Chronic Neurologic Lyme Disease: The Landmark Study That Changed Our Understanding
Findings from a landmark chronic neurologic Lyme disease study
Cognitive symptoms, neuropathy, fatigue, and normal spinal fluid findings
How the research influenced diagnosis, treatment, and recovery
Chronic neurologic Lyme disease can involve memory problems, sleep disturbance, depression, irritability, nerve pain, numbness, tingling, fatigue, headaches, hearing changes, and other neurologic symptoms. A landmark study published in the New England Journal of Medicine helped establish these manifestations as an important area of clinical investigation.
The study, published in 1990, was conducted by investigators who included Dr. Alan Steere, the physician credited with helping identify Lyme disease in 1977. Its findings changed how physicians and researchers understood the potential neurologic consequences of Lyme disease.
In describing chronic neurologic Lyme disease, the study contributed to the recognition of other persistent or chronic manifestations, including Lyme encephalopathy, autonomic dysfunction, neuropsychiatric Lyme disease, post-Lyme disease symptoms, post-Lyme disease syndrome, and post-treatment Lyme disease syndrome. [2–8]
Symptoms of Chronic Neurologic Lyme Disease Reported in the Landmark Study
The 1990 paper, entitled Chronic Neurologic Manifestations of Lyme Disease, examined 27 patients with chronic manifestations. [1]
Together, these patients demonstrated that chronic neurologic Lyme disease could affect multiple parts of the nervous system and substantially impair daily functioning.
The most common symptoms included:
- Memory loss
- Depression
- Sleep disturbance
- Irritability
- Difficulty finding words
- Spinal or radicular pain
- Distal paresthesias, including tingling or pins-and-needles sensations
- Sensory loss
- Fatigue
- Headache
- Hearing loss
- Tinnitus
- Fibromyalgia symptoms
Less common findings included lower motor neuron weakness, ankle hyporeflexia, upper motor neuron weakness, hyperreflexia, and increased muscle tone.
Can chronic neurologic Lyme disease occur with a normal spinal tap?
The study described chronic neurologic manifestations in patients whose spinal fluid testing was largely normal. Only 2 of the 27 patients had an abnormal spinal tap. One had a pleocytosis of seven cells, and another had an elevated IgG index.
This finding is clinically important because a normal spinal tap did not exclude the neurologic manifestations described in this patient group. Spinal fluid results must be interpreted within the broader clinical picture, including the patient’s history, symptoms, examination findings, and other diagnostic evidence.
The study’s description of chronic neurologic Lyme disease would have a profound influence on clinical practice and future research.
When this landmark study was published in 1990, I had already spent several years caring for patients with similar neurologic presentations. As an internist and epidemiologist, I relied on individualized clinical assessment because many patients did not fit the traditional descriptions of Lyme disease available at the time. Seeing these cases carefully documented in the medical literature validated many of the clinical patterns I had been observing in practice and reinforced the importance of recognizing chronic neurologic manifestations of Lyme disease.
Ten Important Findings from the Landmark Study
1. Neurologic symptoms could develop months or years after the initial illness
The time between an erythema migrans rash and chronic nervous system involvement ranged from as little as one month to as long as 14 years.
This wide interval demonstrated that neurologic manifestations did not always develop immediately after the initial signs of Lyme disease.
2. Mild encephalopathy was the most common presentation
Most patients presented with mild encephalopathy characterized by memory loss, depression, sleep disturbance, irritability, and difficulty finding words.
The authors described patients who forgot names, missed appointments, misplaced objects, and relied on daily lists to compensate for their memory problems.
Ten patients had symptoms of depression, and three sought psychiatric care or received antidepressant medication. Eight experienced excessive daytime sleepiness, while seven reported extreme irritability. Five had subtle language disturbances, particularly difficulty finding words.
3. Chronic neurologic Lyme disease affected some patients’ ability to work
Although most patients remained able to work, the illness had substantial occupational consequences for several individuals. Three patients quit their jobs, three reduced their hours to part time, and two retired early.
These findings demonstrated that even when neurologic symptoms were described as mild, they could still interfere with daily function, concentration, reliability, and employment.
4. Polyneuropathy was common
Seventy percent of the patients had evidence of polyneuropathy.
Eleven experienced pain in the cervical, thoracic, or lumbosacral regions of the spine, often accompanied by tingling, burning, spasms, or shooting pain involving a limb or the trunk.
Seven patients had distal paresthesias alone, with intermittent tingling or pins-and-needles sensations in the hands or feet.
Sixteen of the 19 patients with polyneuropathy had findings consistent with axonal polyneuropathy, including subtle abnormalities affecting distal motor or sensory nerve conduction.
5. One patient developed progressive leukoencephalitis
One patient developed leukoencephalitis six years after antibiotic treatment. The illness included progressive stiffness, moderate weakness, increased muscle tone in the right arm and both legs, and incontinence.
The patient improved following treatment with intravenous antibiotics.
6. Fatigue was often a major symptom
Most patients experienced marked fatigue, which was frequently one of the most significant symptoms of their illness.
Fatigue occurred alongside cognitive, sensory, pain, and sleep-related symptoms and could contribute to substantial limitations in daily functioning.
7. Approximately half of the patients experienced headaches
Approximately half of the patients reported headaches. The authors described them as mild to severe, episodic, and non-pounding.
The headaches occurred in global, hemicranial, bifrontal-temporal, or occipital distributions. They were not accompanied by nausea, visual aura, or somatosensory aura.
8. Hearing loss and tinnitus occurred in some patients
Four patients had mild-to-moderate unilateral hearing loss, which was sometimes accompanied by tinnitus.
These findings demonstrated that chronic neurologic Lyme disease could involve auditory symptoms as well as cognitive and peripheral nerve complaints.
9. Some patients had symptoms of fibromyalgia
Four patients had symptoms consistent with fibromyalgia.
The overlap between neurologic symptoms, fatigue, widespread pain, sleep disturbance, and fibromyalgia-like symptoms may complicate the clinical evaluation of patients with persistent illness.
10. Many patients improved after intravenous ceftriaxone, but recovery was often incomplete
Seventeen patients improved after two weeks of intravenous ceftriaxone. However, the authors reported that recovery was seldom complete.
Six patients, representing 22% of the study group, initially improved and then relapsed. Four patients, representing 15%, did not improve.
The authors raised several possible explanations for these outcomes:
“The likely reason for relapse is failure to eradicate the spirochete completely with a two-week course of intravenous ceftriaxone therapy. On the other hand, the patients who did not improve may have had irreversible damage to the nervous system, particularly since the response to therapy tended to be worse in patients with longer duration of illness.” [1]
Why the Study Changed Our Understanding of Lyme Disease
Chronic Neurologic Manifestations of Lyme Disease became a landmark paper because it documented persistent cognitive, sensory, pain, fatigue, and functional symptoms in a carefully described group of patients.
Before the 1990 study, Lyme disease was often viewed primarily as an acute infection that could be effectively treated with a 10- to 21-day course of antibiotics. The study drew greater attention to the potential for ongoing neurologic illness, incomplete recovery, relapse, and lasting nervous system injury.
The paper has since been cited hundreds of times in the medical literature and remains one of the most influential publications describing chronic neurologic manifestations of Lyme disease. More than three decades later, I continue to find many of its clinical observations relevant when evaluating patients with persistent neurologic symptoms suggestive of Lyme disease.
A Later Study of Lyme Encephalopathy
The investigators later conducted another study involving 18 patients who met strict criteria for Lyme encephalopathy. [2]
The most common symptoms included:
- Memory loss
- Minor depression
- Somnolence
- Headache
- Irritability
- Hearing loss or tinnitus
- Neuropathy
The patients with Lyme encephalopathy were treated with intravenous ceftriaxone for one month, compared with the two-week course used in the earlier chronic neurologic Lyme disease study.
At follow-up, 50% were described as greatly improved. Two additional patients, representing 11%, were somewhat improved. [2]
Additional Research on Persistent Neurologic Symptoms
Other researchers continued to examine the severity and treatment of persistent neurologic symptoms associated with Lyme disease.
Fallon and colleagues evaluated patients with Lyme encephalopathy who had previously received antibiotic treatment. The investigators used standardized measures of cognition, fatigue, pain, and physical functioning to assess illness severity and treatment response. [3]
The study found short-term cognitive improvement following additional intravenous ceftriaxone, although the cognitive benefit was not sustained after treatment ended. Some measures of physical functioning and pain improved among selected patients, while adverse events also occurred. [3]
These findings illustrate the difficulty of studying persistent neurologic symptoms. Patients may differ in illness duration, prior treatment, neurologic involvement, functional impairment, and response to additional therapy.
Why Chronic Neurologic Lyme Disease Remains Controversial
The 1990 chronic neurologic Lyme disease paper has not been without controversy.
Some physicians recognize the existence and potential severity of persistent manifestations of Lyme disease and support individualized clinical judgment when evaluating patients who remain ill. [9]
Other physicians and professional organizations remain skeptical that persistent symptoms necessarily indicate ongoing infection and have emphasized alternative explanations, standardized treatment recommendations, and the risks of prolonged antibiotic therapy. [10]
The terminology has also evolved. Researchers and clinicians have used phrases including chronic neurologic Lyme disease, Lyme encephalopathy, post-Lyme disease, post-Lyme disease syndrome, and post-treatment Lyme disease syndrome to describe overlapping but not always identical patient groups.
These terms should not automatically be treated as interchangeable. They may reflect differences in diagnostic criteria, objective findings, prior treatment, symptom duration, and assumptions about the biological mechanisms responsible for persistent illness.
The Study’s Continuing Clinical Importance
Regardless of the continuing debate, the landmark study had a significant impact on both researchers and clinicians.
It documented that patients with Lyme disease could experience prolonged cognitive symptoms, neuropathy, fatigue, headaches, hearing changes, pain, and functional impairment. It also demonstrated that routine spinal fluid findings could be normal in most of the patients studied.
The study raised enduring questions about delayed neurologic involvement, incomplete recovery, relapse after treatment, irreversible nervous system injury, and the optimal duration of antibiotic therapy.
More than three decades later, these questions continue to shape research into persistent manifestations of Lyme disease and the search for more reliable diagnostic tools and more effective treatments.
Frequently Asked Questions
What are the symptoms of chronic neurologic Lyme disease?
Symptoms described in the landmark study included memory loss, difficulty finding words, sleep disturbance, depression, irritability, fatigue, headaches, spinal or radicular pain, numbness, tingling, sensory loss, hearing loss, tinnitus, and polyneuropathy. Less common findings included weakness, abnormal reflexes, and increased muscle tone.
Can chronic neurologic Lyme disease occur with a normal spinal tap?
Yes. In the 1990 study, only 2 of 27 patients had clearly abnormal spinal fluid findings. A normal spinal tap therefore did not exclude the chronic neurologic manifestations described in that study. Spinal fluid results must be interpreted alongside the patient’s history, examination, symptoms, and other diagnostic information.
Can Lyme disease cause memory problems and difficulty finding words?
The patients in the landmark study commonly reported memory loss and difficulty finding words. Some forgot names, missed appointments, misplaced objects, or relied on written lists to compensate for cognitive difficulties.
Can Lyme disease cause peripheral neuropathy?
Peripheral nerve involvement was common in the study. Seventy percent of patients had polyneuropathy, including burning, tingling, shooting pain, sensory symptoms, and subtle abnormalities affecting distal motor or sensory nerve conduction.
Can chronic neurologic Lyme disease improve with treatment?
Many patients in the original study improved after intravenous ceftriaxone, but recovery was often incomplete. Some patients relapsed, and others did not improve. Treatment response may vary according to illness duration, neurologic involvement, previous therapy, irreversible injury, and other clinical factors.
Clinical Takeaway
The landmark 1990 study helped establish that Lyme disease may be associated with persistent cognitive symptoms, peripheral neuropathy, fatigue, headaches, hearing changes, pain, and functional impairment.
It also demonstrated that chronic neurologic manifestations could be described in patients whose spinal fluid findings were largely normal and that improvement following treatment was not always complete.
More than three decades later, this landmark study continues to influence how clinicians recognize, evaluate, and investigate chronic neurologic manifestations of Lyme disease.
Related Articles
Explore related discussions of neurologic manifestations, autonomic symptoms, and persistent illness associated with Lyme disease:
Neurologic Lyme Disease Symptoms
Autonomic Dysfunction and Lyme Disease
Post-Treatment Lyme Disease Syndrome
References
- Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323(21):1438–1444.
- Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis. 1999;180(2):377–383.
- Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008;70(13):992–1003.
- Fallon BA, Nields JA, Burrascano JJ, Liegner K, DelBene D, Liebowitz MR. The neuropsychiatric manifestations of Lyme borreliosis. Psychiatr Q. 1992;63(1):95–117.
- Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease: A randomized double-masked clinical trial. Neurology. 2003;60(12):1923–1930.
- Mygland A, Ljøstad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. 2010;17(1):8–16.e1–e4.
- Aucott JN. Posttreatment Lyme disease syndrome. Infect Dis Clin North Am. 2015;29(2):309–323.
- Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: The clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9):1103–1135.
- Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089–1134.
Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.
Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention
