Neurologic Complications of Tick-Borne Diseases

Tick-borne diseases are becoming increasingly common, with a 40% increase in reported tick-borne diseases over the 4 years from 2019 to 2022.¹ Ticks are a vector for a wide range of infectious organisms including viruses, bacteria, and parasites, with the type and prevalence of tick-borne diseases varying by geographic region. Although many tick-borne infections do not have neurologic sequela, neurologic manifestations of such infections are important to recognize and will become more common as tick-borne disease incidence continues to increase.

Neurologic manifestations of tick-borne diseases range from nonspecific meningitic presentations to more specific syndromes, such as polyradiculitis, as seen in Lyme disease, or cerebellitis, as seen in Powassan virus encephalitis. In addition to the clinical syndrome, obtaining a thorough patient exposure and travel history are critical to guiding workup. Diagnostic testing varies by infectious agent with molecular methods (ie, polymerase chain reaction [PCR]), serologic testing, or direct detection using microscopy being the most common methods. Treatment similarly varies by infectious agent (Table).

Lyme Disease

Lyme disease, caused by the bacterial spirochete Borrelia burgdorferi, is the most common tick-borne illness in the United States, with approximately half a million cases reported annually.² Lyme disease is often considered for individuals presenting with a wide variety of neurologic symptoms, but the scope of neurologic Lyme disease is likely much narrower. Typical manifestations of early neurologic Lyme disease include cranial neuritis (most commonly facial neuritis), lymphocytic meningitis, or painful radiculoneuritis (Bannwarth syndrome), with the relative prevalence of these syndromes varying by region.³

In a series from North America, 12.5% of individuals with Lyme disease were reported to have neurologic manifestations, with 8.4% presenting with facial palsy, 3.8% with radiculoneuropathy, 1.3% with lymphocytic meningitis, and <1% with encephalitis.⁴ In Europe, in a series of individuals specifically diagnosed with neurologic Lyme disease, 70% had painful radiculoneuritis, 45% had cranial neuritis (84 of 88 cases involved the facial nerve), 38% had headache, and 17% had extremity weakness (presumably another manifestation of radiculoneuritis).⁵ These differences may be explained by the different prevalence of Borrelia species, with B. burgdorferi being most common in North America and B. afzelii and B. garinii being most common in Europe.⁶ These neurologic syndromes can overlap with 25% of individuals with neurologic Lyme disease in Denmark having both painful radiculoneuritis and cranial nerve palsy.⁵

Lyme radiculoneuritis typically starts with severe, asymmetric radicular pain involving any spinal level, progressing to weakness or sensory loss corresponding to the affected nerve roots.³ The facial nerve is the most commonly affected cranial nerve, and facial neuritis can be bilateral.⁵ Involvement of other cranial nerves is less common, but it does occur.⁵ Contrast-enhanced MRI may show enhancement of the affected cranial nerves or nerve roots but has limited sensitivity and specificity.

Lyme encephalitis is often discussed, but the reported prevalence in the United States is <1%, and a combined 2002 systematic review plus 20-year Scandinavian cohort study (1990–2019; Denmark, Sweden, and Norway) found only 45 published confirmed cases and only 35 cases in their 20-year cohort.^4,7 Joint guidelines from the Infectious Disease Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) recommend Lyme disease testing only in the setting of meningitis, painful radiculoneuritis, mononeuropathy multiplex, or acute cranial neuropathies, and recommend against Lyme disease testing in individuals with other neurologic syndromes, with nonspecific white matter lesions on brain MRI, or without epidemiologic risk factors.⁸

Diagnosis of neurologic Lyme disease starts with serum immunoglobulin G (IgG) and immunoglobulin M (IgM) testing. Most individuals are seropositive at presentation, but serum testing can be repeated in 2 weeks if initially negative and high clinical suspicion remains.⁸ If cerebrospinal fluid (CSF) testing is performed, simultaneous serum and CSF samples should sent for calculation of a CSF:serum IgG index, which is highly specific and sensitive for central nervous system involvement, with the caveat that the index may remain elevated for years after successful treatment of a previous infection.⁸ CSF PCR for Lyme disease testing is recommended against by the IDSA/AAN/ACR guidelines, as its sensitivity is reported at 5% to 17%.⁸ General CSF analysis shows a lymphocytic pleocytosis on the order of 10s to 100s of cells/µL and elevated total protein levels in the range of 72 to 194 mg/dL or higher.⁵

Treatment of neurologic Lyme disease (excluding isolated facial nerve palsy) is typically with 2 to 3 weeks of intravenous (IV) ceftriaxone in North America; in Europe, there is experience with oral doxycycline, and US guidelines allow for transition to oral antibiotics in the absence of parenchymal brain or spinal cord involvement.^8,9

Posttreatment Lyme disease is a syndrome comprising symptoms including fatigue, brain fog, arthralgias, and myalgias and is reported in <20% of individuals after treatment of Lyme disease, although the incidence may be higher in those with neurologic involvement.³ Multiple placebo-controlled trials investigating re-treatment with additional antibiotic courses for posttreatment Lyme disease have not demonstrated a clinically meaningful improvement, but have demonstrated harms; re-treatment for nonspecific symptoms such as fatigue, pain, or brain fog without objective evidence of reinfection or treatment failure is recommended against by the IDSA/AAN/ACR guidelines.^8,10

Other Borrelial Infections

Tick-borne relapsing fever (TBRF) is a tick-borne illness manifesting with relapsing fevers and nonspecific symptoms, including headaches, myalgias, chills, nausea, and vomiting. TBRF is caused by various Borrelia species throughout most of the world, including B. hermsii and B. turicatae most commonly in North America, where it occurs almost exclusively on the western side of the continent.¹¹ Neurologic complications, including meningitis, encephalitis, facial palsy, hemiplegia, radiculopathy, and multiple cranial neuropathies, have been reported in 10% to 40% of individuals.¹¹

Diagnosis can be made by visualization of spirochetes in blood smears taken during an acute febrile episode or by PCR. Serology is less useful in diagnosis of TBRF in contrast to Lyme disease, because TBRF often becomes symptomatic before seroconversion.¹¹ Management is similar to that for Lyme disease, with 14 days of IV ceftriaxone recommended for those with neurologic involvement and 10 days of doxycycline generally used for those without neurologic involvement.¹¹

B. miyamotoi is an emerging infection first isolated in Japan in 1992 and first described to cause human disease in Russia in 2011, with cases since described throughout North America, Europe, and Asia.¹² Seroprevalence among healthy individuals in some areas is approximately 1% and approaches 12% in those suspected of having a tick-borne disease.¹² Most cases present with fever and nonspecific symptoms, including headache, rigors, myalgias or arthralgias, and fatigue. Erythema migrans is described in only 4% of published cases.¹² Meningoencephalitis has been reported in a few individuals, almost all of whom were immunocompromised because of rituximab therapy, although meningoencephalitis in immunocompetent individuals has been reported.^12,13 All individuals with meningoencephalitis had CSF pleocytosis with lymphocytic or mononuclear predominance and a reported range of 50 to 388 cells/µL.¹³ Symptom duration ranged from days to months and included headache, neck stiffness, dizziness, vomiting, anorexia, weakness, sensory impairment, and cognitive impairment. Diagnosis is through PCR of blood or CSF (if concern for meningoencephalitis is present), and treatment is extrapolated from Lyme disease; doxycycline if no concern for neurologic involvement and ceftriaxone if there is concern for neurologic involvement.¹²

Powassan Virus

Powassan virus, first discovered in Powassan, Ontario, Canada, in 1958, is an emerging infection in North America, with 1 case per year described before 2005, approximately 8 cases per year from 2006 through 2015, and 20 to 40 cases per year from 2016 through 2019.¹⁴ Powassan virus is closely related to the tick-borne encephalitis virus found in Europe and Asia, although less is known about Powassan virus than tick-borne encephalitis virus.¹⁴ Powassan virus is carried by the Ixodes scapularis tick—the tick that carries Lyme disease—with prevalence of 1% to 3% in I. scapularis ticks in endemic regions (ie, northeastern and north central United States).¹⁴ Unlike Lyme disease, Powassan virus is transmitted within minutes of tick attachment.¹⁴

Human seroprevalence studies have been variable, with high-risk populations in Wisconsin showing rates >9% but studies among the general population in the Northeast showing rates ≤1% to 2%.¹⁴

Powassan virus is almost exclusively recognized as a neuroinvasive disease, although there are likely many unrecognized cases presenting with febrile illness without progression to neuroinvasive disease.¹⁴ Neurologic manifestations are variable: encephalopathy, focal weakness, ataxia or cerebellar dysfunction, cranial neuropathies, myelopathy, anterior horn cell dysfunction, and chorioretinitis have been described.^14,15 Imaging results are similarly variable and may include T2/fluid-attenuated inversion recovery changes in the basal ganglia, cerebellum, or brainstem; leptomeningeal enhancement; involvement of the cervical spine; or cerebellitis, often causing obstructive hydrocephalus, although 25% to 50% of individuals may have normal results on imaging.^14,15

Diagnosis is generally by serum IgM demonstrating a 4-fold rise between acute and convalescent sera or by detection of IgM in CSF followed by a confirmatory plaque reduction neutralization test.¹⁴ In immunocompromised or hypogammaglobulinemic individuals, CSF PCR adds sensitivity.

There are no proven treatments for Powassan neuroinvasive disease. Case reports describe using high-dose steroids and IV immunoglobulin with mixed success, but there are insufficient data to recommend for or against their use. Mortality rates from neuroinvasive Powassan are upwards of 10%, and persistent neurologic morbidity is common.^14,15

Anaplasmosis and Ehrlichiosis

Anaplasmosis and ehrlichiosis—caused by Anaplasma phagocytophilum and Ehrlichia chaffeensis, respectively—are tick-borne bacteria that infect leukocytes. A. phagocytophilum is transmitted by various Ixodes ticks (including I. scapularis; species vary geographically), and largely infects neutrophils; E. chaffeensis is carried by the lone star tick (Amblyomma americanum), and largely infects monocytes. Both cause nonspecific febrile illnesses, although leukopenia, thrombocytopenia, and transaminase elevations can be clues.¹⁶ Serious neurologic sequelae are uncommon. Meningitis has been reported with ehrlichiosis, whereas CSF changes in anaplasmosis are exceedingly rare.^17,18 Peripheral nervous system syndromes, including demyelinating polyneuropathy and brachial plexopathy, have been reported in association with anaplasmosis, although a causal relationship is difficult to ascertain.¹⁸

Diagnosis can be made by PCR, serology, or direct detection of intracytoplasmic inclusions on a blood smear. Doxycycline is generally the first-line treatment.

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by Rickettsia rickettsii. Infections occur throughout North and South America, with different ticks serving as vectors in different geographic areas. R. rickettsia preferentially causes an infection of vascular endothelial cells.¹⁹ RMSF classically presents with fever, headache, and rash, with the rash starting a few days into the illness on the extremities and then spreading centrally.¹⁹ Nervous system involvement is well described. A series of 80 hospitalized individuals with RMSF found that 35% were discharged with at least 1 neuropsychiatric sequela, including weakness, seizures, ataxia, vision impairment, or coma, and 23% had long-term neurologic sequela, most commonly cognitive impairment.²⁰ A series of 19 individuals (11 children, 8 adults) with rickettsial meningoencephalitis found focal neurologic deficits in half and seizures in 43%. CSF pleocytosis and CSF protein elevation were present in 88% (each), and hypoglycorrhachia was present in 19%. Of 9 children who had an MRI, all had a starry sky pattern with multifocal diffusion restriction or T2 hyperintensities. This was not found in the 3 adults, whose imaging reports described “concern for vasculitis,” acute disseminated encephalomyelitis, or punctate deep lesions.²¹

Diagnosis of RMSF is generally made clinically and presumptively. Convalescent serologies can confirm the diagnosis but may not be detectable during the acute illness, and PCR is specific but not sensitive.¹⁹ Treatment with doxycycline should be started immediately once RMSF is suspected; treatment delay is associated with worse outcomes.^19,20

Tularemia

Tularemia is a bacterial infection caused by Francisella tularensis. F. tularensis is transmitted through multiple routes, including ticks, mosquitos, or horseflies; contact with infected animals (especially rabbits or rodents); contaminated food or water; or inhalation of contaminated material, with tick bites likely the most common source of infection in the United States.²² Clinical manifestations usually include a nonspecific febrile syndrome with adenopathy plus more specific symptoms depending on the site of infection, including skin lesions, pneumonia, ocular disease, or oropharyngeal disease.²³

Tularemic meningitis has been reported, but it is likely rare, with few published cases. The largest review, including 17 cases, found that people with tularemic meningitis had a variety of infectious sources and initial presentations and usually had a marked CSF pleocytosis (>1000 cells/µL), increased CSF protein, hypoglycorrhachia, and a mononuclear predominant leukocytosis.²⁴ Seven of 17 individuals died from the infection.

Diagnosis is difficult acutely, so treatment should be started empirically in an individual with a compatible clinical presentation. Diagnosis is often made by demonstration of a fourfold increase in convalescent serologies, although the organism can be cultured from a clinical specimen in approximately 50% of cases (an indicator of poor prognosis).²³ Infectious disease consultation should be sought to guide treatment, as antibiotic choice is not straightforward. Effective options include aminoglycosides, tetracyclines, and fluoroquinolones; individuals with meningitis may benefit from combination therapy.^23,24

Babesiosis

Babesiosis is a parasitic infection of erythrocytes caused by the protozoan Babesia (mostly Babesia microti) and transmitted by the I. scapularis tick, with an increasing incidence in the United States over the past few decades.²⁵ Clinical manifestations depend on the degree of parasitemia, with most individuals presenting with nonspecific febrile symptoms, but individuals with higher parasitemia burdens (often older individuals or people who are immunocompromised) can develop potentially fatal organ failure.²⁵

Diagnosis can be made by microscopy of blood smears or PCR. Neurologic sequela were investigated in a cohort of 163 consecutive hospitalized individuals with babesiosis in Connecticut.²⁵ More than half had at least 1 neurologic symptom, including headache (32%), confusion or delirium (17%), impaired consciousness (15%), or ataxia or gait disorder (10%). Individuals with confusion, delirium, or impaired consciousness were considerably more likely to have higher peak parasitemia. Of 33 individuals who underwent neuroimaging, there were 2 structural changes not attributed to chronic disease or aging: 1 individual had a stroke attributed to carotid artery stenosis and 1 individual had a subarachnoid hemorrhage attributed to disseminated intravascular coagulation from multiorgan failure. Six individuals underwent lumbar puncture, with none having a CSF nucleated cell count ≥5, and only 1 having an elevated protein level. Neurologic sequela in babesiosis are thought to be from vascular and inflammatory consequences of the infection rather than direct neuroinvasion.²⁵

Conclusion

As tick-borne diseases become more prevalent, it is increasingly important for clinicians to be familiar with their neurologic manifestations. Appropriate testing will vary by clinical syndrome, exposure history, and region, and is not always straightforward. Management varies by infectious agent, and a high index of suspicion is needed, because some infections (eg, RMSF) are difficult to diagnose acutely and require empiric treatment.