcan Cokgor, MD, a neurologist at the Neurology Clinic of Marin in San Anselmo, CA, who has treated patients with Lyme-related neurological complications, takes it a step further.
“I recommend hyperbaric oxygen therapy if it’s financially feasible, as well as biofeedback, neurofeedback, acupuncture, physical or occupational therapy, and osteopathic cranial sacral massage, depending on their complications,” Cokgor said.
Damaged nerves take time to recover, and patients may continue to remain symptomatic for weeks to a few months after antibiotic treatment.11
“You can have prolonged symptoms even if the bug is eradicated,” Weinstein said. “The nervous system, like some other systems, heals slowly. Or there may permanent damage. I’ve seen patients with permanent facial weakness from Lyme, where they didn’t heal, others with prolonged but eventually subsiding pain in the extremities, because healing can take many months. This can occur from inadequate therapy, or in cases where patients don’t seek treatment early enough and there’s already been a lot of damage.”
The clinical presence of a chronic form of Lyme disease—what’s referred to as chronic Lyme—that persists after a confirmed diagnosis and appropriate antibiotic management remains a topic surrounded by ongoing controversies that are beyond the scope of this article.27-30
According to Weinstein, though, one important distinction must be made.
“There are two different terms that must not be confused: one is chronic Lyme, which is very slow healing of damaged nerves and nerve roots that can lead to prolonged symptoms for months or years,” he said. ”The other is post-Lyme syndrome, which is when patients have prolonged symptoms years after Lyme—aches, pains, fatigue, forgetfulness, and other neuropathic symptoms—and there’s no evidence that it’s due to chronic infection, and it’s not known why they still have these symptoms. Treating post-Lyme syndrome is very difficult because we don’t know the cause, and I think it takes a sophisticated doctor to sort it out and give proper treatment.”
Additional difficulties in treating Lyme complications can relate to the experience, geographic location, and clinical philosophy of the practicing physician.
“Patients can get into trouble because they may get a different diagnosis and a different treatment based on the physician they see, which is not a good situation,” Simpson said.
Because Lyme disease is prevalent on the East Coast, awareness of the risks is higher and treatment is more accessible there than in other areas of the country, Bean noted.
Lyme disease has been the subject of extensive study over the past 30 years and a great deal is now understood about its diagnosis and treatment; however, some controversies and misconceptions still remain.4,30 The fact that some patients with Lyme are not properly diagnosed and others continue to experience neurological symptoms after antibiotic treatment has added to this and caused confusion among both physicians and patients.2,11,30
Although additional research and discussion may help improve testing methods and settle ongoing debate, experts say what’s more important now is increasing awareness and education about early diagnosis and treatment of Lyme disease—especially in geographic areas where it’s less common—and helping patients cope with long-term complications like peripheral neuropathy.2,29,30
“The problem is when it starts to spread to new areas where the doctors and the population don’t know much about it,” Weinstein said. “That’s where you can get patients who are left untreated and go on to get more serious issues. In endemic areas, where Lyme is common, patients should know that Lyme can cause these complications.”
Symptoms of peripheral neuropathy in patients who do not have diabetes or other obvious underlying conditions should prompt practitioners to consider Lyme disease as a differential diagnosis, Rhee said.
“Physicians should always ask if there’s been a tick bite, and you should always consider that as a possibility if their symptoms suggest it,” Rhee said. “You have to think about the disease to make a diagnosis.”
Greg Gargiulo is a freelance medical writer based in the San Francisco Bay Area.
- Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007;69(1):91-102.
- Hildenbrand P, Craven DE, Jones R, Nemeskal P. Lyme neuroborreliosis: manifestations of a rapidly emerging zoonosis. Am J Neuroradiol 2009;30(6):1079-1087.
- Centers for Disease Control and Prevention (CDC). Lyme disease: United States, 2003-2004. MMWR Morb Mortal Wkly Rep 2007;56(23):573-576.
- Younger DS. Lyme neuroborreliosis. In: Watts RL, Standaert DG, Obeso J, eds. Motor Disorders. 3rd ed. Brookfield, CT; Rothstein Associates Inc; 2014:575-580.
- Lyme disease. The Foundation for Peripheral Neuropathy website. https://www.foundationforpn.org/livingwithperipheralneuropathy/causes/lymedisease.cfm. Accessed January 30, 2015.
- Lyme disease & other tick-borne illnesses: The Carolina Center’s approach. Carolina Center for Integrative Medicine website. http://www.carolinacenter.com/lyme-disease.html. Accessed January 30, 2015.
- Lyme neuroborreliosis. Lyme Disease Action website. http://www.lymediseaseaction.org.uk/wp-content/uploads/2013/05/LDA003-2-web-version.pdf. Accessed January 30, 2015.
- Pachner AR, Steiner I. Lyme neuroborreliosis: infection, immunity, and inflammation. Lancet Neurol 2007;6(6):544-552.
- Dryden MS, Saeed K, Ogborn S, Swales P. Lyme borreliosis in southern United Kingdom and a case for a new syndrome, chronic arthropod-borne neuropathy. Epidemiol Infect 2015;143(3):561-572.
- Rizvi S, Diamond A. Neurological complications of Lyme disease. Med Health R I 2008;91(7):216-218.
- Halperin JJ. Lyme disease and the peripheral nervous system. Muscle Nerve 2003;28(2):133-143.
- Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18(3):484-509.
- Steere AC. Lyme disease. N Engl J Med 2001;345(2):115-125.
- Johnson L, Wilcox S, Mankoff J, Stricker RB. Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey. Peer J 2014;2:e322.
- Stonehouse A, Studdiford JS, Henry CA. An update on the diagnosis and treatment of early Lyme disease: “focusing on the bull’s eye, you may miss the mark.” J Emerg Med 2010;39(5):e147-e151.
- Lyme Disease. Confirmed Lyme disease cases by age and sex: United States, 2001-2010. Centers for Disease Control and Prevention website. http://www.cdc.gov/lyme/stats/chartstables/incidencebyagesex.html. Updated December 6, 2013. Accessed January 30, 2015.
- How many people get Lyme disease? Centers for Disease Control and Prevention website. http://www.cdc.gov/lyme/stats/humanCases.html. Updated August 23, 2013. Accessed January 30, 2015.
- Pfister HW, Rupprecht TA. Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients. Int J Med Microbiol 2006;296(Suppl 40):11-16.
- Steere AC, Glickstein L. Elucidation of Lyme arthritis. Nat Rev Immunol 2004;4(2):143-152.
- Mygland A, Monstad P. Chronic polyneuropathies in Vest-Agder, Norway. Eur J Neurol 2001;8(2):157-165.
- Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain 1990;113(Pt 4):1207-1221.
- Coyle PK. Lyme disease. Curr Neurol Neurosci Rep 2002;2(6):479-487.
- Neuropathy in U.S. skyrocketing. Neuropathy Association website. http://www.neuropathy.org/site/News2?id=8445&news_iv_ctrl=1101. Published May 13, 2013. Accessed January 30, 2015.
- Younger DS, Orsher S. Lyme neuroborreliosis: Preliminary results from an urban referral center employing strict CDC criteria for case selection. Neurol Res Int 2010;2010:525206.
- Centers for Disease Control and Prevention. Lyme disease: United States, 2000. MMWR Morb Mortal Wkly Rep 2002;51(2):29-31.
- Schuyler D. Two opposing camps offer insight into treatment of neurologic Lyme disease. Psychiatric Times. http://www.psychiatrictimes.com/articles/two-opposing-camps-offer-insight-treatment-neurologic-lyme-disease. Published September 1, 2006. Accessed January 23, 2015.
- Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am 2008;22(2):341-360.
- Hurley RA, Taber KH. Acute and chronic Lyme disease: controversies for neuropsychiatry. J Neuropsychiatry Clin Neurosci 2008;20(1):iv-6.
- Ljøstad U, Mygland Å. Chronic Lyme; diagnostic and therapeutic challenges. Acta Neurol Scand Suppl 2013;(196):38-47.
- Halperin JJ, Baker P, Wormser GP. Common misconceptions about Lyme disease. Am J Med 2013;126(3):264.e1-264.e7.