Relapsing fever, as the name implies, is characterized by recurrent acute episodes of fever. These are followed by periods of defervescence of increasing duration. The infection is caused by various spirochete species of the Borrelia genus. Spirochetes are a unique species of bacteria that also cause syphilis, Lyme disease, and leptospirosis.[1] The fever relapses result from spirochetal antigenic variation. Relapsing fever, if untreated, may be fatal.
Relapsing fever is an arthropod-borne infection spread by lice (Pediculus humanus) and ticks (Ornithodoros species). Two main forms of this infection exist: tickborne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF).
TBRF is caused by 8 or more Borrelia species (eg, Borrelia hermsii, Borrelia turicatae, Borrelia parkeri,Borrelia duttonii), while LBRF is caused solely by Borrelia recurrentis.[1]
TBRF and LBRF vary significantly in terms of epidemiology. A soft-bodied tick (Ornithodoros) transmits multiple Borrelia species that cause endemic relapsing fever, whereas the human body louse transmits B recurrentis, which causes an epidemic form of relapsing fever. Unlike hard ticks, Ornithodoros adult ticks are able to live for many years, feed repeatedly on blood meals, lay eggs, and perpetuate their life cycle.[2] In addition, Ornithodoros ticks may survive long periods in a fasting state. In fact, Ornithodoros turicata ticks have been known to transmit spirochetes in the laboratory setting after 7 years without a blood meal.[2]
Humans are the sole host of B recurrentis, while mammals (eg, cattle, pigs, prairie dogs, ground and tree squirrels, chipmunks) and reptiles (lizards, snakes, gopher tortoises) may serve as a reservoir for tickborne Borrelia species.[2]
Relapsing fever is found in the United States in domestic dogs residing in forest cabins. B turicatae[3] and the recently identified B hermsii have also been reported in domesticated dogs.
The first reported case of TBRF in the United States was identified in 1905 in New York. The patient had previously traveled to Texas.[4] In the United States, where fewer than 30 cases of TBRF are diagnosed each year,[5] B hermsii and B turicatae cause most outbreaks. A recently discovered Borrelia species, Borrelia miyamotoi, has been found in hard-bodies ticks in regions where Lyme disease is endemic. B miyamotoi may coexist with Borrelia burgdorferi[6, 7, 8] and Babesia[8] .
TBRF is reported worldwide, except Antarctica, Australia, and the Pacific Southwest.
LBRF is uncommon in the United States but is occasionally observed in travelers returning from endemic regions (see International). The last reported outbreak of LBRF in the United States occurred in 1871.[9]
Spirochetes are wavy filamentous bacteria with one or more flagellae at each end.[1] Most borrelial spirochetes measure 10-30 µm long X 0.2 µm wide. In TBRF, the spirochetes are transmitted via the bite of an infected tick, whereas, in LBRF, contact with hemolymph from the human body louse (eg, from scratching-induced louse crushing) is the mode of spirochete transfer.
Most Ornithodoros tick bites occur at night and go unnoticed in most individuals.[10] Other described modes of transmission in the literature include blood transfusions, a laboratory worker who was bitten by an infected monkey with gingival bleeding, and intravenous drug use.[2] In rare cases, transplacental transmission has been reported.[11] The spirochete is not transmitted via aerosol, saliva, urine, feces, or semen.
The recently discovered B miyamotoi species is transmitted by tick bite and may be transmissible via blood transfusion.[12] Recent data demonstrate that this species resists human complement-mediated killing.[13]
Spirochetes enter breaks in the skin or mucous membranes, gain access to the vasculature, and disseminate to the spleen, bone marrow, liver, lungs, kidneys, and CNS. All it takes is a single spirochete to initiate the infectious process.
Borrelia species are able to induce cycles of disease by varying antigen expression and by displaying new outer-surface proteins during the disease course. The antigenic variants are referred to as serotypes.
The phenomenon of antigenic variation contributes to the recurring nature of relapsing fever.[14]
These proteins are named either variable small proteins or variable large proteins and are encoded within plasmid DNA. Alteration of these proteins prevents elimination of the spirochetes by the immune system, leading to recurrent febrile episodes.[2] In 2008, Thein et al identified and described the first porin of relapsing fever, Oms38, which is present in the outer membranes of B hermsii, B turicatae, B duttonii, and B recurrentis.[15]
The ability of a single spirochete to switch expression among antigenically distinct VSP and VLP genes allows escape from an individual host’s immune response. Allelic polymorphism or genetic variability of VSP and VLP genes within the total spirochete population may help to evade herd immunity.[16]
Recent experiments in mice have shown that interleukin-10 (IL-10) may play a protective role in down-regulating inflammation and spirochete load.[17, 18] Extraordinarily high serum IL-10 levels have been found in patients with LBRF in whom the disease course is relatively mild.[18] Hemorrhage and thrombosis were more commonly observed in IL-10–deficient mice.[18]
United States
TBRF has been reported in 14 states west of the Mississippi river, including Arizona, California, Colorado, Idaho, Kansas, Montana, Nevada, New Mexico, Oklahoma, Oregon, Texas, Utah, Washington, and Wyoming.[19] It has also been reported in Ohio. TBRF usually occurs during the summer in people who are on vacation and/or who are traveling to mountainous regions (elevation >8000 ft).[19] Cases of TBRF have been reported in persons inhabiting seasonally occupied lake areas and cabins infested with rodents and/or their ticks. During winter, the ticks are attracted to heat and carbon dioxide generated from indoor fires.[19]
Most (74%) patients diagnosed with TBRF in the United States between 1990 and 2011 had onset of illness from June to September, with a peak during July to August (52%). In Texas, cases occurred more frequently (67%) during November to March, and 11 cases (61%) were associated with spelunking.[20]
International
TBRF is endemic in Canada (southern portion of British Columbia), Mexico, Central and South America, central Asia, Africa, the Mediterranean region, and Russia.[21]
LBRF is endemic in Ethiopia and Sudan, especially during the rainy season. The disease typically occurs in areas of war, famine, mass migrations, or overcrowding.[5] Homeless people in crowded shelters are also at risk of LBRF. In a study of 930 homeless people in Marseilles, France, body lice were found in 22%, and immunoglobulin G (IgG) to B recurrentis was found in 15 individuals.[22]
In 2015, several cases of LBRF were reported among asylum seekers from Eritrea in the Netherlands, Switzerland, and Germany.[23, 24, 25, 26]
In 2016, more cases of LBRF were reported in refugees from East Africa[27] who were residing in Germany.
The prevalence of Borrelia hispanica was reported to be 20.5% among febrile patients in northwestern Morocco.[28]
The prevalence of B miyamotoi among Ixodes ricinus ticks in Europe was up to 3.2%, according to studies conducted from 2003-2014.[29]
In the United States, TBRF carries a low mortality rate. Overall, TBRF carries a mortality rate of less than 2% (in treated patients) to 4-10% (in untreated individuals).[30] LBRF carries a higher mortality rate, with a case-fatality rate of 4% (in treated patients) to 40% (in untreated individuals).[31] Two species of Borrelia associated with a relatively high rate of relapsing fever–related fatality include B recurrentis (causes LBRF; found in Africa, South America, Europe, and Asia) and B duttoni (causes TBRF; found in East Africa and transmitted by the soft tick Ornithodoros moubata).[2]
Poor prognostic indicators include coma on admission, bleeding, myocarditis, hepatic failure, bronchopneumonia, or co-infection with malaria,[32, 33] typhus, or typhoid fever.[34]
Natives of areas with LBRF endemicity usually experience a milder form of the disease than visitors.
Antibiotic treatment of relapsing fever commonly results in Jarisch-Herxheimer reaction (JHR; see Complications). This reaction tends to be more severe in patients with LBRF treated with penicillin. Pretreatment with steroids does not seem to alter this reaction.
TBRF has been linked to complications during pregnancy, resulting in neonatal death (up to 50%), spontaneous abortion, and premature birth (see Complications).[35]
Relapsing fever has no racial predilection.
Relapsing fever has no sexual predilection.
The hallmark of both louse-borne relapsing fever (LBRF) and tickborne relapsing fever (TBRF) is two or more episodes of high fever (usually >39°C and up to 43°C), headaches, and myalgias. The clinical manifestations are also similar. The mean incubation time is 7 days (range, 4-18 or more days).[36]
Fever occurs in conjunction with spirochetemia. In TBRF, the initial febrile episode lasts an average of 3 days (range, 12 h to 17 d),[35] with an average of 7 days between the initial episode and first relapse. In LBRF, the first febrile episode usually lasts longer, 5.5 days on average (range, 4-10 d), with an average of 9 days between the first episode and first relapse. Patients may feel well between episodes, but the febrile periods are characterized by crises marked by labile blood pressures and pulse. The risk of death is greatest during and immediately following the period of hypotension.[5]
Other symptoms of relapsing fever include chills, arthralgias, myalgias, nausea/vomiting, abdominal pain, mental status changes (and other neurologic symptoms [below]), nonproductive cough, diarrhea, dizziness, headache, neck stiffness, photophobia, rash, and dysuria.
Adult respiratory distress syndrome (ARDS) may occur during TBRF crises.[19]
Neurologic symptoms occur more often in TBRF and can include facial paralysis, hemiplegia, radiculopathy, and myelitis. In both TBRF and LBRF, delirium, and, in some cases, coma, can ensue. Case reports of meningoencephalitis have been described in recently discovered B miyamotoi infection in immunocompromised individuals.[37]
LBRF is associated with a higher incidence of jaundice, petechiae, hemoptysis, epistaxis, and CNS involvement.[35]
On average, individuals with TBRF experience 3 relapses, while those with LBRF experience only one.[5] Fever tends to be milder with relapses, which result from antigenic variation of the spirochete's outer-surface proteins.[2]
Findings in patients with relapsing fever include mental status changes, petechiae, hepatosplenomegaly, abdominal tenderness, jaundice, eschars, abnormal lung function, possible neurologic deficits (cranial nerve palsies, focal deficits), conjunctival suffusion, and the ocular findings listed above.[5, 31]
Petechiae and ecchymoses are more common in patients with LBRF than in those with TBRF.[38, 39] Bleeding results from a combination of thrombocytopenia, impaired clotting factor production, and vessel occlusion from spirochetes, red cells, and platelets
The organomegaly and lung and CNS abnormalities are more commonly associated with LBRF, secondary to direct invasion of spirochetes. Rash is reported more often in patients with TBRF.[31]
Myocarditis is common in both TBRF and LBRF. On cardiac examination, gallops may be auscultated.
As noted above, neurologic findings are more common in TBRF and result from direct spirochetal CNS invasion. Both meningitis and meningoencephalitis have been reported and can lead to resultant hemiplegia or aphasia. Bell palsy (unilateral or bilateral) has also been reported in TBRF, due to seventh or eighth cranial nerve involvement.
In LBRF, CNS symptoms result from spirochetemia rather than direct spirochetal invasion. Findings include mental status changes, neck stiffness, and subarachnoid hemorrhage.
Tickborne relapsing fever (TBRF) is definitively confirmed in the laboratory with direct observation of spirochetes in manually inspected peripheral blood smears during episodes of fever. A thin smear or thick drop of blood is deposited on a microscope slide, which is then stained with either Wright or Giemsa, and examined under oil immersion. On average, 5 organisms are visible per oil immersion field. See the image below.
View Image | Peripheral blood smear in relapsing fever. (Image originally printed in Blevins SM, Greenfield RA, Bronze MS. Blood smear analysis in babesiosis, ehrl.... |
Thick smears are more sensitive than thin smears and can detect one log fewer organisms (ie, 104/mL of blood).
Peripheral blood smears yield a sensitivity of 70%,[40] and the technique is more sensitive in TBRF than in louse-borne relapsing fever (LBRF).
Smears performed between relapses do not demonstrate the organism and should be repeated when the fever reappears. Inexperience in reading smears or a low index of suspicion for the infection may also result in false-negative blood smear results.[2] The spirochetes are too slender to be visualized in light microscopy wet mounts.
Direct or immunofluorescence staining
These techniques may also be used to visualize spirochetes using a fluorescence microscope.
This may show spirochetes in the blood.
This may show red cells colliding with spirochetes.[2]
These include normal to mildly increased leukocyte counts, anemia, thrombocytopenia, increased liver enzyme levels, and prolonged coagulation parameters.
In patients with neurologic involvement, CSF studies show mononuclear pleocytosis and a mildly elevated protein level.[5]
Microscopically, recognition of Borrelia may be enhanced by Pappenheim-stained cytospin preparation from CSF, and, to increase the sensitivity, preparation with acridine orange may be performed.
Successful treatment of neuroborreliosis may be assessed by checking a chemokine level for CXCL13. This has been identified as a potentially sensitive and specific biomarker for diagnosing acute neuroborreliosis (eg, due to B burgdorferi, as well as other spirochetes, such as Treponema pallidum).[41]
No special imaging is required in relapsing fever. Imaging would be performed only to evaluate suspected intracranial hemorrhage or other complications.
Chest radiography may reveal pulmonary edema.
Quantitative buffy coat is 100 times more sensitive than thick films in vitro and may be useful in diagnosis of relapsing fever. However, it requires special equipment.[42]
The organism can be grown in culture using a specific liquid medium developed by Kelly.[43] In this technique, a couple of drops of blood are added to the medium, which is incubated at 30-37°C and kept for 2-6 weeks. Dark-field microscopy is used to periodically check for spirochetes.
In the research setting, the patient’s blood can be inoculated into mice and the spirochetes amplified in murine blood.[9]
Monoclonal antibodies can be used to diagnose B hermsii infection.[44]
Polymerase chain reaction (PCR) amplification has been developed for identification of most Borrelia species.[45] A real-time PCR assay for B recurrentis was described in 2003, and it does not cross-react with other Borrelia species.[46] PCR can be performed on blood or on culture medium growing Borrelia. Species identification is possible.[47] Confirmatory PCR testing for B hermsii is available only at reference laboratories.
A multiplex real-time PCR assay targeting the 16S rRNA gene is now available for the detection of all four borreliae: GLPQ gene detecting B crocidurae, the RECN gene detecting B duttonii/B recurrentis, and RECC gene detecting B hispanica. Multiplex real-time PCR assay yielded 100% sensitivity and specificity for B duttonii/B recurrentis and B. hispanica, and 99% sensitivity and specificity for B crocidurae when applied to 398 blood specimens. These findings provide proof-of-concept that multiplex real-time PCR is a new tool for diagnosis of borreliae that cause relapsing fever, especially in Africa, where multiple Borrelia subspecies may cause relapsing fever concurrently.[48]
Immunofluorescent staining, dark-field microscopy, and serologic testing can also be performed.
Serologies: Antibodies to Borrelia species can be detected with enzyme immunoassays. With this technique, TBRF is confirmed with (1) a 4-fold rise in titers between acute and convalescent samples or (2) a single reactive sample. However, few laboratories perform these assays, and the sensitivity needs to be improved. Enzyme-linked immunosorbent assay (ELISA) is most commonly performed using B hermsii as the antigen. False-positive ELISA results have been noted in patients infected with other Borrelia species. In addition, false-positive results for syphilis and Lyme disease have been described.[49, 50]
An immunoreactive protein termed glycerophosphoryl diester phosphodiesterase (G1pQ) has been identified in spirochetes that cause relapsing fever. It recognizes antibodies produced during relapsing fever but, unlike serological testing, does not recognize the antibodies made in Lyme disease or syphilis.[2] The G1pQ assay is not commercially available.
Spirochetes may be detected in tissue using silver stains (eg, Warthin-Starry or modified Dieterle). Alternatively, they may be visualized with immunofluorescence using antibodies.[10]
On gross pathology, endothelial cell edema, microvascular leakage, perivascular mononuclear infiltrates, microabscesses, and hemorrhage may be seen. In fatal LBRF, myocarditis with histiocytic infiltrates and microhemorrhages may be observed. In the liver and spleen, focal necrotic areas may be noted.[36] Other organs in which the spirochetes have been identified include the brain, eye, and kidney.[36, 51] The degree of severity in relapsing fever directly relates to the number of blood spirochetes.[52]
For decades, penicillins and tetracyclines have been the treatment of choice in relapsing fever. In vitro, Borrelia species are also susceptible to cephalosporins, macrolides, and chloramphenicol, although less data are available on these antibiotics.[30, 21] Borrelia species are relatively resistant to fluoroquinolones, sulfa drugs, rifampin, aminoglycosides, and metronidazole.
The efficacy of treatment can be demonstrated by noting clearance of spirochetes in the blood, usually occurring within 8 hours of administration of an effective antibiotic.[30, 53]
In adults with louse-borne relapsing fever (LBRF), oral treatment consists of a single dose of tetracycline 500 mg, doxycycline 200 mg, or, when tetracyclines are contraindicated, erythromycin 500 mg.
Treatment of tickborne relapsing fever (TBRF) is the same as that for LBRF, except the treatment duration is 7-10 days owing to reported relapses of 20% or greater after single-dose treatment.[36, 54, 55] In oral treatment for TBRF, tetracycline 500 mg every 6 hours, doxycycline 100 mg twice daily, or, if tetracyclines are contraindicated, erythromycin 500 mg every 6 hours, can be used.
In adults, intravenous therapy with doxycycline, erythromycin, tetracycline, or procaine penicillin G should be used when oral therapy is not tolerated.[2]
Procaine penicillin G[2] may be administered at a single dose of 600,000 IU in adult patients with LBRF or 600,000 IU daily in patients with TBRF.[2]
For TBRF with neurologic involvement, penicillin G 3 million units IV every 4 hours or ceftriaxone 2 g IV daily (or 1 g IV twice daily) are likely to work well, given that these regimens are efficacious for Lyme disease.[5]
In children younger than 8 years and in pregnant or nursing women, erythromycin 12.5 mg/kg is preferred.[2] Older children can also take oral tetracycline 12.5 mg/kg, oral doxycycline 5 mg/kg, or intramuscular penicillin G procaine 200,000-400,000 units. Antibiotic therapy can trigger a Jarisch-Herxheimer reaction, which is described in Complications. The reaction is more common in LBRF (about 80%)[30] but also occurs in TBRF (54% in one series).[30]
No treatment is currently defined for recently discovered B miyamotoi infection, and treatment as for Lyme disease is recommended, including treatment as for CNS Lyme disease in patients with neurologic B miyamotoi infection manifestations.
Consultation with an infectious disease specialist may be helpful.
A critical care specialist and/or pulmonologist should be consulted for patients with relapsing fever who are severely ill.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In louse-borne relapsing fever (LBRF), single-dose therapy is recommended, as only one relapse typically occurs. Therapy for tickborne relapsing fever (TBRF) is extended to 7-10 days, as this form is characterized by multiple relapses.
Clinical Context: Long-acting parenteral penicillin (IM only) to treat moderately severe infections caused by penicillin G-sensitive microorganisms.
In adults, administer by deep IM injection only into upper, outer quadrant of buttock. In infants and small children the midlateral aspect of the thigh may be a better site for administration.
Clinical Context: Third-generation cephalosporin with broad-spectrum gram-negative activity; has lower efficacy against gram-positive organisms but higher efficacy against resistant organisms; highly stable in presence of beta-lactamases (penicillinase and cephalosporinase) of gram-negative and gram-positive bacteria; bactericidal activity results from inhibiting cell-wall synthesis by binding to 1 or more penicillin-binding proteins; exerts antimicrobial effect by interfering with synthesis of peptidoglycan (major structural component of bacterial cell wall); bacteria eventually lyse because activity of cell-wall autolytic enzymes continues while cell-wall assembly is arrested. Ceftriaxone may be used for CNS involvement in tickborne relapsing fever.
Clinical Context: Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. May be used for CNS involvement in tickborne relapsing fever.
Clinical Context: Acts by inhibiting bacterial protein synthesis. Binds reversibly to the 50S subunit of bacterial 70S ribosome and prevents attachment of the amino acid-containing end of the aminoacyl-tran to acceptor site on ribosome. Active in vitro against a wide variety of bacteria, including gram-positive, gram-negative, aerobic, and anaerobic organisms. Well-absorbed from GI tract and metabolized in the liver, where it is inactivated by conjugation with glucuronic acid and then excreted by the kidneys. Oral form is not available in the United States.
Clinical Context: Broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clinical Context: Treats gram-positive and gram-negative infections, as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Clinical Context: Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Borrelia species that cause relapsing fever are sensitive to antibiotic agents.
Louse-borne relapsing fever (LBRF) can be prevented by eliminating circumstances that promote louse infection (eg, crowding, homelessness) and good personal hygiene (eg, changing clothes at frequent intervals, bathing, boiling and washing clothes and bedding).
Delousing with 1% lindane, DDT powder, or Lysol is useful in shelters and in patients and household contacts.
Avoiding rodents can prevent tickborne relapsing fever (TBRF). This includes use of appropriate clothing and tick repellents when entering tick-infested areas.
Postexposure prophylaxis is recommended in individuals who have been exposed to ticks in a high-risk environment. An initial dose of doxycycline 200 mg the first day followed by 100 mg daily for 4 days was found to be 100% efficacious in a double-blind, placebo-controlled trial of 93 subjects.[56] If doxycycline is unavailable, tetracycline 500 mg 4 times daily for 4 days may be administered.
No vaccine is currently available for relapsing fever.
Vaccines are in development.[57]
During episodes of spirochetemia, the organisms may invade the brain, eye, inner ear, heart, or liver.[5] CNS involvement is more common in TBRF than in LBRF[5] ; however, eschars, ARDS, cranial nerve palsies, focal neurologic deficits, uveitis, iritis or iridocyclitis, splenic rupture, and myocarditis may be seen in both TBRF and LBRF.[2, 58] Myelitis, radiculopathy, hemiplegia, stupor, and even coma have also been reported.[59, 60]
ARDS has been reported in both TBRF and LBRF and may have previously been underrecognized in TBRF.[19] From 1995-2004, two cases of ARDS were reported in patients with TBRF in Nevada and California.[2] In the state of Washington, 3 cases of ARDS were found in patients with TBRF from 1996-2005.[2]
Relapsing fever may be more dangerous in patients with impaired B-cell function or asplenia. T-cell deficiency/impairment does not seem to play a role in acute relapsing fever.[50]
Treatment of relapsing fever usually results in a Jarisch-Herxheimer reaction, especially following penicillin therapy. The reaction is characterized by fever, chills, rigors, diaphoresis, tachycardia, and hypotension. Cytokines, especially tumor-necrosis factor (TNF)–alpha, IL-6, and IL-8, have all been implicated.[30] The reaction usually occurs within 2-4 hours of administration of the antibiotic. Patients should be observed closely for this reaction, as it can mimic a febrile crisis and may be dangerous.
Relapsing fever in pregnant women increases the risk of spontaneous abortions and severe maternal infection, as well as the risk of ARDS and the Jarisch-Herxheimer reaction.[61] Only twelve cases of TBRF during pregnancy have been reported in North America.[62] Transplacental transmission of the bacteria is also a risk.[30]
Several clinical features portend a poorer prognosis. These include stupor or coma, bleeding, myocarditis,[63] hepatic dysfunction, pneumonia, and coinfection with typhus, typhoid, or malaria.[30]
For more information, see Mortality/Morbidity.
Patients should be educated on avoidance and/or elimination of arthropod vectors.
For excellent patient education resources, see eMedicineHealth's patient education article Ticks.
Peripheral blood smear in relapsing fever. (Image originally printed in Blevins SM, Greenfield RA, Bronze MS. Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease. Cleve Clin J Med. Jul 2008;75(7):521-30. Reprinted with permission from the Cleveland Clinic.)
Peripheral blood smear in relapsing fever. (Image originally printed in Blevins SM, Greenfield RA, Bronze MS. Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease. Cleve Clin J Med. Jul 2008;75(7):521-30. Reprinted with permission from the Cleveland Clinic.)